CHAKRABARTI PARTHA P (US)
CHEN NING (US)
DOHERTY ELIZABETH M (US)
FOTSCH CHRISTOPHER H (US)
HAN NIANHE (US)
KELLY MICHAEL G (US)
LIU QINGYIAN (US)
NORMAN MARK HENRY (US)
WANG XIANGHONG (US)
ZHU JIAWANG (US)
OGNYANOV VASSIL I (US)
BO YUNXIN Y (US)
CHAKRABARTI PARTHA P (US)
CHEN NING (US)
DOHERTY ELIZABETH M (US)
FOTSCH CHRISTOPHER H (US)
HAN NIANHE (US)
KELLY MICHAEL G (US)
LIU QINGYIAN (US)
NORMAN MARK HENRY (US)
OGNYANOV VASSIL I (US)
WANG XIANGHONG (US)
ZHU JIAWANG (US)
| US4753934A | 1988-06-28 | |||
| US3940422A | 1976-02-24 | |||
| US3853561A | 1974-12-10 | |||
| JPS63154663A | 1988-06-27 | |||
| US20030087922A1 | 2003-05-08 |
| 1. | A compound having the structure: wherein: R'is or a naphthyl or saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7 ; R is H, hydroxy, halo, Chalky ! substituted by 0,1 or 2 substituents selected from Rl°, or a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7 ; or R'and R2 together are R3 is H or Cl 4alkyl ; or R'and R3 together are R4 is R4 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C19alkyl, C14haloalkyl, halo, nitro, cyano,ORa, S(=O)nC16alkyl, OC14haloalkyl, OC16alkylNRaRan OC16alkylORa, OCs 6alkylC (=O) ORa,NRaRa,NRaC, 4haloalkyl,NRaC, 6alkylNRaRa, NRaC16alkylORa, C(=O)C16alkyl, C(=O)OC16alkyl, OC(=O)C16alkyl, C(=O)NRaC16alkyl andNRaC(=O)C16alkyl ; or R4 is 10membered bicyclic ring comprising fused 6membered rings, containing 0,1, 2,3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORa, NRaRa, C16alkyl and Cl 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =O ; except that when R'is 4chlorophenyl, 3bromophenyl, 3nitrophenyl, 2nitro3chlorophenyl, 3,4methylenedioxyphenyl, 3methylthiophenyl or 2,3, 4methoxyphenyl, then R4 is not phenyl substituted by 1 or 2 substituents selected from halo and C14alkyl ; and R'and R 4 are not both 3, 4methylenedioxyphenyl ; and when E1 is 4trifluoromethylphenyl, then R4 is not pyridinyl, 2methyl4aminoquinolinyl or 3, 3dimethyl1, 3dihydroindol2 on6yl ; Rs is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC19alkylNRaRa, OC16alkylORa, NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa or NRaC16alkylORa; or R5 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S; R6 is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylORa, NRaRa, NRaC14haloalkyl, NRaC16alkylNRa orNRa C16alkylORa ; or R 5 and R6 together are a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0,1, 2 or 3 substituents selected from halo, C16alkyl, (=O), OC16alkyl, NRaC16alkyl, C16alkylORa and C16alkylNRaRa, and the available N atoms of the bridge are substituted by Ra, C, 6alkylORa or Cl 6alkylNRaRa ; R7 is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylORa, 4haloalkyl,NRaC, 6alkylNRaRa orNRaC, 6alkylORa ; R8 is independently, at each instance, H, C19alkyl, C14haloalkyl, halo nitro, cyano,OC, 6alkyl,OCl 4haloalkyl,OC, 6alkylNRaRa,OC 6alkylORa, NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa or NRaC16alkylORa ; or R7 and R8 together are a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0, 1, 2 or 3 substituents selected from halo, Cl 6alkyl, (=O), OC16alkyl, NRaC16alkyl, C16alkylORa and Cl 6alkylNRaRa, and the available N atoms of the bridge are substituted by Ra, Cl 6alkylORa or Cl 6alkylNRaRa ; R9 is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano,OC16alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylORa, NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa or NRaC16alkylORa ; Rl° is independently, at each instance, H, C19alkyl, C13alkylORa, C14haloalkyl, halo, nitro, cyano,ORa,S (=O)n C16alkyl, OC14haloalkyl, OCs 6alkylNRaRa,OCI 6alkylORa,OCI 6alkylC (=O) ORa,NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa, NRaC16alkylORa, C(=O)C16alkyl, C(=O)OC16alkyl, OC(=O)C16alkyl, C(=O)NRaC16alkyl or NRaC (=O) Cl 6alkyl ; R is independently, at each instance, H, C19alkyl, C13alkylORa, CI4haloalkyl, halo, nitro, cyano, ORa, S(=O)nC16alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylRe, OC16alkylORa, OC16alkylC(=O)ORa, <NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa, NRaC16alkylORa, C=O)C16alkyl, C(=O)OC16alkyl, OC(=O)C16alkyl, C(=O)NRaC16alkyl or NRaC (=O) Cz 6alkyl ; or Rl° and Rl l together are a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, ORa, C16alkylORa,C16alkyl, NRaRa, C16alkylNRaRa, C(=O)ORa, C(=O)NRaRa, C13alkylC(=O)ORa, C13alkylC(=O)NRaRa, OC(=O)C16alkyl, _NRaC(=O)C16alkyl, C13alkylOC(=O)C16alkyl or C13alkylNRaC(=O)C16alkyl, and any nitrogen atoms in the bridge are substituted by H,Cl 6alkylORa, C16alkyl, C16alkylNRaRa, C13alkylC(=O)ORa, C13alkylC5=O)NRaRa, C13alkylOC(=O)C16alkyl, C13alkylNRaC16alkyl, C(=O)R@ or C13alkylRen wherein if R", R", Rl3 and R14 are all H, then R11 is not OC, 6alkylNR3Ra orOC, 6alkylORa ; R12 is independently, at each instance, H, Cul 9alkyl, C13alkylORa, C14haloalkyl, halo, nitro, cyano,ORa,S (=O)nC16alkyl, OC14ahloalkyl, OCI 6alkylNRaRa,OCI 6alkylORa,OC, 6alkylC (=O) ORa,NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa, NRaC16alkylORa, C(=O)C16alkyl, C(=O)OC16alkyl, OV(=O)C16alkyl, C(=O)NRaC16alkyl or NRaC (=O) C, 6alkyl ; or Rl l and Rl2 together are a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, ORa, C16alkylORa, C16alkyl, NRaRa, C16alkylNRaRa, C(=O)ORa, C(=O)NRaRa, C13alkylC(=O)ORa, C13alkylC(=O)NRaRa, OC(=O)C16alkyl, NRaC(=O)C16alkyl, C13alkylOC(=O)C16alkyl or C13alkylNRaC(=O)C16alkyl, and any nitrogen atoms in the bridge are substituted by H,Cl 6alkylORa, C16alkyl, C16alkylNRaRa, C13alkylC(=O)ORa, C13alkylC(=O)NRaRa, C13alkylOC(=O)C16alkyl, C13alkylNRaC(=O)C16alkyl, C(=O)Rc or C13alkylRc; when R1 is 4C16alkylphenyl or 2, 4dimethylphenyl, then R'1 is Clgalkyl, Cl 4haloalkyl, halo, nitro, cyano, ORa, S(=O)nC16alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylRc, OC16alkylORa, OC16alkylC(=O)ORa, NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa, NRaC16alkylORa, C(=O)C16alkyl, C(=O)OC16alkyl, OC(=O)C16alkyl, C(=O)NRaC16alkyl or NRaC (=O) Cl 6alkyl ; or R10 and R11 together are L3NRa, respectively, or L40, respectively ; or R11 and R12 are NRaL3, L3NRa, OL4orL4O; or R12 is NRaRb ; or R4 is 10membered bicyclic ring comprising fused 6membered rings, containing 0,1, 2,3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORa, NRaRa, C, 6alkyl and Cl 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =O ; or R4 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 1,2 or 3 substituents independently selected from C29alkyl, Cl 4haloalkyl, halo, nitro, cyano,ORa,S (=O) nC]6alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylORa, OC16alkylC(=O)ORa, NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa, NRaC16alkylORa, C(=O)C16alkyl, C(=O)OC16alkyl, OC(=O)C16alkyl, C(=O)NRaC16alkyl and NRaC (=O) Cl 6alkyl ; Rl3 is independently, at each instance, H, Cl 9alkyl,Cl 3alkylORa, C14haloakyl, halo, nitro, cyano, ORa, S(=O)nC16alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylORa, OC16alkylOR3, NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa, NRaC16alkulORa, C(=O)C16alkyl, C (=O) OCl 6alkyl,OC (=O) Cl 6alkyl,C (=O) NRaCl 6alkyl or NRaC(=O)C16alkyl ; Rl4 is independently, at each instance, H, C19alkyl, C13alkylORa, Cl 4haloalkyl, halo, nitro, cyano, ORa, S(=O)nC16alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylORa, OC16alkylC(=O)ORa, NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa, NRaC16alkylORa, C(=O)C16alkyl, C(=O)OC1 6alkyl, OC(=O)C16alkyl, C(=O)NRaC16alkyl or NRaC (=O) Cl 6alkyl ; Ra is independently, at each instance, H, phenyl, benzyl or C16alkyl ; Rb is H, C16alkyl, C(=O)C16alkyl, C16alkylORa ; Ru ils phenyl substituted by 0,1 or 2 groups selected from halo, C13haloalkyl, ORa and NRaRa; or Ru ils a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0,1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents selected from halo, C13haloalkyl, ORa and NRaRa ; Ll is a bond,CH2CH2orCH=CH ; L2 is NRa, O, S(=O)n, N=CH, CH2NRa, CH=N or NRaCH2; L3 is a 2or 3atom, saturated or unsaturated, bridge containing 1,2 or 3 carbon atoms and 0,1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, =0,OR, <BR> <BR> <BR> <BR> CI 6alkylOR,CI 6alkyl,NRaR3,Cl 6alkylNRaRa,C (=O) ORa,C (=O) NRaRa<BR> <BR> <BR> <BR> <BR> <BR> CI 3alkylC (=O) ORa,Cl 3alkylC (=O) NRaRa,OC (=O) CI 6alkyl, NRaC(=O)C16alkyl, C13alkylOC(=O)C16alkyl or C13alkylNRaC(=O)C16alkyl, and any nitrogen atoms in the bridge are substituted by H, C16alkylORa, CI 6alkyl,CI 6alkylNRaRa,Cs 3alkylC (=O) ORa,Cs 3alkylC (=O) NRaRa, C13alkylOC(=O)C16alkyl, C13alkylNRaC(=O)C16alkyl, C(=O)Ra or C13alkylR@ ; L4 is a 2or 3atom, saturated or unsaturated, bridge containing 1,2 or 3 carbon atoms and 0 or 1 atoms independently selected from O, N and S, wherein at least one of the carbon atoms in the bridge is substituted by =0,OR, C16alkylORa, C16alkyl, NRaRa, C16alkylNRaRa, C(=O)OC16alkyl, C(=O)NRaRa, C13alkylC(=O)ORa, C1@alkylC(=O)NRaC16alkyl, OC(=O)C16alkyl, NRaC(=O)C16alkyl, C1@alkylOC(=O)C16alkyl or C13alkylNRaC(=O)C16alkyl, and any nitrogen atoms in the bridge are substituted by II, C16alkylORa, C16alkyl, C16alkylNRaRa, C13alkylC(=O)ORa, C13alkylC(=O)NRaRa, C13alkylOC(=O)C1 6alkyl, C13alkylNRaC(=O)C16alkyl, C(=O)R@ or C13alkylR@ ; X is O, S or NRa ; or X and R2 together are =NCH=CH, =CO, =CS, or =CNRa; Yis NHorO ; and n is independently, at each instance, 0,1 or 2; with the proviso that when R'is 4chlorophenyl, then R4 is not 3methoxyphenyl. |
| 2. | A compound according to Claim 1, wherein: R'is or a naphthyl or saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R5, R6 and R7 ; R2 is H, hydroxy, halo, Cl 6alkyl substituted by 0,1 or 2 substituents selected from Rlo, or a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7 ; and R3 is H or C14alkyl. |
| 3. | A compound according to Claim 1, wherein R'is. |
| 4. | A compound according to Claim 3, wherein R7 is independently, at each instance, C2 9alkyl or Cl 4haloalkyl. |
| 5. | A compound according to Claim 1, wherein R'is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7. |
| 6. | A compound according to Claim 5, wherein R2 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R. |
| 7. | A compound according to Claim 2, wherein R2 is or a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7. |
| 8. | A compound according to Claim 7, wherein R2 is. |
| 9. | A compound according to Claim 7, wherein R2 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R and R. |
| 10. | A compound according to Claim 2, wherein R1 and R2 together are. |
| 11. | A compound according to Claim 2, wherein R'and R3 together are. |
| 12. | A compound according to Claim 2, wherein X and R2 together are =NCH=CH, =CO, =CS, or =CNRa. |
| 13. | A compound according to any one of Claims 2,4, 5,8 or 9, wherein: R4 is Rb is H, C16alkyl, C(=O)C16alkyl, C16alkylORa ; and YZ isNRaorO. |
| 14. | A compound according to any one of Claims 2,4, 5,8 or 9, wherein: R4 is L3 iS a 2or 3atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0 or 1 atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, =0,ORa, <BR> <BR> <BR> <BR> CI 6alkylORa,CI 6alkyl,NRaRa,C, 6alkylNRaRa,C (=O) ORa,C (=O) NRaRa C13alkylC(=O)ORa, C13alkylC(=O)NRaRa, OC(=O)C16alkyl, <BR> <BR> <BR> <BR> NRaC (=O) CI 6alkyl,CI 3alkylOC (=O) Cl 6alkyl orCI 3alkylNRaC (=O) CI 6alkyl, and any nitrogen atoms in the bridge are substituted by H,Cl 6alkylORa, CI 6alkyl,Cl 6alkylNRaRa,CI 3alkylC (=O) ORa,CI 3alkylC (=O) NRaRa, C13alkylOC(=O)C16alkyl, C13alkylNRaC(=O)C16alkyl, C(=O)R@ or C13alkylR@ ; Rb is H, Cul 6alkyl,C (=O) C 6alkyl, Cl 6alkylORa ; and Y2 is NRb or O,. |
| 15. | A compound according to any one of Claims 2,4, 5,8 or 9, wherein: R4 is L3 is a 2or 3atom, saturated or unsaturated, bridge containing 1,2 or 3 carbon atoms and 0,1 or 2 atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, =0,ORa, C16alkylORa, C16alkyl, NRaRa, C16alkylNRaRa, C(=O)ORa, C(=O)NRaRa, CI 3alkylC (=O) ORa,CI 3alkylC (=O) NRaRa,OC (=O) CI 6alkyl, NRaC(=O)C16alkyl, C13alkylOC(=O)C16alkyl or C13alkylNRaC(=O)C16alkul, and any nitrogen atoms in the bridge are substituted by H, C16alkylORa, C16alkyl, C16alkylNRaRa, C13alkylC(=O)ORa, C13alkylC(=O)NRaRa, CI 3alkylOC (=O) C16alkyl, C13alkylNRaC(=O)C16alkyl, C(=O)R@ or C13alkylR@ ; Rb is H, C16alkyl, C(=O)C16alkyl, C1 6alkylORa ; and y2 isNRborO. |
| 16. | A compound according to any one of Claims 2,4, 5,8 or 9, wherein: R4 is L3 is a 2or 3atom, saturated or unsaturated, bridge containing 1,2 or 3 carbon atoms and 0,1 or 2 atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, =0,ORa, C16alkylORa, C16alkyl, NRaRa, C16alkylNRaRa, C(=O)ORa, C(=O)NRaRa, C13alkyl(=O)ORa, C13alkylC(=O)NRaRa, OC(=O)C16alkyl, NRaC(=O)C16alkyl, C13alkylOC(=O)C16alkyl or C13alkylNRaC(=O)C16alkyl, and any nitrogen atoms in the bridge are substituted by H, C1 6alkylORa, C16alkyl, C16alkylNRaRa, C13alkylC(=O)ORa, C13alkylC(=O)NRaRa, C13alkylOC(=O)C16alkyl, C13alkylNaC(=O)C16alkyl, C(=O)R@ or C, 3alkylRC ; Rb is H, C6alkyl,C (=O) C,6alkyl, C,6alkylORa ; and Y2 isNRborO. |
| 17. | A compound according to any one of Claims 2,4, 5,8 or 9, wherein: R4 is Rb is H, Chalky kyl,C (=O) C16alkyl, C16alkylORa ; and y2 is NRa or O,. |
| 18. | A compound according to any one of Claims 2,4, 5,8 or 9, wherein: R4 is 10membered bicyclic ring comprising fused 6membered rings, containing 0,1, 2,3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORa, NRaRa, C16alkyl and C, 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =0. |
| 19. | A compound according to any one of Claims 2,4, 5,8 or 9, wherein: R4 is Rl° is independently, at each instance, H, Cl9alkyl,C_3alkylORa, C14haloalkyl, halo, nitro, cyano,ORa,S (=O)nC16alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylORa, OC16alkylC(=O)ORa, NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa, NRaC16alkylORa, C(=O)C16alkyl, C(=O)OC16alkyl, OC(=O)C16alkyl, C(=O)NRaC16alkyl or NRaC (=O) Cl 6alkyl ; R"is independently, at each instance, H, Chalky OR C, 4haloalkyl, halo, nitro, cyano, ORa, S(=O)nC16alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylRc, OC16alkylORa, OC16alkylC(=O)ORa, NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa, NRaC16alkylORa, C(=O)C16alkyl, C(=O)OC16alkyl, OC(=O)C16alkyl, C(=O)NRaC16alkyl or NRaC(=O)C16alkyl ; Cl 6alkylNR R ; R is independently, at each instance, H, C19alkyl, C13alkylORa, C14haloalkyl, halo, nitro, cyano, ORa, S(=O)nC16alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylORa, OC16alkylC(=O)ORa, NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa, NRaC16alkylORa, C(=O)C16alkyl, C(=O)OC16alkyl, OC(=O)C16alkyl, C(=O)NRaC16alkyl or NRaC (=O) C, 6alkyl ; R is independently, at each instance, H, C, alkyl, C13alkylORa, C14haloalkyl, halo, nitro, cyano, ORa, S(=O)nC16alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylORa, OC16alkylC(=O)ORa, NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa, NRaC16alkylORa, C(=O)C16alkyl, C(=O)OC16alkyl, OC(=O)C16alkyl, C(=O)NRaC16alkyl or NRaC (=O) C, 6alkyl ; and R is independently, at each instance, H, C19alkyl, C13alkylOR3, C, 4haloalkyl, halo, nitro, cyano, ORa, S(=O)nC16alkyl, OC14haloalkyl, OC16alkylNRaRa, OC16alkylORa, OC16alkylC(=O)ORa, NRaRa, NRaC14haloalkyl, NRaC16alkylNRaRa, NRaC16alkylORa, C(=O)C1 6alkyl, C(=O)OC16alkyl, OC(=O)C16alkyl, C(=O)NRaC16alkyl or NRaC (=O) Cl 6alkyl ; wherein one of R° and RIZ is not H. |
| 20. | A compound according to any one of Claims 2,4, 5,8 or 9, wherein R4 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, Cl 4haloalkyl,ORa and NR R. |
| 21. | A compound having the structure: or any pharmaceuticallyacceptable salt thereof, wherein: n is independently, at each instance, 0,1 or 2. R'is or R'is a naphthyl substituted by 0,1, 2 or 3 substituents independently selected from R ; or Rl is Rt substituted by 1,2 or 3 substituents independently selected from R ; R15 is, independently, in each instance, Rl°, C18alkyl substituted by 0,1 or 2 substituents selected from R10, phenyl substituted by 0,1, 2 or 3 substituents independently selected from R'°, or a saturated or unsaturated 5or 6membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from Rlo ; R16 is, independently, in each instance, H, halo,NH2,NHCl 3alkyl, N(C13alkyl)C13alkyl or Cl 3alkyl ; R4 is R4 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C, 9alkyl, Cl 4haloalkyl, halo, nitro, cyano, oxo, ORd, S(=O)nC16alkyl, OC14haloalkyl, OC26alkylNRdRd, OC26alkylORd, OC16alkylC(=O)ORd, NRdRd, NRdC14haloalkyl, NRdC26alkylNRdRd, NRdC26alkylORd, C(=O)C16alkyl, C(=O)OC1 6alkyl, OC(=O)C1 6alkyl, C (=O) NRdC, 6alkyl andNRdC (=O) Ct 6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any nitrogen atoms in the bridge are substituted by H, C16alkylORd, C16alkyl, C16alkylNRdRd, 3alkylC (=O) ORd,Cs 3alkylC (=O) NRdRd,C, 3alkylOC (=O) C, 6alkyl, C13alkylNRdC(=O)C16alkyl, C(=O)R@ or C13alkylIR@ ; or R4 is 10membered bicyclic ring comprising fused 6membered rings, containing 0,1, 2,3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORd, NRdRd, C16alkyl and C13haloalkyl ; and saturated carbon atoms may be additionally substituted by =O ; but in no instance is R4 3, 5 ditrifluoromethylphenyl or 3trifluoromethyl4fluorophenyl ; R is independently, at each instance, H, C, salkyl, C, 4haloalkyl, halo, nitro, cyano, OC1 @@alkyl, OC14haloalkyl, OC 26alkylNRdRd, OC26alkylORd, NRdRd, NRdC14haloalkyl, NRdC26alkylNRdRd, NRdC26alkylORd, naphthyl, CO2(C16alkyl), C(=O)(C16alkyl), C(=O)NRdRd, NRdC(=O)Rd, NRdC(=O)NRdRd, NRdCO2(C16alkyl), C18alkylORd, C16alkylNRdRd, S = )C y6alkyl),S (=O) 2NRdRd,NRdS (=O) y6alkyl),OC (=O) NRdRd, a phenyl ring substituted with 0,1, 2, or 3 substituents independently selected from R'° ; or R is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S, substituted with 0, 1, 2, or 3 substituents independently selected from Rl° ; R6 is independently, at each instance, H, C15alkyl, C14haloalkyl, halo, OC16alkyl, OC14haloalkyl, OC26alkylNRdRd, OC26alkylORd, NRdRd, NRdC14haloalkyl, NRdC26alkylNRdRd or NRdC26alkylORd, C18alkylORd, C16alkylNRdRd, S(C16alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from Rl° ; or R6 is a saturated or unsaturated 5 or 6membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3 substituents independently selected from Rio ; R7 is independently, at each instance, H, C18alkyl, C14haloalkyl, halo, OC16alkyl, OC14haloalkyl, OC26alkylNRdRd, OC26alkylORd, NRdRd,NRdC, 4haloalkyl,NRdC2 6alkylNRdRd,NRdC2 6alkylORd, C18alkylORd, C16alkylNRdRd or S(C16alkyl) ; or R7 is a saturated or unsaturated 4or 5membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, Cl 2haloalkyl and Cl 3alkyl ; R8 is independently, at each instance, H, C15alkyl, C14haloalkyl, halo, OC16alkyl, OC14haloalkyl, OC26alkylNRdRd, OC26alkylORd, NRdRd, NRdC14haloalkyl, NRdC26alkylNRdRd, NRdC26alkylORd, C18alkylORd, C16alkylNRdRd, S(C16alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from R'°, or R8 is a saturated or unsaturated 5 or 6membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from R'° ; R9 is independently, at each instance, H, C18alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC26alkylNRdRd, 4haloalkyl,NRdC26alkylNRdRd or 6alkylORd,CO2 (CI 6alkyl),C (=O) (CI 6alkyl),C (=O) NRdRd, NRdC(=O)(C16alkyl), NRdC(=O)NRdRd, NRdCO2(C16alkyl) C16alkylORd, C16alkylNRdRd, S(=O)n(C16alkyl), S(=O)2NRdRd, NRdS (=O) 2 (Cl 6alkyl),OC (=O) NRdRd, a phenyl ring substituted with 0, 1,2, or 3 substituents independently selected from Rl° ; or R9 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from Rl° ; or R9 is a saturated or unsaturated 4or 5membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, C, 2haloalkyl and Cl 3alkyl ; wherein at least one of R5, R, R7, R8 and R9 is C18alkyl, C14haloalkyl, halo, OC14haloalkyl, OC26alkylNRdRd, OC26alkylORd, NRdC14haloalkyl, 6alkylNRdRd,NRdC2 6alkylORd,CI 8alkylORd,Cz 6alkylNRdRd orS (Cl 6alkyl) ; Rl° is independently, at each instance, selected from H, Chalky 8alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), c(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C1 8alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S (=O) (CI 8alkyl),S (=0) 2 (C, 8alkyl),S (=0) 2NRdRd, S (=0) 2N (Rd) C (=O) (C 8alkyl), S(=O)2N(Rd) C (=O) O (C18alkyl), S (=0) 2N (Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NRdRd,N (Rd) C (=NRd) NRdRd, N(Rd) S (=O) 2 (C,8alkyl),N (Rd) S (=O) 2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd ; or R'° is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5, 6or 7membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, <BR> <BR> <BR> C (=O) (Ci 8alkyl),C (=O) O (Ci 8alkyl),C (=O) NRdRd,C (=NRd) NRdRd,ORd OC(=O)(C16alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C1 _$alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd) C (=O) (C, 8alkyl), S(=O) 2N (Rd)C(=O)O(C18alkyl), S (=0) 2N (Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd)C(=O)O(C18alkyl), N(Rd) C (=O) NRdRd,N (Rd) C (=NRd) NRdRd, N(Rd) S (=O) 2 (C, 8alkyl), N(Rd)S(=O)2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd ; or Rl° is Chalky ! substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C (=O) NRdRd,C (=NRd) NRdRd,ORd,OC (=O) (C, 8alkyl),OC (=O) NRdRd, OC(=O) N (Rd) S (=0) 2 (C18alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (Cl 8alkyl),S (=0) 2NRdRd, S(=O)2N(Rd) C (=O) (C1 8alkyl), S(=O)2N(Rd) C (=O) O (CI 8alkyl), S(=O)2N(Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C1 8alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NRdRd,N (Rd) C (=NRd) NRdRd, N(Rd) S (=O) 2 (C13alkyl), N(Rd) S (=O) 2NRdRd, NRdC26alkylNRdRd and 6alkylORd ; R11 is independently, at each instance, selected from H, Cl 8alkyl, C, 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C1 8alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd) C (=O) (C, 8alkyl),S (=0) 2N (Rd) C (=O) O C18alkyl), S (=0) 2N (Rd) C (=O) NRdRd, NRdRd, N(Rd)C(Rd)C(=O)(C18alkyl), N(Rd) C (=O) O (C, 8alkyl), N(Rd) C (=O) NR R,N (R) C (=NRd) NRdRd, N(Rd) S (=O) 2 (C, 8alkyl),N (Rd) S (=O) 2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd ; or R"is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5, 6or 7membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC (=O) (CI8alkyl),OC (=O) NRdRd,OC (=O) N (Rd) S (=0) 2 (C18alkyl), OC26alkylNRdRd, OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S (=0) 2NRdRd,S (=0) 2N (Rd) C (=O) (C, 8alkyl),S (=0) 2N (Rd) C (=O) O (C _alkyl), S(=O)2N(Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C _alkyl), N(Rd) C (=O) O (Cl 8alkyl),N (R) C (=O) NR R,N (R) C (NRd) NRdRd, N(Rd) S (=O) 2 (C18alkyl), N(Rd)S(=O)2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd ; or R11 is C14alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C, 8alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd) C (=O) (C1 kyl),S (=0) 2N (Rd) C (=O) O (C18alkyl), S(=O)2N(Rd) C (=O) NRdRd, NRdRd, N(Rd) C (=O) (CI 8alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NRdRd, N(Rd) C (=NRd) NRdRd, N(Rd) S (=O) 2 (C18alkyl), N(Rd) S (=O) 2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd ; or R10 and R11 together are a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, C18alkyl, C14haloalkyl, halo, cyano, nitro, C (=O) (C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC (=O) NRdRd,OC (=O) N (Rd) S (=0) 2 (C1 8alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (CI8alkyl),S (=0) 2 NRdRd, S(=O)2N(Rd) C (=O) (C18alkyl), S(=O)2N(Rd) C (=O) O (C18alkyl), S (=0) 2N (Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NRdRd,N (Rd) C (=NRd) NRdRd, N(Rd) S (=O) 2 (C18alkyl), N(Rd)S(=O)2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd, and any nitrogen atoms in the bridge are substituted by H, C16alkylORd, C16alkyl, C16alkylNRdRd, C13alkylC(=O)ORd, C13alkylC(=O)NRdRd, C13alkylOC(=O)C16alkyl, C13alkylNRdC(=O)C16alkyl, C(=O)Rf or C13alkylRf ; R12 is independently, at each instance, selected from H, C18alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C18alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O)(C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd) C (=O) (C18alkyl), S(=O)2N(Rd) C (=O) O (CI 8alkyl), S (=0) 2N (Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd) C (=O) O (C,8aIkyi),N (R") C (=O) NRdRd,N (Rd) C (=NRd)NRdRd, N(Rd) S (=O) 2 (C18alkyl), N(Rd) S (=O) 2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd ; or Rl2 is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5, 6or 7membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from Cl 8alkyl, C, 4haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C18alkyl), OC2 OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd) C (=O) (C18alkyl), S(=O)2N(Rd) C (=O) O (C18alkyl), S (=0) 2N (Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C 8alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NRdRd, N(Rd)C(=NRd)NRdRd, N (Rd) S (=O) 2 (C18alkyl), N(Rd)S(=O)2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd ; or Rl2 is C14alkyl substituted by 0, 1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C (=O) NRdRd,C (=NRd) NRdRd,ORd,OC (=O) (C, 8alkyl),OC (=O) NRdRd, OC(=O) N (Rd) S (=0) 2 (C18alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRdRd, S (=0) 2N (Rd) C (=O) (C, 8alkyl), S(=O)2N(Rd) C (=O) O (C18alkyl), S (=O) 2N (Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd)C(=O)O(C18alkyl), N(Rd) C (=O) NRdRdN (Rd) C (=NRd)NRdRd, N(Rd) S (=O) 2 (C18alkyl), N(Rd) S (=O) 2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd ; wherein if R11 or R13 is CF3, then Rl2 is not F; or R11 and R12 together are a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC (=O) N (Rd) S (=0) 2 (CI_8alkyl),OC26alkylNRdRd,OC26alkylORd,SRd, S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRdRd, S (=0) 2N (Rd) C (=O) (C18alkyl), S(=O)2N(Rd) C (=O) O (C 18alkyl), S (=0) 2N (Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NRdRd,N (Rd) C (=NRd) NRdRd, N(Rd)S(=O) 2 (C18alkyl), N(Rd)S(=O)2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd, and any nitrogen atoms in the bridge are substituted by H, C16alkylORd, C16alkyl, C16alkylNRdRd, C13alkylC(=O)ORd, C13alkylC(=O)NRdRd, C13alkylOC(=O)C16alkyl, C13alkylNRdC(=O)C16alkyl, C(=O)Rf or C13alkylRf ; Rl3 is independently, at each instance, selected from H, C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C (=O) NRdRdC (=NRd) NRdRd,ORd,OC (=O) (Cs 8alkyl),OC (=O) NR R, OC(=O) N (Rd) S (=0) 2 (CI 8alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (C, 8alkyl),S (=O) 2NRdRd, S (=0) 2N (Rd) C (=O) (C 8alkyl), S(=O)2N(Rd) C (=O) O (CI 8alkyl), S(=O)2N(Rd) C (=O) NRdRd, NRdRd, N(Rd)C(=O)(C18alkyl), N(Rd) C (=O) O (C1 8alkyl), N(Rd) C (=O) NRdRd,N (Rd) C (=NRd) NRdRd, N(Rd) S (=0) 2 (C,salkyl),N (Rd) S (=0) 2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd ; or Rl3 is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5, 6or 7membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl), C(=O)(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C,. 8alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl),S(=O)2(C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd) C (=O) (C _8alkyl),S (=0) 2N (Rd) C (=O) O (C18alkyl), S(=O)2N(Rd) C (=O) NRdRd, NRdRd, N(Rd) C (=O) (C1 8alkyl), N(Rd)C(=O)O(C18alkyl), N(Rd) C (=O) NRdRd, N(Rd)C(=NRd)NRdRd, N(Rd) S (=0) 2 (C1 8alkyl), N(Rd)S(=O)2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd ; or R13 is Cl 4alkyl substituted by 0,1, 2 or 3 groups selected from Ci 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C (=O) NRdRd,C (=NRd) NRdRd,ORd,OC (=O) (C,8alkyl),OC (=O) NRdRd, OC(=O) N (Rd) S (=0) 2 (C18alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S (=O) (C, 8alkyl),S (=0) 2 (C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd) C (=O) (C 8alkyl), S(=O)2N(Rd) C (=O) O (C _8alkyl), S(=O)2N(Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C1 _alkyl), N(Rd)C(=O)O(C18alkyl), N(Rd) C (=O) NR R,N (R) C (=NRd) NRdRd, N(Rd) S (=0) 2 (Ci 8alkyl),N (Rd) S (=0) 2NRdRd, NRdC26alkylNRdRd and 6alkylORd ; R'4 is independently, at each instance, selected from H, C, 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C,_8alkyl),OC26alkylNRdRd,OC26alkylORd,SRd, S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRdRd, S (=0) 2N (Rd) C (=O) (C18alkyl), S(=O)2N(Rd) C (=O) O (C, 8alkyl), S(=O)2N(Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C 8alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NRdRd,N (Rd) C (=NRd) NRdRd, N(Rd) S (=0) 2 (C, 8alkyl),N (Rd) S (=0) 2NRdRd, NRdC26alkylNRdRd and 6alkylORd ; or R14 is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5, 6or 7membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C18alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd) C (=O) (C _8alkyl),S (=0) 2N (Rd) C (=O) O (C 8alkyl), S(=O)2N(Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NRdRd, N(Rd) C (=NRd) NRdRd, N(Rd) S (=0) 2 (Cl8alkyl),N (Rd) S (=0) 2NRdRd,NRdC26alkylNRdRd and 6alkylORd ; or R14 is C14alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C18alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd) C (=O) (C18alkyl), S(=O) 2N (Rd) C (=O) O (CI 8alkyl), S(=O)2N(Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd)C(=O)O(C18alkyl), N(Rd)C(=O)NRdRd, N(Rd)C(=NRd)NRdRd, N(Rd) S (=0) 2 (C, 8alkyl),N (Rd) S (=0) 2NRdRd, NRdC26alkylNRdRd and 6alkylORd ; Rd is independently, at each instance, H, phenyl, benzyl or c16alkyl ; Re is a heterocycle selected from the group of thiophene, pyrrole, 1, 3oxazol, 1,3thiazole, 1,3, 4oxadiazole, 1,3, 4thiadiazole, 1,2, 3oxadiazole, 1, 2, 3thiadiazole, 1H1, 2, 3triazole, isothiazole, 1,2, 4oxadiazole, 1,2, 4 thiadiazole, 1,2, 3,4oxatriazole, 1,2, 3,4thiatriazole, 1H1, 2,3, 4tetraazole, 1,2, 3,5oxatriazole, 1,2, 3,5thiatriazole, furan, imidazol1yl, imidazol4yl, 1,2, 4 triazol4yl, 1, 2, 4triazol5yl, isoxazol3yl, isoxazol5yl, pyrazol3yl, pyrazol 5yl, thiolane, pyrrolidine, tetrahydrofuran, 4, 5dihydrothiophene, 2pyrroline, 4,5dihydrofuran, pyridazine, pyrimidine, pyrazine, 1,2, 3triazine, 1,2, 4triazine, 1,2, 4triazine, 1,3, 5triazine, pyridine, 2H3,4, 5,6tetrahydropyran, thiane, 1,2 diazaperhydroine, 1,3diazaperhydroine, piperazine, 1,3oxazaperhydroine, morpholine, 1,3thiazaperhydroine, 1,4thiazaperhydroine, piperidine, 2H3,4 dihydropyran, 2, 3dihydro4Hthiin, 1,4, 5, 6tetrahydropyridine, 2H5,6 dihydropyran, 2,3dihydro6Hthiin, 1,2, 5, 6tetrahydropyridine, 3,4, 5,6 tetrahydropyridine 4Hpyran, 4Hthiin, 1, 4dihydropyridine, 1,4dithiane, 1,4 dioxane, 1,4oxathiane, 1,2oxazolidine, 1, 2thiazolidine, pyrazolidine, 1,3 oxazolidine, 1, 3thiazolidine, imidazolidine, 1,2, 4oxadiazolidine, 1,3, 4 oxadiazolidine, 1,2, 4thiadiazolidine, 1,3, 4thiadiazolidine, 1,2, 4triazolidine, 2 imidazoline, 3imidazoline, 2pyrazoline, 4imidazoline, 2, 3dihydroisothiazole, 4,5dihydroisoxazole, 4, 5dihydroisothiazole, 2,5dihydroisoxazole, 2,5 dihydroisothiazole, 2, 3dihydroisoxazole, 4,5dihydrooxazole, 2,3 dihydrooxazole, 2,5dihydrooxazole, 4,5dihydrothiazole, 2, 3dihydrothiazole" 2, 5dihydrothiazole, 1, 3, 4oxathiazolidine, 1,4, 2oxathiazolidine, 2, 3dihydro1H [1, 2,3] triazole, 2, 5dihydrolH [1, 2,3] triazole, 4, 5dihydrolH [1, 2,3] triazole, 2, 3dihydrolH [1, 2,4] triazole, 4, 5dihydrolH [1, 2,4] triazole, 2,3dihydro [1, 2,4] oxadiazole, 2, 5dihydro[1, 2,4] oxadiazole, 4, 5dihydro [1, 2,4] thiadiazole, 2, 3dihydro [1, 2,4] thidiazole, 2, 5dihydro [1, 2,4] thiadiazole, 4, 5dihydro [1, 2,4] thiadiazole, 2,5dihydro [1, 2,4] oxadiazole, 2, 3dihydro [1, 2,4] oxadiazole, 4,5 dihydro [1, 2,4] oxadiazole, 2, 5dihydro [1, 2,4] thiadiazole, 2, 3dihydro [1, 2,4] thiadiazole, 4, 5dihydro [1, 2,4] thiadiazole, 2, 3dihydro [1, 3,4] oxadiazole, 2,3 dihydro [1, 3,4] thiadiazole, [1, 4,2] oxathiazole, [1, 3,4] oxathiazole, 1,3, 5 triazaperhydroine, 1,2, 4triazaperhydroine, 1,4, 2dithiazaperhydroine, 1,4, 2 dioxazaperhydroine, 1,3, 5oxadiazaperhydroine, 1,2, 5oxadiazaperhydroine, 1,3, 4thiadiazaperhydroine, 1,3, 5thiadiazaperhydroine, 1,2, 5 thiadiazaperhydroine, 1,3, 4oxadiazaperhydroine, 1,4, 3oxathiazaperhydroine, 1,4, 2oxathiazaperhydroine, 1,4, 5,6tetrahydropyridazine, 1,2, 3,4 tetrahydropyridazine, 1,2, 3,6tetrahydropyridazine, 1,2, 5,6tetrahydropyrimidine, 1,2, 3, 4tetrahydropyrimidine, 1,4, 5, 6tetrahydropyrimidine, 1,2, 3,6 tetrahydropyrazine, 1,2, 3,4tetrahydropyrazine, 5, 6dihydro4H [1, 2] oxazine, 5,6 dihydro2H[1, 2] oxazine, 3, 6dihydro2H [1, 2] oxazine, 3,4dihydro2H [1, 2] oxazine, 5, 6dihydro4H [1, 2] thiazine, 5, 6dihydro2H [1, 2] thiazine, 3,6 dihydro2H [1, 2] thiazine, 3, 4dihydro2H [1, 2] thiazine, 5,6dihydro2H [1, 3] oxazine, 5, 6dihydro4H [1, 3] oxazine, 3, 6dihydro2H [1, 3] oxazine, 3,4 dihydro2H [1, 3] oxazine, 3,6dihydro2H [1, 4] oxazine, 3,4dihydro2H [1, 4] oxazine, 5, 6dihydro2H [1, 3] thiazine, 5, 6dihydro4H [1, 3] thiazine, 3,6 dihydro2H [1, 3] thiazine, 3, 4dihydro2H [1, 3] thiazine, 3,6dihydro2H [1, 4] thiazine, 3,4dihydro2H [1, 4] thiazine, 1, 2,3, 6tetrahydro[1, 2,4] triazine, 1, 2,3, 4tetrahydro [1, 2,4] triazine, 1, 2,3, 4tetrahydro[1, 3,5] triazine, 2,3, 4,5 tetrahydro[1, 2,4] triazine, 1, 4,5, 6tetrahydro[1, 2,4] triazine, 5,6dihydro [1, 4,2] dioxazine, 5, 6dihydro[1, 4,2] dioxazine, 5, 6dihydro[1, 4,2] dithiazine, 2,3 dihydro[1, 4,2] dioxazine, 3, 4dihydro2H [1, 3,4] oxadiazine, 3,6dihydro2H [1, 3,4] oxadiazine, 3, 4dihydro2H [1, 3,5] oxadiazine, 3,6dihydro2H [1, 3,5] oxadiazine, 5, 6dihydro2H [1, 2,5] oxadiazine, 5,6dihydro4H [1, 2,5] oxadiazine, 3, 4dihydro2H [1, 3,4] thiadiazine, 3,6dihydro2H [1, 3,4] thiadiazine, 3, 4dihydro2H [1, 3,5] thiadiazine, 3,6dihydro2H [1, 3,5] thiadiazine, 5, 6dihydro2H [1, 2,5] thiadiazine, 5,6dihydro4H [1, 2,5] thiadiazine, 5, 6dihydro2H [1, 2,3] oxadiazine, 3, 6dihydro2H [1, 2,5] oxadiazine, 5, 6dihydro4H [1, 3,4] oxadiazine, 3, 4dihydro2H [1, 2,5] oxadiazine, 5, 6dihydro2H [1, 2,3] thiadiazine, 3,6dihydro2H [1, 2,5] thiadiazine, 5, 6dihydro4H [1, 3,4] thiadiazine, 3,4dihydro2H [1, 2,5] thiadiazine, 5, 6dihydro[1, 4,3] oxathiazine, 5, 6dihydro[1, 4,2] oxathiazine, 2, 3dihydro[1, 4,3] oxathiazine, 2, 3dihydro[1, 4,2] oxathiazine, 4,5 dihydropyridine, 1, 6dihydropyridine, 5,6dihydropyridine, 2Hpyran, 2Hthiin, 3,6dihydropyridine, 2,3dihydropyridazine, 2,5dihydropyridazine, 4,5 dihydropyridazine, 1, 2dihydropyridazine, 2, 3dihydropyrimidine, 2,5 dihydropyrimidine, 5,6dihydropyrimidine, 3, 6dihydropyrimidine, 4,5 dihydropyrazine, 5,6dihydropyrazine, 3,6dihydropyrazine, 4,5dihydropyrazine, 1,4dihydropyrazine, 1, 4dithiin, 1,4dioxin, 2H1, 2oxazine, 6H1, 2oxazine, 4H 1,2oxazine, 2H1, 3oxazine, 4H1, 3oxazine, 6H1, 3oxazine, 2H1, 4oxazine, 4H1, 4oxazine, 2H1, 3thiazine, 2H1, 4thiazine, 4H1, 2thiazine, 6H1, 3 thiazine, 4H1, 4thiazine, 2H1, 2thiazine, 6H1, 2thiazine, 1,4oxathiin, 2H, 5H 1,2, 3triazine, lH, 4H1, 2,3triazine, 4, 5dihydro1, 2, 3triazine, 1H, 6H1,2, 3 triazine, 1, 2dihydro1, 2, 3triazine, 2, 3dihydro1, 2,4triazine, 3H, 6H1,2, 4 triazine, 1H, 6H1, 2, 4triazine, 3, 4dihydro1, 2,4triazine, 1H, 4H1, 2, 4triazine, 5, 6dihydro1, 2,4triazine, 4, 5dihydro1, 2, 4triazine, 2H, 5H1, 2,4triazine, 1,2 dihydro1, 2, 4triazine, 1H,4H1, 3,5triazine, 1, 2dihydro1, 3,5triazine, 1,4, 2 dithiazine, 1,4, 2dioxazine, 2H1, 3,4oxadiazine, 2H1, 3,5oxadiazine, 6H1,2, 5 oxadiazine, 4H1, 3,4oxadiazine, 4H1, 3,5oxadiazine, 4H1, 2,5oxadiazine, 2H 1,3, 5thiadiazine, 6H1, 2,5thiadiazine, 4H1, 3, 4thiadiazine, 4H1,3, 5 thiadiazine, 4H1, 2,5thiadiazine, 2H1, 3,4thiadiazine, 6H1, 3,4thiadiazine, 6H 1,3, 4oxadiazine and 1,4, 2oxathiazine, wherein the heterocycle is optionally vicinally fused with a saturated or unsaturated 5, 6or 7membered ring containing 0,1 or 2 atoms independently selected from N, O and S; Rf is phenyl substituted by 0, 1 or 2 groups selected from halo, C14alkyl, C, 3haloalkyl,ORd andNRdRd ; or Rr is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0,1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents selected from halo, Cl 4alkyl, C, 3haloalkyl,ORd andNRdRd ; and Rg is hydrogen orCH3. |
| 22. | The compound according to Claim 21, wherein Rl6 is halo,NH2, NHC13alkyl, N(C13alkyl)C13alkyl or C13alkyl. |
| 23. | The compound according to Claim 21, wherein Rl° is independently, at each instance, C, salkyl, Cl 4haloalkyl, halo, cyano, nitro, C (=O) (Cs 8alkyl),C (=O) O (CI salkyl),C (=O) NRdRd,C (=NRd) NRdRd,ORd OC (=O) (CI 8alkyl),OC (=O) NRdRd,OC (=O) N (Rd) S (=0) 2 (CI salkyl) OC2 OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O)2NRdRd, S(=O) 2N (Rd) C (=O) (C 18alkyl),S (=0) 2N (Rd) C (=O) O (C18alkyl), S (=0) 2N (Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C 18alkyl), N(Rd)C(=O)O(C18alkyl), N(Rd) C (=O) NRdRd, N(Rd)C(=NRd)NRdRd, N(Rd)S(=O)2(C18alkyl), N(Rd) S (=0) 2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd ; or Rl° is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1, 2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5, 6or 7membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C18alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd)C(=O)(C18alkyl), S(=O)2N(Rd) C (=O) O (C18alkyl), S(=O)2N(Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd)C(=O)NRdRd, N(Rd)NRdRd, N(Rd)S(=O) 2 (Ci salkyl)N (Rd) S (=0) 2NRdRd,NRaC26alkylNRdRd and 6alkylORd ; or Rl° is Cl 4alkyl substituted by 0, 1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C, 8alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd) C (=O) (C18alkyl), S(=O)2N(Rd) C (=O) O (C, 8alkyl), S(=O)2N(Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd) C (=O) O (Cl 8alkyl),N (R) C (=O) NRdRd,N (Rd) C (=NRd) NRdRd, N(Rd) S (=0) 2 (C18alkyl), N(Rd) S (=0) 2NRdRd,NRdC26alkylNRdRd and NRdC26alkylORd. |
| 24. | The compound according to any one of Claim 21, wherein R'is. |
| 25. | The compound according to Claim 24, wherein R7 is C15alkyl, halo or C, 4haloalkyl. |
| 26. | The compound according to Claim 21, wherein R'is naphthyl substituted by 0,1, 2 or 3 substituents independently selected from R5. |
| 27. | The compound according to Claim 21, wherein R1 is Re substituted by 0,1, 2 or 3 substituents independently selected from R5. |
| 28. | The compound according to Claim 27, wherein R'is Re substituted by 1,2 or 3 substituents independently selected from R5. |
| 29. | The compound according to Claim 21, wherein R4 is. |
| 30. | The compound according to Claim 29, wherein R'° and R"together are a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) (Cl 8alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C, 8alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRdRd, S (=0) 2N (Rd) C (=O) (C1 salkyl)S (=0) 2N (Rd) C (=O) O (C18alkyl), S(=O)2N(Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NRdRd,N (Rd) C (=NRd) NRdRd, N(Rd) S (=O) 2 (C18alkyl), N(Rd)S(=O)2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd, and any nitrogen atoms in the bridge are substituted by H, C16alkylORd, C16alkyl, C16alkylNRdRd, C13alkyl=O)ORd, C13alkylC(=O)NRdRd, C13alkylOC(=O)C16alkyl, C13alkylNRdC(=O)C16alkyl, C(=O)Rf or C13alkylRf ; or R11 and R12 together are a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (R d) S (=0) 2 (C, 8alkyl),OC26alkylNRdRd, OR,SR,S (=O) (C18alkyl), S(=O)2(C18alkyl), S(=O)2NRdRd, S (=0) 2N (Rd) C (=O) (C18alkyl), S(=O)2N(Rd) C (=O) O (C, 8alkyl), S (=0) 2N (Rd) C (=O) NRdRd, NRdRd, N(Rd)C(=O)(C18alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NR R,N (R) C (=NRd) NRdRd, N(Rd) S (=O) 2 (C18alkyl), N(Rd) S (=O) 2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd, and any nitrogen atoms in the bridge are substituted by H, C16alkylORd, C16alkyl, C16alkylNRdRd, C13alkylC(=O)ORd, C13alkylC(=O)NRdRd, C13alkylOC(=O)C16alkyl, C13alkylNRdC(=O)C16alkyl, C(=O)Rf or C13alkylRf. |
| 31. | The compound according to Claim 21, wherein R4 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C19alkyl, C14haloalkyl, halo, nitro, cyano, oxo, ORd, S(=O)nC16alkyl, OC14haloalkyl, OC26alkylNRdRd, OC26alkylORd, OC16alkylC(=O)ORd, NRdRd, NRdC14haloalkyl, NRdC26alkylNRdRd, NRdC26alkylORd, C(=O)C16alkyl, C(=O)OC16alkyl, OC(=O)C16alkyl, C(=O)NRdC16alkyl and NRdC (=O) Cl 6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any nitrogen atoms in the bridge are substituted by H, C16alkylORd, C16alkyl, C16alkylNRdRd, C13alkylC(=O)ORd, C13alkylC(=O)NRdRd, C13alkylOC(=O)C16alkyl, C13alkylNRdC(=O)C16alkyl, C(=O)Rf or C13alkylRf. |
| 32. | The compound according to Claim 31, wherein R4 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 1,2 or 3 substituents independently selected from C19alkyl, Cl 4haloalkyl, halo, nitro, cyano, oxo,ORd,S (=O) CC 6alkyl,OC_4haloalkyl, OC26alkylNRdRd, OC26alkylORd, OC16alkylC(=O)ORd, NRdRd, 4haloalkyl,NRdC2 6alkylNRdRd,NRdC2 6alkylORd,C (=O) C1 6alkyl, C (=O) OCI 6alkyl,OC (=O) Cl 6alkyl,C (=O) NRdCl 6alkyl and NRdC (=O) Cl 6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any nitrogen atoms in the bridge are substituted by H, C16alkylORd, C16alkyl, C16alkylNRdRd, C13alkylC(=O)ORd, C13alkylC(=O)NRdRd, C13alkylOC(=O)C16alkyl, C13alkylNRdC(=O)C16alkyl, C(=O)Rf or Cl 3alkylRf. |
| 33. | The compound according to Claim 21, wherein or R4 is 10membered bicyclic ring comprising fused 6membered rings, containing 0,1, 2,3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORd, NRdRd, Cs 6alkyl and C, 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =0. |
| 34. | The compound according to Claim 33, wherein R4 is 10membered bicyclic ring comprising fused 6membered rings, containing 1,2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORd, NRdRd, C, 6alkyl and Cl 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =0. |
| 35. | A compound having the structure: or any pharmaceuticallyacceptable salt thereof, wherein: n is independently, at each instance, 0,1 or 2; o is independently, at each instance, 0,1, 2 or 3; Y is NH, O or S ; R'is or Ru ils a naphthyl substituted by 0,1, 2 or 3 substituents independently selected from R5 ; or R'is R'substituted by 1,2 or 3 substituents independently selected from R5 ; R15 is, independently, in each instance, Rl°, C18alkyl substituted by 0,1 or 2 substituents selected from R10, phenyl substituted by 0, 1, 2 or 3 substituents independently selected from R10, or a saturated or unsaturated 5or 6membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R'° ; Rl6 is, independently, in each instance, H, halo,NH2,NHCI3alkyl, N(C13alkyl)C13alkyl or Chalky ! ; R4 is a saturated or unsaturated 5or 6membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C, 4haloalkyl, halo, cyano, nitro, C (=O) R°,C (=O) OR°,C (=O) NR"'R"', C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R",OC26alkylNRmRm,OC26alkylORm,SRm,S (=O) R", S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NrmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O) 2N (Rm) C (=O) R', S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm) C (=O) OR',N (Rm) C (=O) NRmRs,N (Rm) C (=NR"') NRmRs, N (Rm) S (=0) 2Rs, N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) Rn,C (=O) ORn,C (=O) NR'Rm,C (=NR') NR'R',OR', OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R",OC26alkylNRmR"', kylOR',SR',S (=O) R',S (=0) 2R',S (=0) 2NR'R', S(=O)2N(Rm) C (=O) R",S (=0) 2N (Rm) C (=O) OR',S (=0) 2N (Rm) C (=O) NR'"R"', NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NrmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C (=O) NR"'R',C (=NR"') NRmRs,ORs,OC (=O) Rs,OC (=O) NRmR', OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmRs,NRmRs,N (Rm) C (=O) R',N (Rm) C (=O) ORs, N (R"') C (=O) NRmRs, N (Rm) C (=NRm) NRmRs,N (Rm) S (=0) 2R', N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =0 groups; but in no instance is R4 3, 5ditrifluoromethylphenyl or 3trifluoromethyl4fluorophenyl ; R5 is independently, at each instance, H, C15alkyl, C14haloalkyl, halo, nitro, cyano,OCI 6alkyl, OC14haloalkyl, OC26alkylNRdRd, OC26alkylORd, NRdRd, NRdC14haloalkyl, NRdC26alkylNRdRd, NRdC26alkylORd, naphthyl, C02 (CI6alkyl),C (=O) (CI6alkyl),C (=O) NRdRd,NRdC (=O) Rd, NRdC(=O)NRdRd, NRdCO2(C16alkyl), C18alkylORd, C16alkylNRdRd, S(=O)2(C16alkyl), S(=O)2NRdRd, NRdS(=O)2(C16alkyl), OC(=O)NRdRd, a phenyl ring substituted with 0,1, 2, or 3 substituents independently selected from R10 ; or R5 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from 0, N and S, substituted with 0,1, 2, or 3 substituents independently selected from Rl° ; R6 is independently, at each instance, H, Cl 5alkyl, Cl 4haloalkyl, halo, OC16alkyl, OC14haloalkyl, OC26alkylNRdRd, OC26alkylORd, NRdRd, NRdC14haloalkyl, NRdC26alkylNRdRd or NRdC26alkylORd, C18alkylORd, 6alkylNRdRd,S (CI 6alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from Rl° ; or R6 is a saturated or unsaturated 5 or 6membered ring heterocycle containing 1,2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R'° ; R7 is independently, at each instance, H, C18alkyl, C14haloalkyl, halo, OC16alkyl, OC14haloalkyl, OC26alkylNRdRd, OC26alkylORd, NRdRd, NRdC14haloalkyl, NRdC26alkylNRdRd, NRdC26alkylORd, C18alkylORd, C16alkylNRdRd or S(C16alkyl) ; or R7 is a saturated or unsaturated 4or 5membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, C12haloalkyl and C13alkyl ; R8 is independently, at each instance, H, C15alkyl, C14haloalkyl, halo, OC16alkyl, OC14haloalkyl, OC26alkylNRdRd, OC26alkylORd, NRdRd, NRdC14haloalkyl, NRdC26alkylNRdRd, NRdC26alkylORd, C18alkylORd, Cl 6alkylNRdRd,S (CI 6alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from Rl°, or R8 is a saturated or unsaturated 5 or 6membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from Rl° ; R9 is independently, at each instance, H, C18alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC26alkylNRdRd, OC26alkylORd,NRdRd,NRdC l 4haloalkyl,NRdC26alkylNRdRd or NRdC26alkylORd, CO2(C16alkyl), C(=O)(C16alkyl), C(=O)NRdRd, <BR> <BR> <BR> NRdC (=O) (Cs 6alkyl),NRdC (=O) NRdRd,NRdCO2 (CI 6alkyl),<BR> <BR> <BR> <BR> <BR> <BR> CI salkylORd,CI 6alkylNRdRd,S (=O) n (CI 6alkyl),S (=0) 2NRdRd, NRdS (=O) 2 (C, 6alkyl),OC (=O) NRdRd or a (CRqRq) ophenyl wherein the phenyl is substituted with 0,1, 2, or 3 substituents independently selected from R'° ; or R9 is(CRqRq) OHet wherein Het is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from R10 ; or R9 is a saturated or unsaturated 4or 5membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, C12haloalkyl and C13alkyl ; wherein at least one of R5, R6, R7, R8 and R9 is Cl 8alkyl, C, 4haloalkyl, halo,OC, 4haloalkyl,OC26alkylNRdRd, OC26alkylORd, NRdC14haloalkyl, NRdC26alkylNRdRd, NRdC26alkylORd, C18alkylORd, C16alkylNRdRd or S(C16alkyl) ; R'° is independently, at each instance, selected from H, C, 8alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) (C1 8alkyl),C (=O) O (C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C18alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S (=O) (C1 8alkyl),S (=0) 2 (C18alkyl), S(=O)2NRdRd, S(=O) 2N (Rd) C (=O) (C 8alkyl), S(=O)2N(Rd)C(=O)O(C18alkyl), S (=0) 2N (Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NRdRd, N(Rd) C (=NRd)NRdRd, N(Rd) S (=0) 2 (C18alkyl), N(Rd)S(=O)2NRdRd, NRdC26alkylNRdRd and NRdC26alkylORd ; or Rl° is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5, 6or 7membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C18alkyl), OC2 OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S (=0) 2NRdRd,S (=0) 2N (Rd) C (=O) (C18alkyl), S(=O)2N(Rd) C (=O) O (C18alkyl), S (=0) 2N (Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd)C(=O)O(C18alkyl), N(Rd) C (=O) NR R,N (R) C (=NRd) NRdRd, N(Rd) S (=0) 2 (C18alkyl), N(Rd) S (=0) 2NRdRd,NRdC26alkylNRdRd and NRdC26alkylORd ; or R'° is Cl 4alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C (=O) NRdRd,C (=NRd) NRdRd,ORd,OC (=O) (CIsalkyl),OC (=O) NRdRd, OC(=O) N (Rd) S (=0) 2(C18alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (C, 8alkyl),S (=0) 2NRdRd, S(=O)2N(Rd) C (=O) (C18alkyl), S(=O)2N(Rd) C (=O) O (C, 8alkyl), S(=O) 2N (Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C18alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NRdRd, N(Rd) C (=NRd)NRdRd, N(Rd) S (=0) 2 (CI8alkyl),N (Rd) S (=0) 2NRdRd, NRdC26alkylNRdRd and 6alkylORd ; Rd is independently, at each instance, H, phenyl, benzyl or Cl 6alkyl ; Re is a heterocycle selected from the group of thiophene, pyrrole, 1,3oxazole, 1, 3thiazole, 1,3, 4oxadiazole, 1, 3, 4thiadiazole, 1,2, 3oxadiazole, 1,2, 3thiadiazole, 1H1, 2, 3triazole, isothiazole, 1,2, 4oxadiazole, 1,2, 4 thiadiazole, 1,2, 3,4oxatriazole, 1,2, 3,4thiatriazole, 1H1, 2,3, 4tetraazole, 1,2, 3,5oxatriazole, 1,2, 3,5thiatriazole, furan, imidazol1yl, imidazol4yl, 1,2, 4 triazol4yl, 1, 2, 4triazol5yl, isoxazol3yl, isoxazol5yl, pyrazol3yl, pyrazol 5yl, thiolane, pyrrolidine, tetrahydrofuran, 4, 5dihydrothiophene, 2pyrroline, 4,5dihydrofuran, pyridazine, pyrimidine, pyrazine, 1,2, 3triazine, 1,2, 4triazine, 1,2, 4triazine, 1,3, 5triazine, pyridine, 2H3,4, 5,6tetrahydropyran, thiane, 1,2 diazaperhydroine, 1,3diazaperhydroine, piperazine, 1,3oxazaperhydroine, morpholine, 1,3thiazaperhydroine, 1,4thiazaperhydroine, piperidine, 2H3, 4 dihydropyran, 2,3dihydro4Hthiin, 1,4, 5, 6tetrahydropyridine, 2H5,6 dihydropyran, 2,3dihydro6Hthiin, 1,2, 5, 6tetrahydropyridine, 3,4, 5,6 tetrahydropyridine, 4Hpyran, 4Hthiin, 1, 4dihydropyridine, 1,4dithiane, 1,4 dioxane, 1,4oxathiane, 1, 2oxazolidine, 1, 2thiazolidine, pyrazolidine, 1,3 oxazolidine, 1, 3thiazolidine, imidazolidine, 1,2, 4oxadiazolidine, 1,3, 4 oxadiazolidine, 1,2, 4thiadiazolidine, 1,3, 4thiadiazolidine, 1, 2, 4triazolidine, 2 imidazoline, 3imidazoline, 2pyrazoline, 4imidazoline, 2,3dihydroisothiazole, 4,5dihydroisoxazole, 4, 5dihydroisothiazole, 2,5dihydroisoxazole, 2,5 dihydroisothiazole, 2,3dihydroisoxazole, 4,5dihydrooxazole, 2,3 dihydrooxazole, 2,5dihydrooxazole, 4,5dihydrothiazole, 2, 3dihydrothiazole" 2, 5dihydrothiazole, 1, 3, 4oxathiazolidine, 1,4, 2oxathiazolidine, 2, 3dihydrolH [1, 2,3] triazole, 2, 5dihydrolH [1, 2,3] triazole, 4, 5dihydrolH [1, 2,3] triazole, 2, 3dihydro1H [1, 2,4] triazole, 4, 5dihydrolH [1, 2,4] triazole, 2,3dihydro [1, 2,4] oxadiazole, 2, 5dihydro [1, 2,4] oxadiazole, 4, 5dihydro [1, 2,4] thiadiazole, 2, 3dihydro [1, 2,4] thidiazole, 2, 5dihydro [1, 2,4] thiadiazole, 4, 5dihydro [1, 2,4] thiadiazole, 2, 5dihydro [1, 2,4] oxadiazole, 2,3dihydro [1, 2,4] oxadiazole, 4,5 dihydro [1, 2,4] oxadiazole, 2, 5dihydro [1, 2,4] thiadiazole, 2, 3dihydro [1, 2,4] thiadiazole, 4, 5dihydro [1, 2,4] thiadiazole, 2, 3dihydro [1, 3,4] oxadiazole, 2,3 dihydro [1, 3,4] thiadiazole, [1, 4,2] oxathiazole, [1, 3,4] oxathiazole, 1,3, 5 triazaperhydroine, 1,2, 4triazaperhydroine, 1,4, 2dithiazaperhydroine, 1,4, 2 dioxazaperhydroine, 1,3, 5oxadiazaperhydroine, 1,2, 5oxadiazaperhydroine, 1,3, 4thiadiazaperhydroine, 1,3, 5thiadiazaperhydroine, 1,2, 5 thiadiazaperhydroine, 1,3, 4oxadiazaperhydroine, 1,4, 3oxathiazaperhydroine, 1,4, 2oxathiazaperhydroine, 1,4, 5,6tetrahydropyridazine, 1,2, 3,4 tetrahydropyridazine, 1,2, 3,6tetrahydropyridazine, 1,2, 5, 6tetrahydropyrimidine, 1,2, 3, 4tetrahydropyrimidine, 1,4, 5, 6tetrahydropyrimidine, 1,2, 3,6 tetrahydropyrazine, 1,2, 3,4tetrahydropyrazine, 5, 6dihydro4H [1, 2] oxazine, 5,6 dihydro2H [1, 2] oxazine, 3, 6dihydro2H [1, 2] oxazine, 3,4dihydro2H [1, 2] oxazine, 5, 6dihydro4H [1, 2] thiazine, 5, 6dihydro2H [1, 2] thiazine, 3,6 dihydro2H[1,2] thiazine, 3, 4dihydro2H [1, 2] thiazine, 5,6dihydro2H [1, 3] oxazine, 5, 6dihydro4H [1, 3] oxazine, 3, 6dihydro2H [1, 3] oxazine, 3,4 dihydro2H [1, 3] oxazine, 3, 6dihydro2H [1, 4] oxazine, 3,4dihydro2H [1, 4] oxazine, 5, 6dihydro2H [1, 3] thiazine, 5, 6dihydro4H [1, 3] thiazine, 3,6 dihydro2H [1, 3] thiazine, 3, 4dihydro2H [1, 3] thiazine, 3,6dihydro2H [1, 4] thiazine, 3, 4dihydro2H [1, 4] thiazine, 1, 2,3, 6tetrahydro[1, 2,4] triazine, 1, 2,3, 4tetrahydro[1, 2,4] triazine, 1, 2,3, 4tetrahydro[1, 3,5] triazine, 2,3, 4,5 tetrahydro[1, 2,4] triazine, 1, 4,5, 6tetrahydro[1, 2,4] triazine, 5,6dihydro [1, 4,2] dioxazine, 5, 6dihydro[1, 4,2] dioxazine, 5, 6dihydro[1, 4,2] dithiazine, 2,3 dihydro[1, 4,2] dioxazine, 3, 4dihydro2H [1, 3,4] oxadiazine, 3,6dihydro2H [1, 3,4] oxadiazine, 3, 4dihydro2H [1, 3,5] oxadiazine, 3,6dihydro2H [1, 3,5] oxadiazine, 5, 6dihydro2H [1, 2,5] oxadiazine, 5,6dihydro4H [1, 2,5] oxadiazine, 3, 4dihydro2H [1, 3, 4] thiadiazine, 3,6dihydro2H [1, 3,4] thiadiazine, 3, 4dihydro2H [1, 3,5] thiadiazine, 3,6dihydro2H [1, 3,5] thiadiazine, 5, 6dihydro2H [1, 2,5] thiadiazine, 5,6dihydro4H [1, 2,5] thiadiazine, 5, 6dihydro2H [1, 2,3] oxadiazine, 3,6dihydro2H [1, 2,5] oxadiazine, 5, 6dihydro4H[1, 3,4] oxadiazine, 3,4dihydro2H [1, 2,5] oxadiazine, 5, 6dihydro2H[1, 2,3] thiadiazine, 3,6dihydro2H [1, 2,5] thiadiazine, 5, 6dihydro4H[1, 3, 4] thiadiazine, 3,4dihydro2H [1, 2,5] thiadiazine, 5, 6dihydro[1, 4,3] oxathiazine, 5, 6dihydro[1, 4,2] oxathiazine, 2, 3dihydro[1, 4,3] oxathiazine, 2, 3dihydro[1, 4,2] oxathiazine, 4,5 dihydropyridine, 1, 6dihydropyridine, 5, 6dihydropyridine, 2Hpyran, 2Hthiin, 3,6dihydropyridine, 2,3dihydropyridazine, 2,5dihydropyridazine, 4,5 dihydropyridazine, 1, 2dihydropyridazine, 2,3dihydropyrimidine, 2,5 dihydropyrimidine, 5, 6dihydropyrimidine, 3,6dihydropyrimidine, 4,5 dihydropyrazine, 5,6dihydropyrazine, 3,6dihydropyrazine, 4,5dihydropyrazine, 1,4dihydropyrazine, 1,4dithiin, 1,4dioxin, 2H1, 2oxazine, 6H1, 2oxazine, 4H 1,2oxazine, 2H1, 3oxazine, 4H1, 3oxazine, 6H1, 3oxazine, 2H1, 4oxazine, 4H1, 4oxazine, 2H1, 3thiazine, 2H1, 4thiazine, 4H1, 2thiazine, 6H1,3 thiazine, 4H1, 4thiazine, 2H1, 2thiazine, 6H1, 2thiazine, 1,4oxathiin, 2H, SH 1,2, 3triazine, 1H, 4H1, 2,3triazine, 4, 5dihydro1, 2,3triazine, 1H, 6H1,2, 3 triazine, 1, 2dihydro1, 2, 3triazine, 2, 3dihydro1, 2,4triazine, 3H, 6H1,2, 4 triazine, 1H, 6H1, 2,4triazine, 3, 4dihydro1, 2,4triazine, 1H, 4H1, 2, 4triazine, 5, 6dihydro1, 2,4triazine, 4, 5dihydro1, 2, 4triazine, 2H, 5H1, 2, 4triazine, 1,2 dihydro1, 2,4triazine, 1H, 4H1, 3, 5triazine, 1, 2dihydro1, 3,5triazine, 1,4, 2 dithiazine, 1,4, 2dioxazine, 2H1, 3,4oxadiazine, 2H1, 3,5oxadiazine, 6H1,2, 5 oxadiazine, 4H1, 3,4oxadiazine, 4H1, 3,5oxadiazine, 4H1, 2,5oxadiazine, 2H 1,3, 5thiadiazine, 6H1, 2,5thiadiazine, 4H1, 3,4thiadiazine, 4H1,3, 5 thiadiazine, 4H1, 2,5thiadiazine, 2H1, 3,4thiadiazine, 6H1, 3,4thiadiazine, 6H 1,3, 4oxadiazine and 1,4, 2oxathiazine, wherein the heterocycle is optionally vicinally fused with a saturated or unsaturated 5, 6or 7membered ring containing 0,1 or 2 atoms independently selected from N, O and S; Rf is phenyl substituted by 0,1 or 2 groups selected from halo, C14alkyl, Cl 3haloalkyl,ORd andNRdRd ; or Rf is a saturated or unsaturated 5or 6membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0,1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents selected from halo, Cl 4alkyl, Cl 3haloalkyl,ORd andNRdRd ; Rg is hydrogen orCH3; R'is independently at each instance H or R R"is independently at each instance C, 8alkyl, phenyl or benzyl ; Rq is independently in each instance H, C14alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) R°,C (=O) OR",C (=O) NR"'Rm,C (=NRm) NR"'Rm,ORm, OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=0) 2R",OC26alkylNR°Rm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm,N (Rm) C (=O) R",N (Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; and Rs is Rn substituted by 0, 1, 2 or 3 substituents independently selected from R9. |
| 36. | The compound according to any one of Claim 35, wherein Y is NH. |
| 37. | The compound according to any one of Claim 35, wherein Y is 0. |
| 38. | The compound according to any one of Claim 35, wherein Y is S. |
| 39. | The compound according to any one of Claim 35, wherein R'is. |
| 40. | The compound according to Claim 39, wherein R7 is Cl 5alkyl halo or Cl 4haloalkyl. |
| 41. | The compound according to Claim 35, wherein R'is a naphthyl substituted by 0,1, 2 or 3 substituents independently selected from R5. |
| 42. | The compound according to Claim 35, wherein R1 is Re substituted by 1,2 or 3 substituents independently selected from R5 ;. |
| 43. | The compound according to Claim 35, wherein Rl5 is phenyl substituted by 0,1, 2 or 3 substituents independently selected from R'°. |
| 44. | The compound according to Claim 35, wherein Rl5 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from Rlo. |
| 45. | The compound according to Claim 35, wherein R15 is Chalky) substituted by 0,1 or 2 substituents selected from Rl°. |
| 46. | The compound according to Claim 35, wherein R 15 is selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C1 8alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd) S (=0) 2 (C18alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRdRd, S (=0) 2N (Rd) C (=O) (C, 8alkyl), S(=O)2N(Rd) C (=O) O (C18alkyl), S (=0) 2N (Rd) C (=O) NRdRd,NRdRd,N (Rd) C (=O) (C1 8alkyl), N(Rd)C(=O)O(C18alkyl), N(Rd)C(=O)NRdRd, N(Rd)C(=NRd)NRdRd, N (Rd) S (=0) 2 (C,8alkyl),N (Rd) S (=0) 2NRdRd,NRdC26alkylNRdRd and 6alkylORd ; or R'° is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5, 6or 7membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from C, 8alkyl, Cs 4haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl), C(=O)O(C18alkyl), C(=O)NRdRd, C(=NRd)NRdRd, ORd, OC(=O)(C18alkyl), OC(=O)NRdRd, OC(=O) N (Rd)S(=O)2(C18alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd) C (=O) (C1 8alkyl),S (=0) 2N (Rd) C (=O) O (C18alkyl), S(=O)2N(Rd) C (=O) NRdRd, NRdRd, N(Rd)C(=O)(C18alkyl), N(Rd) C (=O) O (C, 8alkyl), N(Rd) C (=O) NR R,N (R) C (=NRd) NRdRd, N(Rd) S (=0) 2 (C18alkyl), N(Rd) S (=0) 2NRdRd, _NRaC26alkylNRdRd and 6alkyl0Rd ; or R'° is C14alkyl substituted by 0,1, 2 or 3 groups selected from C, 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C (=O) NRdRdC (=NRd) NRdRd,ORd,OC (=O) (Cl 8alkyl),OC (=O) NR R, OC(=O) N (Rd) S (=0) 2 (C18alkyl), OC26alkylNRdRd, OC26alkylORd, SRd, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRdRd, S(=O)2N(Rd) C (=O) (C, 8alkyl),S (=0) 2N (Rd)C(=O)O(C18alkyl), S(=O)2N(Rd)C(=O)NrdRd, NRdRd, N(Rd) C (=O) (C18alkyl), N(Rd) C (=O) O (C18alkyl), N(Rd) C (=O) NRdRd,N (Rd) C (=NRd)NRdRd, N(Rd) S (=0) 2 (C, 8alkyl),N (Rd) S (=0) 2NRdRd, NRdC26alkylNRdRd and C26alkylOR. |
| 47. | The compound according to Claim 35, wherein R16 is, independently, in each instance, halo, NH2, NHC13alkyl, N(C13alkyl)C13alkyl or C13alkyl. |
| 48. | The compound according to Claim 35, wherein R4 is an unsaturated 6membered ring containing 0 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) OR, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC (=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm, NRmRm, N (Rm) C (=O) Rn, N(Rm)C(=O)ORn, N (R"') C (=O) NRmRm, N (Rm) C (=NRm) NRmRm,N (Rm) S (=O) 2Rn, N (R"') S (=0) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C (=O) OR,C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs OC OC(=O)NRmRs, OC(=O)N(Rm)S(=O)2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, (=0) 2N (Rm) C (=O) ORs,S (=0) 2N (Rm) C (=O) NRmRs,NRmRs,N (R"') C (=O) R', N(Rm) C (=O) OR',N (R"') C (=O) NR"'R',N (Rm) C (=NRm) NR"'R', N(Rm) S (=O) 2R',N (Rm) S (=0) 2NR"'R',NR"'C26alkylNRmR',NR"'C26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, C (=O) Rn,C (=O) ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm) C(=O)NRmRm, NRmRm, N(Rm) C (=O) Rn,N (Rm) C (=O) ORn, N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C (=O) NRmRsC (=NRm) NRmRs,ORs,OC (=O) Rs,OC (=O) NRmRs, OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmR',OC26alkylORs,SRs,S (=O) RS, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm) C (=O) NRmRs,NRmR',N (Rm) C (=O) Rs,N (Rm) C (=O) ORs, N (R"') C (=O) NRmR',N (Rm) C (=NRm) NR"'R',N (Rm) S (=0) 2R', N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =0 groups. |
| 49. | The compound according to Claim 35, wherein R4 is a saturated or unsaturated 5or 6membered ring containing 1, 2 or 3 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C (=O) Rn,C (=O) OR", C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm) C (=O) Rn,S (=O) 2N (Rm) C (=O) OR', S(=O) 2N (R"') C (=O) NRmRm,NRmRm,N (Rm) C (=O) Rn, N(Rm) C (=O) OR', N (R"') C (=O) NRmRm,N (Rm) C (=NRm) NRmRm,N (Rm) S (=O) 2Rn, N (Rm) S (=O) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm) C (=NR"') NR'"R', N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) OR",C (=O) NR"'R"',C (=NR"') NRmRm,OR", OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R",OC26alkylNRmR"', OC26alkylORm,SRm,S (=O) R°,S (=0) 2R",S (=0) 2NRmR"', S(=O)2N(Rm) C (=O) Rn, S(=O)2N(Rm) C (=O) ORn, S(=O)2N(Rm) C (=O) NRmRm, NR"'R"',N (R"') C (=O) Rn7N (Rm) C (=O) OR",N (Rm) C (=O) NRmRm N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs,OC (=O) NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNRmRs,OC26alkylORs,SR',S (=O) RS, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm) C (=O) NR°'Rs,NRmRs,N (Rm) C (=O) R',N (Rm) C (=O) ORs, N(Rm) C (=O) NR'R',N (Rm) C (=NRm) NRmRs, N (Rm) S (=0) 2Rs, N(Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =0 groups; but in no instance is R4 3, 5ditrifluoromethylphenyl or 3trifluoromethyl4fluorophenyl. |
| 50. | The compound according to Claim 35, wherein R4 is a saturated or unsaturated 6membered ring containing 0 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) OR",C (=O) NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O) 2N (Rm) C (=O) R",S (=O) 2N (Rm) C (=O) OR", S(=O) 2N (Rm) C (=O) NRmRm, NRmRm, N (Rm) C (=O) Rn,N (Rm) C (=O) OR", N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm) S (=O) 2Rn, N (Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC (=O) NRmRS,OC (=O) N (R"') S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) Rs, N (R°') C (=O) OR',N (R"') C (=O) NRmRs, N (R"') C (=NR"') NRmRs, N(Rm) S (=0) 2Rs, N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C, 4alkyl substituted by 1 or 2 groups selected from C12haloalkyl, halo, cyano, nitro, C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2R°,OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NR"'R',NRR',N (Rm) C (=O) R',N (Rm) C (=O) OR', N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N (Rm) S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; but in no instance is R4 3, 5ditrifluoromethylphenyl or 3trifluoromethyl4fluorophenyl. |
| 51. | The compound according to Claim 35, wherein R4 is a saturated or unsaturated 5or 6membered ring containing 1,2 or 3 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC (=O) NRmRm,OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N (Rm) C (=O) Rn, N(Rm) C (=O) OR",N (Rm) C (=O) NRmRm, N(Rm) C (=NRm) NR"'R'",N (R"') S (=0) 2Rn, N (R"') S (=0) 2NRmRm, NR"'C26alkylNR"'Rm,NR"'C26alkylOR"',C (=O) R',C (=O) ORS, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm) C (=O) Rs,S (=0) 2N (Rm) C (=O) ORs, S(=O)2N(Rm) C (=O) NRmRs, NRmRs, N (Rm) C (=O) Rs,N (Rm) C (=O) ORs, N (R"') C (=O) NRmRs, N (Rm) C (=NRm) NRmRs,N (Rm) S (=0) 2Rs, N (R"') S (=O) 2NRmR',NRmC26alkylNR"'R',NRmC26alkylORs and Ci_4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, <BR> <BR> <BR> C (=O) Rn,C (=O) ORn,C (=O) NRmRm,C (=NRm) NRmRm, ORm OC (=O) Rn OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2R",OC26alkylNR"'R"',OC26alkylOR"', SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) R",N (Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (R"') S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S (=0) 2N (Rm) C (=O) NRmRs, NRmRs, N (Rm) C (=O) Rs,N (Rm) C (=O) ORs, N (R'") C (=O) NR'"R',N (Rm) C (=NR"') NRmRs,N (Rm) S (=0) 2Rs, N (R"') S (=O) 2NRmRs,NRmC26alkylNR"'R',NR°'C26alkylORs ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; but in no instance is R4 3, 5ditrifluoromethylphenyl or 3trifluoromethyl4fluorophenyl. |
| 52. | The compound according to Claim 35, wherein R9 is H. |
| 53. | The compound according to Claim 35, wherein R9 is independently, at each instance, C18alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC26alkylNRdRd, OC26alkylORd, NRdRd, NRdCI4haloalkyl,NRdC26alkylNRdRd orNRdC2_6alkylORd,CO2 (CI 6alkyl), C(=O)(C16alkyl), C(=O)NRdRd, NRdC(=O)(C16alkyl), NRdC(=O)NRdRd, NRdCO2(C16alkyl), C18alkylORd, C16alkylNRdRd, S(=O)n(C16alkyl), S (=O) 2NRdRd,NRdS (=O) ay6alkyl) orOC (=O) NRdRd. |
| 54. | The compound according to Claim 35, wherein R9 is a (CRqRq) ophenyl wherein the phenyl is substituted with 0,1, 2, or 3 substituents independently selected from R10. |
| 55. | The compound according to Claim 35, wherein R9 is (CRqRq) oHet wherein Het is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from R° ; or R9 is a saturated or unsaturated 4 or 5membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, Cl 2haloalkyl and C13alkyl. |
| 56. | A compound having the structure: or any pharmaceuticallyacceptable salt thereof, wherein: YisOorS ; n is independently, at each instance, 0,1 or 2. Ru ils or Ru ils a naphthyl substituted by 0,1, 2 or 3 substituents independently selected from R5 ; or R'is R'substituted by 1, 2 or 3 substituents independently selected from R5 ; R'5 is, independently, in each instance, Rl°, C18alkyl substituted by 0,1 or 2 substituents selected from Rl°, (CH2) nphenyl substituted by 0,1, 2 or 3 substituents independently selected from R'°, or a saturated or unsaturated 5or 6membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, the heterocycle and bridge being substituted by 0,1, 2 or 3 substituents independently selected from Rl° ; Rl6 is, independently, in each instance, H, halo, NH2, NHC13alkyl, N(C13alkyl)C13alkyl, OC13alkyl, C12haloalkyl, OC12haloalkyl or Chalky ! ; R4 is wherein when Rl is bromophenyl, methylphenyl or trifluoromethylphenyl, R4 is not trifluoromethylphenyl or trifluoromethylhalophenyl ; or R4 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, wherein each of the carbon atoms of the heterocycle is substituted by H, C, _9alkyl, C, 4haloalkyl, halo, cyano, oxo,OR",S (=O) nCI_6alkyl, OC14haloalkyl, OC26alkylNRhRh, OC26alkylORh, OC16alkylC(=O)ORh, NR"R",NRhCI_4haloalkyl,NRhC26alkylNRhRh,NRhC26alkylOR", C (=O) CI 6alkyl,C (=O) OC, 6alkyl,OC (=O) Cl 6alkyl,C (=O) NRhCl 6alkyl or NRhC (=O) Cl 6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and each of the available nitrogen atoms in the heterocycle are substituted by H, C16alkylORh, C16alkyl, C16alkylNRhRh, C13alkylC(=O)ORh, C13alkylC(=O)NRhRh, C13alkylOC(=O)C16alkyl, C13alkylNRhC(=O)C16alkyl, C(=O)Rj or C13alkylRj ; or R4 is an 8, 9, 10or 11membered bicyclic ring, containing 0,1, 2,3 or 4 N atoms and 0,1 or 2 atoms selected from S and O with the remainder being carbon atoms, wherein each of the carbon atoms of the ring is substituted by H, Cl aalkyl, C, 4haloalkyl, halo, cyano, oxo,OR, S(=O)nC16alkyl, OC14haloalkyl, OC26alkylNRhRh, OC26alkylORh, OC16alkylC(=O)ORh, NRhRh, NRhC14haloalkyl, NRhC26alkylNRhRh, 6alkylORh,C (=O) CI 6alkyl,C (=O) OCl 6alkyl,OC (=O) Cs 6alkyl, C(=O)NRhC16alkyl or NRhC(=O)C16alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any available nitrogen atoms in the ring are substituted by H, C16alkylORh, C16alkyl, C16alkylNRhRh, C13alkylC(=O)ORh, C13alkylC(O)NRhRh, C13alkylOC(=O)C16alkyl, C13alkylNRhC(=O)C16alkyl, C(=O)Rj or C13alkylRj ; R5 is independently, at each instance, H, C15alkyl, C14haloalkyl, halo, nitro,OC, 6alkyl, OC14haloalkyl, OC26alkylNRhRh, OC26alkylORh, NRhRh, NRhC14haloalkyl, NRhC26alkylNRhRh, NRhC26alkylORh, naphthyl, C02 (C, 6alkyl),C (=O) (CI_6alkyl),C (=O) NR''R",NRhC (=O) Rh, NRhC(=O)NRhRh, NRhCO2(C16alkyl), C18alkylORh, C16alkylNRhRh, S(=O) n (CI6alkyl),S (=0) 2NRhRh,NRhS (=0) zWalkyl),OC (=O) NRhRh, a phenyl ring substituted with 0,1, 2, or 3 substituents independently selected from R1° ; or R5 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S, substituted with 0,1, 2, or 3 substituents independently selected from R'0 ; R6 is independently, at each instance, H, C15alkyl, C14haloalkyl, halo, OC16alkyl, OC14haloalkyl, OC26alkylNRhRh, OC26alkylORh, NRhRh, NRhC14haloalkyl, NRhC26alkylNRhRh or NRhC26alkylORh, C18alkylORh, Cl 6alkylNRhRh,S (CI 6alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from Rl° ; or R6 is a saturated or unsaturated 5 or 6membered ring heterocycle containing 1,2 or 3 atoms selected from 0, N and S substituted with 0,1, 2, or 3 substituents independently selected from Rlo ; R7 is independently, at each instance, H, C18alkyl, C14haloalkyl, bromo, OC16alkyl, OC14haloalkyl, OC26alkylNRhRh, OC26alkylORh, NRhRh, NRhC14haloalkyl, NRhC26alkylNRhRh, NRhC26alkylORh, Cl C18alkylORh, C16alkylNRhRh or S(C16alkyl) ; or R7 is a saturated or unsaturated 4or 5membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, C12haloalkyl and Cl 3alkyl ; R8 is independently, at each instance, H, C15alkyl, C14haloalkyl, halo, OC16alkyl, OC14haloalkyl, OC26alkylNRhRh, OC26alkylORh, NRhRh, NRhC14haloalkyl, NRhC26alkylNRhRh, NRhC26alkylORh, C18alkylORh, C16alkylNRhRh, S(C16alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from Rl°, or R8 is a saturated or unsaturated 5 or 6membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from Rlo ; R9 is independently, at each instance, H, C18alkyl, C14haloalkyl, halo, nitro, OC1 6alkyl, OC14haloalkyl, OC26alkylNRhRh, OC26alkylORh, NRhRh, NRhC14haloalkyl, NRhC26alkylNRhRh or NRhC26alkylORh, CO2(C16alkyl), C(=O)(C16alkyl), C(=O)NRhRh, NRhC(=O)(C16alkyl), NRhC(=O)NRhRh, NRhCO2(C16alkyl), C18alkylORh, C16alkylNRhRh, S(=O)n(C16alkyl), S(=O)2NRhRh, NRhS (=O) 2 (CI 6alkyl),OC (=O) NRhRh, a phenyl ring substituted with 0, 1,2, or 3 substituents independently selected from Rl° ; or R9 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from Rl° ; wherein at least one of R5, R6, R7, R8 and R9 is C18alkyl, C14haloalkyl, halo, OC14haloalkyl, OC26alkylNRhRh, OC26alkylORh, NRhC14haloalkyl, NRhC26alkylNRhRh, NRhC26alkylORh, C18alkylORh, C16alkylNRhRh orS (CI 6alkyl) ; or R9 is a saturated or unsaturated 4or 5membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, Cl 2haloalkyl and Cl 3alkyl ; Rl° is independently, at each instance, selected from H, C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) (Cl 8alkyl),C (=O) O (CI 8alkyl), C (=O) NRhRh,C (=NRh) NRhR",OR",OC (=O) (CI8alkyl),OC (=O) NRhR", OC(=O) N (Rh) S (=0) 2 (C1 kyl),OC26alkylNRhR",OC26alkylOR",SRh, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRhRh, S (=0) 2N (Rh) C (=O) (C18alkyl), S(=O)2N()Rh) C (=O) O (C 8alkyl), S (=0) 2N (Rh) C (=O) NRhRh,NRhRh,N (Rh) C (=O) (C18alkyl), N(Rh) C (=O) O (CI 8alkyl),N (R) C (=O) NRhR",N (R") C (=NRh) NRhRh, N (R") S (=O) 2 (C18alkyl), N(Rh) S (=O) 2NRhRh, NRhC26alkylNRhRh and NRhC26alkylORh ; or Rl° is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1 or 2 atoms selected from N, O and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl), C(=O)O(C18alkyl), C(=O)NRhRh, C(=NRh)NRhRh, ORh, OC (=O) (CI 8alkyl),OC (=O) NRhRh,OC (=O) N (Rh) S (=0) 2 (CI 8alkyl), OC26alkylNRhRh, OC26alkylORh, SRh, S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRhRh, S(=O)2N(Rh) C (=O) (CI_8alkyl),S (=0) 2N (Rh) C (=O) O (C18alkyl), S (=0) 2N (Rh) C (=O) NRhRh, NRhRh, N(Rh) C (=O) (C18alkyl), N (R") C (=O) O (C18alkyl), N(Rh) C (=O) NR R,N (R) C (=NRh)NRhRh, N (R h) S (=0) 2 (C18alkyl), N(Rh) S (=O) 2NRhRh, NRhC26alkylNRhRh and NRhC26alkylORh ; or Rl° is Cul 4alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)NRhRh, C(=NRh)NRhRh, ORh, OC(=O)(C18alkyl), OC(=O)NRhRh, OC(=O) N (Rh) S (=0) 2 (C18alkyl), OC26alkylNRhRh, OC26alkylORh, SRh, S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRhRh, S(=O)2N(Rh) C (=O) (C18alkyl), S(=O)2N(Rh) C (=O) O (C18alkyl), S(=O)2N(Rh) C (=O) NRhRh,NRhRh,N (R") C (=O) (C 18alkyl), N(Rh) C (=O) O (C18alkyl), N(Rh) C (=O) NR R,N (R) C (=NRh) NRhRh, N (R") S (=0) 2 (C18alkyl), N(Rh) S (=O) 2NRhRh, NRhC26alkylNRhRd and 6alkylORh ; R"is independently, at each instance, selected from H, C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) (C1 8alkyl),C (=O) O (CI 8alkyl), C(=O)NRhRh, C(=NRh)NRhRh, ORh, OC(=O)(C18alkyl), OC(=O)NRhRh, OC(=O) N (Rh) S (=0) 2 (CI 8alkyl),OC2 6alkylNRhRh,OC2 6alkylORh,SRh, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRhRh, S(=O)2N(Rh) C (=O) (C 8alkyl), S(=O)2N(Rh) C (=O) O (C18alkyl), S(=O)2N(Rh) C (=O) NR"R",NRhRh,N (R") C (=O) (C18alkyl), N(Rh) C (=O) O (C18alkyl), N(Rh) C (=O) NRhRh, N(Rh) C (=NRh) NRhRh, N(Rh) S (=O) 2 (C18alkyl), N(Rh) S (=O) 2NRhRh, NRhC26alkylNRRhRh and NRhC26alkylORh ; or R"is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5, 6or 7membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl),C(=O)O(C18alkyl),C(=O)NRhRh,C(=NRh)NRhRh,ORh, OC(=O)(C18alkyl),OC(=O)NRhRh,OC(=O) N (Rh) S (=0) 2 (C18alkyl), OC26alkylNRhRh,OC26alkylORh, SRh,S(=O)(C18alkyl),S(=O) 2 (C18alkyl), S(=O)2NRhRh,S(=O)2N(Rh) C (=O) (C 8alkyl,S(=O)2N(Rh) C (=O) O (C 18alkyl), S (=0) 2N (R") C (=O) NRhRh,NR"R",N (R") C (=O) (C18alkyl), N(Rh) C (=O) O (C18alkyl),N(Rh) C (=O) NR R,N (R) C (=NRh)NRhRh, N(Rh) S (=O) 2 (C18alkyl),N(Rh) S (=O) 2NRhRh,NRhC26alkylINRhRh and NRhC26alkylORh;orR11 is C14alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl),C(=O)O(C18alkyl), C (=O) NRhR",C (=NR") NR"Rh,OR",OC (=O) (CI8alkyl),OC (=O) NRhRh, OC(=O) N (Rh) S (=0) 2 (C18alkyl),OC26alkylINRhRh,OC26alkylORh,SRh, S(=O)(C18alkyl),S(=O) 2 (C, 8alkyl),S (=0) 2NRhRh, S (=0) 2N (Rh) C (=O) (C 8alkyl),S(=O)2N(Rh) C (=O) O (C _alkyl), S (=0) 2N (Rh) C (=O) NRhRh,NRhRh,N(Rh) C (=O) (C18alkyl), N(Rh) C (=O) O (C18alkyl),N(Rh) C (=O) NRhRh,N(Rh) C (=NRh) NRhRh, N(Rh) S (=O) 2 (C18alkyl),N(Rh)S(=O)2NRhRh,NRhC26alkylNRhRh and 6alkylORh ; Rl2 is independently, at each instance, selected from H, C18alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) O (C1 8alkyl),C(=O)NRhRh, C(=NRh)NRhRh,ORh,OC(=O)(C18alkyl),OC(=O)NRhRh, OC(=O) N (Rh) S (=0) 2 (C, 8alkyl),OC26alkylNR"Rh,OC26alkylORh,SR", S(=O)(C18alkyl),S(=O) 2 (C,aalkyl),S (=0) 2NRhRh, S (=0) 2N (R") C (=O) (C 8alkyl),S(=O)2N(Rh) C (=O) O (C18alkyl), S(=O)2N(Rh) C (=O) NRhRh,NRhRh,N(Rh) C (=O) (C18alkyl), N(Rh) C (=O) O (C18alkyl),N(Rh) C (=O) NRhRh,N (Rh) C (=NRh) NRhRh, N (R") S (=0) 2 (C,galkyl),N (R") S (=O) 2NRhRh,NRhC26alkylINRhRh and NRhC26alkylORh ; or Rl2 is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1, 2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5, 6or 7membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C18alkyl,C14haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl),C(=O)O(C18alkyl),C(=O)NRhRh,C(=NRh)NRhRh,ORh, OC(=O)(C18alkyl),OC(=O)NRhRh,OC(=O) N (Rh) S (=0) 2 (C18alkyl), OC2 6alkylNRhRh,OC26alkylORh,SRh,S(=O)(C18alkyl),S(=O) 2 (C18alkyl), S(=O)2NRhRh,S(=O)2N(Rh) C (=O) (CI 8alkyl),S (=0) 2N (Rh) C (=O) O (C18alkyl), S (=O) 2N (Rh) C (=O) NRhRh,NRhRh,N (Rh) C (=O) (C 8alkyl), N(Rh)C(=O)O(C18alkyl),N(Rh)C(=O)NRhRh,N(Rh)C(=NRh)NRhRh, N(Rh) S (=O) 2 (C18alkyl),N(Rh) S (=O) 2NRhRh,NRhC26alkylNRhR"and NRhC26alkylORh ; or Rl2 is C14alkyl substituted by 0,1, 2 or 3 groups selected from C14haloalkyl halo, cyano, nitro,C (=O) (CI 8alkyl),C (=O) O (CI 8alkyl), C(=O)NRhRh,C(=NRh)NRhRh,ORh,OC(=O)(C18alkyl),OC(=O)NRhRh, OC(=O) N (Rh) S (=0) 2 (C18alkyl),OC26alkylNRhRh,OC26alkylORh,SRh, S(=O)(C18alkyl),S(=O) 2 (C, 8alkyl),S (=0) 2NRhRh, S (=0) 2N (Rh) C (=O) (C18alkyl),S(=O)2N(Rh) C (=O) O (C18alkyl), S(=O)2N(Rh)C(=O)NRhRh,NRhRh,N(Rh)C(=O)(C18alkyl), N(Rh) C (=O) O (Ct 8alkyl),N (R) C (=O) NRhRh,N(Rh) C (=NRh)NRhRh, N(Rh) S (=O) 2 (C18alkyl),N(Rh) S (=O) 2NRhRh,NRhC26alkylNRhRh and 6alkyl0Rh ; R13 is independently, at each instance, selected from H, C18alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl),C(=O)O(C18alkyl), C(=O)NRhRh,C(=NRh)NRhRh,ORh,OC(=O)(C18alkyl),OC(=O)NRhRh, OC(=O) N (Rh) S (=0) 2 (C18alkyl),OC26alkylNRhRh,OC26alkylORh,SRh, S(=O)(C18alkyl),S(=O)2(C18alkyl),S(=O)2NRhRh, S(=O) 2N (Rh) C (=O) (C18alkyl),S(=O)2N(Rh) C (=O) O (C1 8alkyl), S(=O)2N(Rh) C (=O) NRhRh,NRhRh,N(Rh) C (=O) (C18alkyl), N(Rh) C (=O) O (C18alkyl), N(Rh) C (=O) NR R,N (R) C (=NR") NRhRh, N(Rh) S (=O) 2 (Cl 8alkyl),N (Rh) S (=O) 7NRhRh,NRhC26alkyl[NRhRh and NRhC26alkyl]ORh ; or R13 is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5, 6or 7membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl), C(=O)O(C18alkyl), C(=O)NRhRh, C(=NRh)NRhRh, ORh, OC(=O)(C18alkyl), OC(=O)NRhRh, OC(=O) N (Rh) S (=O)2(C18alkyl), OC26alkyl[NRhRh, OC26alkyl]ORh, SRh, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRhRh, S(=O)2N(Rh)C(=O)(C18alkyl), S(=O)2NN(Rhh)C(=O)O(C18alkyl), S(=O)2N(Rh)C(=O)NRhRh, NRhRh, N(Rh) C (=O) (C18alkyl), N(Rh) C (=O) O (C18alkyl), N(Rh) C (=O) NRhRh,N (Rh) C (=NR") NRhRh, N(Rh) S (=O) 2 (C kyl),N (R h) S (=O) 2NRhRh, NRhC26alkyl[NRhRh and NRhC26alkyl]ORh; or Rl3 is Cl 4alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C (=O) NR"Rh,C (=NRh) NRhR",ORh,OC (=O) (CI_8alkyl),OC (=O) NRhR", OC(=O) N (Rh) S (=0) 2 (CI 8alkyl), OC26alkyl]NRhRh, OC26alkyl]ORh, SRh, S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRhRh, S (=0) 2N (Rh) C (=O) (C, 8alkyl), S(=O)2N(Rh) C (=O) O (C18alkyl), S (=0) 2N (Rh) C (=O) NRhRh, NRhRh, NRhRh, N(Rh) C (=O) (C _alkyl), N(Rh) C (=O) O (C1 8alkyl), N(Rh) C (=O) NRhRh, N(Rh) C (=Rh)NRhRh, N(Rh) S (=O) 2 (CI_8alkyl),N (R") S (=O) 2NRhR",NRhC26alkylNRhRh and 6alkylORh ; R'4 is independently, at each instance, selected from H, C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) (C1 8alkyl), C(=O)O(C18alkyl), C(=O)NRhRh, C(=NRh)NRhRh, ORh, OC(=O)(C18alkyl), OC(=O)NRhRh, OC(=O) N (Rh) S (=0) 2 (Ci 8alkyl, OC26alkylNRhRh, OC26alkyl]ORh, SRh, S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRhRh, S(=O) 2N (Rh) C (=O) (C 8alkyl)2 S(=O)2N(Rh) C (=O) O (C 8alkyl), S(=O) 2N (Rh) C (=O) NRhRh,NR"R",N (R") C (=O) (CI 8alkyl), N (R") C (=O) O (C18alkyl), N(Rh) C (=O) NRhRh,N (Rh) C (=NRh)NRhRh, N(Rh) S (=O) 2 (C18alkyl), N(Rh) S (=O) 2NRhRh, NRhC26alkylNRhRh and NRhC26alkylORh ; or Rl4 is a saturated or unsaturated 5, 6or 7membered monocyclic or 6, 7, 8, 9, 10or 11membered bicyclic ring containing 1 or 2 atoms selected from N, O and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl), C(=O)O(C18alkyl), C(=O)NRhRh, C(=NRh)NRhRh, ORh, OC (=O) (C, 8alkyl),OC (=O) NRhRh,OC (=O) N (Rh) S (=0) 2 (C18alkyl), OC2 OC26alkylNRhRh, OC26alkylORh, SRh, S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRhRh, S(=O)2N(Rh) C (=O) (C18alkyl), S(=O)2N(Rh) C (=O) O (C18alkyl), S (=0) 2N (Rh) C (=O) NR"R',NRhRh,N (Rh) C (=O) (C18alkyl), N (R") C (=O) O (C18alkyl),N(Rh) C (=O) NRhRh,N (Rh) C (=NRh) NR''R\ N (R") S (=0) 2 (C18alkyl), N(Rh) S (=O) 2NRhRh, NRhC26alkylNRhRh and NRhC26alkylORh ; or R1@ is Cl 4alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)NRhRh, C(=NRh)NRhRh, ORh, OC(=O)(C18alkyl), OC(=O)NRhRh, OC(=O) N (Rh) S (=0) 2(C18alkyl), OC26alkylNRhRh, OC26alkylORh, SRh, S (=O) (CI 8alkyl),S (=0) 2 (CI 8alkyl),S (=0) 2NRhRh, S(=O) 2N (Rh) C (=O) (C18alkyl), S(=O)2N(Rh) C (=O) O (C18alkyl), S(=O)2N(Rh) C (=O) NRhRh,NR"R",N (R") C (=O) (C _8alkyl), N(Rh)C(=O)O(C18alkyl), N(Rh)C(=O)NRhRh, N(Rh)C(+NRh)NRhRh, N(Rh) S (=O) 2 (C18alkyl), N(Rh) S (=O) 2NRhRh, NRhC26alkylNrhRh and 6alkylORh ; Rh is independently, at each instance, H, phenyl, benzyl or Cl 6alkyl, the phenyl, benzyl and Cl 6alkyl being substituted by 0,1, 2 or 3 substituents selected from halo, C14alkyl, C13haloalkyl, OC14alkyl, NH2, NHC14alkyl, N(C14alkyl)C14alkyl ; Ri is a heterocycle selected from the group of thiophene, pyrrole, 1,3 oxazol, 1, 3thiazol5yl, 1,3, 4oxadiazole, 1,3, 4thiadiazole, 1,2, 3oxadiazole, 1,2, 3thiadiazole, 1Hl, 2, 3triazole, isothiazole, 1,2, 4oxadiazole, 1,2, 4 thiadiazole, 1,2, 3,4oxatriazole, 1,2, 3,4thiatriazole, 1Hl, 2,3, 4tetraazole, 1, 2,3, 5oxatriazole, 1,2, 3, 5thiatriazole, furan, imidazol1yl, imidazol3yl, imidazol4yl, 1,2, 4triazole, 1,2, 4triazole, isoxazole, pyrazol3yl, pyrazol4yl, pyrazol5yl, thiolane, pyrrolidine, tetrahydrofuran, 4,5dihydrothiophene, 2 pyrroline, 4,5dihydrofuran, pyridazine, pyrimidine, pyrazine, 1,2, 3triazine, 1,2, 4triazine, 1,2, 4triazine, 1, 3, 5triazine, pyridine, 2H3,4, 5,6tetrahydropyran, thiane, 1,2diazaperhydroine, 1, 3diazaperhydroine, piperazine, 1,3 oxazaperhydroine, morpholine, 1,3thiazaperhydroine, 1,4thiazaperhydroine, piperidine, 2H3, 4dihydropyran, 2,3dihydro4Hthiin, 1,4, 5,6 tetrahydropyridine, 2H5,6dihydropyran, 2,3dihydro6Hthiin, 1,2, 5,6 tetrahydropyridine, 3,4, 5, 6tetrahydropyridine, 4Hpyran, 4Hthiin, 1,4 dihydropyridine, 1,4dithiane, 1,4dioxane, 1,4oxathiane, 1, 2oxazolidine, 1,2 thiazolidine, pyrazolidine, 1,3oxazolidine, 1,3thiazolidine, imidazolidine, 1,2, 4 oxadiazolidine, 1,3, 4oxadiazolidine, 1,2, 4thiadiazolidine, 1,3, 4thiadiazolidine, 1,2, 4triazolidine, 2imidazolin1yl, 2imidazolin2yl, 2imidazolin5yl, 3 imidazoline, 2pyrazoline, 4imidazoline, 2, 3dihydroisothiazole, 4,5 dihydroisoxazole, 4,5dihydroisothiazole, 2,5dihydroisoxazole, 2,5 dihydroisothiazole, 2,3dihydroisoxazole, 4,5dihydrooxazole, 2,3 dihydrooxazole, 2,5dihydrooxazole, 4, 5dihydrothiazole, 2, 3dihydrothiazole" 2, 5dihydrothiazole, 1,3, 4oxathiazolidine, 1,4, 2oxathiazolidine, 2, 3dihydrolH [1, 2,3] triazole, 2, 5dihydro1H [1, 2,3] triazole, 4, 5dihydro1H [1, 2,3] triazol1yl, 4, 5dihydro1H[l, 2,3] triazol3yl, 4, 5dihydro1H [1, 2,3] triazol5yl, 2,3 dihydro1H [1, 2,4] triazole, 4, 5dihydrolH [1, 2,4] triazole, 2,3dihydro [1, 2,4] oxadiazole, 2, 5dihydro [1, 2,4] oxadiazole, 4, 5dihydro [1, 2,4] thiadiazole, 2, 3dihydro [1, 2,4] thidiazole, 2, 5dihydro [1, 2,4] thiadiazole, 4, 5dihydro [1, 2,4] thiadiazole, 2, 5dihydro [1, 2,4] oxadiazole, 2, 3dihydro [1, 2,4] oxadiazole, 4,5 dihydro [1, 2,4] oxadiazole, 2,5dihydro [1, 2,4] thiadiazole, 2, 3dihydro [1, 2,4] thiadiazole, 4, 5dihydro [1, 2,4] thiadiazole, 2, 3dihydro [1, 3,4] oxadiazole, 2,3 dihydro [1, 3,4] thiadiazole, [1, 4,2] oxathiazole, [1, 3,4] oxathiazole, 1,3, 5 triazaperhydroine, 1,2, 4triazaperhydroine, 1,4, 2dithiazaperhydroine, 1,4, 2 dioxazaperhydroine, 1,3, 5oxadiazaperhydroine, 1,2, 5oxadiazaperhydroine, 1,3, 4thiadiazaperhydroine, 1,3, 5thiadiazaperhydroine, 1,2, 5 thiadiazaperhydroine, 1,3, 4oxadiazaperhydroine, 1,4, 3oxathiazaperhydroine, 1,4, 2oxathiazaperhydroine, 1,4, 5,6tetrahydropyridazine, 1,2, 3,4 tetrahydropyridazine, 1,2, 3,6tetrahydropyridazine, 1,2, 5,6tetrahydropyrimidine, 1,2, 3, 4tetrahydropyrimidine, 1,4, 5, 6tetrahydropyrimidine, 1,2, 3,6 tetrahydropyrazine, 1,2, 3,4tetrahydropyrazine, 5, 6dihydro4H [1, 2] oxazine, 5,6 dihydro2H [1, 2] oxazine, 3, 6dihydro2H [1, 2] oxazine, 3,4dihydro2H [1, 2] oxazine, 5, 6dihydro4H [1, 2] thiazine, 5, 6dihydro2H [1, 2] thiazine, 3,6 dihydro2H [1, 2] thiazine, 3, 4dihydro2H [1, 2] thiazine, 5,6dihydro2H [1, 3] oxazine, 5, 6dihydro4H [1, 3] oxazine, 3, 6dihydro2H [1, 3] oxazine, 3,4 dihydro2H [1, 3] oxazine, 3,6dihydro2H [1, 4] oxazine, 3,4dihydro2H [1, 4] oxazine, 5, 6dihydro2H [1, 3] thiazine, 5, 6dihydro4H [1, 3] thiazine, 3,6 dihydro2H [1, 3] thiazine, 3, 4dihydro2H [1, 3] thiazine, 3,6dihydro2H [1, 4] thiazine, 3, 4dihydro2H [1, 4] thiazine, 1, 2,3, 6tetrahydro [1, 2,4] triazine, 1, 2,3, 4tetrahydro[l, 2,4] triazine, 1, 2,3, 4tetrahydro[l, 3,5] triazine, 2,3, 4,5 tetrahydro[l, 2,4] triazine, 1, 4,5, 6tetrahydro[l, 2,4] triazine, 5,6dihydro [1, 4,2] dioxazine, 5, 6dihydro[l, 4,2] dioxazine, 5, 6dihydro[1, 4,2] dithiazine, 2,3 dihydro[l, 4,2] dioxazine, 3, 4dihydro2H [1, 3,4] oxadiazine, 3,6dihydro2H [1, 3,4] oxadiazine, 3, 4dihydro2H [1, 3,5] oxadiazine, 3,6dihydro2H [1, 3,5] oxadiazine, 5, 6dihydro2H [1, 2,5] oxadiazine, 5,6dihydro4H [1, 2,5] oxadiazine, 3, 4dihydro2H [1, 3,4] thiadiazine, 3,6dihydro2H [1, 3,4] thiadiazine, 3, 4dihydro2H [1, 3,5] thiadiazine, 3,6dihydro2H [1, 3, 5] thiadiazine, 5, 6dihydro2H [1, 2,5] thiadiazine, 5,6dihydro4H [1, 2,5] thiadiazine, 5, 6dihydro2H [1, 2,3] oxadiazine, 3,6dihydro2H [1, 2,5] oxadiazine, 5, 6dihydro4H [1, 3,4] oxadiazine, 3,4dihydro2H [1, 2, 5]oxadiazine, 5, 6dihydro2H [1, 2,3] thiadiazine, 3,6dihydro2H [1, 2,5] thiadiazine, 5, 6dihydro4H[l, 3,4] thiadiazine, 3, 4dihydro2H [1, 2, 5] thiadiazine, 5, 6dihydro[l, 4,3] oxathiazine, 5, 6dihydro[l, 4,2] oxathiazine, 2, 3dihydro[l, 4,3] oxathiazine, 2, 3dihydro[l, 4,2] oxathiazine, 4,5 dihydropyridine, 1, 6dihydropyridine, 5,6dihydropyridine, 2Hpyran, 2Hthiin, 3,6dihydropyridine, 2,3dihydropyridazine, 2,5dihydropyridazine, 4,5 dihydropyridazine, 1, 2dihydropyridazine, 1, 4dihydropyrimidin1yl, 1,4 dihydropyrimidin4yl, 1,4dihydropyrimidin5yl, 1,4dihydropyrimidin6yl, 2,3dihydropyrimidine, 2,5dihydropyrimidine, 5,6dihydropyrimidine, 3,6 dihydropyrimidine, 4,5dihydropyrazine, 5,6dihydropyrazine, 3,6 dihydropyrazine, 4,5dihydropyrazine, 1,4dihydropyrazine, 1,4dithiin, 1,4 dioxin, 2H1, 2oxazine, 6H1, 2oxazine, 4H1, 2oxazine, 2H1, 3oxazine, 4H 1,3oxazine, 6H1, 3oxazine, 2H1, 4oxazine, 4H1, 4oxazine, 2H1, 3thiazine, 2H1, 4thiazine, 4H1, 2thiazine, 6H1, 3thiazine, 4H1, 4thiazine, 2H1, 2 thiazine, 6H1, 2thiazine, 1,4oxathiin, 2H, 5H1, 2,3triazine, 1H, 4H1,2, 3 triazine, 4, 5dihydro1, 2, 3triazine, 1H, 6H1, 2, 3triazine, 1, 2dihydro1, 2,3 triazine, 2, 3dihydro1, 2,4triazine, 3H, 6H1, 2, 4triazine, 1H, 6H1, 2,4triazine, 3, 4dihydro1, 2,4triazine, 1H, 4H1, 2,4triazine, 5, 6dihydro1, 2,4triazine, 4,5 dihydro1, 2, 4triazine, 2H, 5H1, 2,4triazine, 1, 2dihydro1, 2,4triazine, 1H, 4H 1,3, 5triazine, 1, 2dihydro1, 3,5triazine, 1,4, 2dithiazine, 1,4, 2dioxazine, 2H 1,3, 4oxadiazine, 2H1, 3,5oxadiazine, 6H1, 2,5oxadiazine, 4H1,3, 4 oxadiazine, 4H1, 3,5oxadiazine, 4H1, 2,5oxadiazine, 2H1, 3,5thiadiazine, 6H 1,2, 5thiadiazine, 4H1, 3,4thiadiazine, 4H1, 3,5thiadiazine, 4H1,2, 5 thiadiazine, 2H1, 3,4thiadiazine, 6H1, 3,4thiadiazine, 6H1, 3,4oxadiazine, and 1,4, 2oxathiazine, wherein the heterocycle is optionally vicinally fused with a saturated or unsaturated 5, 6or 7membered ring containing 0,1 or 2 atoms independently selected from N, O and S; Ri is phenyl substituted by 0,1 or 2 groups selected from halo, Cl 4alkyl, Cl 3haloalkyl,ORh andNRhRh ; or Ri is a saturated or unsaturated 5or 6membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0,1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents selected from halo, Cl 4alkyl, Cl 3haloalkyl,ORh andNRhRh ; and Rk is hydrogen orCH3. |
| 57. | The compound according to Claim 56, wherein Ru ils. |
| 58. | The compound according to Claim 56, wherein R7 is C26alkyl or Cl 4haloalkyl. |
| 59. | The compound according to Claim 56, wherein R1 is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R5. |
| 60. | The compound according to Claim 56, wherein R'is R'substituted by 1,2 or 3 substituents independently selected from R5. |
| 61. | The compound according to Claim 60, wherein R'is substituted by one substituent selected from halo, Cl 4haloalkyl and C1 5alkyl, and additionally by 0,1 or 2 substituents independently selected from R5. |
| 62. | The compound according to Claim 56, wherein R 15 is H. |
| 63. | The compound according to Claim 56, wherein R'5 is Rl°, C18alkyl substituted by 0,1 or 2 substituents selected from Rl°, or a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, the heterocycle and bridge being substituted by 0,1, 2 or 3 substituents independently selected from Rl° ; or R15 is (CH2)nphenyl substituted by 0,1, 2 or 3 substituents independently selected from H, C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) (Ci 8alkyl), C (=O) O (CI8alkyl),C (=O) NRhRh,C (=NRh) NR"R',OC (=O) (C, 8alkyl), OC (=O) NRhRh,OC (=O) N (Rh) S (=0) 2 (C18alkyl), OC26alkylNRhRh, OC26alkylORh, SRh, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRhRh, S (=0) 2N (Rh) C (=O) (C18alkyl), S(=O)2N(Rh)C(=O)O(C18alkyl), S(=O)2N(Rh) C (=O) NRhRh,NRhRh,N (Rh) C (=O) (Ct8a allyl) N(Rh) C (=O) O (C18alkyl), N(Rh) C (=O) NR R,N (R) C (=NRh) NRhRh, N (R") S (=0) 2 (C18alkyl), N(Rh) S (=0) 2nrhRh, NRhC26alkylNRhRh, 6alkylORh, and Cl 4alkyl substituted by 0, 1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro, C (=O) (C18alkyl), C(=O)O(C18alkyl), (=O)NRhRh, C(=NRh)NRhRh, ORh, OC(=O)(C18alkyl), OC(=O)NRhRh, OC(=O) N (Rh) S (=0) 2 (C, 8alkyl, OC26alkylNRhRh, OC26alkylORh, SRh, S(=O)(C18alkyl), S(=O) 2 (C18alkyl), S(=O)2NRhRh, S(=O) 2N (Rh) C (=O) (C18alkyl), S(=O)2N(Rh) C (=O) O (C18alkyl), S(=O)2N(Rh)C(=O)NRhRh, NRhRh, (Rh)C(=O)(C18alkyl), N(Rh)C(=O)O(C18alkyl), N(Rh)C(=O)NRhRh, N(Rh)C(=NRh)NRhRh, N(Rh) S (=0) 2 (CI_8alkyl),N (R") S (=0) 2NRhRh,NRhC2 6alkylNRhRh and NRhC26alkylORh,. |
| 64. | The compound according to Claim 56, wherein Rl6 is H. |
| 65. | The compound according to Claim 56, wherein R16 is halo, NHC13alkyl, N(C13alkyl)C13alkyl, OC13alkyl, C12haloalkyl, OC12haloalkyl or Cl 3alkyl. |
| 66. | The compound according to Claim 56, wherein R4 is wherein at least one of F10,R11,R12,R13 and R14 is other than Cl 4haloalkyl or halo. |
| 67. | The compound according to Claim 66, wherein at least one of R, R11,R12, R13 and R14 is ORh or NRhRh. |
| 68. | The compound according to Claim 56, wherein R4 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 2, wherein each of the carbon atoms of the heterocycle is substituted by H, C19alkyl, C14haloalkyl, halo, cyano, oxo, ORh, S(=O),C16alkyl, OC14haloalkyl, OCalkylNRhRh, OC26alkylORhn OC16alkylC(=O)ORh, NRhRh, NRhC14haloalkyl, NRhC26alkylNRhRh, NRhC26alkylORh, C (=O) CI 6alkyl,C (=O) OCI 6alkyl,OC (=O) CI 6alkyl,C (=O) NRhCI 6alkyl or NRhC (=O) CI 6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any available nitrogen atoms in the heterocycle are substituted by H, C16alkylORh, C16alkyl, C16alkylNRhRh, C13alkylC(=O)ORh, C13alkylC(=O)NRhRh, C13alkylOC(=O)C16alkyl, C13alkylNRhC(=O)C16alkyl, C(=O)Rj orC13alkylRj. |
| 69. | The compound according to Claim 56, wherein R4 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1 or 2 atoms selected from 0, N and S, wherein each of the carbon atoms of the heterocycle is substituted by H, C19alkyl, C14haloalkyl, halo, cyano, oxo,ORh, <BR> <BR> <BR> S (=O) nCI_6alkyl,OC, 4haloalkyl,OC26alkylNR"Rh,OC2 6alkylORh,<BR> <BR> <BR> <BR> <BR> <BR> OCI 6alkylC (=O) ORh,NRhRh,NRhC1 4haloalkyl,NRhC2 6alkylNRhRh, 6alkylORh,C (=O) CI 6alkyl,C (=O) OCI 6alkyl,OC (=O) CI 6alkyl, C (=O) NRhCs 6alkyl orNRhC (=O) CI 6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any available nitrogen atoms in the bridge are substituted by H,C. 6alkylORh, C16alkyl, C14alkylNRhRh, Cl 3alkylC (=O) ORh,CI 3alkylC (=O) NRhRh,CI 3alkylOC (=O) CI 6alkyl, C13alkylNRhC(=O)C16alkyl, C(=O)Rj or C13alkylRj. |
| 70. | The compound according to Claim 56, wherein R4 is an 8, 9, 10 or 11membered bicyclic ring, containing 1,2, 3 or 4 N atoms and 0,1 or 2 atoms selected from S and O with the remainder being carbon atoms, wherein each of the carbon atoms of the ring is substituted by H, Cl 9alkyl, Cl 4haloalkyl, halo, cyano, oxo,ORh,S (=O) nCl6alkyl,OC, _4haloalkyl,OC26alkylNRhR", OC26alkylOFh, OC16alkylC(=O)orh, NRhRh, NRhC14haloalkyl, NRhC26alkylNRhRh, NRhC26alkylORh, C(=O)C16alkyl, C(=O)OC16alkyl, OC(=O)C16alkyl, C(=O)NRhC16alkyl or NRhC(=O)C16alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any available nitrogen atoms in the ring are substituted by H, C16alkylORh, C16alkyl, C16alkylNRhRh, 3alkylC (=O) ORh,Cl 3alkylC (=O) NRhRh,CI 3alkylOC (=O) CI 6alkyl, C13alkylNGhC(=O)C16alkyl, C(=O)Rj or C13alkylRj. |
| 71. | The compound according to Claim 56, wherein R4 is an 8, 9, 10 or 11membered bicyclic ring, containing 0,1, 2,3 or 4 N atoms and 0,1 or 2 atoms selected from S and O with the remainder being carbon atoms, wherein at least one of the carbon atoms of the ring is substituted by C19alkyl, C14haloalkyl, halo, cyano, oxo,ORh,S (=O) nCl 6alkyl,OCI 4haloalkyl,OC26alkylNRhRh, OC26alkylORh, OC16alkylC(=O)ORh, NRhRh, NRhC14haloalkyl, 6alkylNRhRh,NRhC2 6alkylORh,C (=O) CI 6alkyl,C (=O) OCI 6alkyl, OC(=O)C16alkyl, C(=O)NRhC16alkyl or NRhC(=O)C16alkyl. |
| 72. | The compound according to Claim 56, wherein R5 and R9 are each independently selected from H, Cl 4haloalkyl, halo, nitro,OC16alkyl, OC14haloalkyl, OC26alkylNRhRh, OC26alkylORh, NRhRh, NRhC14haloalkyl, NRhC26alkylNRhRh, NRhC26alkylORh, CO2(C16alkyl), C(=O)(C16alkyl), C(=O)NRhRh, NRhC(=O)Rh, NRhC(=O)NRhRh, NRhCO2(C16alkyl), C18alkylORh, C16alkylNRhRh, S(=O)n(C16alkyl), S(=O)2NRhRh, NRhS(=O) 2 (CI 6alkyl) andOC (=O) NRhRh. |
| 73. | The compound according to Claim 56, wherein R6 and R8 are each independently selected from H, C15alkyl, C14haloalkyl, halo, OC16alkyl, OC14haloalkyl, OC26alkylNRhRh, OC26alkylORh, NRhRh, NRhC14haloalkyl, NrHC26alkylNRhRh or NRhC26alkylORh, C18alkylORh, C16alkylNRhRh and S(C16alkyl). |
| 74. | The compound according to Claim 56, wherein R7 is independently, at each instance, C18alkyl, C14haloalkyl, OC14haloalkyl, OC26alkylNRHRh, OC26alkylORh, NRhRh, NRhC14haloalkyl, NRhC26alkylNRhRh, NRhC26alkylORh, C18alkylORh, C16alkylNRhRh orS (C16alkyl),. |
| 75. | The compound according to Claim 56, wherein Rl° and Rl4 are each independently selected from H, C18alkyl, C14haloalkyl, halo, cyano, nitro, C(=O)(C18alkyl), (C(=O)O(C18alkyl), C(=O)NRhRh, C(=NRh)NRhRh, ORh, OC(=O)(C18alkyl), OC(=O)NRhRh, OC(=O) N (Rh)S(=O)2(C18alkyl), OC26alkylNRHRh, OC26alkylORh, SRh, S(=O)(C18alkyl), S(=O)2(C18alkyl), S (=0) 2NRhRh,S (=0) 2N (Rh) C (=O) (C, 8alkyl),S (=0) 2N (R") C (=O) O (C18alkyl), S(=O)2N(Rh) C (=O) NRhRh,NRhRh,N (Rh) C (=O) (C18alkyl), N (R") C (=O) O (C18alkyl), N(Rh) C (=O) NRhR",N (Rh) C (=Rh)NFhRh, N(Rh) S (=O) 2 (C18alkyl), N(Rh) S (=O) 2NRhRh, NRhC26alkylNRhRh and NRhC26alkylORh and Cl 4alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)NRhRh, C(=NRh)NRhRh, ORh, OC(=O)(C18alkyl), OC(=O)NRhRh, OC(=O) N (Rh) S (=0) 2 (CI 8alkyl),OC26alkylNR"Rh,OC26alkylORh,SR", S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRhRh, S (=0) 2N (Rh) C (=O) (C, 8alkyl), S(=O)2N(Rh) C (=O) O (C, 8alkyl), S (=0) 2N (R") C (=O) NRhRh,NR"Rh,N (R") C (=O) (C18alkyl), N(Rh) C (=O) O (C, 8alkyl),N (Rh) C (=O) NRhRh, N(Rh) C (=NRh) NRhRh, N(Rh) S (=O) 2 (C18alkyl), N(Rh) S (=O) 2NRhRh, NRhC26alkylNRhRh and NRhC26alkylORh. |
| 76. | The compound according to Claim 56, wherein R'1 and R 13 are independently, at each instance, selected from H, C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C(=O)NRhRh, C(=NRh)NRhRh, ORh, OC(=O)(C18alkyl), OC(=O)NRhRh, OC(=O) N (Rh) S (=0) 2 (C18alkyl), OC26alkylNRhRh, OC26alkylORh, SRh, S(=O)(C18alkyl), S(=O) 2 (C, 8alkyl),S (=0) 2NR"R", S(=O) 2N (Rh) C (=O) (C18alkyl), (S(=O)2N(Rh) C (=O) O (C18alkyl), S(=O)2N(Rh) C (=O) NRhRh, NRhRh, N(Rh) C (=O) (C18alkyl), N(Rh) C (=O) O (C18alkyl), N(Rh) C (=O) NRhRh,N (Rh) C (=NRh) NRhRh, N(Rh) S (=0) 2 (Ct8alkyl),N (Rh) S (=O) 2NRhR",NRhC26alkylNRhRh, NRhC26alkylORh and C14alkyl substituted by 0, 1, 2 or 3 groups selected from C1 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C(=O)NRhRh, C(=NRh)NRhrh, ORh, OC(=O)(C18alkyl), OC(=O)NRhRh, OC(=O) N (Rh) S (=0) 2 (C18alkyl), OC26NRhrh, OC26alkylORh, SRh. S(=O)(C18alkyl), S(=O)2(C18alkyl), S(=O)2NRhRh, S(=O)2N(Rh) C (=O) (C18alkyl), S(=O)2N(Rh) C (=O) O (C, 8alkyl), S(=O)2N(Rh) C (=O) NR"Rh,NRhR",N (R") C (=O) (c18alkyl), N(rh) C (=O) O (C18alkyl)n N(Rh) C (=O) NRhRh, N(Rh) C (=NRh)NRhRh, N(Rh) S (=O) 2 (C18alkyl), N(Rh) S (=0) 2NRhRh,NRnC26alkylNRhRh and NRhC26alkylORh. |
| 77. | The compound according to Claim 56, wherein R12 is independently, at each instance, selected from H, C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) O (C18alkyl), C(=O)NRhRh, ORh, OC(=O)(C18alkyl), OC(=O)NRhRh, OC(=O) N (Rh) S (=0) 2 (C18alkyl), OC26alkylNRhRh, OC26alkylORh, QSRh, S(=O)(C18alkyl), (S(=O) 2 (C, 8alkyl), (=O)2NRhRh, S(=O)2N(Rh) C (=O) (C18alkyl), S(=O)2N(Rh) C (=O) O (C, 8alkyl), S=O)2N(Rh) C (=O) NRhRh, NRhRh, N(Rh)C(=O)(C18alkyl), N(Rh) C (=O) O (C18alkyl), N(Rh) C (=O) NRhRh, N(Rh)C(=NRh)NRhRh, N(Rh) S (=0) 2 (C,8alkyl),N (Rh) S (=0) 2NRhRh,NR"C26alkylNRhRh and 6alkyl0Rh ; or Rl2 is C14alkyl substituted by 0,1, 2 or 3 groups selected from C, 4haloalkyl, halo, cyano, nitro,C (=O) (C18alkyl), C(=O)O(C18alkyl), C (=O) NRhR",C (=NRh) NR"Rh,ORh,OC (=O) (Clgalkyl),OC (=O) NR"R", OC(=O) N (Rh) S (=0) 2 (C18alkyl), OC26alkylNRhRh, OC24alkylORh, SRh, S(=O)(C18alkyl), S(=O) 2 (C, 8alkyl), S(=O)2NRhRh, S(=O)2N(Rh) C (=O) (C18alkyl), S(=O) 2N (Rh) C (=O) O (Cl 8alkyl), S (=0) 2N (Rh) C (=O) NRhRh,NRhRh,N (Rh) C (=O) (C, 8alkyl), N (R") C (=O) O (Cl 8alkyl),N (R) C (=O) NRhRh, N(Rh) C (=NR") nrhRh, N(Rh) S (=0) 2 (C,8alkyl),N (R") S (=0) 2NRhRh, NRhC216alkylNRhRh and NRhC26alkylORh. |
| 78. | The compound according to Claim 56, wherein Y is 0. |
| 79. | The compound according to Claim 56, wherein Y is S. |
| 80. | A compound having the structure: wherein: X is O, S or NRm ; n is independently, at each instance, 0,1 or 2; o is independently, at each instance, 0, 1, 2 or 3; Rm is independently at each instance H or Rn ; Rn is independently at each instance Cl 8alkyl, phenyl or benzyl ; Rq is independently in each instance H, C17alkyl, C14haloalkyl, halo, cyano, nitro, C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm. NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, $N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; Rs is Rn sugstituted by 0,1, 2 or 3 substituents independently selected from Rq ; R3 is H or C14alkyl ; R5 is H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OCalkylNRmRm, OC16alkylORm, NRmRm, NRm C14haloalkyl, NRmC16alkylNRmRm, NRmC16alkylORm, or (CH2)nRc R6 is, independently at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, or NRmC16alkylNRmRm ; R is H, NRmC16alkylORm halo, nitro, C19alkyl, C14haloalkyl, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm; and (A) R' is R2 is H,ORm, halo, Cl 3haloalkyl or C, 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) ORn,C (=O) NRmRm, C(=NRm)NRmRm, OR, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm, NRmRm, N (Rm) C (=O) R",N (Rm) C (=O) OR", (N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm) S (=O) 2Rn, N(Rm) S (=O) 2NR"'Rm,NR"'C26alkylNRmRm,NR"'C26alkylOR"',C (=O) R', C (=O) ORs,C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs, OC(=O)NRmRs, OC(=O) N (R"') S (=0) 2R',OC26alkylNR"'R',OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S 2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) Rs, N(Rm) C (=O) OR',N (Rm) C (=O) NRmRs,N (Rm) C (=NRm) NRmRs, N(Rm)S(=O)Rs, N(Rm), N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Cul 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2R",OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O),N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) Rn,N (Rm) C (=O) ORn,N (Rm) C (=O) NRmRm N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> NR"'C26alkylNRmRm,C (=O) Rs,C (=O) ORs,C (=O) NRmRs,C (=NR"') NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)ORs, S(=O)2N(Rm)C(=O)NRmrs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is Cl 9alkyl, Cl 4haloalkyl, halo, nitro, cyano,OC 6alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRm C16alkylORm ; R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic or 7, 8, 9, 10or 11membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C (=O) R°,C (=O) OR°,C (=O) NRmRm,C (=NR"') NR"'Rm,OR"', OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OCE26alkylORm, SGm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=o) NR'R, NRmRm, N(Rm) C (=O) R",N (R"') C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, (N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORM ; and Y is 0 or NH; or (B) R'is R2 is H,ORm, halo, Cl 3haloalkyl or C16alkyl; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C, 4haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O)N(Rm)S(=O)2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmrm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N (R"') S (=0) 2NR"'Rm,NR°'C26alkylNRmRm,NRmC26alkylORm,C (=O) R', C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNR"'Rs,OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)N(Rm)C((=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)c(=O)Rs, N (Rm) C (=O) ORs,N (Rm) C (=O) NRmRs,N (R"') C (=NR"') NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, C (=O) R",C (=O) ORn,C (=O) NRmRm,C (=NRm) NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O) 2N (Rm) C (=O) Rn,S (=0) 2N (Rm) C (=O) ORn, QS(=O)2N(Rm) C (=O) NRmRm, NRmRm, N(Rm) C (=O) Rn,N (Rm) C (=O) ORn, N(Rm) C (=O) NR"'R"\ N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)nrmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, (=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R',N (R') C (=O) OR',N (rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(rm)S(=O)2NRmrs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R is C1 9alkyl, Cl 4haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmrm, OC16alkylORm, NRmRm, NRmC14haloalyl, NRmC16alkylNRmRm or NRC16alkylORm ; R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic or 7, 8, 9, 10or 11membered bicyclic ring containing 0, 1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C (=O) R",C (=O) ORn, C(=O)NRmRm, C(=NRm)NRMRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SR, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NR"'RI",N (Rm) C (=O) R",N (R"') C (=O) OR",N (R"') C (=O) NRmR"', N (R"') C (=NRm) NRmRm, N (Rm) S (=0) 2R",N (Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; and Yis O or NH ; or (C) R'is R2 is H, ORm, halo, C13haloalkyl or C16alkyl ; R4 is a saturated, partiallysaturated or unsaturated 8, 9, 10 or 11membered bicyclic heterocycle containing 1,2, 3,4 or 5 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin6yl, 4,5, 6,7tetrahydrobenzo [b] thiophen2yl, benzothiazol 2yl, 2,3dihydrobenzo [1, 4] dioxin6yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C19alkyl, oxo, C14haloalkyl, halo, nitro, cyano,ORm,S (=O)nC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRm C14haloalkyl, NRm C16alkylNRmRm, NRmC16alkylORm, C(=O)C16alkyl, OC(=O)C16alkyl, C(=O)NRmC16alkyl, NRmC(=O)C16alkylc(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNR"'R', OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)c(=O)ORs, S(=O) 2N (Rm) C (=O) NRmRs, NR"'R',N (R"') C (=O) R',N (Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O)N(Rm)S(=O)2Rn, OC26alkylNRmRm, OC26alkylORm, Srm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2n(Rm) C (=O) NRmrm, N (Rm) C (=O) R",N (Rm) C (=O) ORn, N (R"') C (=O) NRmRm,N (Rm) C (=NRm) NRmRm, N (Rm) S (=O) 2Rn N(Rm)S(=O)2NRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNRmR', OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S (=0) 2N (R'") C (=O) R',S (=0) 2N (Rm) C (=O) OR',S (=0) 2N (Rm) C (=O) NRRs, NRmRs, N(Rm) C (=O) R',N (R') C (=O) OR',N (Rm) C (=O) NOR', (Rm) C(=NRmNRmrs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; wherein R4 is not 2aminocarbonuylmethyl2,3dihydrobenso[1, 4] dioxin8yl, 2cyanomethyl 2,3dihydrobenzo [1, 4] dioxin8yl, quinolin3yl, 3Hquinazolin4on3yl, benzo [1, 3] dioxol5yl, 3, 3dimethyl1, 3dihydroindol2on6yl or 4,4dimethyl 3, 4dihydro1Hquinolin2on7yl ; R is C18alkyl, C15haloalkyl, I or Br R9 is H, C19alkyl, C14haloalkyl, halo, nitro, cyano,OCl6alkyl,OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm, NRmC16alkylORm, or(CH2)nRc; R9 is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmrm or NRmC16alkylORm ; Y is NH; and Z is CR8 or N; or (D) R'is R2 is Cl 6alkyl substituted by 1, 2 or 3 substituents selected from C, 4haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) OR",C (=O) NRmRm, C(=NR)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O)N(Rm)S(=O)2Rn, OC26alkylNRmrm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm) C (=O) NRmRm, NRmRm, N (Rm) C (=O) R",N (Rm) C (=O) OR", N(Rm)C(=O)NRmRm, N(rm)C(=NRm)NRmRm, N(Rm) S (=O) 2Rn, N (R"') S (=O) 2NRmRm,NR"'C26alkylNRmRm orNR"C26alkylORm ; or R2 is(C(Rq)2)ophenyl, wherein the phenyl is substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, C (=O) Rn,C (=O) ORn, C (=O) NRmR',C (=NRm) NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OR',SRm,S (=O) Rn,S (=0) 2Rn, S (=0) 2NRmRm, S(=O) 2N (Rm) C (=O) Rn7S (=0) 2N (Rm) C (=O) OR°,S (=0) 2N (R"') C (=O) NRmRm, NRmrm, N(Rm)C(=O)Rn, N(rm)C(=O)ORN, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmrm, N(Rm) S (=0) 2Rn, N (Rm)S(=O)2NRmrm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORsn SRs, S(=O)Rs, (=0) 2Rs, S(=O)2NRmRs, S(=O)2(Rm)c(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmR',NRmR',N (Rm) C (=O) Rs,N (Rm) C (=O) ORs, N(Rm) C (=O) NRmR',N (Rm) C (=NRm) NRmRs, N (Rm) S (=0) 2R', N (Rm) S (=O) 2NRmRs, NRmc26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRRm, ORM, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, 6alkylNRmRm,C (=O) R',C (=O) ORs, C (=O) NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O) 2N (Rm) C (=O) R',S (=0) 2N (Rm) C (=O) ORs, S (=0) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NR"'C26alkylNRmRs,NRmC26alkylORs andNRmC26alkylORm ; or R2 is(C(Rq)2)oRr, wherein Ru ils a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) Rn, C (=O) OR, C(=O)NRmRm, (=NRm)NRmRm, ORm, OC(=O)ùRn, OC(=O)NRmRm, OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmrm, OC26alkylORm, SRm, S(=O)Rn, S 2Rn, S(=O)2NRmRm, S(=O)2N(rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, NRm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm) S (=O) 2Rn, N (Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R', N (R"') C (=O) OR',N (R"') C (=O) NRmRs, N (R) C (=NR"') NRmRs, N (R"') S (=0) 2Rs, N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C12haloalkyl, halo, cyano, nitro,C (=O) Rn,C (=O) ORn,C (=O) NRmRm, C (=NRm) NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRn, OC(=O) N (Rm) S (=0) 2Rn,OC2 6alkylNRmRm, OC26alkylORm, SRm,; S(=O)Rn, S(=O)2Rn, (S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NR"'R"',N (R"') C (=O) Rn,N (Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(rm)S(=O)2Rn, N(rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, (=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2n(Rm)C(=O)ORs, X(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, (Rm) C (=NRm) NRmR',N (Rm) S (=0) 2R',N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs andNRmC26alkylORm ; R4 is a saturated or unsaturated 5or 6membered ring containing 0, 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C, 8alkyl, C, 4haloalkyl, halo, cyano, nitro,C (=O) Rn,C (=O) ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC (=0) N (Rm) S 2Rn, OC26alkylNRmRm, OC26alkylORm, srm, (=O)Rn S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm,NRmRm,N (Rm) C (=O) Rn, N (Rm) C (=O) OR", N(rm )C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm) S (=O) 2NR"'R"',NRmC26alkylNRmRm,NRmC26alkylOR",C (=O) R', C (=O) OR,C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs OC (=O) NRmRs,OC (=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R', N (Rm) C (=O) ORs, N(Rm) C (=O) NRmR',N (Rm) C (=NRm) NR R, N (R"') S (=0) 2Rs,N (Rm) S (=0) 2nrmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmrm, OC(=O) N (Rm) S (=0) 2Rnn OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2R5, S(=O)NRmRs, (=0) 2N C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NR R,N (Rm) C (=O) Rs,N (Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRC26almkylORs and NRmC26alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C28alkyl, C15haloalkyl, I, Br; R9 is independently, at each instance, H, Cl CI4haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmRm, NRmC1 or NRmC, 6alkylORm ; Y is NH; and Z is CR8 or N; or (E) R'is R2 is H, ORm, Cl, C13haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, C(=O)NRmRm, C(=NRm)NRmRm, ORn, OC(=O)Rn, OC(=O)NRmRm, OC(=O)N(Rm)S(=O)2Rn, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, 6NRm) S (=O) 2NRmrm, NRmC26alkylNRmRm, NRmC26alkylORm, (=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNRmR',OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, (=0) 2N(Rm)C(=O)ORs, S(=O)2N(Rm)CNRmRs, NRmRs, N(Rm) C (=O) Rs, Nrm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm) C (=NRm) NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C (=O) Rn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R",OC26alkyINR"'R"',OC26alkylORm, SRm,S SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C=NGm)NRmRs, ORs, OC(=O)Rs,OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC2_6alkylNRmR', OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm) C (=O) R',S (=O) 2N (Rm) C (=O) OR',S (=O) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm) C (=O) Rs,N (Rm) C (=O) OR',N (Rm) C (=O) NRmrs, N (R"') C (=NRm) NRmRs,N (Rm) S (=0) 2R',N (Rm) S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26akylORm ; wherein R4 is not unsubstituted phenyl ; R9 is independently, at each instance, H, Cl 9alkyl, Cl 4haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRm C14haloalkyl, NRmC16alkylNRmRm or NRmCI 6alkylORm ; Y is NH; and Z is CR8 or N. |
| 81. | A compound according to Claim 80, wherein: R'is R2is H,OR', halo, C, 3haloalkyl or C, 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R°,OC26alkylNR"'Rm,OC26alkylOR"',SR"',S (=O) R", S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm) C (=O) Rn, S (=0) 2N (Rm) C (=O) OR S (=0) 2N (R"') C (=O) NRmRm,NRmRm,N (Rm) C (=O) Rn, N (Rm) C (=O) OR", N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm) S (=O) 2R, N (Rm) S (=O) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm) C (=O) ORs,N (Rm) C (=O) NRmRs,N (Rm) C (=NRm) NR'"R', N(Rm) S (=0) 2R',N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC2 6alkylORm,SRm,S (=O) Rn,S (=0) 2Rn,S (=0) 2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NR"'R°',N (R"') C (=O) Rn, N(Rm) C (=O) ORn,N (Rm) C (=O) NRmR', N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm) C (=O) R',S (=0) 2N (Rm) C (=O) ORs, S (=O) 2N (Rm) C (=O) NRmR', NRmRs, N(Rm) C (=O) Rs,N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is Cl 9alkyl, C, 4haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic or 7, 8, 9, 10or 11membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) Rn,C (=O) ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NrmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NR"'R"',N (R"') C (=O) Rn,N (Rm) C (=O) OR",N (R"') C (=O) NRmRm, N (R"') C (=NRm) NRmRm, N (Rm) S (=0) 2Rn,N (Rm) S (=O) 2NR"'R"', NRmC26alkylNRmRm or NRmC26alkylORm ; and Y is 0 or NH. |
| 82. | A compound according to Claim 81, wherein: R4 is a saturated or unsaturated 5or 6membered ring containing 0, 1, 2 or 3 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1,2 or 3 substituents independently selected from C 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) Rn, N(Rm) C (=O) OR",N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs,OC (=O) NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNRmR',OC26alkylORs,SR',S (=O) RS, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm) C (=O) R',S (=0) 2N (Rm) C (=O) OR', S(=O)2N(Rm) C (=O) NRmRs, NRmRs, N (Rm) C (=O) Rs,N (Rm) C (=O) OR', N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N (Rm) S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from CI2haloalkyl, halo, cyano, nitro, <BR> <BR> <BR> C (=O) R,C (=O) OR,C (=O) NR'R',C (=NRm) NR'Rm,ORm,OC (=O) R OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm) C (=O) NRmRm,NR'Rm, N (R"') C (=O) Rn, N(Rm) C (=O) ORn, N(Rm) C (=O) NR"'R"', N(Rm) C (=NRm) NRmR',N (R") S (=0) 2R',N (Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups. |
| 83. | A compound according to Claim 81, wherein R4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, <BR> <BR> <BR> C (=O) R",C (=O) OR",C (=O) NRmRm,C (=NR"') NR"'Rm,ORm,OC (=O) R", OC OC(=O)NRmRm, OC(=O)N(Rm)S(=O)2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) Rn, N(Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O) 2N (Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmRs,NRmR',N (Rm) C (=O) Rs,N (Rm) C (=O) OR', N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N (R"') S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R",OC26alkylNR"'R"',OC2_6alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, (=0) 2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmR', OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm C (=O) Rs, N (Rm) C (=O) ORs, N (Rm) C (=O) NRmR', N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs andNRmC26alkylORm ; and the bridge carbon atoms are substituted with 0,1 or 2 =O groups. |
| 84. | A compound according to Claim 81, wherein R7 is C19alkyl, C14haloalkyl, halo, OC16alkyl, OC14haloalkyl, NRmRm or NRmCs 4haloalkyl. |
| 85. | A compound according to Claim 81, wherein R7 is C15alkyl, C14haloalkyl, I, Br or Cl. |
| 86. | A compound according to Claim 81, wherein R7 is tertbutyl or trifluoromethyl. |
| 87. | A compound according to Claim 81, wherein R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic ring containing 0,1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP. |
| 88. | A compound according to Claim 81, wherein R° is a saturated, partiallysaturated or unsaturated 6membered ring containing 0,1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP. |
| 89. | A compound according to Claim 81, wherein Y is O. |
| 90. | A compound according to Claim 81, wherein Y is NH. |
| 91. | A compound according to Claim 80, wherein: R'is R2 is H,ORm, halo, C, 3haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from Ci 8alkyl, C, 4haloalkyl, halo, cyano, nitro,C (=O) Rn,C (=O) ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R°,OC26alkylNRmR"',OC26alkylORm,SRm,S (=O) R", S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm) S (=O) 2Rn, N(Rm) S (=O) NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C (=O) ORs,C (=O) NRmRs,C (=NRm) NRmRs,ORsOC (=O) Rs OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm) C (=O) OR',N (R"') C (=O) NRmR',N (Rm) C (=NR"') NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC2 6alkylOR,SRm,S (=O) Rn,S (=0) 2Rn,S (=0) 2NRmRm S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) Rn,N (Rm) C (=O) ORnN (Rm) C (=O) NR'"R"', N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R5, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) Rs,N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm) C (=NRm) NRmRs, N (Rm) S (=0) 2Rs,N (Rm) S (=0) 2NRmR', NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C, 9alkyl, Cl 4haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm; [C18alkyl, C15haloalkyl, I, Br or Cl] R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic or 7, 8, 9, 10or 11membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance C18alkyl, C14haloalkyl, halo, cyano, nitro, C (=O) Rn,C (=O) ORn, *C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S (=O) Rn,S (=O) 2R°,S (=O) 2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) Rn, N(Rm) C (=O) ORn, N(Rm) C (=O) NR"'R'", (Rm) C (=NRm) NR'Rm,N (Rm) S (=0) 2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; and YisOorNH. |
| 92. | A compound according to Claim 91, wherein R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C, 8alkyl, C, 4haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) Rn, N(Rm) C (=O) ORn,N (Rm) C (=O) NR"'R"', N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, 6alkylNRmRm,NRmC2 6alkylORm,C (=O) Rs,C (=O) ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O)N(Rm)S(=O)2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm) C (=O) NRmR',NRmR',N (Rm) C (=O) Rs, N(Rm) C (=O) OR', N(Rm) C (=O) NRmRsN (Rm) C (=NRm) NRmRs, N (Rm) S (=0) 2R, N (R"') S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NrmRm, ORm, OC(=O)Rn, OC (=O) NRmRm,OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26aklylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm) C (=O) OR°,N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs,OC (=O) Rs,OC (=O) NRmRs,OC (=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs,SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O) 2N (Rm) C (=O) Rs,S (=O) 2N (Rm) C (=O) OR',S (=0) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups. |
| 93. | A compound according to Claim 91, wherein R4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C, 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2R",OC26alkylNR"'Rm,OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn (=0) 2N(Rm)C(=O)ORn, S(=O) 2N (Rm)C(=O)NRmRm, NRmRm N (R"') C (=O) Rn, N(Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NR'R',NR'C26alkylOR',C (=O) R',C (=O) OR', C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNR"'RS,OC26alkylORs,SR',S (=O) R', S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm) C (=O) R',S (=0) 2N (Rm) C (=O) OR', S(=O)2N(Rm) C (=O) NRmRs,NRmRs,N (Rm) C (=O) Rs,N (Rm) C (=O) ORs, N (R"') C (=O) NR"'R',N (Rm) C (=NRm) NRmRs, N(Rm)S(=O)2Rs, N (Rm) S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2Rn,OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) Rn,N (Rm) C (=O) OR",N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmR', N(Rm) C (=NRm) NRmRs, N (Rm) S (=0) 2R',N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs andNRmC26alkylORm ; and the bridge carbon atoms are substituted with 0,1 or 2 =O groups. |
| 94. | A compound according to Claim 91, wherein R7 is C19alkyl, C14haloalkyl, halo, OC16alkyl, OC14haloalkyl, NRmRm or NRmC14haloalkyl. |
| 95. | A compound according to Claim 91, wherein R7 is C15alkyl, C14haloalkyl, I, Br or Cl. |
| 96. | A compound according to Claim 91, wherein R7 is tertbutyl or trifluoromethyl. |
| 97. | A compound according to Claim 91, wherein R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic ring containing 0, 1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP. |
| 98. | A compound according to Claim 91, wherein R° is a saturated, partiallysaturated or unsaturated 6membered ring containing 0,1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP. |
| 99. | A compound according to Claim 91, wherein Y is O. |
| 100. | A compound according to Claim 91, wherein Y is NH. |
| 101. | A compound according to Claim 80, wherein: R'is R2 is H,ORm, halo, Cl 3haloalkyl or C16alkyl ; R4 is a saturated, partiallysaturated or unsaturated 8, 9, 10 or 11membered bicyclic heterocycle containing 1, 2,3, 4 or 5 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin6yl, 4,5, 6,7tetrahydrobenzo [b] thiophen2yl, benzothiazol 2yl, 2,3dihydrobenzo [1, 4] dioxin6yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from Cs 9alkyl, oxo, Cl 4haloalkyl, halo, nitro, cyano,OR"',S (=O)nC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm, NRmC16alkylORm, C(=O)C,6alkyl, OC(=O)C16alkyl, C(=O)NRmC16alkyl, NRmC(=O)C16alkyl C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs,OC (=O) Rs,OC (=O) NRmRs,OC (=O) N (Rm) S (=0) 2R',OC26alkylNRmRs, OC26alkylORs, SRs S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S (=O) 2N (R"') C (=O) R',S (=0) 2N (Rm) C (=O) OR',S (=O) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, C (=O) Rn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R°,OC26alkylNRmR"',OC26alkylORm,SRm,S (=O) R°, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NR"'R"',N (R"') C (=O) R,N (Rm) C (=O) OR, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm) S (=O) 2Rn, <BR> <BR> <BR> (Rm) S (=) 2NRmRm,C (0) Rs,C (=O) ORs,C (=O) NR"'Rs,C (=NRm) NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; wherein R4 is not 2aminocarbonylmethyl2, 3dihydrobenzo [1, 4] dioxin8yl, 2cyanomethyl 2,3dihydrobenzo [1, 4] dioxin8yl, quinolin3yl, 3Hquinazolin4on3yl, benzo [1, 3] dioxol5yl, 3, 3dimethyl1, 3dihydroindol2on6yl or 4, 4dimethyl 3, 4dihydro1Hquinolin2on7yl ; R7 is C18alkyl, C15haloalkyl, I or Br; R9 is H, C19alkyl, C14haloalkyl, halo, nitro, cyano,OC, 6alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; Y is NH ; and Z is CR8 or N. |
| 102. | 201 A compound according to Claim 101, wherein R4 is a heterocycle selected from indole, 3Hindole, benzo [b] furan, benzothiophene, 1Hindazole, benzimidazole, benzthiazole, IHbenzotriazole, 7quinoline, 8quinoline, 1,2, 3,4 tetrahydroquinoline, isoquinoline, cinnoline, phthalazine, quinazoline and quinoxaline, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C, 9alkyl, oxo, Cs 4haloalkyl, halo, nitro, cyano, <BR> <BR> <BR> <BR> ORm,S (=O) nCl 6alkyl,OCI 4haloalkyl,OC1 6alkylNRmRm,OCI 6alkylORm,<BR> <BR> <BR> <BR> <BR> <BR> <BR> 4haloalkyl,NRmC, 6alkylNRmRm,NRmC, 6alkylORm,<BR> <BR> <BR> <BR> <BR> <BR> <BR> C (=O) Cl 6alkyl,OC (=O) C, 6alkyl,C (=O) NRmC, 6alkyl,NRmC (=O) C, 6alkyl C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNR"'R',OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R', N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm) C (=NR"') NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C12haloalkyl, halo, cyano, nitro, C (=O) R",C (=O) NRmR',C (=NRm) NRn'Rm,OR"',OC (=O) R', OC(=O)NRmRm, OC(=O)N(Rm)S(=O)2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O), S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkyORm. |
| 103. | A compound according to Claim 101, wherein R4 is a heterocycle selected from 6indole, 7indole, 63Hindole, 73Hindole, 6benzo [b] furan, 7 benzo [b] furan, 6benzothiophene, 7benzothiophene, 61Hindazole, 71H indazole, benzimidazole, benzthiazole, IHbenzotriazole, 7quinoline, 8 quinoline, 71,2, 3, 4tetrahydroquinoline, 81, 2,3, 4tetrahydroquinoline, isoquinolin7yl, isoquinolin8yl, 7cinnoline, 8cinnoline, phthalazine, 7 quinazoline, 8quinazoline and quinoxaline, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C, 9alkyl, oxo, C14haloalkyl, halo, nitro, cyano, ORm, S (=O) nC, 6alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14halolakyl, NRmC16alkylNRmRm, NRmC16alkylORm, C(=O)C16alkyl, OC(=O)C16alkyl, C(=O)NRmC16alkyl, NRmC(=O)C16alkyl C(=O)R5, C(=O)ORs, C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs,OC (=O) NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NR"'R',NRR',N (Rm) C (=O) R',N (Rm) C (=O) OR', N (R"') C (=O) NRmRs,N (Rm) C (=NR"') NR'"R\N (Rm) S (=0) 2R', N (Rm) S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R",OC26alkylNR"'Rm,OC26alkylOR'", SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm)C(=O)NRmRm, N(Rm)C(=O)Rn, N(Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, N (Rm) C (=NRm) NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC2_6alkylNR"'R',OC26alkylORs,SRs,S (=O) R',S (=0) 2Rs,S (=O) 2NRmR', S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm) C (=O) OR',N (Rm) C (=O) NRmRS N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm. |
| 104. | A compound according to Claim 101, wherein R9 is C19alkyl, C, 4haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14halolakyl, NRmC16alkylNRmRm or NRmC16alkylORm. |
| 105. | A compound according to Claim 101, wherein R9 is H. |
| 106. | A compound according to Claim 101, wherein Z is CR. |
| 107. | A compound according to Claim 101, wherein Z is N. |
| 108. | A compound according to Claim 101, wherein R7 is tertbutyl or trifluoromethyl. |
| 109. | A compound according to Claim 80, wherein: R'is R2 is C, 6alkyl substituted by 1,2 or 3 substituents selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) Rn,C (=O) OR",C (=O) NRmRm, C (=NRm) NRmRm,ORm,OC (=O) Rn,OC (=O) NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm,NRmR',N (Rm) C (=O) R,N (Rm) C (=O) OR", N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm) S (=O) 2NRmRm,NR"'C26alkylNRmR" andNR"'C26alkylORm ; or R2 is R2 is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R5, R6 and R7 ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C, 4haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C (=NRm) NRmR"',OR"',OC (=O) R",OC (=O) NRn'R"', OC(=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)R,; S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm, NRmRm, N(Rm) C (=O) R,N (R') C (=O) OR N(Rm)C(=O)NRmRm, N(Rm)C(=NR)NRmRm, N(Rm) S (=O) 2Rn, N (R"') S (=0) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNR"'R',OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, N(Rm) C (=O) NRmR',N (Rm) C (=NR"') NRmRs, N(Rm) S (=0) 2Rs,N (Rm) S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Chalky ! substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) R°,C (=O) OR°,C (=O) NR"'R"',C (=NRm) NR"'Rm,OR"', OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) R",N (Rm) C (=O) OR",N (Rm) C (=O) NR'"R"', N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm) C (=O) Rs,S (=0) 2N (Rm) C (=O) OR',S (=0) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N5rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =0 groups; R7 is C28alkyl, C15haloalkyl, I, Br; R9 is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; Y is NH; and Z is CR8 or N. |
| 110. | A compound according to Claim 109, wherein R2 is C16alkyl substituted by 1,2 or 3 substituents selected from Cl 4haloalkyl, halo, cyano, nitro, C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm) C (=O) NRmRm, NRmRm, N(Rm) C (=O) R",N (R"') C (=O) oRn7N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, andNRmC26alkylORm ;. |
| 111. | A compound according to Claim 109, wherein R2 is (C (Rq) 2) ophenyl, wherein the phenyl is substituted by 0,1, 2 or 3 substituents independently selected from C, 8alkyl, Ci 4haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC2alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, (=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm)C(=O)NRmRm, NRmRm, N (R"') C (=O) Rn,N (Rm) C (=O) OR",N (Rm) C (=O) NRmRm, N (R"') C (=NRm) NRmRm,N (Rm) S (=0) 2Rn, N(Rm) S (=O) 2NrmRm NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs,OC (=O) NRmRs, OC (=O) N (Rm) S (=0) 2R',OC26alkylNRmRs,OC26alkylORs,SRs,S (=O) RS, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmRs, NRmRs, N (Rm) C (=O) Rs,N (Rm) C (=O) OR', N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm) S (=0) 2Rs, N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C12haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC OC(=O)NRmRm, OC(=O)N(Rm)S(=O)2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) R",N (Rm) C (=O) OR",N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNRmR', OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRsN (Rm) C (=O) Rs,N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm. |
| 112. | A compound according to Claim 109, wherein R2 is (C(Rq)2)0Rr, wherein Rr is a saturated or unsaturated 5or 6membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C1. 4haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) OR",C (=O) NRmRm, C (=NRm) NRmRm,ORm,OC (=O) R,OC (=O) NRmR OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm) S (=O) 2Rn, N (Rm) S (=0) 2NR"'Rm,NR"'C26alkylNRmRm,NR"'C26alkylORm,C (=O) R', C (=O) OR',C (=O) NRmR',C (=NRm) NRmRs,ORs,OC (=O) R, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O) 2N (Rm)C(=O)Rs, (=0) 2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N (Rm) C (=NRm) NRmRs, N (Rm) S (=0) 2Rs,N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) Rn,C (=O) ORn,C (=O) NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn,OC2 6alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm) C (=O) NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)c(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> <BR> NRmC26alkylNRmRm,C (=O) Rs,C (=O) ORs,C (=O) NR"'Rs,C (=NR"') NR"'R', ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs,SR',S (=O) Rs,S (=0) 2R',S (=0) 2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) Rs,N (Rm) C (=O) ORs, N(Rm) C (=O) NRmRs N (Rm) C (=NRm) NRmRs,N (Rm) S (=0) 2R\N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; 113. |
| 113. | A compound according to Claim 109, wherein R4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2RnOC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) R",N (Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNR"'R',OC26alkylORs,SRs,S (=O) Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O), S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm) C (=O) NRmRs, NRmRs, N (Rm) C (=O) R',N (Rm) C (=O) ORs, N(Rm) C (=O) NRmR',N (Rm) C (=NRm) NRmRs, N (Rm) S (=0) 2Rs, N (R"') S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC (=O) NRmRm,OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, @ (Rm) C (=O) R',N (R') C (=O) OR n,N (R') C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm and NRmC26alkylORm ; and the bridge carbon atoms are substituted with 0,1 or 2 =O groups. |
| 114. | A compound according to Claim 109, wherein R7 is tertbutyl or trifluoromethyl. |
| 115. | A compound according to Claim 109, wherein R9 is H. |
| 116. | A compound according to Claim 109, wherein Z is CR. |
| 117. | A compound according to Claim 109, wherein Z is N. |
| 118. | A compound according to Claim 80, wherein: R'is R2 is H, ORm, Cl, C13haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 2, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, C(=O)NRmRm, C(=NRm)NRmRm, ORn, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rn) S (=0) 2R",OC26alkylORm,SRm,S (=O) R,S (=0) 2R S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRmNRmRm,N (Rm) C (=O) R",N (Rm) C (=O) OR N (Rm) C (=O) NRmRm,N (Rm) C (=NRm) NRmRm,N (Rm) S (=O) 2Rn, N (R"') S (=0) 2NRmR"',NR"'C26alkylNR"'R"',NRmC2 6alkylOR"',C (=O) R', C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (R"') S (=0) 2R',OC26alkylNRmRs,OC26alkylORs, SRs,S (=O) Rs,S (=0) 2Rs,S (=0) 2NRmRs,S (=0) 2N (Rm) C 0) Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R', N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm) C (=NRm) NRmRs, N (Rm) S (=O) 2Rs, N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) NR"'R"',C (=NRm) NRmRm, ORm, OC (=O) Rn, OC OC(=O)NRmRm, OC(=O)N(Rm)S(=O)2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N (Rm) C (=O) R",N (Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm and NRmC26alkylORm ; wherein R4 is not unsubstituted phenyl ; R9 is independently, at each instance, H, C, _9alkyl, C, 4haloalkyl, halo, nitro, cyano, OC1 6alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; Y is NH; and Z is CR8 or N. |
| 119. | A compound according to Claim 118, wherein R4 is a saturated or unsaturated 5or 6membered ring containing 1,2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) NRmRm,C (=NRm) NRmRm,OR", OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2Rn, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm)C(=O)NRmRm, NRmRm, N (R"') C (=O) R",N (R"') C (=O) ORn,N (Rm) C (=O) NRmRm, N(Rm)C(=NRm), N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O)N(Rm)S(=O)2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm) S (=O) 2Rs, N (R"') S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, C (=O) Rn,C (=O) NRmRm,C (=NRm) NRmRm,ORm,OC (=O) Rn OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm) C (=O) ORn, S(=O)2N(Rm) C (=O) NRmRm, NRmRm, N (R"') C (=O) Rn,N (Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, andNR'C26alkylORm ;. |
| 120. | A compound according to Claim 118, wherein Z is CR. |
| 121. | A compound according to Claim 118, wherein Z is N. |
| 122. | A compound having the structure: wherein: X is 0, S or NRm ; n is independently, at each instance, 0,1 or 2; o is independently, at each instance, 0,1, 2 or 3; Rm is independently at each instance H or R" ; R"is independently at each instance C18alkyl, phenyl or benzyl ; Rq is independently in each instance H, C14alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, 6alkylORm,SRm,S (=O) Rn,S (=O) 2Rn,S (=0) 2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)N(Rm)C(=O)NRmRm, NR"'R"',N (Rm) C (=O) Rn, N(Rm) C (=O) OR",N (Rm) C (=O) NRmRm N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, kylNR'R' orNR'C26alkylOR' ; Rs is Rn substituted by 0,1, 2 or 3 substituents independently selected from Rq ; R3 is H or C14alkyl ; R5 is H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm, NRmC16alkylORm, or (CH2)nRc R6 is, independently at each instance, H, C19alkyl, C14 haloalkyl, halo nitro, cyano, OC16alkyl, OC14halolakyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC, 6alkylORm ; R8 is H, Cl galkyl, Cl_4haloalkyl, halo, nitro, cyano,OCl 6alkyl, OCl 4haloalkyl,OCI 6alkylNRmRm,OCI 6alkylORm,NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; and (A) R'is R2 is H,ORm, halo, C, 3haloalkyl or C16alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C, 4haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) OR",C (=O) NRmRm, C (=NR"') NR"'Rm,ORm,OC (=O) R°,OC (=O) NRmR"', OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NR'R',NR'R',N (R') C (=O) R",N (R') C (=O) OR, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm) S (=O) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNRmR',OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm) C (=O) NRmRsNRmRs,N (Rm) C (=O) R', N (R"') C (=O) ORs, N(Rm) C (=O) NRmRs, N (Rm) C (=NR"') NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) Rn,C (=O) ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R",OC26alkylNR"'Rm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) Rn,N (Rm) C (=O) OR",N (R"') C (=O) NRmRm N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs,OC (=O) Rs,OC (=O) NRmR',OC (=O) N (Rm) S (=0) 2R',OC26alkylNRmR', OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm) C (=O) Rs,S (=0) 2N (R"') C (=O) ORs,S (O) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm) C (=NRm) NRmRs,N (Rm) S (=O) 2Rs,N (Rm) S (=0) 2NRmR', NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =0 groups; R7 is C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic or 7, 8, 9, 10or 11membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm,SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S (=0) 2N (R'") C (=O) Rn,S (=0) 2N (Rm) C (=O) ORn, S(=O)2NRm) C (=O) NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm) C (=O) OR",N (R"') C (=O) NRmR N (R) C (=NRm) NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; and YisOorNH ; or (B) R'is R2 is H,OR"', halo, Cl 3haloalkyl or C 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) R", C(=O)ORn, C(=O)NRmRm, C (=NR"') NR"'Rm,ORm,OC (=O) R°,OC (=O) NRmRm, OC(=O)N(Rm)S(=O)2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NR'Rm,NR'Rm,N (Rm) C (=O) R",N (Rm) C (=O) OR N (Rm) C (=O) NR'Rm,N (Rm) C (=NRm) NRmRm, N(Rm) S (=0) 2R", N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC OC(=O)NRmRs, OC(=O)N(Rm)S(=O)2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N (Rm) C (=O) OR',N (Rm) C (=O) NR'"R',N (Rm) C (=NRm) NRmR', N(Rm)S(=O)2Rs,N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkyloRs and Cul 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) OR",C (=O) NR"'Rm,C (=NRm) NR"'R"',OR"', OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm,S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, RmRm, N(Rm) C (=O) R",N (Rm) C (=O) OR",N (Rm) C (=O) NR"'R"', N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)Ors, C(=O)NRmRs, C(=NRm)NRmRs, ORs, Oc(=O)Rs, OC(=O)NRMRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNR"'Rs, OC26alkylORs, SRs, S(=O)R5, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRm C16alkylORm ; R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic or 7, 8, 9, 10or 11membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, C, 4haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) OR",C (=O) NRmRm,C (=NRm) NRmRm, ORm, OC (=O) R",OC (=O) NRmRm,OC (=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC2 6alkylOR"',SRm,S (=O) R",S (=0) 2R°,S (=0) 2NR"'R"', S(=O)2N(Rm) C (=O) R",S (=O) 2N (Rm) C (=O) OR",S (=0) 2N (Rm) C (=O) NRmRm, NRmRm, N(Rm) C (=O) Rn, N(Rm) C (=O) ORnN (Rm) C (=O) NRmRm, N(Rm) C (=NRm) NR'Rm,N (Rm) S (=0) 2Rn,N (Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; and Y is O or NH ; or (C) R'is R2 is H,OR"', halo, C13haloalkyl or Cl 6alkyl ; R4 is a saturated, partiallysaturated or unsaturated 8, 9, 10 or 11membered bicyclic heterocycle containing 1,2, 3,4 or 5 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin6yl, 4,5, 6,7tetrahydrobenzo [b] thiophen2yl, benzothiazol 2yl, 2,3dihydrobenzo [1, 4] dioxin6yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C19alkyl, oxo, C14haloalkyl, halo, nitro, cyano,ORm,S (=O)nC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRMRm, NRMC14haloalkyl, NRmC16alkylNRmRm, NRmC16alkylORm, C(=O)C16alkyl, OC(=O)C16alkyl, C(=O)NRmC16alkyl, NRmC(=O)C16alkylC(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORS,OC (=O) R',OC (=O) NRmR',OC (=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm) C (=O) Rs, S (=0) 2N (Rm) C (=O) OR',S (=0) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm) C (=O) R',N Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N (R"') C (=NRm) NRmRs, N (Rm) S (=0) 2Rs,N (Rm) S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26almumPRs a,d C14akyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmR',N (Rm) C (=O) Rn, N(Rm)C(=O)ORn, (Rm) C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, 6alkylNRmRs,NRmC26alkylORs andNRmC26alkylORm ; wherein R4 is not 2aminocarbonylmethyl2,3dihydrobenzol[1, 4] dioxin8yl, 2cyanomethyl 2, 3dihydrobenzo [1, 4] dioxin8yl, quinolin3yl, 3Hquinazolin4on3yl, benzo [1, 3] dioxol5yl, 3, 3dimethyl1, 3dihydroindol2on6yl or 4, 4dimethyl 3, 4didhydro1Hquinolin2on7yl ; R7 is C18alkyl, C15haloalkyl, I or Br R9 is H, C19alkyl, C14haloalky, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm, NRmC16alkylORm, or (Ch2)nRc ; R9 is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC1 6alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; Y is NH; and Z is CR8 or N; or (D) R'is R2 is Cl 6alkyl substituted by 1,2 or 3 substituents selected from Ci4haloalkyl, halo, cyano, nitro,C (=O) R n,C (=O) OR',C (=O) NR'R', C (=NR') NR'R',OR',OC (=O) R,OC (=O) NR'R, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm,NRmRm,N (Rm) C (=O) Rn, N (Rm) C (=O) OR N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N (Rm) S (=O) 2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; or R2 is (C (Rq) 2) ophenyl, wherein the phenyl is substituted by 0,1, 2 or 3 substituents independently selected from Cl. 8alkyl, C, 4haloalkyl, halo, cyano, nitro,C (=O) R°,C (=O) OR",C (=O) NR"'R"',C (=NRm) NR"'Rm,ORm, OC (=O) R",OC (=O) NR"'R"',OC (=O) N (Rm) S (=0) 2Rn,OC2 6alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S((=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmRs,NRmR',N (Rm) C (=O) R',N (Rm) C (=O) ORs, N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N (R"') S (=O) 2NRmRs,NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC (=O) NR'Rm,OC (=O) N (Rm) S (=O) 2R°,OC26alkylNRmRm,OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N (R"') C (=O) R",N (Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, <BR> <BR> <BR> <BR> (R') C (=NRm) NRmR',N (Rm) S (=0) 2R',N (Rm) S (=0) 2NRmRm,<BR> <BR> <BR> <BR> <BR> <BR> NRmC26alkylNRmRm,C (=O) R',C (=O) OR',C (=O) NR"'RS,C (=NR"') NR"'R', ORs,OC (=O) Rs,OC (=O) NRmR',OC (=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S (=0) 2N (R"') C (=O) Rs, S (=0) 2N (Rm) C (=O) ORs, S (=0) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NR"'R', N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm; or R2 is (C(Rq)2)oRr, wherein Rr is a saturated or unsaturated 5or 6membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) OR", C(=O)NRmRm, C(=NRm)NRmRm, ORm, Oc(=O)Rn, OC(=O)NRmRm, OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) R,N (R) C (=0) OR", N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm) S (=O) 2Rn, N (R"') S (=O) 2NRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O) 2N (Rm)C(=O)Rs, (=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R', N(Rm) C (=O) OR',N (R"') C (=O) NRmRs,N (R"') C (=NRm) NRmRs, N (Rm) S (=0) 2Rs,N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C, 4alkyl substituted by 1 or 2 groups selected from Ci 2haloalkyl, halo, cyano, nitro, C (=O) Rn,C (=O) OR",C (=O) NRmRm, C (=NRm) NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(R''') C (=O) Rn,S (=0) 2N (Rm) C (=O) ORn, S(=O)2N(Rm) C (=O) NRmRm, NRmRm, N(Rm) C (=O) Rn, N (Rm) C (=O) OR",N (Rm) C (=O) NRmR N(Rm) C (=NRm) NRmRm, N (Rm) S (=0) 2Rn, N(Rm) S (=O) 2NRmR', NRmC26alkylNRmRm, C(=O)Rs, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S (=0) 2N (Rm) C (=O) R',S (=0) 2N (Rm) C (=O) OR',S (=0) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkyloRs and NRmC26alkylORm ; R4 is a saturated or unsaturated 5or 6membered ring containing 0, 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R,OC26alkylNRmRm,OC26alkylORm,SRm,S (=O) R S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm,NRmRm, N(Rm) C (=O) R,N (Rm) C (=O) OR N (Rm) C (=O) NRmRm,N (Rm) C (=NRm) NRmRm,N (Rm) S (=O) 2Rn, N (Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNR"'RS,OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm) C (=O) ORs,N (Rm) C (=O) NRmRs,N (R"') C (=NRm) NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2R",OC26alkylNRmR"', OC26alkylOR"',SRm,S (=O) R",S (=0) 2R",S (=0) 2NRmRm, S (=0) 2N (Rm) C (=O) Rn,S (=O) 2N (Rm) C (=O) ORn, S(=O)2N(Rm) C (=O) NRmRm, NRmRm, N(Rm) C (=O) Rn,N (Rm) C (=O) OR",N (Rm) C (=O) NRmRm N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm) C (=O) R',S (=0) 2N (Rm) C (=O) OR, S (=0) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) ORs,N (Rm) C (=O) NRmR', N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs,, NRmC26alkylNRmRs, NRmC26alkylORs andNRmC26alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C28alkyl, C15haloalkyl, I, Br; R9 is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, or NRmC, 6alkylORm ; Y is NH; and Z is CR8 or N; or (E) R'is R2 is H, ORm, Cl, C13haloalkyl, or C, 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, C(=O)NRmRm, C(=NRm)NRMRm, ORn, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC36alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm, NRmRm, N (Rm) C (=O) R",N (Rm) C (=O) OR", N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm)C(=O)NRmRs, NRmRs,N(Rm) C (=O) R', N (Rm) C (=O) OR',N (Rm) C (=O) NRmR',N (R) C (=NR"') NR"'R', N(Rm) S (=0) 2R',N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) NR'Rm,C (=NRm) NRmRm,ORm,OC (=O) R OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRMRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRMC26alkylNRmRm, C(=O)Rs,C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORS,OC (=O) Rs,OC (=O) NR"'R',OC (=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm) C (=NRm) NRmRs, N (Rm) S (=0) 2R',N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; wherein R4 is not unsubstituted phenyl; R9 is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalky, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; Y is NH ; and Z is CR8 or N. |
| 123. | A compound according to Claim 122, wherein: R'is R2 is H, ORm, halo, C13haloalkyl or C, 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) R°,C (=O) OR",C (=O) NR"'Rm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC)(=O) N (Rm) S (=O) 2R", OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm, NRmRm, N (Rm) C (=O) R,N (Rm) C (=O) OR N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm, NRmc26alkylORm, C(=O)Rs, C (=O) ORs,C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs, OC (=O) NR'Rs,OC (=O) N (Rm) S (=0) 2Rs,OC26alkylNR"'R',OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O) 2N (Rm) C (=O) R', S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) Rs, N (R"') C (=O) ORs,N (Rm) C (=O) NR"'R',N (R"') C (=NR"') NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs, and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, oRm, OC(=O)Rn, Oc(=O)NRmRm, OC(=O) N (Rm) S (=O) 2R",OC26alkylNR"'R"', OC26alkylORm,SR"',S (=O) R",S (=0) 2R",S (=O) 2NR"'R"', S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm)C(=O)NRmRm, NRmRmN (Rm) C (=O) R",N (Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (R"') S (=0) 2R',OC26alkylNRmR', OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and nRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is Cl 9alkyl, C, 4haloalkyl, halo, nitro, cyano,OCl 6alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14halaoalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic or 7, 8, 9, 10or 11membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C (=O) R",C (=O) ORn,C (=O) NRmRm,C (=NRm) NRmRmORm OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=0) 2R",OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2NR(Rm) C (=O) NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, nRmC26alkylNRmRm or NRmC26alkylORm ; and YisOorNH. |
| 124. | A compound according to Claim 123, wherein: R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1,2 or 3 substituents independently selected from C, 8alkyl, C, 4haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=0) 2R",OC26alkylNR"'Rm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmR, S(=O)2N(Rm) C (=O) Rn, S(=O)2N(Rm) C (=O) OR",S (=O) 2N (Rm) C (=O) NR"'R'", NR Rm, N (Rm) C (=O) Rn, N(Rm) C (=O) OR",N (Rm) C (=O) NRmRm N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC (=O) N (Rm) S (=0) 2Rs,OC26alkylNRmR',OC26alkylORs,SRs,S (=O) RS, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmR',NRmR',N (Rm) C (=O) Rs,N (Rm) C (=O) OR', N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N (Rm) S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, <BR> <BR> <BR> C (=O) R",C (=O) OR",C (=O) NRmRm,C (=NRm) NRmRm,OR"',OC (=O) R", OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R°,OC26alkylNRmR"',OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> NRmC26alkylNR"'Rm,C (=O) R',C (=O) ORs,C (=O) NRmR',C (=NRm) NRmR', ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNR"'Rs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRS, NRmRs, N(Rm) C (=O) Rs,N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm) C (=NRm) NRmR',N (Rm) S (=0) 2RsN (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs and NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups. |
| 125. | A compound according to Claim 123, wherein R4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORnm, OC(=O)Rn, OC (=O) NRmRm,OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm) C (=O) OR",S (=0) 2N (R"') C (=O) NRmRm, NRmRm, N (Rm) C (=O) Rn, N(Rm) C (=O) ORn,N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)R5, C(=O)ORs, C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs,OC (=O) NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs,S(=O)2N(rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm) C (=O) NR'Rs,NR'Rs,N (Rm) C (=O) R',N (Rm) C (=O) ORs, N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N (R"') S (=0) 2NRmR',NR"'C26alkylNR"'R',NRmC26alkylORs and C1 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, s(=O)2N(Rm)C(=O)NRmRm, NRmRm, (Rm) C (=O) R n,N (Rm) C (=O) OR',N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs, OC2 6alkylORs,SRs,S (=O) RS,S (=0) 2R',S (=0) 2NRmR', S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRS,N (R"') C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; and the bridge carbon atoms are substituted with 0,1 or 2 =O groups. |
| 126. | A compound according to Claim 123, wherein R7 is Cl 9alkyl, C14haloalkyl, halo, OC16alkyl, OC14haloalkyl, NRmRm or NRmC, 4haloalkyl. |
| 127. | A compound according to Claim 123, wherein R7 is Cl 5alkyl, C, 4haloalkyl, I, Br or Cl. |
| 128. | 127 A compound according to Claim 123, wherein R7 is tertbutyl or trifluoromethyl. |
| 129. | A compound according to Claim 123, wherein R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic ring containing 0,1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP. |
| 130. | A compound according to Claim 123, wherein R° is a saturated, partiallysaturated or unsaturated 6membered ring containing 0,1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP. |
| 131. | A compound according to Claim 123, wherein Y is O. |
| 132. | A compound according to Claim 123, wherein Y is NH. |
| 133. | A compound according to Claim 122, wherein: R'is R2 is H, ORm, halo, C13haloalkyl, or Cl 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) OR",C (=O) NR'Rm, C (=NR"') NR"'Rm,ORm,OC (=O) R",OC (=O) NRmR"', OC(=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm) C (=O) NRmRm, NRmRm, N(Rm) C (=O) R,N (R) C (=O) OR N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm) S (=O) 2Rn, N (R"') S (=O) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C (=O) ORs,C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs, OC NRmRs, OC(=O) N(Rm)S(=O)2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs,S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, (=0) 2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) Rs, N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) OR",C (=O) NRmRm,C (=NRm) NRmR"',OR"', OC(=O)Rn, Oc(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R°,OC26alkylNR"'R"', OC26alkylORm,SR"',S (=O) R",S (=0) 2R",S (=O) 2NR"'Rm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm,N (Rm) C (=O) Rn, N(Rm) C (=O) ORn,N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NR"'C26alkylNR"R"',C (=O) R',C (=O) ORs,C (=O) NRmRs,C (=NR"') NR"'R', ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OR',SR',S (=O) Rs,S (=0) 2R',S (=0) 2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NR"'R',N (R"') C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs,N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C19alkyl, C14haloalkyl,halo, nitro, cyano, OC16alkyl, OC14halaolkyl, OcC16alkylNRmRm, OCC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRMRm or NRmC16alkylORm ; [C,. 8alkyl, C15haloalkyl, I, Br or Cl] R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic or 7, 8, 9, 10or 11membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, kylOR',SR',S (=O) R n,S (=0) 2R n,S (=0) 2NR'Rm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, s(=O)2N(Rm)C(=O)NRmRm, NR R,N (Rm) C (=O) Rn, N(Rm) C (=O) OR°,N (R"') C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRMRm or NRmC26alkylORm ; and YisOorNH. |
| 134. | A compound according to Claim 133, wherein R4 is a saturated or unsaturated 5or 6membered ring containing 0, 1, 2 or 3 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, Oc(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R",OC26alkylNR"'R",OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N (R"') C (=O) Rn, N(Rm) C (=O) OR",N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, nRmC26alkylORm, C(=O)Rs, C(=O)ORs, C (=O) NR"'Rs,C (=NR"') NR"'R',OR',OC (=O) RS,OC (=O) NR"'RS, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkyloRs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmRs,NRmRs, N (Rm) C (=O) R',N (Rm) C (=O) OR', N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm) S (=O) 2NRmRs, NRmC26alkylnRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) R2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N (Rm) C (=O) R",N (R"') C (=O) OR",N (R"') C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> <BR> NR"'C26alkylNR"'R"',C (=O) Rs,C (=O) ORs,C (=O) NRmR',C (=NR"') NRmR', ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNR"'R', kylOR',SRs,S (=O) Rs,S (=0) 2Rs, S (=0) 2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm)C(=O)NRmRs, NRmRs,N(Rm) C (=O) R',N (Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs,N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups. |
| 135. | A compound according to Claim 133, wherein R4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC (=O) NRmR',OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkyulORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N (Rm) C (=O) Rn, N(Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm,C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, Oc=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkyloRs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmR',NR'R',N (R"') C (=O) Rs,N (Rm) C (=O) ORs, N (Rm) C (=O) NRmRs, N (Rm) C (=NR"') NRmRs,N (Rm) S (=0) 2Rs, N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O) 2N (Rm) C (=O) R', S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N (Rm) C (=O) R",N (Rm) C (=O) OR",N (R°') C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2RS,OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N (R"') C (=NRm) NRmRs,N (Rm) S (=0) 2R',N (Rm) S (=O) 2NRmRs NRmC26alkylNRmRs,NRmC26alkylORs andNRmC26alkylORm ; and the bridge carbon atoms are substituted with 0,1 or 2 =O groups. |
| 136. | A compound according to Claim 133, wherein R7 is Chalky !, Cl 4haloalkyl, halo,OCl 6alkyl,OCl 4haloalkyl,NRmRm or<BR> NRmCz 4haloalkyl. |
| 137. | A compound according to Claim 133, wherein R7 is C15alkyl, C14haloalkyl, I, Br or Cl. |
| 138. | A compound according to Claim 133, wherein R7 is tertbutyl or trifluoromethyl. |
| 139. | A compound according to Claim 133, wherein R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic ring containing 0,1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP. |
| 140. | A compound according to Claim 133, wherein R° is a saturated, partiallysaturated or unsaturated 6membered ring containing 0, 1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP. |
| 141. | A compound according to Claim 133, wherein Y is O. |
| 142. | A compound according to Claim 133, wherein Y is NH. |
| 143. | A compound according to Claim 122, wherein: R'is R2 is H,OR"', halo, Cl 3haloalkyl or Cl 6alkyl ; R4 is a saturated, partiallysaturated or unsaturated 8, 9, 10 or 11membered bicyclic heterocycle containing 1,2, 3,4 or 5 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin6yl, 4,5, 6,7tetrahydrobenzo [b] thiophen2yl, benzothiazol 2yl, 2,3dihydrobenzo [1, 4] dioxin6yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C19alkyl, oxo, C14haloalkyl, halo, nitro, cyano,ORm,S (=O)nC16alkyl, OC14haloalkyl, OC6alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm, NRm C16alkylORm, C(=O)C16alkyl, OC(=O)C16alkyl, C(=O)NRmC16alkyl, <BR> <BR> <BR> <BR> NR"'C (=O) C, _6alkylC (=O) R',C (=O) OR',C (=O) NRmR',C (=NRm) NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNR"'R', OC26alkylORs,SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R',N (R"') C (=O) OR',N (Rm) C (=O) NRmRs, N (R"') C (=NRm) NRmRs,N (Rm) S (=0) 2Rs,N (Rm)S(=O)2NRmRs, NrmC26alkylNRmRs, NRmC26alkylORs, and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) Rn, C(=O)NRmRm, C (=NRm) NRmRm,ORm,OC (=O) Rn,OC (=O) NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm,N (Rm) C (=O) R',N (Rm) C (=O) OR N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(NRm)NRmRs, ORs, OC(=O)Rs,OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC2_6alkylNRmR', OC36alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm) S (=0) 2R',N (Rm) S (=0) 2NRmRs, NR°'C26alkylNR"'R',NRmC26alkylORs andNR"'C26alkylORm ; wherein R4 is not 2aminocarbonylmethyl2, 3dihydrobenzo [1, 4] dioxin8yl, 2cyanomethyl 2,3dihydrobenzo [1, 4] dioxin8yl, quinolin3yl, 3Hquinazolin4on3yl, benzo [1, 3] dioxol5yl, 3, 3dimethyl1,3dihydroindol2on6yl or 4,4dimethyl 3, 4dihydro1hquinolin2on7yl ; R7 is C18alkyl, C15haloalkyl, I or Br; R9 is H, C19aklyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalky, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or, NRmC16alkylORm ; Y is NH ; and Z is CR8 or N. |
| 144. | A compound according to Claim 143, wherein R4 is a heterocycle selected from indole, 3Hindole, benzo [b] furan, benzothiophene, 1Hindazole, benzimidazole, benzthiazole, IHbenzotriazole, 7quinoline, 8quinoline, 1,2, 3,4 tetrahydroquinoline, isoquinoline, cinnoline, phthalazine, quinazoline and quinoxaline, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from Cl 9alkyl, oxo, Cl 4haloalkyl, halo, nitro, cyano, ORm, S(=O)nC16alkyl, oCC14halaokyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm, NRmC16alkylORm, C(=O)C16alkyl, OC(=O)C16alkyl, C(=O)NRmC16alkyl, NRmC(=O)C16alkyl C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, Ors, Oc(=O)Rs, OC (=O) NRmR',OC (=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O) 2N (Rm) C (=O) Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N (R"') C (=O) ORs, N(Rm) C (=O) NRmRs,N (R"') C (=NR"') NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NrmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, C (=O) Rn, C (=O) NRmRm,C (=NRm) NRmRm,ORm,OC (=O) Rn, OC (=O) NRmRm,OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRl, S(=O)2N(Rm) C (=O) Rn, S(=O)2N(Rm) C (=O) OR",S (=0) 2N (Rm) C (=O) NR"'R"',N (Rm) C (=O) R", N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm) C (=NRm) NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, Oc26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRS,N (R"') C (=O) Rs,N (Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNR"'Rs,NRmC26alkylORs andNR"'C26alkylOR"'. |
| 145. | A compound according to Claim 143, wherein R4 is a heterocycle selected from 6indole, 7indole, 63Hindole, 73Hindole, 6benzo [b] furan, 7 benzo [b] furan, 6benzothiophene, 7benzothiophene, 61Hindazole, 71H indazole, benzimidazole, benzthiazole, 1Hbenzotriazole, 7quinoline, 8 quinoline, 71,2, 3,4tetrahydroquinoline, 81,2, 3,4tetrahydroquinoline, isoquinolin7yl, isoquinolin8yl, 7cinnoline, 8cinnoline, phthalazine, 7 quinazoline, 8quinazoline and quinoxaline, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from Cl 9alkyl, oxo, Cl 4haloalkyl, halo, nitro, cyano,ORm,S (=O)nC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm, NRmC16alkylORm, C(=O)C16alkyl, OC=O)C16alkyl, C(=O)NRmC16alkyl, NRmC(=O)C16alkyl C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs,OC26alkylORs,SR',S (=O) RS, (=O)2Rs, S(=O)2 NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmRs,NRmR',N (Rm)à C (=O) Rs,N (Rm) C (=O) ORs, N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N (Rm) S (=0) 2NR"'R',NRmC26alkylNRmRs,NRmC26alkylORs and CI_4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn, S(O) 2N (R') C (=O) OR',S (=0) 2N (Rm) C (=O) NRmRm,N (Rm) C (=O) R', N(Rm)C(=O)ORn,N(Rm)C(=O)NRmRm,N(Rm) C (=NRm) NRmRm, N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm,C(=O)Rs,C(=O)ORs,C(=O)NRmRs, C(=NRm)NRmRs,ORs,OC(=O)Rs,OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs,OC26alkylORs,SRs,S(=O)Rs,S(=O)2Rs,S(=O)2NRmRs, S(=O)2N(Rm) C (=O) RssS (=O) 2N (Rm) C (=O) OR',S (=O) 2N (Rm) C (=O) NRmRs, NRmRs,N(Rm) C (=O) R',N (Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N(Rm) C (=NRm) NRmRs,N (Rm)S(=O)2Rs,N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs and NRmC26alkylORm,. |
| 146. | A compound according to Claim 143, wherein R9 is C19alkyl, C14haloalkyl, halo, nitro, cyano,OC16alkyl,OC14haloalkyl, OC16alkylNRmRm,OC16alkylORm,NRmRm,NRmC14haloalkyl, NR3C16alkylNRmRm or NRmC16alkylORm,. |
| 147. | A compound according to Claim 143, wherein R9 is H. |
| 148. | A compound according to Claim 143, wherein Z is CR8. |
| 149. | A compound according to Claim 143, wherein Z is N. |
| 150. | A compound according to Claim 101, wherein R7 is tertbutyl or trifluoromethyl. |
| 151. | A compound according to Claim 122, wherein: R1 is R2 is Cl 6alkyl substituted by 1, 2 or 3 substituents selected from Cl 4haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) ORn,C (=O) NR3Rm, C(=NRm)NRmRm,ORm,OC(=O)Rn,OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R,;OC26alkylNRmRm,OC26alkylOrm,SRm,S(=O)Rn, S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm,NRmRm,N(Rm) C (=O) R,N (Rm) C (=O) OR N(Rm)C(=O)NRmRm,N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn, N (R"') S (=O) 2NRmRm,NRmC26alkylNRmRm and NRmC26alkylORm ; or R2 is R2is a saturated or unsaturated 5or 6membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7 ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) ORn,C (=O) NRmRm, C(=NRm)NRmRm,ORm,OC(=O)Rn,OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn,OC26alkylNRmRm,OC26alkylORm,SRm,S(=O)Rn, S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm,NRmRm,N(Rm) C (=O) R,N (Rm) C (=O) OR', N (R"') C (=O) NR'Rm,N (Rm) C (=NRm) NRmRm,N (Rm) S (=O) 2Rn, N (R"') S (=0) 2NRmRm,NRmC26alkylNRmRm,NRmC26alkylORm,C(=O)Rs, C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs,ORs,OC(=O)Rs, OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs,OC26alkylORs, SRs,S(=O)Rs,S(=O)2Rs,S(=O)2NRmRs,S(=O)2N(Rm)C(=O)Rs, S 2N(Rm)C(=O)ORs,S(=O)2N(Rm)C(=O)NRmRs,NRmRs,N(Rm)C(=O)Rs, N (Rm) C (=O) OR',N (Rm) C (=O) NRmR',N (Rm) C (=NRm) NRmRs, N (Rm) S (=0) 2RsN (Rm) S (=O) 2NR"'R',NR"'C26alkylNRmR',NR"'C26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, C (=O) R",C (=O) OR",C (=O) NR'Rm,C (=NRm) NRmRm,ORm OC(=O)Rn,OC(=O)NRmRm,OC(=O) N (Rm) S (=0) 2Rn,OC26alkylNRmRm, OC26alkylORm,SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm, S 2N C(=O)Rn,S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm, NRmRm,N(Rm) C (=O) Rn,N (Rm) C (=O) OR",N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm,C(=O)Rs,C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs, ORs,OC (=O) Rs,OC (=O) NRmRs,OC (=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs, OC26alkylORs,SRs,S(=O)Rs,S=O)2Rs,S=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs,S(=O)2N(Rm)C(=O)ORs,S(=O)2N(Rm)C(=O)NRmRs, NRmRs,N(Rm) C (=O) Rs,N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs,N(Rm)S(=O)2Rs,N(Rm)S(=O)2NRmRs, NRmC26alkylBRmRs,NRmC26alkylORs and NRmC26alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C28alkyl,C15haloalkyl,1, Br; R9 is independently, at each instance, H, Cl 9alkyl, Cl 4haloalkyl, halo, nitro, cyano,OC16alkyl,OC14haloalkyl,OC16alkylNRmRm, OC16alkylORm,NRmRm,NRmC14haloalkyl,NRmC16alkylNRmRm or NRmC16alkylORm ; Y is NH ; and Z is CR8 or N. |
| 152. | A compound according to Claim 151, wherein R2 is Chalky ! substituted by 1,2 or 3 substituents selected from C, 4haloalkyl, halo, cyano, nitro, C (=O) R°,C (=O) ORn,C(=O)NRmRm,C(=NRm)NRmRm,ORm, OC(=O)Rn,OC(=O)NRmRm,OC(=O) N (Rm) S (=0) 2Rn,OC26alkylNRmRm, OC26alkylORm,SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm, S(=O)2N(Rm)C(O)Rn,S(O)2N(Rm)C(=O)ORn,S(=O) 2N (Rm)C(=O)NRmRm, NRmRm,N(Rm) C (=O) Rn,N(Rm) C (=O) ORn,N (Rm) C (=O) NR'R', N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm and NRmC26alkylORm ;. |
| 153. | A compound according to Claim 151, wherein R2 is (C (Rq) 2) phenyl, wherein the phenyl is substituted by 0,1, 2 or 3 substituents independently selected from Ci. 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C(=O)Rn,C(=O)ORn,C(=O)NRmRm,C(=NRm)NRmRm,ORm,OC(=O)Rs, OC (=O) NR'Rm,OC (=O) N (Rm) S (=O) 2Rn,OC26alkylNRmRm,OC26alkylORm, SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm,NRmRm, N (Rm) C (=O) Rn,N (Rm) C (=O) OR",N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> NRmC26alkylNR"'R"',NR"'C26alkylOR"',C (=O) R',C (=O) ORS,<BR> <BR> <BR> <BR> <BR> C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs,OC (=O) NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNRmR',OC26alkylORs,SRS,S (=O) Rs, S(=O)2Rs,S(=O)2NRmRs,S(=O)2N(Rm)C(=O)Rs,S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm) C (=O) NRmRs,NRmRs,N (Rm) C (=O) R',N (Rm) C (=O) OR', N(Rm) C (=O) NRmRs,N(Rm) C (=NRm) NRmRs,N(Rm) S (=0) 2Rs, N(Rm) S (=O) 2NRmRs,NRmC26alkylNRmRs,NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, <BR> <BR> <BR> C (=O) Rn,C (=O) ORn,C (=O) NRmRm,C (=NRm) NRmRm, ORm OC (=O) Rn OC(=O)NRmRm,OC(=O) N (Rm) S (=0) 2Rn,OC26alkylNRmRm,OC26alkylORm, SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm,NRmRm, N(Rm)C(=O)Rn,N(Rm) C (=O) ORs,N(Rm) C (=O) NR"'Rm, N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm,C(=O)Rs,C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs, ORs,OC(=O)Rs,OC(O)NRmRs,OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNR"'RS, OC26alkylORs,SRs,S(=O)Rs,S(=O)2Rs,S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs,S(=O)2N(Rm)C(=O)ORs,S(=O)2N(Rm)C(=O)NRmRs, NRmRs,N (Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs,N(Rm)S(=O)2Rs,N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs and NRmC26alkylORm,. |
| 154. | A compound according to Claim 151, wherein R2 is (C (Rq) 2) oRr, wherein Ru ils a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) Rs,C(=O)ORn,C(=O)NRmRm, C(=NRm)NRmRm,ORm,OC(=O)Rn,OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R°,OC26alkylNR"'Rm,OC26alkylORm,SRm,S (=O) R", S(=O)Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRmNRmRm,N (Rm) C (=O) R",N (Rm) C (=O) OR N (Rm) C (=O) NR'R',N (Rm) C (=NRm) NRmRm,N (Rm) S (=O) 2Rn, N (Rm) S (=0) 2NRmRm,NRmC26alkylNRmRm,NRmC26alkylORm,C(=O)Rs, C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs,ORs,OC(=O)Rs, OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmR',OC26alkylORs, SRs,S(=O)Rs,S(=O)2Rs,S(=O)2NRmRs,S(=O)N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs,S(=O) 2N (R') C (=O) NRmR',NRmR',N (Rm) C (=O) Rs, N(Rm) C (=O) ORs,N (Rm) C (=O) NRmRs,N (R) C (=NR"') NRmRs, N(Rm) S (=0) 2Rs,N (Rm) S (=0) 2NR"'Rs,NR"'C2 6alkylNR"'Rs,NR"'C26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,C (=O) Rn,C(=O)ORs,C(=O)NRmRm,C(=NRm)NRmRm,ORm, OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=O) 2R°,OC26alkylNR"'Rm, OC26alkylORm,SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm, NRmRm,N(Rm) C (=O) R",N (Rm) C (=O) ORn,N(Rm) C (=O) NRmRm, N(Rm) C (=NRm) NRmRm,N (Rm) S (=0) 2Rn,N (Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm,C(=O)Rs,C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs, OR',OC (=O) R',OC (=O) NRmRs,OC (=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs, OC2 6alkylORs,SRs,S (=O) R',S (=0) 2R',S (=0) 2NR"'Rs, S(=O)2N(Rm)Cs(=O)Rs,S(=O)2N(Rm)C(=O)ORs,S(=O)2N(Rm)C(=O)NRmRs, NRmRs,N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs,N(Rm)S(=2)Rs,N(Rm)S(=O)2NRmRs, NRmC26alkylNR"'R',NRmC26alkylORs andNR"'C26alkylORm ;. |
| 155. | A compound according to Claim 151, wherein R4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, C, 4haloalkyl, halo, cyano, nitro, C(=O)Rn,C(=O)ORs,C(=O)NRmRm,C(=NRm)NRmRm,ORm,OC(=O)Rs, OC(=O)NRmRm,OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRm,OC26alkylORm, SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm,NRmRm, N (Rm) C (=O) R",N (Rm) C (=O) OR",N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm,NRmC26alkylORm,C(=O)Rs,C(=O)ORs, C(=O)NRmRs,C(=NRm)NRmRs,ORs,OC(=O)Rs,OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNRmRs,OC26alkylORs,SRs,S (=O) R S(=O)2Rs,S(O)2NRmRs,S(=O)2N(Rm)C()O)Rs,S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmRsNRmRs,N (Rm) C (=O) Rs,N (Rm) C (=O) ORs, N(Rm)C(=O)NRmRs,N(Rm)C(=NRm)NRmRs,N(Rm)S(=O)2Rs, N(Rm) S (=O) 2NR"'RS,NR"'C26alkylNR"'R',NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C(=O)Rn,C(=O)ORn,C(=O)NRmRm,C(=NRm)NRmRm,ORm,OC(=O)Rn, OC(=O)NRmRm,OC(=O)N(Rm)S(=O)2Rn,OC26alkylNRmRm, OC26alkylORm, SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn,S(=O) 2N (Rm=C(=O)NRmRm,NRmRm, N (R"') C (=O) Rn,N(Rm)C(=O)ORn,N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm and NRmC26alkylORm ; and the bridge carbon atoms are substituted with 0,1 or 2 =0 groups. |
| 156. | A compound according to Claim 151, wherein R7 is tertbutyl or trifluoromethyl. |
| 157. | A compound according to Claim 151, wherein R9 is H. |
| 158. | A compound according to Claim 151, wherein Z is CR'. |
| 159. | A compound according to Claim 151, wherein Z is N. |
| 160. | A compound according to Claim 122, wherein: R'is R2 is H,ORm, Cl, CI3haloalkyl or C 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 2, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C, 8alkyl, C, 4haloalkyl, halo, cyano, nitro, C(=O)NRmRm,C(=NRm)NRmRm,ORn,OC(=O)Rn,OC(=O)NRmRm, OC N(Rm)S(=O)2Rn,OC26alkylORm,SRm,S(=O)Rn,S(=O)2Rn, S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (R"') C (=O) NRmRm,NRmRm,N (Rm) C (=O) R",N (Rm) C (=O) OR', N (R"') C (=O) NRmRm,N (Rm) C (=NRm) NRmRm,N (Rm) S (=0) 2Rn, N(Rm)S(=O)2NRmRm,NRmC26alkylNRmRm,NRmC26alkylORm,C(=O)Rs, C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs,ORs,OC(=O)Rs, OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2RS,OC26alkylNRmR',OC26alkylORs, Rs,S(=O)Rs,S(=O)2Rs,S(=O)2NRmRs,S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs,S(=O)2N(Rm)C(=O)NRmRs,NRmRs,N(Rm)C(=O)Rs, N(Rm) C (=O) OR',N (R"') C (=O) NRmRs,N (R') C (=NRm) NRmRs, N (R"') S (=0) 2R',N (Rm) S (=O) 2NRmRs,NRmC26alkylNRmRs,NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C (=O) R",C (=O) NRmRm,C (=NRm) NRmRm,ORm,OC (=O) Rn, OC(=O)NRmRm,OC(=O) N (Rm) S (=0) 2Rn,OC26alkylNRmRm,OC26alkylORm, SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm,NRmRm, N(Rm) C (=O) R",N (R"') C (=O) OR",N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm and NRmC26alkylORm; wherein R4 is not unsubstituted phenyl ; R9 is independently, at each instance, H, C19alkyl,C14haloalkyl, halo, nitro, cyano,OC1 6alkyl,OC14haloalkyl,OC16alkylNRmRm, OC16alkylORm,NRmRm,NRmC14haloalkyl,NRmC16alkylNRmRm or NRmC16alkylORm ; Y is NH; and Z is CR8 or N. |
| 161. | A compound according to Claim 160, wherein R4 is a saturated or unsaturated 5or 6membered ring containing 1,2 or 3 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from Cl 8alkyl, C, 4haloalkyl, halo, cyano, nitro,C (=O) NR"'Rm,C (=NRm) NRmRm,OR", OC(=O)Rn,OC(=O)NRmRm,OC(=O) N (Rm) S (=0) 2Rn,OC26alkylORm,SRm, S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm,S(=O) 2N (Rm) C (=O) Rn, S(=O)2N(Rm)C(=O)ORn,S(=O) 2N (Rm)C(=O)NRmRm,NRmRm, N (R"') C (=O) R",N (Rm) C (=O) ORn,N (Rm) C (=O) NRmRm, N(Rm) C (=NRm) NRmRm,N (Rm) S (=0) 2Rn,N (Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm,NRmC26alkylORm,C(=O)Rs,C(=O)ORs, C(=O)NRmRs,C(=NRm)NRmRs,ORs,OC(=O)Rs,OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNRmRs,OC2_6alkylORs,SR',S (=O) Rs, S(=O)2Rs,S(=O)2NRmRs,S(=O)2N(Rm)C(=O)Rs,S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm) C (=O) NR'"R\NR"'R',N (Rm) C (=O) Rs,N (Rm) C (=O) ORs, N (Rm) C (=O) NRmRs,N (Rm) C (=NRm) NRmRs,N (Rm) S (=0) 2Rs, N (R"') S (=O) 2NRmRs,NRmC26alkylNRmRs,NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, C (=O) R°,C (=O) NR"'R"',C (=NR"') NRmRn',ORm,OC (=O) R", OC(=O)NRmRm,OC(=O) N (Rm) S (=0) 2Rn,OC26alkylNRmRm,OC26alkylORm, SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm,NRmRm, N (Rm) C (=O) Rn,N(Rm) C (=O) OR",N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm and NRmC26alkylORm ;. |
| 162. | A compound according to Claim 160, wherein Z is CR. |
| 163. | A compound according to Claim 160, wherein Z is N. |
| 164. | A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein the compounds is selected from: (2E)3 [4 (tertbutyl) phenyl]Nphenylprop2enamide, (2E)N (3, 4dimethoxyphenyl)3 [4 (tertbutyl) phenyl] prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N (4hydroxy3methoxyphenyl) prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N (25, 6,7, 8tetrahydronaphthyl) prop2enamide, (2E)N (2H, 3H, 4Hbenzo [3,4e] 1, 4oxazaperhydroin6yl)3 [4 (tert butyl) phenyl]prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N (3oxo (2H, 4Hbenzo [3,4e] 1, 4oxazaperhydroin 6yl) ) prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N (4methyl3oxo (2Hbenzo [3,4e] 1, 4 oxazaperhydroin6yl)) prop2enamide, (2E)3[4(tertbutyl)phenyl]N(4methyl (2H, 3Hbenzo [3, 4e] 1, 4 oxazaperhydroin6yl)) prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N (3oxo (2H, 4Hbenzo [e] 1, 4oxazaperhydroin7 yl)) prop2enamide, (2E)N (2H, 3H, 4Hbenzo [e] 1, 4oxazaperhydroin7yl)3 [4 (tert butyl) phenyl] prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N (4methyl3oxo (2Hbenzo [e] 1, 4 oxazaperhydroin7yl) ) prop2enamide, (2E) 3 [4(tertbutyl)phenyl]N(4methyl (2H, 3Hbenzo [e] 1, 4oxazaperhydroin 7yl)) prop2enamide, ethyl 6 { (2E)3 [4 (tertbutyl) phenyl] prop2enoylamino}2H, 3H, 4H benzo [e] 1, 4oxazaperhydroine2carboxylate, (2E)3 [4 (tertbutyl) phenyl]N [2 (hydroxymethyl) (2H, 3H, 4Hbenzo [3,4e] 1, 4 oxazaperhydroin6yl)] prop2enamide, (2E)N [ (3S)3 (hydroxymethyl) (2H, 3Hbenzo [e] 1, 4dioxan6yl)]3 [4 (tert butyl) phenyl] prop2enamide, (2E) N [ (3R)3 (hydroxymethyl) (2H, 3Hbenzo [e] 1, 4dioxan6yl)]3 [4 (tert butyl) phenyl] prop2enamide, (2E)N[(2R)2(hydroxymethyl) (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)]3 [4 (tert butyl) phenyl] prop2enamide, (2E)N[(2S)2(hydroxymethyl) (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)]3 [4 (tert butyl) phenyl]prop2enamide, <BR> <BR> <BR> <BR> (2E) 3 [4 (tertbutyl) phenyl]N (71, 2,3, 4tetrahydroquinolyl) prop2enamide, (2E) 3 [4(tertbutyl)phenyl]N(1methyl(71, 2,3, 4tetrahydroquinolyl)) prop2 enamide, (2E)3 [4 (tertbutyl) phenyl]N (2oxo (61, 3, 4trihydroquinolyl)) prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N (2oxo (71, 3, 4trihydroquinolyl)) prop2enamide, (2E) 3 [4 (tertbutyl) phenyl]N (3hydroxyphenyl) prop2enamide, 2 (3 { (2E)3 [4 (tertbutyl) phenyl] prop2enoylamino} phenoxy) acetic acid, (2E)3 [4 (tertbutyl) phenyl]N [3 (2hydroxyethoxy) phenyl] prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N [3 (2methoxyethoxy) phenyl] prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N {3 [2 (1, 3dioxobenzo [c] azolin2 yl) ethoxy] phenyl} prop2enamide, (2E)N [3 (2Aminoethoxy) phenyl]3 [4 (tertbutyl) phenyl] prop2enamide, (2E)3 [4 (tertbutyl) phenyl]Nindolin6ylprop2enamide, (2E)3[4(tertbutyl)phenyl]N(1methylindolin6yl) prop2enamide, (2E)N (lAcetyl3, 3dimethylindolin6yl)3 [4 (tertbutyl) phenyl] prop2 enamide, (2E)3 [4 (tertbutyl) phenyl]N (1, 3, 3trimethylindolin6yl) prop2enamide, (2E)3[4(tertbutyl)phenyl]N(1methylindol6yl)prop2enamide, (2E)3[4(tertbutyl)phenyl]N(1methylindol5yl) prop2enamide, (2E)3[4(tertbutyl)phenyl]N(1methylindolin5yl) prop2enamide, (2E)Nbenzoxazol5yl3 [4 (tertbutyl) phenyl] prop2enamide, (2E)Nbenzoxazol6yl3 [4 (tertbutyl) phenyl] prop2enamide, (2E) Nbenzo [b] furan5yl3 [4 (tertbutyl) phenyl] prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N (2, 3dihydrobenzo [b] furan5yl) prop2enamide, N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)3, 3bis (4methylphenyl) prop2enamide, (2E)N (2H, 3Hbenzo [3, 4e] 1, 4dioxan6yl)3 [4 (tertbutyl) phenyl]2 methylprop2enamide, (2E)N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)3[4(tertbutyl) phenyl] 2 ethylprop2enamide, (2E)N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)3 (4cyclopropylphenyl) prop2 enamide, (2E)N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)3[6(tertbutyl) (3pyridyl)] prop2 enamide, (2E)N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)3[3(tertbutyl)phenyl]prop2 enamide, (2E)N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)3[2fluoro4(trifl uoromethyl) phenyl] prop2enamide, (2E)N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)3 [2, 3difluoro4 (trifluoromethyl) phenyl] prop2enamide, (2E)N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)3 [2, 4bis (trifluoromethyl) phenyl] prop2enamide, (2E)3[2fluoro4(trifluoromethyl)phenyl]Nindol5ylprop2enamide, (2E)3[2, 3difluoro4(trifluoromethyl) phenyl]Nindol5ylprop2enamide, (2E)3 [2, 4bis (trifluoromethyl) phenyl]Nindol5ylprop2enamide, N (2H, 3Hbenzo [e] 1, 4dioxan6yl) (2Z)3 [4 (tertbutyl) phenyl]3 [4 (trifluoromethyl) phenyl] prop2enamide, (2E)N (2H, 3Hbenzo [e] 1, 4dioxan6yl)3 [4 (tertbutyl) phenyl]4phenylbut2 enamide, (2E)N (2H, 3Hbenzo [e] 1, 4dioxan6yl)3 [4 (tertbutyl) phenyl]5methylhex2 enamide, N (2H, 3Hbenzo [e] 1, 4dioxan6yl) (2Z)3 [4 (tertbutyl) phenyl]3iodoprop2 enamide, (2E)N (2H, 3Hbenzo [e] 1, 4dioxan6yl)3 (3aminophenyl)3 [4 (tert butyl) phenyl] prop2enamide, ethyl (4E)5 (N (2H, 3Hbenzo [e] 1, 4dioxan6yl) carbamoyl)4 [4 (tert butyl) phenyl] pent4enoate, 3methoxyphenyl (2E)3 [4 (tertbutyl) phenyl] prop2enoate, N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)(2Z)3[4(tertbutyl) phenyl] 3 hydroxyprop2enamide, N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl) [7 (tertbutyl) (3isoquinolyl)] carboxamide, N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl) (2Z)3 [4 (tertbutyl) phenyl] prop2 enamide, N (2H, 3Hbenzo [e] 1, 4dioxan6yl) (2Z)3 [4 (tertbutyl) phenyl]3phenylprop2 enamide, (2E)N (2H, 3Hbenzo [e] 1, 4dioxan6yl)3 [4 (tertbutyl) phenyl]3phenylprop 2enamide, (2E)3 [4 (tertbutyl) phenyl]N [1 (Nmethylcarbamoyl) (lHindazol6yl)] prop 2enamide, (2E)3 [4 (tertbutyl) phenyl]N {4chloro3 [ (methylamino) carbonylamino] phenyl} prop2enamide, (2E)3 [4 (tertbutyl) phenyl]Nquinoxalin6ylprop2enamide, (2E)N(1acetyl(71, 2,3, 4tetrahydroquinol yl))3 [4 (tertbutyl) phenyl] prop2 enamide, <BR> <BR> <BR> (2E) 3 [4(tertbutyl) phenyl]N[1(2methoxyethyl) indol6yl] prop2enamide,<BR> <BR> <BR> <BR> <BR> (2E) 3 [4(tertbutyl) phenyl]N[1(2methoxyethyl) indol5yl] prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N [ 1 (2hydroxyethyl) indol6yl] prop2enamide, (2E)3[4(tertbutyl)phenyl]N[1(2hydroxyethyl)indol5yl] prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N [2 (hydroxymethyl) indol5yl] prop2enamide, (2E)N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)3[6(tertbutyl)2methyl (3 pyridyl) prop2enamide, <BR> <BR> <BR> (2E)3 [6 (tertbutyl)2methyl (3pyridyl)]Nindol6ylprop2enamide,<BR> <BR> <BR> <BR> <BR> (2E)Nbenzothiazol6yl3[6(tertbutyl)2methyl (3pyridyl)] prop2enamide,<BR> <BR> <BR> <BR> <BR> (2E)3 [6 (tertbutyl)2methyl (3pyridyl)]Nindol5ylprop2enamide, (2E)3[6(tertbutyl)2methyl (3pyridyl)]N[2(hydroxymethyl) indol5yl] prop 2enamide, (2E)3 [6 (tertbutyl) (3pyridyl)]N [2 (hydroxymethyl) indol5yl] prop2 enamide, (2E)3[6(tertbutyl) (3pyridyl)]N[1(2hydroxyethyl) indol5yl] prop2 enamide, (2E)Nindol6yl3 [2methyl6 (trifluoromethyl) (3pyridyl)] prop2enamide, <BR> <BR> <BR> (2E)Nindol5yl3[2methyl6(trifluoromethyl) (3pyridyl)] prop2enamide, (2E)Nbenzothiazol6yl3 [2methyl6 (trifluoromethyl) (3pyridyl)] prop2 enamide, (2E)N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)3[2methyl6(trifluoromethyl) (3 pyridyl) ] prop2enamide, (2E)3 [4 (tertbutyl) phenyl]N [3 (hydroxymethyl)2oxo (71, 3,4 <BR> <BR> <BR> trihydroquinolyl)] prop2enamide,<BR> <BR> <BR> <BR> (2E) N [3 (hydroxymethyl) (71, 2,3, 4tetrahydroquinolyl)]3 [4 (trifluoromethyl) phenyl] prop2enamide, (2E) N [3(hydroxymethyl)1methyl(71, 2,3, 4tetrahydroquinolyl)]3 [4 (trifluoromethyl) phenyl] prop2enamide, (2E)N (2H, 3Hbenzo [e] 1, 4dioxan6yl)3 [4 (tertbutyl) phenyl]5 (1, 3 dioxolan2yl) pent2enamide, (2E)N (2H, 3Hbenzo [e] 1, 4dioxan6yl)3 [4 (tertbutyl) phenyl]4 (3 pyridyl) but2enamide, N (2H, 3Hbenzo [e] 1, 4dioxan6yl) (2Z)3 [4 (tertbutyl) phenyl]4 pyrrolidinylbut2enamide, (2E)N (2H, 3Hbenzo [e] 1, 4dioxan6yl)3 [4 (tertbutyl) phenyl] 6 imidazolylhex2enamide, 3 (4tertbutylphenyl)6imidazol1ylhex2enoic acid benzothiazol6ylamide, (2E)N (2H, 3Hbenzo [e] 1, 4dioxan6yl)3 [2morpholin4yl6 (trifluoromethyl) (3pyridyl) prop2enamide, (2E)N (2H, 3Hbenzo [e] 1, 4dioxan6yl)3 [4 (tertbutyl)2bromophenyl] prop 2enamide, ethyl 2 [ (lE)2 (N (2H, 3Hbenzo [e] 1, 4dioxan6yl) carbamoyl) vinyl]5 (tert butyl) benzoate, (2E)3[2Bromo4(trifluoromethyl)phenyl]Nindol5ylprop2enamide, (2E)Nbenzothiazol6yl3[2bromo4(trifluoromethyl)phenlyl]prop2enamide, (2E)N (2H, 3Hbenzo [e] 1, 4dioxan6yl)3 [2bromo4 (trifluoromethyl) phenyl]prop2enamide, (2E)Nindol5yl3[2(6methoxy(3pyridyl))4(trifluoromethyl)phenyl]prop2 enamide, <BR> <BR> <BR> <BR> (2E)Nindol5yl3 [2 (4pyridyl)4 (trifluoromethyl) phenyl] prop2enamide, (2E)Nindol5yl3 [2 (3pyridyl)4 (trifluoromethyl) phenyl] prop2enamide, tertbutyl 4 {2[(lE)2(Nindol5ylcarbamoyl) vinyl] 5 (trifluoromethyl) phenyl}1, 2,5, 6tetrahydropyridinecarboxylate, (2E)Nindol5yl3[2(1, 3thiazol2yl)4(trifluoromethyl) phenyl] prop2 enamide, (2E)Nindol5yl3 [2 (3pyridylmethyl)4 (trifluoromethyl) phenyl] prop2 enamide, (2E)3 [2 (3pyridyl)4 (trifluoromethyl) phenyl]N (7quinolyl) prop2enamide, (2E)3 [2 (3pyridyl)4 (trifluoromethyl) phenyl]N (3quinolyl) prop2enamide, (2E)Nindol6yl3 [2 (3pyridyl)4 (trifluoromethyl) phenyl] prop2enamide, and N (2H, 3Hbenzo [3,4e] 1, 4dioxan6yl)3 [4 (tertbutyl) phenyl] propanamide. |
| 165. | A compound according to Claim 21, or a pharmaceutically acceptable salt thereof, wherein the compounds is selected from: (4benzo [1, 3] dioxol5ylpyridin2yl)(2,3dihydrobenzo[1, 4] dioxin6yl) amine, (2,3dihydrobenzo [1, 4] dioxin6yl) [4 (4dimethylaminophenyl)pyridin2yl] amine, (2,3dihydrobenzo [1, 4] dioxin6yl) [4 (4fluorophenyl)pyridin2yl]amine, (2,3dihydrobenzo [1, 4] dioxin6yl) [4 (3trifluoromethylphenyl)pyridin2yl] amine, (4benzo [b] thiophen2ylpyridin2yl) (2, 3dihydrobenzo [1, 4] dioxin6yl) amine, 1{4(2(2, 3dihydrobenzo [1, 4] dioxin6ylamino)pyridin4yl]phenyl} ethanone, 1 {4 [2 (2, 3dihydrobenzo [1, 4] dioxin6ylamino)pyridin4yl]phenyl}ethanol, [4 (3, 5bistrifluoromethylphenyl)pyridin2yl] (2, 3dihydrobenzo [1, 4] dioxin 6yl)amine, (2,3dihydrobenzo [1, 4] dioxin6yl) [4 (4trifluoromethoxyphenyl)pyridin2 yl] amine, and quinolin3yl [4 (4trifluoromethylphenyl)pyridin2yl]amine. |
| 166. | A compound according to Claim 56, or a pharmaceutically acceptable salt thereof, wherein the compounds is selected from: <BR> <BR> <BR> <BR> 7 [4 (4trifluoromethylphenyl)pyridin2yloxy]quinoline,<BR> <BR> <BR> <BR> <BR> <BR> <BR> 2 (3methoxyphenoxy)4 (4trifluoromethylphenyl)pyridine,<BR> <BR> <BR> <BR> <BR> <BR> 8 [4 (4trifluoromethylphenyl)pyridin2yloxy]quinolin2ylamine,<BR> <BR> <BR> <BR> <BR> <BR> 4 [4 (4trifluoromethylphenyl)pyridin2yloxy]benzothiazol2ylamine, N{4[4(4trifluoromethylphenyl)pyridin2yloxy]benzothiazol2yl} acetamide, 8 [4 (4trifluoromethylphenyl)pyridin2yloxy]quinoline, and 2methyl5 [4 (4trifluoromethylphenyl)pyridin2yloxy]benzothiazole. |
| 167. | A compound according to Claim 21, or a pharmaceutically acceptable salt thereof, wherein the compounds is selected from:. |
| 168. | A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein the compounds is selected from:. |
| 169. | A pharmaceutical composition comprising a compound according to any one of Claims 1168 and a pharmaceuticallyacceptable diluent or carrier. |
| 170. | The use of a compound according the any one of Claims 1168 as a medicament. |
| 171. | The use of a compound according the any one of Claims 1168 in the manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixedvascular and nonvascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders. |
| 172. | The manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixedvascular and nonvascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, wherein the medicament contains a compound having the structure: wherein: X is 0, S or NR' ; n is independently, at each instance, 0,1 or 2; o is independently, at each instance, 0,1, 2 or 3; Rm is independently at each instance H or Rn ; R nis independently at each instance Cl 8alkyl, phenyl or benzyl ; Rq is independently in each instance H, C14alkyl,C14haloalkyl, halo, cyano, nitro, C (=O) R",C (=O) OR",C (=O) NRn'R"',C (=NR') NR"'R"',OR°', OC(=O)Rn,OC(=O) N (R') S (=0) 2Rn,OC26alkylNRmRm, OC26alkylORm,SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm, NRmRm,N(Rm)C(=O)Rn,N(Rm)C(=O)ORn,N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; Rs is Rn substituted by 0,1, 2 or 3 substituents independently selected from Rq ; R3 is H or Cl 4alkyl ; R5 is H, C19alkyl,C14haloalkyl, halo, nitro, cyano,OC16alkyl, OC14haloalkyl,OC16alkylNRmRm,OC16alkylORm,NRmRm, NRmC14haloalkyl,NRmC16alkylNRmRm,NRmC16alkylORm, or (CH2)nRc R6 is, independently at each instance, H, C19alkyl,C14haloalkyl, halo, nitro, cyano,OC16alkyl,OC14haloalkyl,OC16alkylNRmRm, NRmRm or NRmCI 6alkylORm ; R8 is H, C19alkyl, C14haloalkyl, halo, nitro, cyano,OC16alkyl, OC14haloalkyl,OC16alkylNRmRm,OC16alkylORm,NRmRm, NRmC14haloalkyl,NRmC16alkylNRmRm or NRmC16alkylORm; and (A) R'is R2 is H,ORm, halo, Cl 3haloalkyl or C16alkyl; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0,1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) R n,C (=O) OR',C (=O) NR'R', C(=NRm)NRmRm,ORm,OC(=O)Rn,OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn,OC26alkylNRmRm,OC2 6alkylORm,SRm,S(=O)Rn, S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm,NRmRm,N (Rm) C (=O) R",N (R'") C (=0) OR", N(Rm)C(=O)NRmRm,N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn, N (Rm) S (=0) 2NRmRm,NRmC26alkylNRmRm,NRmC26alkylORm,C(=O)Rs, C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs,ORs,OC(=O)Rs, OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2R',OC26alkylNR"'RS,OC26alkylORs, SRs,S(=O)Rs,S(=O)2Rs,S(=O)2NRmRs,S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs,S(=O)2N(Rm)C(=O)NRmRs,NRmRs,N(Rm) C (=O) R', N(Rm) C (=O) ORs,N(Rm) C (=O) NRmRs,N (R) C (=NRm) NRmRs, N(Rm) S (=0) 2R',N (Rm) S (=0) 2NRmRs,NRmC26alkylNRmRs,NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C(=O)Rn,C(=O)ORn,C(=O)NRmRm,C(=NRm)NRmRm,ORm, OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=O) 2Rn,OC26alkylNRmRm, OC26alkylORm,SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm NR Rm7N (Rm) C (=O) R",N (Rm) C (=O) OR",N (R"') C (=O) NRmRm, N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm,C(=O)Rs,C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs, ORs,OC(=O)Rs,OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs, OC26alkylORs,SRs,S(=O)Rs,S(=O)2Rs,S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs,S(=O)2N(Rm)C(=O)ORs,S(=O)2N(Rm)C(=O)NRmRs, NRmRs,N(Rm) C (=O) Rs,N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs,N(Rm)S(=O)2Rs,N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs and NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C19alkyl,C14haloalkyl, halo, nitro, cyano,OCI 6alkyl, OC14haloalkyl,OC16alkylNRmRm,O C16alkylORm,NRmRm, NRmC14haloalkyl,NRmC16alkylNRmRm or NRmC16alkylORm; R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic or 7, 8, 9, 10or 11membered bicyclic ring containing 0, 1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C (=O) R°,C (=O) ORn,C (=O) NR'Rm,C (=NRm) NRmRm,ORm, OC(=O)Rn,OC(=O)NRmRm,OC(=O) N (Rm) S (=0) 2Rn,OC26alkylNRmRm, OC26alkylORm,SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm, NRmRm,N(Rm)C(=O)Rn,N(Rm)C(=O)ORn,N(Rm)C(=O)NRmRm, N (R"') C (=NRm) NR R,N (R) S (=0) 2Rn,N (Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; and Y is O or NH ; or (B) R'is R2 is H,ORm, halo, C, 3haloalkyl or Cl. 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl,halo,cyano, nitro, C (=O) Rn,C (=O) ORn,C (=O) NRmRm, C(=NRm)NRmRm,ORm,OC(=O)Rn,OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn,OC26alkylNRmRm,OC26alkylORm,SRm,S(=O)Rn, S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm,NRmRm,N (Rm) C (=O) R,N (Rm) C (=O) OR N (Rm) C (=O) NRmRm,N (Rm) C (=NRm) NRmRm,N (Rm) S (=0) 2Rn N (R"') S (=0) 2NRmRm,NRmC26alkylNR"'Rm,NRmC26alkylORm,C (=O) Rs, C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs,ORs,OC(=O)Rs, OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2RS,OC26alkylNRmRs,OC26alkylORs, SRs,S(=O)Rs,S(=O)2R5,S(=O)2NRmRs,S(=O) 2N (Rm)C(=O)R5, S(=O)2N(Rm)C(=O)ORs,S(=O)2N(Rm)C(=O)NRmRs,NRmRs,N(Rm) C (=O) Rs, N (R"') C (=O) OR',N (Rm) C (=O) NRmR',N (Rm) C (=NRm) NR R, (Rm) S 2Rs,N(Rm)S(=O)2NRmRs,NRmC26alkylNRmRs,NRmC26alkylORs, and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C (=O) Rn,C (=O) ORn,C (=O) NRmRm,C(=NRm)NRmRm,ORm, OC(=O)Rn,OC(=O)NRmRm,OC(=O) N (Rm) S (=0) 2Rn,OC2 6alkylNRmRm, OC26alkylORm,SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm, NRmRm,N(Rm) C (=O) Rn,N(Rm) C (=O) OR",N (Rm) C (=O) NRmRm N(Rm)C(=NRm)NRmRm,N(Rm)S(=O2)Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm,C(=O)Rs,C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs, ORs,OC(=O)Rs,OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2Rs,OC2_6alkylNRmRs, OC26alkylORs,SRs,S(=O)2Rs,S(=O)2NRmRs, S 2N(Rm)C(=O)Rs,S(=O)2N(Rm)C(=O)ORs,S(=O)2N(Rm)C(=O)NRmRs, NRmRs,N(Rm) C (=O) R',N (Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N(Rm)C(=NR)NRmRs,N(Rm)S(=O)2Rs,N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs and NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =0 groups; R7 is Cl. 9alkyl, Cl 4haloalkyl, halo, nitro, cyano,OCI 6alkyl, OC14haloalkyl,OC16alkylNRmRm,OC15alkylORm,NRmRm, NRmC14haloalkyl,NRmC16alkylNRmRm or NRmC16alkylORm; R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic or 7, 8, 9, 10or 11membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C (=O) R",C (=O) OR",C (=O) NR'Rm,C (=NRm) NRmRm,ORm OC (=O) R",OC (=O) NRmR"',OC (=O) N (Rm) S (=O) 2R",OC2_6alkylNRmRm, OC26alkylORm,SRm,S(=O)Rn,S(=O)2Rn,S(O)2NRmRm, S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm, NRmRm,N(Rm) C (=O) Rn,N (Rm) C (=O) OR",N (Rm) C (=O) NRmRm N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; and Y is O or NH; or (C) R'is R2 is H,OR"', halo, C13haloalkyl or C16alkyl; R4 is a saturated, partiallysaturated or unsaturated 8, 9, 10 or 11membered bicyclic heterocycle containing 1,2, 3,4 or 5 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin6yl, 4,5, 6,7tetrahydrobenzo [b] thiophen2yl, benzothiazol 2yl, 2,3dihydrobenzo [1, 4] dioxin6yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from Cl 9alkyl, oxo, C14haloalkyl, halo, nitro, cyano,ORm,S (=O) 6alkylOC14haloalkyl,OC16alkylNRmRm, OC16alkylORm,NRmRm,NRmC14haloalkyl,NRmC16alkylNRmRm, <BR> <BR> <BR> NRmCI 6alkylORm,C (=O) CI 6alkyl,OC (=O) CI 6alkyl,C (=O) NRmCI 6alkyl, NRmC(=O)C16alkylC(=O)Rs,C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs, ORs,OC(=O)Rs,OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2R',OC26alkylNR"'R', OC26alkylORs,SRs,S(=O)Rs,S(=O)2Rs,S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs,S(=O)2N(Rm)C(=O)ORs,S(=O)2N(Rm)C(=O)NRmRs, NR"'R',N (R"') C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs,N(Rm)S(=O)2Rs,N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) NRmRm, C (=NRm) NRmRm,ORm,OC (=O) Rn,OC (=O) NRmRm, OC(=O) N (Rm) S (=0) 2R,OC26alkylNRmRm,OC26alkylOR',SRm,S (=O) R S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn, S (=0) 2N (R"') C (=O) NRmRm,N (Rm) C (=O) R°,N (R"') C (=O) OR°, N (R"') C (=O) NRmRm,N (Rm) C (=NRm) NRmRm,N (Rm) S (=O) 2Rn, N(Rm)S(=O)2NRmRm,C(=O)Rs,C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs, ORS,OC (=O) Rs,OC (=O) NR"'R',OC (=O) N (Rm) S (=0) 2Rs,OC26alkylNR"'R', OC26alkylORs,SRs,S(=O)Rs,S(=O)2Rs,S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs,S(=O)2N(Rm)C(=O)ORs,S(=O) 2N (Rm) C(=O)NRmRs, NRmRs,N(Rm)C(=O)Rs,N(Rm)C(=O)ORs,N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs,N(Rm)S(=O)2Rs,N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs and NRmC26alkylORm; wherein R4 is not 2aminocarbonylmethyl2, 3dihydrobenzo [1, 4] dioxin8yl, 2cyanomethyl 2,3dihydrobenzo [1, 4] dioxin8yl, quinolin3yl, 3Hquinazolin4on3yl, benzo [1, 3] dioxol5yl, 3, 3dimethyl1,3dihydroindol2on6yl or 4, 4dimethyl 3, 4dihydro1Hquinolin2on7yl ; R7 is C18alkyl,C15haloalkyl, I or Br R9 is H, C19alkyl,C14haloalkyl, halo, nitro, cyano, OC16alkyl,OC14haloalkyl, OC16alkylNRmRm,OC16alkylORm,NRmRm,NRmC14haloalkyl, NRmC16alkylNRmRm,NRmC16alkylORm, or (CH2)nRc; R9 is independently, at each instance, H, C19alkyl,C14haloalkyl, halo, nitro, cyano,OC16alkyl,OC14haloalkyl,OC16alkylNRmRm, OC16alkylORm,NRmRm,NRmC14haloalkyl,NRmC16alkylNRmRm or NRmC16alkylORm; Y is NH; and Z is CR8 or N; or (D) R'is R2 is C16alkyl substituted by 1,2 or 3 substituents selected from C, 4haloalkyl, halo, cyano, nitro,C (=O) Rn,C(=O)ORn,C(=O)NRmRm, C(=NRm)NRmRm,ORm,OC(=O)Rn,OC(=O)NRmRm, OC (=0) N (Rm) S (=0) 2Rn,OC26alkylNRmRm,OC26alkylORm,SRm,S(=O)Rn, S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=o)ORn, S(=O) 2N (Rm) C (=O) NRmRm,NRmRm,N(Rm) C (=O) R,N (Rm) C (=O) OR N (Rm) C (=O) NRmRm,N (R') C (=NRm) NRmRm,N (Rm) S (=O) 2Rn, N (Rm) S (=0) 2NRmRm,NRmC26alkylNRmRm or NRmC26alkylORm ; or R2 is (C (Rq) 2) ophenyl, wherein the phenyl is substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C (=O) Rn,C (=O) ORn,C(=O)NRmRm,(C=NRm)NRmRm,ORm, OC(=O)Rn,OC(=O)NRmRm,OC(=O) N (Rm) S (=0) 2R",OC26alkylNR"'R"', OC2 6alkylORm,SRm,S (=O) Rn,S (=0) 2Rn,S (=0) 2NRmRm, S(=O)2N(Rm) C (=O) Rn,S(=O)2N(Rm) C (=O) ORn,S(=O)2N(Rm) C (=O) NRmRm, NRmRm,N(Rm) C (=O) Rn,N (Rm) C (=O) ORn,N (Rm) C (=O) NRmR N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm NR"'C26alkylNR"'Rm,NRmC26alkylORm,C (=O) Rs,C (=O) ORS, C(=O)NRmRs,C(=NRm)NRmRs,ORs,OC(=O)Rs,OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNRmR',OC26alkylORs,SR',S (=O) R S(=O)2Rs,S(=O)2NRmRs,S(=O)3N(Rm)C(=O)Rs,S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm) C (=O) NRmRs,NRmRs,N (Rm) C (=O) R',N (Rm) C (=O) OR', N(Rm)C(=O)NRmRs,N(Rm)C(=NRm)NRmRs,N(Rm)S(=O)2Rs, N(Rm) S (=O) 2NRmRs,NRmC26alkylNRmRs,NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, <BR> <BR> <BR> C (=O) R,C (=O) OR,C (=O) NRmRm,C (=NRm) NR'Rm,ORm,OC (=O) R OC (=O) NRmR',OC (=O) N (Rm) S (=0) 2R",OC26alkylNRmRm,OC26alkylORm, SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm,NRmRm, N(Rm) C (=O) R',N (Rm) C (=O) OR",N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm,C(=O)Rs,C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs, ORS,OC (=O) Rs,OC (=O) NRmR',OC (=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs, kylORs,SR',S (=O) R',S (=0) 2R',S (=0) 2NRmRs, S(=O)2N(Rm)C(=O)Rs,S(=O)2N(Rm)C(=O)ORs,S(=O)2N(Rm)C(=O)NRmRs, NRmRs,N (Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs,N(Rm)S(=O)2Rs,N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs and NRmC26alkylORm ; or R2 is (C (Rq) 2) oRr, wherein Rr is a saturated or unsaturated 5or 6membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl,C14haloalkyl, halo, cyano, nitro,C (=O) Rn,C (=O) OR', C(=O)NRmRm,C(=NRm)NRmRm,ORm,OC(=O)Rn,OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn,OC26alkylNRmRm,OC26alkylORm,SRm,S(=O)Rn, S(=O)2Rn,S=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm,NRmRm,N (Rm) C (=O) R",N (Rm) C (=O) OR', N(Rm)C(=O)NRmRm,N(Rm)C(=NRm)NRmRm,N(Rm) S (=O) 2R, N(Rm) S (=0) 2NRmRm,NRmC26alkylNRmRm,NRmC26alkylOR",C (=O) R', C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs,ORs,OC(=O)Rs, OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs,OC26alkylORs, SRs,S=O)Rs,S(=O)2Rs,S(=O)2NRmRs,S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs,S=O)2N(Rm)C(=O)NRmRs,NRmRs,N(Rm)C(=O)Rs, N(Rm) C (=O) OR',N (Rm) C (=O) NRmRs,N (R"') C (=NRm) NRmRs, N (R"') S (=0) 2R',N (Rm) S (=0) 2NRmRS,NR"'C26alkylNR"'Rs,NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C (=O) R",C (=O) OR",C (=O) NR"'Rm,C (=NRm) NRmRm,OR"', OC(=O)Rn,OC(=O)NRmRm,OC(=O) N (Rm) S (=0) 2R°,OC26alkylNR"'R"', OC26alkylORm,SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm, NRmRm,N(Rm) C (=O) Rn,N (Rm) C (=O) ORn,N (Rm) C (=O) NRmRm N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm,C(=O)Rs,C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs, ORs,OC(=O)Rs,OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs, OC2 6alkylORs,SR',S (=O) R',S (=0) 2R',S (=0) 2NRmR', S(=O)2N(Rm)C(=O)Rs,S(=O)2N(Rm)C(=O)ORs,S(=O) 2N (Rm)C(=O)NRmRs, NRmRs,N(Rm) C (=O) Rs,N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm) C (=NRm) NRmRs,N (Rm) S (=0) 2R',N (Rm) S (=O) 2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs andNRmC26alkylORm; R4 is a saturated or unsaturated 5or 6membered ring containing 0, 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from Cul 8alkyl, C14haloalkyl, halo, cyano, nitro,C (=O) Rn,C(=O)ORs,C(=O)NRmRm, C(=NRm)NRmRm,ORm,OC(=O)Rn,OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2R,OC26alkylNRmRm,OC26alkylORm,SRm,S (=O) R S(=O)2Rn,S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmRmNRmRm,N (Rm) C (=O) R,N (Rm) C (=O) OR N (Rm) C (=O) NRmRm,N (Rm) C (=NRm) NR'Rm,N (Rm) S (=O) 2Rn, N(Rm) S (=0) 2NRmRm,NRmC26alkylNRmRm,NRmC26alkylORm,C(=O)Rs, C (=O) ORs,C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs, OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs,OC26alkylORs, SRs,S(=O)Rs,S(=O)2Rs,S(=O)NRmRs,S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs,S(=O) 2N (Rm)C(=O)NRmRs,NRmRs,NRmRs,N(Rm) C (=O) Rs, N (R"') C (=O) OR',N (Rm) C (=O) NRmRs,N (Rm) C (=NR"') NRmRs, N (Rm) S (=0) 2Rs,N (Rm) S (=O) 2NRmRs,NRmC26alkylNRmRs,NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C12haloalkyl,halo, cyano, nitro, C (=O) RnnC(=O)ORn,C(=O)NRmRm,C(=NRm)NRmRm,ORm, OC(=O)Rn,OC(=O)NRmRm,OC(=O) N (Rm) S (=0) 2Rn,OC2 6alkylNRmRm, OC26alkylORm,SRm,S(=O)Rn,S(=O)2Rn,S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn,S(=O)2N(Rm)C(=O)ORn,S(=O)2N(Rm)C(=O)NRmRm, NRmRm,N(Rm)C(=O)Rn,N(Rm)C(=O)ORn,N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm,N(Rm)S(=O)2Rn,N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm,C(=O)Rs,C(=O)ORs,C(=O)NRmRs,C(=NRm)NRmRs, ORs,OC(=O)Rs,OC(=O)NRmRs,OC(=O) N (Rm) S (=0) 2R',OC26alkylNR"'R', OC26alkylORs,SR',S (=O) R',S (=0) 2R',S (=0) 2NRmR', S(=O)2N(Rm)C(=O)Rs,S(=O)2N(Rm)C(=O)ORs,S(=O)2N(Rm)C(=O)NRmRs, NRmRs,N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs,N(Rm)S(=O)2Rs,N(Rm)S(=P)2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs and NRmC26alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =0 groups; R7 is C28alkyl,C15haloalkyl,I, Br; R9 is independently, at each instance, H, Cl 9alkyl, Cl 4haloalkyl, halo, nitro, cyanoOC16alkyl,OC14haloalkylOC16alkylNRmRm, OC16alkylORm,NRmRm,NRmC14haloalkyl,NRmC16alkylNRmRm or NRmCI6alkylOR ; Y is NH ; and Z is CR8 or N ; or (E) R1 is R2 is H,ORm, Cl, Cl3haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C (=O) NR"'Rm,C (=NRm) NRmRm,OR°,OC (=O) R",OC (=O) NR"'Rm, OC(=O)N(Rm)S(=O)2Rn,OC26alkylORm,SRm,S(=O)Rn,S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S (=0) 2N (R"') C (=O) NRmRm, NRmRm, N (R') C (=O) R",N (Rm) C (=O) OR N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm) S (=0) 2Rm, N (Rm) S (=0) 2NRmRm,NRmC26alkylNRmR",N"'C26alkylOR"',C (=O) R', C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs,OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(RM)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R', N(Rm) C (=O) ORs,N (Rm) C (=O) NR'R',N (Rm) C (=NRm) NR"'R', N (Rm) S (=0) 2Rs,N (Rm) S (=0) 2NRmR',NRmC26alkylNRmR',NR'C26alkylOR' and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) Rn, C (=O) NRmRm,C (=NRm) NRmRm, ORm, OC (=O) R", OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) Rs,N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NR"'C26alkylNR"'R',NR"'C26alkylORs andNRmC26alkylOR"' ; wherein R4 is not unsubstituted phenyl ; R7 is C26alkyl, C15haloalkyl, I or Br; R@ is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; Y is NH; and Z is CR8 or N. |
| 173. | The manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixedvascular and nonvascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, wherein the medicament contains a compound having the structure: wherein: X is O, S or NRm ; n is independently, at each instance, 0,1 or 2; o is independently, at each instance, 0, 1, 2 or 3; Rm is independently at each instance H or R Rn is independently at each instance Cl 8alkyl, phenyl or benzyl ; RI is independently in each instance H, C14alkyl, C14haloalkyl, halo, cyano, ni tro,C (=O) Rn,C (=O) ORn,C (=O) NRmRm,C (=NRm) NRmRm,ORm OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=O) 2Rn,OC2 6alkylNRmRm, 6alkylORm,SRm,S (=O) Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O) 2N (Rm) C (=O) R",S (=0) 2N (Rm) C (=O) OR",S (=O) 2N (Rm) C (=O) NRmRm, NRmRm, N(Rm) C (=O) R",N (R"') C (=O) ORn,N (Rm) C (=O) NR"'R"', N (R"') C (=NRm) NRmRm, N (Rm) S (=0) 2Rn, N (Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; Rs is Rn substitued by 0,1, 2 or 3 substituents independently selected from Rq ; R3 is H or C14alkyl; R5 is H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, <BR> <BR> <BR> NRmC14haloalkyl, NRmC16alkylNRmRm, NRmC16alkylORm, or (CH2)nR@ R6 is, independently at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, or NRmC16alkylORm ; R8 is H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; and (A) R'is R@ is H, ORm, halo, C13haloalkyl or C16alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) Rn,C (=O) OR",C (=O) NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC (=0) N (Rm) S 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S 2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm) C (=O) OR", S(=O)2N(Rm) C (=O) NR'R',NR'R',N (Rm) C (=O) Rn, N (Rm) C (=O) OR", N (R"') C (=O) NRmRm, N (Rm) C (=NRm) NRmRm,N (Rm) S (=0) 2R, N (R"') S (=0) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2RS,OC26alkylNRmR',OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R', N (Rm) C (=O) OR',N (Rm) C (=O) NRmR',N (Rm) C (=NRm) NRmRs, N (Rm) S (=0) 2R',N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C (=O) Rn, C(=O)ORs, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R°,OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm) C(=O)NRmRm, NRmRm,N (Rm) C (=O) Rn,N (Rm) C (=O) ORn, N (Rm) C (=O) NRmRm, N(Rm) C (=NR"') NRmRm, N(Rm) S (=O) 2Rn, N(Rm) S (=O) 2NR"'R"', <BR> <BR> <BR> <BR> NR"'C2_6alkylNR"'Rm,C (=O) R',C (=O) OR',C (=O) NRmRs,C (=NR"') NR"'R', ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, 6alkylORs,SRs,S (=O) R',S (=0) 2R',S (=0) 2NRmRs, S(=O)2N(Rm) C (=O) R',S (=O) 2N (Rm) C (=O) OR',S (=O) 2N (Rm) C (=O) NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =0 groups; R7 is C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic or 7, 8, 9, 10or 11membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance C18alkyl, C14haloalkyl, halo, cyano, nitro, C (=O) Rn,C (=O) OR",C (=O) NRmRm,C (=NR"') NRmR"',OR"', OC(=O)Rn, CO(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R",OC26alkylNR"'Rm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, <BR> <BR> <BR> S(=O)2N(Rm)C(=O)R@, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) R",N (R"') C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; and YisOorNH ; or (B) R'is R2 is H, ORm, halo, Cl 3haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C18alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) R°,C (=O) OR°,C (=O) NR"'Rm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) Rn, N (Rm) C (=O) OR", N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N (R"') S (=O) 2NR"'Rm,NR"'C26alkylNRmR"',NRmC26alkylORm,C (=O) R', C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC OC NRmRs, OC(=O)N(Rm)S(=O)2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, (Rm) C (=O) OR',N (Rm) C (=O) NRmRs,N (Rm) C (=NR"') NRmRs, N(Rm) S (=0) 2Rs, N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Chalky ! substituted by 1 or 2 groups selected from C12haloalkyl, halo, cyano, nitro, C (=O) Rn,C (=O) ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC (=O) Rn,OC (=O) NRmRm,OC (=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC2 6alkylORm,SRm,S (=O) Rn,S (=0) 2Rn,S (=0) 2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) Rn,N (Rm) C (=O) OR",N (Rm) C (=O) NRmRm N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)R5, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs,OC (=O) Rs,OC (=O) NRmR',OC (=O) N (Rm) S (=0) 2Rs,OC26alkylNRmRs, OC2 6alkylORs,SRs,S (=O) Rs,S (=0) 2Rs,S (=O) 2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm) C (=NRm) NRmRs, N (Rm) S (=0) 2R',N (Rm) S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =0 groups; R7 is Cl 9alkyl, Cl 4haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; R° is a saturated, partiallysaturated or unsaturated 5, 6or 7membered monocyclic or 7, 8, 9, 10or 11membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) OR°,C (=O) NRmRm,C (=NRm) NRmRm,OR"', OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R",OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NR'"R"',N (R"') C (=O) Rn,N (Rm) C (=O) ORn, N(Rm) C (=O) NRmRm N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm ; and Y is 0 or NH; or (C) R'is R2 is H,OR"', halo, CI3haloalkyl or Cl 6alkyl ; R4 is a saturated, partiallysaturated or unsaturated 8, 9, 10 or 11membered bicyclic heterocycle containing 1,2, 3,4 or 5 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin6yl, 4,5, 6,7tetrahydrobenzo [b] thiophen2yl, benzothiazol 2yl, 2,3dihydrobenzo [1, 4] dioxin6yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C19alkyl, oxo, C14haloalkyl, halo, nitro, cyano,ORm,S (=O) nec, 6alkyl, OC1 NRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm, NRmC16alkylORm,C(=O)C16alkyl, OC(=O)C16alkyl, C(=O)NRmC16alkyl, NRmC(=O)C16alkyl C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs,OC (=O) Rs,OC (=O) NRmRs,OC (=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, (=0) 2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs,N (Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm) C (=NRm) NRmR',N (Rm) S (=0) 2Rs,N (Rm) S (=0) 2NRmRs NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cs 2haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) NRmRm, C (=NRm) NRmRm,ORm,OC (=O) Rn,OC (=O) NRmRm, OC(=O) N (Rm) S (=0) 2R",OC26alkylNR"'R"',OC26alkylOR"',SRm,S (=O) R°, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S (=0) 2N (R"') C (=O) NRmRm, N (R') C (=O) R",N (R"') C (=O) OR", N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm@ N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (R') C(=O)NRmRs, NRmRs, N(Rm) C (=O) Rs,N (Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N(Rm) C (=NRm) NR"'R',N (Rm) S (=0) 2R',N (Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm; wherein R4 is not 2aminocarbonylmethyl2,3dihydrobenzo@1, 4] dioxin8yl, 2cyanomethyl 2, 3dihydrobenzo [1, 4] dioxin8yl, quinolin3yl, 3Hquinazolin4on3yl, benzo [1, 3] dioxol5yl, 3, 3dimethyl1, 3dihydroindol2on6yl or 4,4dimethyl 3, 4dihydrolHquinolin2on7yl ; R7 is C18alkyl, C15haloalkyl, I or Br R9 is H, Cl _9alkyl, C, 4haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRm C16alkylNRmRm, NRmC16alkylORm, or (CH2)nR@ ; R9 is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmCI6alkylOR' ; Y is NH ; and Z is CR@ or N; or (D) R'is R2 is C, 6alkyl substituted by 1,2 or 3 substituents selected from Cl 4haloalkyl, halo, cyano, nitro, C (=O) R",C (=O) OR@, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC (=0) N (Rm)S(=O)2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm,NR'Rm,N (Rm) C (=O) Rn, N (Rm) C (=O) OR", N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N (Rm) S (=O) 2NRmRm, NRmC26alkylNRmRm or NRmC26alkylORm; or R2 is (C(Rq) 2) 0phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from C18alkyl, C14haloalkyl, halo, cyano, nitro, C (=O) Rn,C (=O) ORn,C (=O) NRmRm,C (=NRm) NRmRm,ORm OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R",OC26alkylNRmR"', 6alkylOR,SRm,S (=O) Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm)C(=O)ORn, N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C (=O) NRmR',C (=NRm) NR'R',OR',OC (=O) R",OC (=O) NRmR, OC(=O) N (Rm) S (=0) 2Rs,OC26alkylNR"'R',OC26alkylORs,SR',S (=O) RS, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm) C (=O) NRmRs, NRmRs, N (Rm) C (=O) R',N (Rm) C (=O) OR', N(Rm) C (=O) NRmRs, N(Rm) C (=NRm) NRmRs, N(Rm) S (=0) 2Rs, N(Rm) S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from C12haloalkyl, halo, cyano, nitro, C(=O)Rn, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC OC(=O)NRmRm, OC(=O)N(Rm)S(=O)2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm)C(=O)Rn, N(Rm) C (=O) ORn, N(Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, OR',OC (=O) Rs,OC (=O) NR"'RS,OC (=O) N (Rm) S (=0) 2R',OC26alkylNRmRS, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O) 2N (Rm) C (=O) Rs, S(=O) 2N (Rm) C (=O) OR',S (=0) 2N (Rm) C (=O) NRmRs, SNRmRs, N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm ; or R2 is (C(R@)2)oRr, wherein Rr is a saturated or unsaturated 5or 6membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from C, 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) Rn, C (=O) OR", C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC (=O) N (Rm) S (=O) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O) 2N (Rm) C (=O) NRmRm, NRmRm, N (Rm) C (=O) Rn, N (Rm) C (=O) OR N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N (Rm) S (=O) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm) C (=O) OR',N (Rm) C (=O) NRmRs,N (R') C (=NRm) NrmRs, N(Rm) S (=0) 2R',N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and C14alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, C(=O)R@, C(=O)ORn, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, <BR> <BR> <BR> S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)OR@, S(=O)2N(Rm)C(=O)NRmRm, NRmRmN (Rm) C (=O) Rn,N (Rm) C (=O) ORn,N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, kylNRmR',C (=O) Rs,C (=O) OR',C (=O) NRmRs, C (=NRm) NRmRs. ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, 6alkylORs,SRs,S (=O) Rs,S (=0) 2Rs,S (=0) 2NRmRs, S 2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, N(Rm)C(=O)NRmRs, N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and NRmC26alkylORm; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3or 4atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,C (=O) Rn,C (=O) ORn,C (=O) NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm) C (=O) NRmRm, NRmRm, N (Rm) C (=O) Rn, N (Rm) C (=O) OR", N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm) S (=O) 2Rn, N(Rm) S (=0) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C (=O) ORs,C (=O) NRmRs,C (=NRm) NRmRs,ORs,OC (=O) Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, (=0) 2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R', N (R°') C (=O) OR',N (Rm) C (=O) NRmRs,N (R"') C (=NRm) NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs, NRmC26alkylOR5 and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) Rn,C (=O) OR",C (=O) NRmRm, C (=NRm) NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2Rn, OC26alkylNRmRm, OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm)C(=O)Rn, S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N(Rm) C (=O) Rn, N(Rm) C (=O) ORn,N (Rm) C (=O) NR"'R"', N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O) 2N (R') C(=O)NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmR', N(Rm)C(=NRm)NRmRs, N(Rm)S(=O)2Rs, N(Rm)S(=O)2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs andNRmC26alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C28alkyl, C15haloalkyl, I, Br; R9 is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm ; Y is NH; and Z is CR8 or N; or (E) R'is R2 is H, ORm, C@, C13haloalkyl or C16alkyl ; R4 is a saturated or unsaturated 5or 6membered ring containing 0,1, 2 or 3 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, OC N (Rm) S (=0) 2R,OC26alkylORm,SRm,S (=O) R,S (=0) 2R S (=0) 2NRmRm,S (=0) 2N (R') C (=O) Rn, S(=O)2N(Rm) C (=O) OR, S(=O)2N(Rm) C (=O) NRmRm,NRmRm,N (Rm) C (=O) Rn, N (Rm) C (=O) OR N(Rm)C(=O)NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm) S (=O) 2R, N (R"') S (=0) 2NRmRm, NRmC26alkylNRmRm, NRmC26alkylORm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O)N(Rm)S(=O)2Rs, OC26alkylNRmRs, OC26alkylORs, SRs, S(=O)Rs, S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm)C(=O)Rs, N(Rm) C (=O) ORs,N (Rm) C (=O) NRmRs, N (Rm) C (=NRm) NRmRs, N (Rm) S (=0) 2Rs, N (Rm) S (=O) 2NRmRs, NRmC26alkylNRmRs, NRmC26alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,C (=O) R",C (=O) NRmRm, C (=NRm) NRmRm, ORm, OC (=O) Rs, OC(=O)NRmRm, OC(=O) N (Rm) S (=0) 2R°,OC26alkylNRmRm,OC26alkylORm, SRm, S(=O)Rn, S(=O)2Rn, S(=O)2NRmRm, S(=O)2N(Rm) C (=O) R S(=O)2N(Rm)C(=O)ORn, S(=O)2N(Rm)C(=O)NRmRm, NRmRm, N (Rm) C (=O) R",N (Rm) C (=O) OR",N (Rm) C (=O) NRmRm, N(Rm)C(=NRm)NRmRm, N(Rm)S(=O)2Rn, N(Rm)S(=O)2NRmRm, NRmC26alkylNRmRm, C(=O)Rs, C(=O)ORs, C(=O)NRmRs, C(=NRm)NRmRs, ORs, OC(=O)Rs, OC(=O)NRmRs, OC(=O) N (Rm) S (=0) 2R',OC26alkylNRmR', kylORs,SR',S (=O) R',S (=0) 2R',S (=0) 2NRmRs, (=0) 2N(Rm)C(=O)Rs, S(=O)2N(Rm)C(=O)ORs, S(=O)2N(Rm)C(=O)NRmRs, NRmRs, N(Rm) C (=O) R',N (Rm) C (=O) OR',N (Rm) C (=O) NRmRs, N(Rm) C (=NRm) NRmRs,N (Rm) S (=0) 2Rs,N (Rm) S (=0) 2NRmRs, NRmC26alkylNRmRs,NRmC26alkylORs andNRmC26alkylORm ; wherein R4 is not unsubstituted phenyl; R7 is C26alkyl, C15haloalkyl, I or Br; R9 is independently, at each instance, H, C19alkyl, C14haloalkyl, halo, nitro, cyano, OC16alkyl, OC14haloalkyl, OC16alkylNRmRm, OC16alkylORm, NRmRm, NRmC14haloalkyl, NRmC16alkylNRmRm or NRmC16alkylORm; Y is NH ; and Z is CR8 or N. |
| 174. | A pharmaceutical composition comprising a compound according to any one of Claims 1168 and a pharmaceuticallyacceptable diluent or carrier. |
60/339,161 filed December 10,2001, 60/344,737, filed December 21,2001, 60/383,331, filed May 22,2002 and 60/402,422, filed August 8,2002, which are hereby incorporated by reference.
Background The vanilloid receptor 1 (VR1) is the molecular target of capsaicin, the active ingredient in hot peppers. Julius et al. reported the molecular cloning of VR1 (Caterina et al. , 1997). VR1 is a non-selective cation channel which is activated or sensitized by a series of different stimuli including capsaicin and resiniferatoxin (exogenous activators), heat & acid stimulation and products of lipid bilayer metabolism, anandamide (Premkumar et al., 2000, Szabo et al. , 2000, Gauldie et al. , 2001, Olah et al. , 2001) and lipoxygenase metabolites (Hwang et al. , 2000). VR1 is highly expressed in primary sensory neurons (Caterina et al., 1997) in rats, mice and humans (Onozawa et al. , 2000, Mezey et al. , 2000, Helliwell et al. , 1998, Cortright et al. , 2001). These sensory neurons innervate many visceral organs including the dermis, bones, bladder, gastrointestinal tract and lungs; VR1 is also expressed in other neuronal and non-neuronal tissues including but not limited to, CNS nuclei, kidney, stomach and T-cells (Nozawa et al. , 2001, Yiangou et al. , 2001, Birder et al., 2001). Presumably expression in these various cells and organs may contribute to their basic properties such as cellular signaling and cell division.
Prior to the molecular cloning of VR1, experimentation with capsaicin indicated the presence of a capsaicin sensitive receptor, which could increase the activity of sensory neurons in humans, rats and mice (Holzer, 1991; Dray, 1992, Szallasi and Blumberg 1996,1999). The results of acute activation by capsaicin in humans was pain at injection site and in other species increased behavioral sensitivity to sensory stimuli (Szallasi and Blumberg, 1999). Capsaicin application to the skin in humans causes a painful reaction characterized not only by the perception of heat and pain at the site of administration but also by a wider area of hyperalgesia and allodynia, two characteristic symptoms of the human
condition of neuropathic pain (Holzer, 1991). Taken together, it seems likely that increased activity of VR1 plays a significant role in the establishment and maintenance of pain conditions. Topical or intradermal injection of capsaicin has also been shown to produce localized vasodilation and edema production (Szallasi and Blumberg 1999, Singh et al., 2001). This evidence indicates that capsaicin through it's activation of VR1 can regulate afferent and efferent function of sensory nerves. Sensory nerve involvement in diseases could therefore be modified by molecules which effect the function of the vanilloid receptor to increase or decrease the activity of sensory nerves.
VR1 gene knockout mice have been shown to have reduced sensory sensitivity to thermal and acid stimuli (Caterina et al., 2000) ). This supports the concept that VR1 contributes not only to generation of pain responses (i. e. via thermal, acid or capsaicin stimuli) but also to the maintenance of basal activity of sensory nerves. This evidence agrees with studies demonstrating capsaicin sensitive nerve involvement in disease. Primary sensory nerves in humans and other species can be made inactive by continued capsaicin stimulation. This paradigm causes receptor activation induced desensitization of the primary sensory nerve-such reduction in sensory nerve activity in vivo makes subjects less sensitive to subsequent painful stimuli. In this regard both capsaicin and resinferatoxin (exogenous activators of VR1), produce desensitization and they have been used for many proof of concept studies in in vivo models of disease (Holzer, 1991, Dray 1992, Szallasi and Blumberg 1999).
VR1 agonists or antagonists have use as analgesics for the treatment of pain of various genesis or aetiology, for example acute, inflammatory and neuropathic pain, dental pain and headache, particularly vascular headache such as migraine, cluster headache and mixed vascular syndromes as well as non- vascular, tension headache. They are also useful as anti-inflammatory agents for the treatment of inflammatory diseases or conditions, for example the treatment of arthritis and rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders (e. g. uvetis), inflammatory or unstable bladder disorders (e. g. cystitis and urinary incontinence), psoriasis and skin complaints with inflammatory components, as well as other chronic inflammatory conditions.
They are, in particular, useful in the treatment of inflammatory pain and associated hyperalgesia and allodynia. They are also useful in the treatment of neuropathic pain and associated hyperalgesia and allodynia, e. g. trigeminal or herpetic neuralgia, diabetic neuropathy pain, causalgia, sympathetically maintained pain and deafferentation syndromes such as brachial plexus avulsion.
They are also indicated for the use in the prophylactic or curative treatment of asthma, of epithelial tissue damage or dysfunction, e. g. spontaneous lesions, of herpes simplex, and in the control of disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular e. g. for treating wounds, burns, allergic skin reactions, pruritis and vitiligo, for the prophylactic or curative treatment of gastrointestinal disorders such as gastric ulceration, duodenal ulcers, inflammatory bowel disease and diarrhea, gastric lesions induced by necrotising agents, for example ethanol or chemotherapeutic agents, hair growth, for the treatment of vasomotor or allergic rhinitis and for the treatment of bronchial disorders or bladder disorders, such as bladder hyper-reflexia.
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Summary The present invention comprises a new class of compounds useful in the treatment of diseases, such as vanilloid-receptor-mediated diseases and other maladies, such as inflammatory or neuropathic pain and diseases involving sensory nerve function such as asthma, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, urinary incontinence, migraine and psoriasis. In particular, the compounds of the invention are useful for the treatment of acute,
inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders. Analogously, the invention also comprises pharmaceutical compositions comprising the compounds, methods for the treatment of vanilloid-receptor-mediated diseases, such as inflammatory or neuropathic pain, asthma, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, urinary incontinence, migraine and psoriasis diseases, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
The compounds of the invention are represented by the following general structure or a pharmaceutically acceptable salt thereof, wherein A, Ri, R2, R3, R4, X and Y are defined below.
The foregoing merely summarizes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way. All patents, patent applications and other publications recited herein are hereby incorporated by reference in their entirety.
Detailed Description One aspect of the current invention relates to compounds having the general structure: wherein: RI is or a naphthyl or saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7 ; R2 is H, hydroxy, halo, C, 6alkyl substituted by 0,1 or 2 substituents selected from R'°, or a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7 ; or Rl and R2 together are
R3 is H or C, 4alkyl ; or R'and R3 together are
R4 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0,1, 2 or 3 substituents independently selected from Cl 9alkyl, C, 4haloalkyl, halo, nitro, cyano, -ORa, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa,
-NRa-C, 6alkylORa,-C (=O) C, 6alkyl,-C (=O) OCI 6alkyl,-OC (=O) C1 6alkyl, -C (=O) NRaCl 6alkyl and-NRaC (=O) Cl 6alkyl ; or R4 is 10-membered bicyclic ring comprising fused 6-membered rings, containing 0,1, 2,3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, OR', NRaRa, C1-6alkyl and Cl 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =O ; except that when R1 is 4-chlorophenyl, 3-bromophenyl, 3-nitrophenyl, 2-nitro-3-chlorophenyl, 3,4-methylenedioxyphenyl, 3-methylthiophenyl or 2,3, 4-methoxyphenyl, then R4 is not phenyl substituted by 1 or 2 substituents selected from halo and CI-4alkyl ; and R'and R4 are not both 3, 4-methylenedioxyphenyl ; and when R'is 4-trifluoromethylphenyl, then R4 is not pyridinyl, 2-methyl-4-aminoquinolinyl or 3, 3-dimethyl-1, 3-dihydro-indol-2- on-6-yl ; R5 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OC, -6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, - NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa or -NRa-C1-6alkylORa ; or R5 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S; R6 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, - NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa or -NRa-C1-6alkylORa ; or R5 and R6 together are a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0, 1, 2 or 3 substituents selected from halo, C1-6alkyl, (=O), -OC1-6akyl, -NRaC1-6alkyl, -C1-6alkylORa and CI 6alkylNRaRa, and the available N atoms of the bridge are substituted by Ra, -C1-6alkylORa or C1-6alkylNRaRa ; R7 is independently, at each instance, H, Cl 9alkyl, Cl 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, - 4haloalkyl,-NRa-C, 6alkylNRaRa or-NRa-Cl 6alkylORa ;
R8 is independently, at each instance, H, C, _alkyl, C, 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, - NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa- or -NRa-C1-6alkylORa ; or R7 and R8 together are a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0,1, 2 or 3 substituents selected from halo, C1-6alkyl, (=O), -O-C1-6alkyl, -NRaC1-6alkyl, -C1-6alkylORa and Ci-6a) kylNR''R", and the available N atoms of the bridge are substituted by Ra, - 6alkylORa or Cl 6alkylNRaRa ; R9 i independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, - NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRA or -NRa-C1-6alkylORa ; Rl° is independently, at each instance, H, C1-9alkyl, -C1-3alkylORa, C, 4haloalkyl, halo, nitro, cyano,-ORa,-S (=O) nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, - NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa -C(=O)C1-6alkyl, -C (=O) OC, 6alkyl,-OC (=O) C, 6alkyl,-C (=O) NRaCl 6alkyl or -NRaC(=O)C1-6alkyl ; R"is independently, at each instance, H, C1-9alkyl, -C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano,-ORa,-S (=O) nC, 6alkyl,-O-C_4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylRc, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl or -NRaC (=O) Cl 6alkyl ; or R10 and R11 together are a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, -ORa, -C1 6a -6alkyl, -NRaRa, -C1-6alkylNRaRa, -C(=O)ORa, -C(=O)NRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -OC(=O)C1-6alkyl, -NRaC(=O)C1-6alkyl, -C1-3alkylOC(=O)C1-6alkyl or -C1-3alkylNRa(=O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, -C1-6alkylORa,
-C1-6alkyl, -C1-6alkylNRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRaC(=O)C1-6alkyl, -C(=O)Rc or -C1-3alkylRc ; wherein if R10, R12, R13 and Rl4 are all H, then Rl 1 is not -O-C1-6alkylNRaRa or -O-OC1-6alkylORa ; R is independently, at each instance, H, C1-9alkyl, -C1-3alkylORa, C, 4haloalkyl, halo, nitro, cyano, -ORa, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, - NRa -C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl or -NRaC (=O) Cl 6alkyl ; or R 11 and R12 together are a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, -ORa, -C1-6alkylORa, -C1-6alkyl, -NRaRa, -C1-6alkylNRaRa, -C(=O)ORa, -C(=O)NRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -OC(=O)C1-6alkyl, -NRaC(O)C1-6alkyl, -C1-3alkylOC(=O)C1-6alkyl or -C1-3alkylNRaC(=O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H,-Cl 6alkylORa, -C1-6alkyl, -C1-6alkylNRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRaC(=O)C1-6alkyl, -C(=O)Rc or -C1-3alkylRc, when R'is 4-C, _6alkylphenyl or 2, 4-dimethylphenyl, then R11 is C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -ORa, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl, - O-C1-6alkylNRaRa, -O-C1-6alkylRc, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl or -NRaC (=O) Cl 6alkyl ; or Rl° and Rl l together are-L3-NRa-, respectively, or -L4-o-, respectively; or R11 and R12 are -NRa-L3-, -L3NRa-, -L3-NRa-, O-L4- or -L4-O-; or R12 is-NRaRb ; or R4 is 10-membered bicyclic ring comprising fused 6-membered rings, containing 0,1, 2,3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORa, NRaRa, C, 6alkyl and C, 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =O ; or R4 is a saturated
or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 1,2 or 3 substituents independently selected from C2-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-ORa,-S (=O) nCI 6alkyl, <BR> <BR> <BR> -O-CI 4haloalkyl,-O-CI 6alkylNRaRa,-O-CI 6alkylORa,-O-Cz 6alkylC (=O) ORa, -NRaRa, -NRa-C1-4-haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl and -NRaC (=O) C, 6alkyl ; Rl3 is independently, at each instance, H, C1-9alkyl, -C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano,-ORa,-S (=O) C, _6alkyl,-O-C, 4haloalkyl, - O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl or - NRaC (=O) C, 6alkyl ; R'4 is independently, at each instance, H, Chalky -9alkyl, -C1-3alkylORa, C, 4haloalkyl, halo, nitro, cyano,-ORa,-S (=O) nCl-6alkyl,-O-C, 4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C (=O) OC 6alkyl,-OC (=O) Cl 6alkyl,-C (=O) NRaC 6alkyl or -NRaC (=O) CI 6alkyl ; Ra is independently, at each instance, H, phenyl, benzyl or C1-6alkyl; Rb is H, C1-6alkyl, -C(=O)C1-6alkyl, C1-6alkyl-O-Ra ; Rc is phenyl substituted by 0,1 or 2 groups selected from halo, C1-3haloalkyl, -ORa and -NRaRa; or Rc is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0,1 or 2 oxo groups, wherein the
heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents selected from halo, C, 3haloalkyl,-ORa and-NRaRa ; Ll is a bond,-CH2CH2-or-CH=CH- ; L2 is NRa, O, S (=O)",-N=CH-,-CH2NRa-,-CH=N-or-NRaCH2- ; L3 is a 2-or 3-atom, saturated or unsaturated, bridge containing 1,2 or 3 carbon atoms and 0,1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, =0,-OR, -C1-6alkylORa, -C1-6alkyl, -NRaRa, -C1-6alkylNRaRa, -C(=O)ORa, -C(=O)NRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -OC(=O)C1-6alkyl, -NRaC(=O)C1-6alkyl, -C1-3alkylOC(=O)C1-6alkyl or -C1-3alkylNRaC(=O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H,-Cl 6alkylORa, -C1-6alkyl, -C1-6alkylNRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRaC(=O)C1-6alkyl, -C(=O)Rc or -C1-3alkylRc ; L4 is a 2-or 3-atom, saturated or unsaturated, bridge containing 1,2 or 3 carbon atoms and 0 or 1 atoms independently selected from O, N and S, wherein at least one of the carbon atoms in the bridge is substituted by =0,-OR, - 6alkylORa,-C, 6alkyl,-NRaRa,-C, 6alkylNRaRa,-C (=O) OCl 6alkyl, -C(=O)NRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaC1-6alkyl, -OC (=O) C, 6alkyl,-NRaC (=O) C 6alkyl,-C, 3alkylOC (=O) C, 6alkyl or -C1-3alkylNRaC(=O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, -C1-6alkylORa, -C1-6alkyl, -C1-6alkylNRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRaC(=O)C1-6alkyl, -C(=O)Rc or -C1-3alkylRc ; X is O, S or NRa ; or X and R2 together are =N-CH=CH-, =C-O-, =C-S-, or =C Y is NH or O ; and n is independently, at each instance, 0,1 or 2; with the proviso that when R'is 4-chlorophenyl, then R4 is not 3-methoxyphenyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is
or a naphthyl or saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R5, R6 and R7 ; R2 is H, hydroxy, halo, C1-6alkyl substituted by 0,1 or 2 substituents selected from Rl°, or a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R ; and R3 is H or Cl 4alkyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is independently, at each instance, C29alkyl or C1-4haloalkyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7.
In another embodiment, in conjunction with the novel compound embodiments above and below, R2 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7.
In another embodiment, in conjunction with the novel compound embodiments above and below, R2 is or a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7.
In another embodiment, in conjunction with the novel compound embodiments above and below, R2 is
In another embodiment, in conjunction with the novel compound embodiments above and below, R is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7.
In another embodiment, in conjunction with the novel compound embodiments above and below, R1 and R2 together are In another embodiment, in conjunction with the novel compound embodiments above and below, R'and R3 together are
In another embodiment, in conjunction with the novel compound embodiments above and below, X and R2 together are =N-CH=CH-, =C-O-, =C-S-, or =C-NRa-.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is
Rb is H, C1-6alkyl, -C(=O)C1-6alkyl, C1-6alkyl-O-Ra ; and y2 is-NRa-or-O-.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is
L3 iS a 2-or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0 or 1 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, =0,-OR, -C1-6alkylORa, -C1-6alkyl, -NRaRa, -C1-6alkylNRaRa, -C(=O)ORa, -C(=O)NRaRa, -Cl 3alkylC (=O) ORa,-C, 3alkylC (=O) NRaRa,-OC (=O) C, 6alkyl, -NRaC(=O)C1-6alkyl, -C1-3alkylOC(=O)C1-6alkyl or -C1-3alkylNRaC(=O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H,-Cl 6alkylORa, -C1-6alkyl, -C1-6alkylNRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRaC(=O)C1-6alkyl, -C(=O)Rc or -C1-3alkylRc; Rb is H, C1-6alkyl, -C(=O)C1-6alkyl, C1-6alkyl-O-Ra ; and y2 is-NRb-or-O-.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is L3 is a 2-or 3-atom, saturated or unsaturated, bridge containing 1,2 or 3 carbon atoms and 0,1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, =0,-OR, -C1-6alkylORa, -C1-6alkyl, -NRaRa, C1-6alkylNRaRa, -C(=O)ORa, -C(=O)NRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -OC(=O)C1-6alkyl, -NRaC(=O)C1-6alkyl, -C1-3alkylOC(=O)C1-6alkyl or -C1-3alkylNRaC(=O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H,-CI-6alkylOR, -C1-6alkyl, -C1-6alkylNRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRaRaC(=O)C1-6alkyl, -C(=O)Rc or -C1-3alkylRc ; Rb is H, C, 6alkyl,-C (=O) C, 6alkyl, Cl 6alkyl-O-Ra ; and y2 is-NRb-or-O-.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is L3 iS a 2-or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, =O,-ORa, - C1-6alkylORa, -C1-6alkyl, -NRaRa, -C1-6alkylNRaRa, -C(=O)ORa, -C(=O)NRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -OC(=O)C1-6alkyl, -NRaC(=O)C1-6alkyl, -C1-3alkylOC(=O)C1-6alkyl or -C1-3alkylNRaC(=O)C1-6alkyl,
and any nitrogen atoms in the bridge are substituted by H,-Cl 6alkylORa, <BR> <BR> <BR> -Cl 6alkyl,-C, 6alkylNRaRa,-C, 3alkylC (=O) ORa,-C, 3alkylC (=O) NRaRa, -C1-3alkylOC(=O)C1-alkyl, -C1-3alkylNRaC(=O)C1-6alkyl, -C(=O)Rc or -C1-3alkylRc; Rb is H, C1-6alkyl, -C(=O)C1-6alkyl, C1-6alkyl-O-Ra ; and y2 is-NRb-or-O-.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is
Rb is H, C1-6alkyl, -C(=O)C1-6alkyl, C1-6alkyl-O-Ra ; and dz is - NRa- or -O-.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is 10-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2,3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORa, NRaRa, Cl 6alkyl and Cl 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =O.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is R'° is independently, at each instance, H, Cl -9alkyl, -C1-3alkylORa, C1-7haloalkyl, halo, nitro, cyano,-ORa,-S (=O) nC1-6alkyl, -O-C1-4haloalkyl, - O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa -C1-6alkylNRaRa, -NRa -C1-6alkylORa, -C(=O)C1-6alkyl,
-C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl or -NRaC(=O)C1-6alkyl ; Rll is independently, at each instance, H, C1-9alkyl, -C1-3alkylORa, Cl 4haloalkyl, halo, nitro, cyano,-ORa,-S (=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylRc, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC-16alkyl or -NRaC(=O)C1-6alkyl ; C1-6alkylNRaRa ; R is independently, at each instance, H, C, OR C 4haloalkyl, halo, nitro, cyano,-ORa,-S (=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -Na-C1-6alkylORa, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl or -NRaC (=O) Cl 6alkyl ; is independently, at each instance, H, C1-9alkyl, -C1-3alkylORa, Cl 4haloalkyl, halo, nitro, cyano, -ORa, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl, - O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkyl(=O)ORa, -NRaRa, <BR> <BR> <BR> - 4haloalkyl,-NRa-C, 6alkylNRaRa,-NRa-C, 6alkylORa,-C (=O) C, 6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl or -NRaC (=O) Cl 6alkyl ; and R14 is independently, at each instance, H, C1-6alkyl, -C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, -ORa, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl, - O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C (=O) OCs 6alkyl,-OC (=O) C 6alkyl,-C (=O) NRaC, 6alkyl or -NRaC (=O) Cl 6alkyl ; wherein one of R10 and Rl2 is not H.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents selected from halo, C » haloalkyl,-OR'and-NRaRa.
Another aspect of the invention relates to a compound having the structure: or any pharmaceutically-acceptable salt thereof, wherein: n is independently, at each instance, 0, 1 or 2.
R'is or R'is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R ; or Rl is Re substituted by 1,2 or 3 substituents independently selected from R R15 is, independently, in each instance, Rl°, C1-8alkyl substituted by 0,1 or 2 substituents selected from R10,- phenyl substituted by 0,1, 2 or 3 substituents independently selected from R10, or a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R'° ; Rl6 is, independently, in each instance, H, halo,-NH2,-NHC, 3alkyl, -N(C1-3alkyl)C1-3alkyl or C1-3alkyl ;
R4 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C, 9alkyl, C, 4haloalkyl, halo, nitro, cyano, oxo, -ORd, -S(=O)nC1-6alkyl, -OC1-4haloalkyl, -OC2-6alkylNRdRd, -OC2-6alkylORd, -OC, 6alkylC (=O) ORd,-NRdRd,-NRdCz 4haloalkyl,-NRdC2 6alkylNRdRd, - NRdC2-6alkylORd, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, OC(=O)C1-6aalkyl -C(=O)NRdC1-6alkyl and -NRdC(=O)C1-6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any nitrogen atoms in the bridge are substituted by H, -C1-6alkylORd, -C1-6alkyl, -C1-6alkylNRdRd, -C1-3alkylC(=O)ORd, -C1-3alkylC(=O)NRdRd, -C1-3alkylC(=O)C1-6alkyl, - C1-3alkylNRdC(=O)C1-6alkyl, -C(=O)Rf or -C1-3alkylRf ; or R4 is 10-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2,3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORd, NRdRd, Cl 6alkyl and Cl 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =O ; but in no instance is R43, 5- ditrifluoromethylphenyl or 3-trifluoromethyl-4-fluorophenyl ; Rs is independently, at each instance, H, C1-5alkyl, C1-4haloalkyl, halo, nitro, cyano,-OCI 6alkyl,-OC, 4haloalkyl,-OC26alkylNRdRd,-OC26alkylORd, - NRdRd, -NRdC1-4haloalkyl, -NRdC2-6alkylNRdRd, -NRdC2-6alkylORd, naphthyl, <BR> <BR> <BR> - C02 (C,_6alkyl),-C (=O) (C,-6alkyl),-C (=O) NRdRd,-NRdC (=O) Rd,<BR> <BR> <BR> <BR> <BR> <BR> -NRdC (=O) NRdRd,-NRdCO2 (C, 6alkyl),-C, 8alkylORd,-C, 6alkylNRdRd,
-S(=O)n(C1-6alkyl), -S(=O)2NRdRd, NRdS(=O)2(C1-6alkyl), -OC(=O)NRdRd, a phenyl ring substituted with 0,1, 2, or 3 substituents independently selected from Rl° ; or R is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S, substituted with 0,1, 2, or 3 substituents independently selected from Rlo ; R6 is independently, at each instance, H, C1-5alkyl, C1-4haloalkyl, halo, -OC1-6alkyl, -OC4-4haloalkyl, -OC2-6alkylNRdRd, -OC2-6alkylORd, -NRdRd, - NRdC1-4haloalkyl, -NRdC2-6alkylNRdRd or -NRdC2-6alkylORd, -C1-8alkylORd, - 6alkylNRdRd,-S (Cl 6alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected from Rl° ; or R6 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from RIO R7 is independently, at each instance, H, C1-8alkyl, C1-4haloalkyl, halo,-OCl 6alkyl,-OC, 4haloalkyl,-OC26alkylNRdRd,-OC26alkylORd, - 4haloalkyl,-NRdC2 6alkylNRdRd,-NRdC2 6alkylORd, -Cl C1-8alkylORd, -C1-6alkylNRdRd or -S(C1-6alkyl) ; or R7 is a saturated or unsaturated 4-or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, Cl 2haloalkyl and Cl 3alkyl ; Rg is independently, at each instance, H, CI-5alkyl, CI-4haloalkyl, halo, -OC1-6alkyl, OC1-4haloalkyl, -OC2-6alkylNRdRd, -OC2-6alkylORd, -NRdRd, -NRdC1-4haloalkyl, -NRdC2-6alkylNRdRd, NRdC2-6alkylORd, -C1-8alkylORd, -C1-6alkylNRdRd, -S(C1-6alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from Rl°, or R8 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R'o ; R9 is independently, at each instance, H, C1-8alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -OC1-4haloalkyl, -OC2-6alkylNRdRd, - OC2-6alkylORd,-NRdRd,-NRdC, 4haloalkyl,-NRdC2-6alkylNRdRd or -NRdC2-6alkylORd, -CO2(C1-6alkyl), -C(=O)(C1-6alkyl), -C(=O)NRdRd, -NRdC (=O) (C, 6alkyl),-NRdC (=O) NRdRd,-NRdCO2 (C, 6alkyl), -C1-8alkylORd, -C1-6alkylNRdRd, -S(=O)n(C1-6alkyl), -S(=O)2NRdRd, -NRdS(=O) 2 (C, 6alkyl),-OC (=O) NRdRd, a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R'° ; or R9 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from Rl° ; or R9 is a saturated or unsaturated 4-or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, Cl 2haloalkyl and Cl 3alkyl ; wherein at least one of R, R, R, R8 and R9 is C1-8alkyl, C1-4haloalkyl, halo, -OC1-4haloalkyl, - OC2-6alkylNRdRd, -OC2-6alkylORd, -NRdC1-4haloalkyl, - NRdC2-6alkylNRdRd, -NRdC2-6alkylORd, -C1-8alkylORd, -C1-6alkylNRdRd or-S (C1-6alkyl) ; R'° is independently, at each instance, selected from H, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OCd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (Cx -8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S (=O) (C, 8alkyl),-S (=0) 2 (C1-8alkyl), -S(=O)3NRdRd, -S (=0) 2N (Rd) C (=O) (C1-8alkyl), -S(=O)2N(Rd) C (=O) O (C1-8alkyl), -S (=O) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1 8alkyl), -N(Rd) C (=O) O (C1-8alkyl), -N(Rd) C (=O) NRdRd,-N (Rd) C (=NRd) NRdRd, -N(Rd) S (=O) 2 (CI 8alkyl),-N (Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC2-6alkylORd ; or R'° is a saturated or unsaturated 5-, 6-or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6-or 7-membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, <BR> <BR> <BR> -C (=O) (Cs 8alkyl),-C (=O) O (Ct 8alkyl),-C (=O) NRdRd,-C (=NRd) NRdRd,-ORd -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (C1-8alkyl), - OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O) 2 (C1-8alkyl), -S (=0) 2NRdRd,-S (=0) 2N (Rd) C (=O) (C, -8alkyl), -S(=O)2N(Rd) C (=O) O (C, -8alkyl),
-S(=O) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C, -8alkyl), -N(Rd) C (=O) O (C1-8alkyl), -N(Rd) C (=O) NR R,-N (R) C (=NRd) NRdRd, -N(Rd) S (=O) 2 (C1-8alkyl), -N(Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC26alkylORd ; or Rl° is Cl 4alkyl substituted by 0,1, 2 or 3 groups selected from C, 4haloalkyl, halo, cyano, nitro,-C (=O) (Cl -8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C18alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (C1-8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O)2(C1-8alkyl), -S(=O)2NRdRd, -S (=0) 2N (Rd) C (=O) (Cl -8alkyl), -S(=O)2N(Rd) C (=O) O (C1-8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd, -NRdRd, -N(Rd)C(=O)(C1-8alkyl), -N(Rd) C (=O) O (C1-8alkyl), -N(Rd)C(=O)NRdRd, -N(Rd) C (=NRd) NRdRd, -N(Rd) S (=O) 2 (C1-8alkyl), -N(Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and - 6alkylORd ; R"is independently, at each instance, selected from H, C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) (C1 8alkyl),-C (=O) O (C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (C, -8alkyl=, -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O) 2 (C, 8alkyl),-S (=0) 2NRdRd, -S(=O) 2N (Rd) C (=O) (C, 8alkyl),-S (=0) 2N (Rd) C (=O) O (C1-8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1-8alkyl), -N(Rd) C (=O) O (C1-8alkyl), -N(Rd) C (=O) NRdRd,-N (Rd) C (=NRd) NRdRd -N(Rd) S (=O) 2 (C1-8alkyl), -N(Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC2-6alkylORd ; or R"is a saturated or unsaturated 5-, 6-or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6-or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, <BR> <BR> <BR> -C (=O) (C, 8alkyl),-C (=O) O (Cl 8alkyl),-C (=O) NRdRd,-C (=NRd) NRdRd,-ORd -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (C1-8alkyl), - OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), S(=O) 2 (C1-8alkyl),
-S(=O)2NRdRd, -S(=O)2N(Rd) C (=O) (C, 8alkyl),-S (=0) 2N (Rd) C (=O) O (CI 8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1-8alkyl), -N(Rd) C (=O) O (C, -8alkyl), -N(Rd) C (=O) NRdRd,-N (Rd) C (=NRd) NRdRd, -N(Rd) S (=O) 2 (C1-8alkyl), -N(Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC2-6alkylORd ; or R11 is C1-4alkyl substituted by 0, 1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) (C, 8alkyl),-C (=O) O (C, _galkyl), -C(=O)NRdRd, -C(=NRd)NRdRD, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NR dRd, -OC(=O) N (Rd)S(=O)2(C1-8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O)2(C1-8alkyl), -S(=O)NRdRd, -S(=O)2N(Rd) C (=O) (C1-8alkyl), -S(=O)2N(Rd)C(=O)O(C1-8alkyl), -S(=O)2N(Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1-8alkyl), -N(Rd) C (=O) O (C1-8alkyl), -N(Rd) C (=O) NR R,-N (R) C (=NRd)NRdRd, -N(Rd) S (=O) 2 (C1-8alkyl), -N(Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC2-6alkylORd ; or R° and R"together are a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) (Cl 8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (Ci-8alkyl),-OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O) 2 (C1 8alkyl),-S (=0) 2NRdRd, -S(=O) 2N (Rd) C (=O) (C1-8alkyl), -S(=O)2N(Rd) C (=O) O (C1-8alkyl), - S (=0) 2N (Rd)C(=O)NRdRd, -NRdRd, -N(Rd)C(=O)(C1-8alkyl), -N(Rd) C (=O) O (C, -8alkyl), -N(Rd) C (=O) NRdRd,-N (Rd) C (=NRd)NRdRd, -N(Rd)S(=O) 2 (Cl 8alkyl),-N (Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC2-6alkylORd, and any nitrogen atoms in the bridge are substituted by H, -C1-6alkylORd, -C1-6alkyl, -C1-6alkylNRdRd,-C1-3alkylC(=O)ORd, -C1-3alkylC(=O)NRdRd, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRdC(=O)C1-6alkyl, -C(=O)Rf or -C1-3alkylRf ; Rl2 is independently, at each instance, selected from H, C1-8alkyl, C, 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd,
-OC(=O) N (Rd) S (=0) 2 (C, -8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O)2(C1-8alkyl), -S(=O)2NRdRd, -S(=O)2N(Rd) C (=O) (C1-8alkyl), -S(=O) 2N (Rd) C (=O) O (C1-8alkyl), -S(=O)2N(Rd) C (=O) NRdRd, -NRdRd, -N(Rd) C (=O) (C1-8alkyl), -N(Rd) C (=O) O (C1-8alkyl), N(Rd) C (=O) NRdRd, -N(Rd) C (=NRd) NRdRd -N (Rd) S (=O) 2 (Cl -8alkyl), -N (Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC2-6alkylORd ; or Rl2 is a saturated or unsaturated 5-, 6-or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6-or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C(=O)(C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, C(=NRd)NRdRd, ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (C, 8alkyl), -OC2 OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O) 2 (C1-8alkyl), -S(=O)2NRdRd, -S(=O)2N(Rd) C (=O) (C1-8alkyl), -S(=O) 2N (Rd) C (=O) O (C1-8alkyl), -S(=O) 2N (Rd) C (=O) NRdRd, -NRdRd, -N(Rd) C (=O) (C1-8alkyl), -N(Rd) C (=O) O (C1-8alkyl), -N(Rd) C (=O) NRdRd, -N(Rd) C (=NRd) NRdRd -N(Rd) S (=O) 2 (C1-8alkyl), -N(Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC26alkylORd ; or R12 is Cl 4alkyl substituted by 0,1, 2 or 3 groups selected from C1-4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (C1 -8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O) 2 (C1-8alkyl), -S(=O)2NRdRd, -S(=O)2N(Rd) C (=O) (C, -8alkyl), -S(=O)2N(Rd) C (=O) O (C, 8alkyl), -S(=O)2N(Rd) C (=O) NRdRd, -NRdRd, -N(Rd) C (=O) (C, 8alkyl), -N(Rd) C (=O) O (C1-8alkyl), -N(Rd) C (=O) NRdRd,-N (Rd) C (=NRd) d) NR d Rd, -N(Rd) S (=O) 2 (C, 8alkyl),-N (Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC26alkylORd ; wherein if R"or R'3 is CF3, then R12 is not F ; or R11 and R12 together are a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long
as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, C1-8alkyl, C1-4haloalkyl, halo cyano, nitro,-C (=O) (C, 8alkyl),-C (=O) O (CI_8alkyl),-C (=O) NRdRd, -C(=NRd)NRdRdn, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd)S(=O) 2 (C, -8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, - S (=O) (C, 8alkyl),-S (=0) 2 (Cl-galkyl),-S (=0) 2NRdRd, -S (=0) 2N (Rd) C (=O) (CI 8alkyl),-S (=0) 2N (Rd) C (=O) O (CI -8alkyl), -S(=O)2N(Rd)C(=O)NRdRd, -NRdRd, -N(Rd)C(=O)(C1-8alkyl), -N(Rd) C (=O) O (C1-8alkyl), -N(Rd) C (=O) NRdRd, -N(Rd)C(=NRd)NRdRd, -N(Rd) S (=O) 2 (C1-8alkyl),-N(Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC2-6alkylORd, and any nitrogen atoms in the bridge are substituted by H, -C1-6alkylORd, -C1-6alkyl, -C1-6alkylNRdRd, -C1-3alkylC(=O)ORd, -C1-3alkylC(=O)NRdRd, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRdC(=O)C1-6alkyl, -C(=O)Rf or -C1-3alkylRf ; Rl3 is independently, at each instance, selected from H, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (C, -8alkyl), -C2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O)2(C1-8alkyl), -S(=O)2NRdRd, -S(=O)2N(Rd) C (=O) (C, 8alkyl),-S (=0) 2N (Rd)C(=O)O(C1-8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1-8alkyl), -N(Rd) C (=O) O (C1-8alkyl), -N(Rd) C (=O) NRdRd,-N (Rd) C (=NRd) NRdRd, -N(Rd)S(=O) 2 (C1-8alkyl), -N(Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC26alkylORd ; or R13 is a saturated or unsaturated 5-, 6-or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6-or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, <BR> <BR> <BR> -C (=O) (Cl 8alkyl),-C (=O) O (C, 8alkyl),-C (=O) NRdRd,-C (=NRd) NRdRd,-ORd - OC (=O) (C, 8alkyl),-OC (=O) NRdRd,-OC (=O) N (Rd) S (=0) 2 (C1-8alkyl),
-OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O)2(C1-8alkyl), -S(=O)2NRdRd, -S(=O) 2N (Rd) C (=O) (C1-8alkyl), -S(=O)2N(Rd) C (=O) O (C1-8alkyl), -S(=O)2N(Rd) C (=O) NRdRd, -NRdRd, -N(Rd)C(=O)(C1-8alkyl), - N (Rd) C (=O) O (C1-8alkyl),-N (Rd) C (=O) NRdRd, -N(Rd)C(=NRd)NRdRd, -N(Rd) S (=O) 2 (C1-8alkyl), -N(Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC2-6alkylORd ; or Rl3 is Cl 4alkyl substituted by 0, 1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (C,_8alkyl),-OC2-6alkylNRdRd,-OC2-6alkylORd,-SRd, -S(=O)(C1-8alkyl), -S(=O)2(C1-8alkyl), -S(=O)2NRdRd, -S(=O)2N(Rd) C (=O) (C, 8alkyl),-S (=0) 2N (Rd) C (=O) O (C, -8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd, -NRdRd, -N(Rd)C(=O)(C1-8alkyl), -N(Rd)C(=O)O(C1-8alkyl), -N(Rd)C(=O)NRdRd, -N(Rd)C(=NRd)NRdRd, -N(Rd) S (=O) 2 (C,-8alkyl),-N (Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and - 6alkylORd ; R'4 is independently, at each instance, selected from H, C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (C, -8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O)2(C1-8alkyl), -S(=O)2NRdRd, -S(=O) 2N (Rd) C (=O) (C, -8alkyl), -S(=O)2N(Rd)C(=O)O(C1-8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1-8alkyl), -N(Rd) C (=O) O (C1-8alkyl), -N(Rd) C (=O) NRdRd,-N (Rd) C (=NRd)NRdRd, -N(Rd) S (=O) 2 (C,-8alkyl),-N (Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC26alkylORd ; or 14 is a saturated or unsaturated 5-, 6-or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6-or 7-membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, -C(=O)(C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd,
-OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=O) 2 (C,_8alkyl), - 6alkylNRdRd,-OC2 6alkylORd,-SRd,-S (=O) (Cl 8alkyl),-S (=0) 2 (C1-8alkyl), -S (=0) 2NRdRd,-S (=0) 2N (Rd) C (=O) (C, -8alkyl), -S(=O) 2N (Rd) C (=O) O (C, -8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1-8alkyl), -N(Rd) C (=O) O (C1-8alkyl), -N(Rd) C (=O) NRdRd, -N(Rd)C(=NRd)NRdRd, -N(Rd) S (=0) 2 (CI 8alkyl),-N (Rd) S (=0) 2NRdRd,-NRdC2 6alkylNRdRd and - 6alkylORd ; or R14 is C1-4alkyl substituted by 0,1, 2 or 3 groups selected from C 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (C1 -8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O)2(C1-8alkyl), -S(=O)2NRdRd, -S (=0) 2N (Rd) C (=O) (C1-8alkyl), -S(=O)2N(Rd) C (=O) O (C, -8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1-8alkyl), -N(Rd) C (=O) O (C1 -8alkyl), -N(Rd) C (=O) NRdRd,-N (Rd) C (=NRd)NRdRd, -N(Rd) S (=0) 2 (C, 8alkyl),-N (Rd) S (=0) 2NRdRd,-NRaC2-6alkylNRdRd and - 6alkyl0Rd ; Rd is independently, at each instance, H, phenyl, benzyl or Chalky ! ; Re is a heterocycle selected from the group of thiophene, pyrrole, 1,3-oxazole, 1, 3-thiazole, 1,3, 4-oxadiazole, 1,3, 4-thiadiazole, 1,2, 3-oxadiazole, 1,2, 3-thiadiazole, 1H-1, 2, 3-triazole, isothiazole, 1,2, 4-oxadiazole, 1,2, 4- thiadiazole, 1,2, 3,4-oxatriazole, 1,2, 3, 4-thiatriazole, 1H-1, 2,3, 4-tetraazole, 1,2, 3, 5-oxatriazole, 1,2, 3,5-thiatriazole, furan, imidazol-1-yl, imidazol-4-yl, 1,2, 4- triazol-4-yl, 1, 2, 4-triazol-5-yl, isoxazol-3-yl, isoxazol-5-yl, pyrazol-3-yl, pyrazol- 5-yl, thiolane, pyrrolidine, tetrahydrofuran, 4,5-dihydrothiophene, 2-pyrroline, 4,5-dihydrofuran, pyridazine, pyrimidine, pyrazine, 1,2, 3-triazine, 1,2, 4-triazine, 1,2, 4-triazine, 1,3, 5-triazine, pyridine, 2H-3,4, 5,6-tetrahydropyran, thiane, 1,2- diazaperhydroine, 1,3-diazaperhydroine, piperazine, 1,3-oxazaperhydroine, morpholine, 1,3-thiazaperhydroine, 1,4-thiazaperhydroine, piperidine, 2H-3,4- dihydropyran, 2,3-dihydro-4H-thiin, 1,4, 5, 6-tetrahydropyridine, 2H-5, 6- dihydropyran, 2,3-dihydro-6H-thiin, 1,2, 5,6-tetrahydropyridine, 3,4, 5,6- tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4-dihydropyridine, 1,4-dithiane, 1,4- dioxane, 1,4-oxathiane, 1, 2-oxazolidine, 1, 2-thiazolidine, pyrazolidine, 1,3-
oxazolidine, 1, 3-thiazolidine, imidazolidine, 1,2, 4-oxadiazolidine, 1,3, 4- oxadiazolidine, 1,2, 4-thiadiazolidine, 1,3, 4-thiadiazolidine, 1, 2, 4-triazolidine, 2- imidazoline, 3-imidazoline, 2-pyrazoline, 4-imidazoline, 2,3-dihydroisothiazole, 4,5-dihydroisoxazole, 4, 5-dihydroisothiazole, 2,5-dihydroisoxazole, 2,5- dihydroisothiazole, 2, 3-dihydroisoxazole, 4, 5-dihydrooxazole, 2,3- dihydrooxazole, 2, 5-dihydrooxazole, 4,5-dihydrothiazole, 2, 3-dihydrothiazole" 2,5-dihydrothiazole, 1,3, 4-oxathiazolidine, 1,4, 2-oxathiazolidine, 2, 3-dihydro-1H- [1,2, 3] triazole, 2, 5-dihydro-1H[1, 2,3] triazole, 4, 5-dihydro-1H-[1, 2,3] triazole, 2, 3-dihydro-lH-[l, 2,4] triazole, 4, 5-dihydro-lH- [1, 2,4] triazole, 2,3-dihydro- [1, 2,4] oxadiazole, 2, 5-dihydro- [1, 2,4] oxadiazole, 4, 5-dihydro-[1, 2,4] thiadiazole, 2, 3-dihydro- [1, 2,4] thidiazole, 2, 5-dihydro- [1, 2,4] thiadiazole, 4,5-dihydro- [1, 2,4] thiadiazole, 2, 5-dihydro[1, 2,4] oxadiazole, 2, 3-dihydro-[1, 2,4] oxadiazole, 4,5- dihydro-[1, 2,4] oxadiazole, 2, 5-dihydro-[1, 2,4] thiadiazole, 2, 3-dihydro-[1, 2,4] thiadiazole, 4, 5-dihydro-[1, 2,4] thiadiazole, 2, 3-dihydro-[1, 3,4] oxadiazole, 2,3- dihydro-[1, 3,4] thiadiazole, [1, 4,2] oxathiazole, [1, 3,4] oxathiazole, 1,3, 5- triazaperhydroine, 1,2, 4-triazaperhydroine, 1,4, 2-dithiazaperhydroine, 1,4, 2- dioxazaperhydroine, 1,3, 5-oxadiazaperhydroine, 1,2, 5-oxadiazaperhydroine, 1,3, 4-thiadiazaperhydroine, 1,3, 5-thiadiazaperhydroine, 1,2, 5- thiadiazaperhydroine, 1,3, 4-oxadiazaperhydroine, 1,4, 3-oxathiazaperhydroine, 1,4, 2-oxathiazaperhydroine, 1,4, 5,6-tetrahydropyridazine, 1,2, 3,4- tetrahydropyridazine, 1,2, 3,6-tetrahydropyridazine, 1,2, 5,6-tetrahydropyrimidine, 1,2, 3, 4-tetrahydropyrimidine, 1,4, 5, 6-tetrahydropyrimidine, 1,2, 3,6- tetrahydropyrazine, 1,2, 3,4-tetrahydropyrazine, 5, 6-dihydro-4H- [1, 2] oxazine, 5,6- dihydro-2H- [1, 2] oxazine, 3, 6-dihydro-2H- [1, 2] oxazine, 3,4-dihydro-2H- [1, 2] oxazine, 5, 6-dihydro-4H- [1, 2] thiazine, 5, 6-dihydro-2H- [1, 2] thiazine, 3,6- dihydro-2H- [1, 2] thiazine, 3, 4-dihydro-2H- [1, 2] thiazine, 5,6-dihydro-2H- [l, 3oxazine, 5, 6-dihydro-4H- [1, 3] oxazine, 3, 6-dihydro-2H- [1, 3] oxazine, 3,4- dihydro-2H- [1, 3] oxazine, 3, 6-dihydro-2H- [1, 4] oxazine, 3,4-dihydro-2H- [1, 4] oxazine, 5, 6-dihydro-2H- [1, 3] thiazine, 5, 6-dihydro-4H- [1, 3] thiazine, 3,6- dihydro-2H- [1, 3] thiazine, 3, 4-dihydro-2H- [1, 3] thiazine, 3,6-dihydro-2H- [1, 4] thiazine, 3, 4-dihydro-2H- [1, 4] thiazine, 1, 2,3, 6-tetrahydro-[1, 2,4] triazine, 1, 2,3, 4-tetrahydro-[1, 2,4] triazine, 1, 2,3, 4-tetrahydro-[1, 3,5] triazine, 2,3, 4,5-
tetrahydro-[1, 2,4] triazine, 1, 4,5, 6-tetrahydro-[1, 2,4] triazine, 5,6-dihydro- [1, 4,2] dioxazine, 5, 6-dihydro- [1, 4,2] dioxazine, 5, 6-dihydro- [1, 4,2] dithiazine, 2,3- dihydro- [1, 4,2] dioxazine, 3, 4-dihydro-2H- [1, 3, 4] oxadiazine, 3,6-dihydro-2H- [1, 3,4] oxadiazine, 3, 4-dihydro-2H-[1 3,5] oxadiazine, 3,6-dihydro-2H- [1, 3,5] oxadiazine, 5, 6-dihydro-2H-[1, 2,5] oxadiazine, 5,6-dihydro-4H- [1, 2,5] oxadiazine, 3, 4-dihydro-2H- [1, 3,4] thiadiazine, 3,6-dihydro-2H- [1, 3,4] thiadiazine, 3,4-dihydro-2H- [1, 3,5] thiadiazine, 3,6-dihydro-2H- [1, 3,5] thiadiazine, 5, 6-dihydro-2H- [1, 2,5] thiadiazine, 5,6-dihydro-4H- [1, 2,5] thiadiazine, 5, 6-dihydro-2H- [1, 2,3] oxadiazine, 3,6-dihydro-2H- [1, 2,5] oxadiazine, 5, 6-dihydro-4H- [1, 3,4] oxadiazine, 3,4-dihydro-2H- [1, 2,5] oxadiazine, 5, 6-dihydro-2H-[1, 2,3] thiadiazine, 3,6-dihydro-2H- [1, 2,5] thiadiazine, 5,6-dihydro-4H- [1, 3,4] thiadiazine, 3,4-dihydro-2H- [1, 2,5] thiadiazine, 5, 6-dihydro- [1, 4,3] oxathiazine, 5, 6-dihydro- [1, 4,2] oxathiazine, 2, 3-dihydro- [1, 4,3] oxathiazine, 2, 3-dihydro- [1, 4,2] oxathiazine, 4,5- dihydropyridine, 1, 6-dihydropyridine, 5, 6-dihydropyridine, 2H-pyran, 2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-dihydropyridazine, 4,5- dihydropyridazine, 1,2-dihydropyridazine, 2,3-dihydropyrimidine, 2,5- dihydropyrimidine, 5, 6-dihydropyrimidine, 3, 6-dihydropyrimidine, 4,5- dihydropyrazine, 5,6-dihydropyrazine, 3,6-dihydropyrazine, 4,5-dihydropyrazine, 1,4-dihydropyrazine, 1,4-dithiin, 1,4-dioxin, 2H-1, 2-oxazine, 6H-1, 2-oxazine, 4H- 1,2-oxazine, 2H-1, 3-oxazine, 4H-1, 3-oxazine, 6H-1, 3-oxazine, 2H-1, 4-oxazine, 4H-1, 4-oxazine, 2H-1, 3-thiazine, 2H-1, 4-thiazine, 4H-1, 2-thiazine, 6H-1,3- thiazine, 4H-1, 4-thiazine, 2H-1, 2-thiazine, 6H-1, 2-thiazine, 1, 4-oxathiin, 2H, 5H- 1, 2,3-triazine, lH, 4H-1, 2,3-triazine, 4, 5-dihydro-1, 2, 3-triazine, 1H, 6H-1,2, 3- triazine, 1, 2-dihydro-1, 2, 3-triazine, 2, 3-dihydro-1, 2,4-triazine, 3H, 6H-1,2, 4- triazine, 1H, 6H-1, 2,4-triazine, 3, 4-dihydro-1, 2,4-triazine, 1H, 4H-1, 2,4-triazine, 5, 6-dihydro-1, 2,4-triazine, 4, 5-dihydro-1, 2, 4-triazine, 2H, 5H-l, 2, 4-triazine, 1, 2- dihydro-1, 2,4-triazine, 1H, 4H-1, 3,5-triazine, 1, 2-dihydro-1, 3,5-triazine, 1,4, 2- dithiazine, 1,4, 2-dioxazine, 2H-1, 3,4-oxadiazine, 2H-1, 3,5-oxadiazine, 6H-1,2, 5- oxadiazine, 4H-1, 3,4-oxadiazine, 4H-1, 3,5-oxadiazine, 4H-1, 2,5-oxadiazine, 2H- 1,3, 5-thiadiazine, 6H-1, 2,5-thiadiazine, 4H-1, 3,4-thiadiazine, 4H-1,3, 5- thiadiazine, 4H-1, 2,5-thiadiazine, 2H-1, 3,4-thiadiazine, 6H-1, 3,4-thiadiazine, 6H-
1,3, 4-oxadiazine and 1,4, 2-oxathiazine, wherein the heterocycle is optionally vicinally fused with a saturated or unsaturated 5-, 6-or 7-membered ring containing 0,1 or 2 atoms independently selected from N, O and S; Rf is phenyl substituted by 0,1 or 2 groups selected from halo, C1-4alkyl, C1-3haloalkyl, -ORd and -NRdRd ; or Rf is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0,1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents selected from halo, C, 4alkyl, Cl 3haloalkyl,-ORd and-NRdRd ; and Rg is hydrogen or-CH3.
In another embodiment, in conjunction with the novel compound embodiments above and below, Rl6 is halo, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)C1-3alkyl or C1-3alkyl, In another embodiment, in conjunction with the novel compound embodiments above and below, Rl° is independently, at each instance, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC (=O) N (Rd) S (=0) 2 (C1-8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S (=O) (C, 8alkyl),-S (=0) 2 (CI 8alkyl),-S (=0) 2NRdRd, -S (=0) 2N (Rd) C (=O) (C, 8alkyl),-S (=0) 2N (Rd) C (=O) O (C1-8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1-8alkyl), -N(Rd) C (=O) O (C1-8alkyl), -N(Rd)C(=O)NRdRd, -N(Rd) C (=NR) NRdRd, -N(Rd) S (=O) 2 (C1-8alkyl), -N(Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC2-6alkylORd ; or R'° is a saturated or unsaturated 5-, 6-or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6-or 7-membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from C, 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,
-C(=O)(C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=O)2(C1-8alkyl), - OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O)2(C1-8alkyl), -S(=O)2NRdRd, -S(=O)2N(Rd)C(=O)(C1-8alkyl), -S(=O)2N(Rd)C(=O)O(C1-8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C _8alkyl), -N(Rd) C (=O) O (C, 8alkyl),-N (Rd) C (=O) NRdRd, -N(Rd) C (=NRd) NRdRd, -N(Rd) S (=O) 2 (C1-8alkyl), -N(Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC26alkylORd ; or Rl° is Cl 4alkyl substituted by 0,1, 2 or 3 groups selected from C, 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl),-C(=O)O(C1-alkyl), - C (=O) NRdRd,-C (=NRd) NRdRd,-ORd,-OC (=O) (Cl-8alkyl),-OC (=O) NRdRd, -OC(=O) N (Rd) S (=0) 2 (C1-8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(+O)(C1-8alkyl), -S(=O)2(C1-alkyl),-S(=O)2NRdRd, -S(=O) 2N (Rd) C (=O) (C1 -8alkyl), -S(=O)2N(Rd) C (=O) O (C1-8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1-8alkyl), -N(Rd) C (=O) O (Cl 8alkyl),-N (R) C (=O) NR R,-N (R) C (=NRd), NRdRd -N(Rd) S (=O) 2 (Cl-aalkyl),-N (Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC2-6alkylORd.
In another embodiment, in conjunction with the novel compound embodiments above and below, Rl is In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is C1-5alkyl,halo or C1-4haloalkyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R1 is naphthyl substituted by 0,1, 2 or 3 substituents independently selected from R5.
In another embodiment, in conjunction with the novel compound embodiments above and below, R1 is Re substituted by 0,1, 2 or 3 substituents independently selected from R.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is Re substituted by 1,2 or 3 substituents independently selected from R.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is In another embodiment, in conjunction with the novel compound embodiments above and below, R° and Together are a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, CI galkyl, C, 4haloalkyl, halo, cyano, nitro, -C-=O)(C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Rd) S (=0) 2 (C, 8alkyl), - OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)2(C1-8alkyl), -S(=O)2NRdRd, -S(=O)2N(Rd) C (=O) (C1-8alkyl), -S(=O) 2N (Rd) C (=O) O (C1-8alkyl), -S(=O) 2N (Rd) C (=O) NRdRd, -NRdRd, -N(Rd) C (=O) (C, 8alkyl), -N(Rd) C (=O) O (Cl 8alkyl),-N (R) C (=O) NR R,-N (R) C (=NRd)NRdRd, -N(Rd) S (=O) 2 (C1-alkyl), -N(Rd) S (=O) 2NRdRd, -NRdC2-6alkylNRdRd and -NRdC2-6alkylORd, and any nitrogen atoms in the bridge are substituted by H, -C1-6alkylORd, -C1-6alkyl, -C1-6alkylNRdRd, -C1-3alkylC(=O)ORd, -C1-3alkylC(=O)NRdRd, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRdC(=O)C1-6alkyl, -C(=O)Rf or -C1-3alkylRf; or R11 and R12 together are a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl),
-C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC (=O) NRdRd,-OC (=O) N (Rd) S (=0) 2 (C1-8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O) 2 (C1-8alkyl), -S(=O)2NRdRd, -S (=0) 2N (Rd) C (=O) (C, 8alkyl),-S (=0) 2N (Rd) C (=O) O (C, 8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd, -NRdRd, -NR(Rd) C (=O) (C, 8alkyl), -N(Rd) C (=O) O (C, 8alkyl),-N (Rd) C (=O) NRdRd,-N (Rd) C (=NRd) NRdRd -N(Rd) S (=O) 2 (CI-8alkyl),-N (Rd) S (=O) 2NRdRd, -NRdC2-6alkylnRdRd and -NRdC26alkylORd, and any nitrogen atoms in the bridge are substituted by H, -C1-6alkylORd, -C1-6alkyl, -C1-6alkylnRdRd, -C1-3alkylC(=O)ORd, -C1-3alkylC(=O)NRdRd, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRdC(=O)C1-6alkyl, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRdC(=O)C1-6alkyl, -C(=O)Rf or -C1-3alkylRf.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0,1, 2 or 3 substituents independently selected from Cialkyi, C)-4haloalkyl, halo, nitro, cyano, oxo, -ORd, -S(=O)nC1-6alkyl, -OC1-4haloalkyl, -OC2-6alkylNRdRd, - OC2-6alkylORd, -OC1-6alkylC(=O)ORd, -NRdRd, -NRdC1-4halolkyl, -NRdC2-6alkylnRdRd, -NRdC2-6alkylORd, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRdC1-6alkyl and -NRdC(=O)C1-6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any nitrogen atoms in the bridge are substituted by H, -C1-6alkylORd, -C1-6alkyl, -C1-6alkylNRdRd, -C1-3alkylC(=O)ORd, -C1-3alkylC(=O)NRdRd, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRdC(=O)C1-6alkyl, -C(=O)Rf or -C1-3alkylRf.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms
being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 1,2 or 3 substituents independently selected from C, _9alkyl, C, 4haloalkyl, halo, nitro, cyano, oxo,-ORd,-S (=O)nC1-6alkyl, -OC1-4haloalkyl, -OC2-6alkylNRdRd, - 6alkylORd,-OC, 6alkylC (=O) ORd,-NRdRd,-NRdC, 4haloalkyl, - 6alkylNRdRd,-NRdC2 6alkylORd,-C (=O) CI 6alkyl,-C (=O) OCs 6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRdC1-alkyl and -NRdC(=O)C1-6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any nitrogen atoms in the bridge are substituted by H, -C1-6alkylORd, -C1-6alyl, -C1-6alylNRdRd, -C1-3alkylC(=O)ORd, -C1-3alylC(=O)NRdRd, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRdC(=O)C1-6alkyl, -C(=O)Rf or -C1-3alkylRf.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is 10-membered bicyclic ring comprising fused 6-membered rings, containing 0,1, 2,3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORd, NRdRd, Cl 6alkyl and Cl 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =O.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is 10-membered bicyclic ring comprising fused 6-membered rings, containing 1,2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORd, NRdRd, C1-6alkyl and Cl 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =O.
Another aspect of the invention relates to a compound having the structure: or any pharmaceutically-acceptable salt thereof, wherein: n is independently, at each instance, 0,1 or 2; o is independently, at each instance, 0, 1, 2 or 3; Y is NH, O or S ; R'is or R'is a naphthyl substituted by 0,1, 2 or 3 substituents independently selected from R5 ; or R'is R'substituted by 1,2 or 3 substituents independently selected from R5 ; R15 is, independently, in each instance, Rl°, C1-8alkyl substituted by 0,1 or 2 substituents selected from R10, -(CH2)nphenyl substituted by 0, 1, 2 or 3 substituents independently selected from Rl°, or a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from Rl° ; Rl6 is, independently, in each instance, H, halo, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)C1-3alkyl or Cl 3alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C, 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S (=O) R°, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) R",-N (R'") C (=O) OR",
-N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2R", - N (R"') S (=0) 2NRmRm,-NR"'C2-6alkylNR"'Rm,-NR°'C2-6alkylOR"',-C (=O) R', - C (=O) OR',-C (=O) NRmR',-C (=NR"') NR°'Rs,-OR',-OC (=O) R', -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs, - (=0) 2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs - N (R"') C (=O) ORs, -N(Rm) C (=O) NRmRs, -N (Rm) C (=NR"') NRmRs, - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, OC OC2-6alkylORm, -SRm,-S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, - N (R"') C (=NRm) NR'Rm,-N (R''') S (=O) 2Rn, -N(Rm) S (=O) 2NRmRm, - NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, - S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm) C (=O) NRmRs,-NRmR',-N (Rm) C (=O) R',-N (Rm) C (=O) OR', -N RRm) C (=O) NRmRs,-N (Rrn) C (="Rm) NRmRs,-N (Rm) S (=0) 2Rs, - N (R"') S (=O) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; but in no instance is R4 3, 5-ditrifluoromethylphenyl or 3-trifluoromethyl-4-fluorophenyl ; R5 is independently, at each instance, H, C1-5alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -OC1-4haloaklyl, -OC2-6alkylNRdRd, -OC2-6alkylORd, -NRdRd, -NRdC1-4haloakyl, -NRdC2-6alkylNRdRd, -NRdC2-6alkylORd, naphthyl, -CO2(C1-6alkyl), -C(=O)(C1-6alkyl), -C(=O)NRdRd, -NRdC(=O)Rd, -NRd(C(=O)NRdRd, -NRdCO2(C1-6alkyl), -C1-8alkylORd, -C1-6alkylNRdRd, -S(=O)n(C1-6alkyl), -S(=O)2NRdRd, -NRdS(=O)2(C1-6alkyl), -OC(=O)NRdRd, a phenyl ring substituted with 0,1, 2, or 3 substituents independently selected from R'° ; or R5 is a saturated or unsaturated 5-or 6-membered ring heterocycle
containing 1, 2 or 3 atoms selected from O, N and S, substituted with 0, 1, 2, or 3 substituents independently selected from Rl° ; R6 is independently, at each instance, H, C1-5alkyl, C1-4haloalkyl, halo, - OC1-6alkyl, -OC1-4haloalkyl, -OC2-6alkylNRdRd, OC2-6alkylORd, -NRdRd, -NRdCt 4haloalkyl,-NRdC26alkylNRdRd or-NRdC26alkylORd,-Cl 8alkylORd, -C1-6alkylNRdRd, -S(C1-6alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from Rl° ; or R6 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3 substituents independently selected from RIO R 7is independently, at each instance, H, C1-8alkyl, C1-4haloalkyl, halo, -OC1-6alkyl, -OC1-4haloalkyl, -OC2-6alkylNRdRd, -OC2-6alkylORd, - NRdRd, -NRdC1-4haloalkyl, -NRdC2-6alkylNRdRd, -NRdC2-6alkylORd, -C1-8alkylORd, -C1-6alkylNRdRd or-S (Cs 6alkyl) ; or R7 is a saturated or unsaturated 4-or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, C1-2haloalkyl and C1-3alkyl ; R is independently, at each instance, H, Cl 5alkyl, Cl 4haloalkyl, halo, -OC1-6alkyl, -OC1-4haloalkyl, -OC2-6alkylNRdRd, -OC2-6alkylORd, -NRdRd, -NRdC, 4haloalkyl,-NRdC2 6alkylNRdRd,-NRdC2 6alkylORd,-CI 8alkylORd, - C1-6alkylNRdRd, -S(C1-6alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from Rl°, or R8 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3 substituents independently selected from Rlo ; R9 is independently, at each instance, H, C1-8alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -OC1-4haloalkyl, -OC2-6alkylNRdRd, -OC26alkylORd,-NRdRd,-NRdCt 4haloalkyl,-NRdC26alkylNRdRd or - C2-6alkylOR,-C02 (C1-6alkyl), -C(=O)(C1-6alkyl), -C(=O)NRdRd, -NRdC(=O)(C1-6alkyl), -NRdC(=O)NRdRd, -NRdCO2(C1-6alkyl), -C1-8alkylORd, -C1-6alkylNRdRd, -S(=O)n(C1-6alkyl), -S(=O)2NRdRd, -NRdS(=O) 2 (C, 6alkyl),-OC (=O) NRdRd or a- (CRqRq) ophenyl wherein the phenyl is substituted with 0,1, 2, or 3 substituents independently selected from Rl° ; or R9 is-(CRqRq) OHet wherein Het is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from R'° ; or R9 is a saturated or unsaturated 4-or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, C1-2haloalkyl and C1-3alkyl ; wherein at least one of R5, R6, R7, R8 and R9 is C1-8alkyl, C1-4haloalkyl, halo, -OC1-4haloalkyl, -OC2-6alkylNRdRd, - OC2-6alkylORd, -NRdC1-4haloalkyl, -NRdC2-6alkylNRdRd, -NRdC2-6alkylORd, -C1-8alkylORd, -C1-6alkylNRdRd or -S(C1-6alkyl) ; Rl° is independently, at each instance, selected from H, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl), -C(=O)O(C1-8alkyl), - C (=O) NRdRd,-C (=NRd) NRdRd,-ORd,-OC (=O) (C,-8alkyl),-OC (=O) NRdRd, -OC(=O) N (Rd) S (=0) 2 (C, -8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O) 2 (C, 8alkyl),-S (=0) 2NRdRd, -S (=0) 2N (Rd) C (=O) (C, -8alkyl), -S(=O)2N(Rd) C (=O) O (C1-8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1-8alkyl), -N(Rd)C(=O)O(C1-8alkyl), -N(Rd)C(=O)NRdRd, -N(Rd)C(=NRd)NRdRd, -N(Rd) S (=O) 2 (CI 8alkyl),-N (Rd) S (=O) 2NRdRd,-NRdC26alkylNRdRd and -NRdC2-6alkylORd ; or Rl° is a saturated or unsaturated 5-, 6-or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6-or 7-membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, -C(=O)(C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, - OC (=O) (CI-8alkyl),-OC (=O) NRdRd,-OC (=O) N (Rd) S (=0) 2 (C1-8alkyl), -OC2 OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S(=O)(C1-8alkyl), -S(=O)2-(C1-8alkyl), - (=0) 2NRdRd, -S(=O)2N(Rd)C(=O)(C1-8alkyl), -S(=O)2N(Rd)C(=O)O(C1-8alkyl), -S(=O)2N(Rd)C(=O)NRdRd, -NRdRd, -N(Rd) C (=O) (C1-8alkyl), -N(Rd)C(=O)O(C1-8alkyl), -N(Rd)C(=O)NRdRd, -N(Rd)C(=NRd)NRdRd, -N(Rd)S(=O)2(C1-8alkyl), -N(Rd)S(=O)2NRdRd, -NRdC2-6alkylNRdRd and
-NRdC26alkylORd ; or R° is Cl 4alkyl substituted by 0,1, 2 or 3 groups selected from C 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl), -C(=O)O(C1-8alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=O)(C1-8alkyl), -OC(=O)NRdRd, -OC(=O) N (Ra) S (=0) 2 (C, -8alkyl), -OC2-6alkylNRdRd, -OC2-6alkylORd, -SRd, -S (=O) (CI 8alkyl),-S (=0) 2 (Cl 8alkyl),-S (=0) 2NRdRd, -S(=O)2N(Rd) C (=O) (C, 8alkyl),-S (=0) 2N (Rd) C (=O) O (Cl 8alkyl), -S (=O) 2N (Rd) C (=O) NRdRa,-NRdRd,-N (Ra) C (=O) (C, 8alkyl), -N(Rd)C(=O)O(C1-8alkyl), -N(Rd)C(=O)NRdRd, -N(Rd) C (=NRd)NRdRd, -N(Rd) S (=O) 2 (C1-8alkyl), -N(Rd)S(=O)2NRdRd, -NRdC2-6alkylNRdRd and - 6alkyl0Rd ; Rd is independently, at each instance, H, phenyl, benzyl or C1-6alkyl ; Rt is a heterocycle selected from the group of thiophene, pyrrole, 1,3-oxazole, 1,3-thiazole, 1,3, 4-oxadiazole, 1,3, 4-thiadiazole, 1,2, 3-oxadiazole, 1,2, 3-thiadiazole, 1H-1, 2, 3-triazole, isothiazole, 1,2, 4-oxadiazole, 1,2, 4- thiadiazole, 1,2, 3,4-oxatriazole, 1,2, 3,4-thiatriazole, 1H-1, 2,3, 4-tetraazole, 1,2, 3, 5-oxatriazole, 1,2, 3,5-thiatriazole, furan, imidazol-1-yl, imidazol-4-yl, 1,2, 4- triazol-4-yl, 1, 2, 4-triazol-5-yl, isoxazol-3-yl, isoxazol-5-yl, pyrazol-3-yl, pyrazol- 5-yl, thiolane, pyrrolidine, tetrahydrofuran, 4,5-dihydrothiophene, 2-pyrroline, 4,5-dihydrofuran, pyridazine, pyrimidine, pyrazine, 1,2, 3-triazine, 1,2, 4-triazine, 1,2, 4-triazine, 1,3, 5-triazine, pyridine, 2H-3,4, 5,6-tetrahydropyran, thiane, 1,2- diazaperhydroine, 1,3-diazaperhydroine, piperazine, 1,3-oxazaperhydroine, morpholine, 1,3-thiazaperhydroine, 1,4-thiazaperhydroine, piperidine, 2H-3, 4- dihydropyran, 2,3-dihydro-4H-thiin, 1,4, 5,6-tetrahydropyridine, 2H-5,6- dihydropyran, 2,3-dihydro-6H-thiin, 1,2, 5, 6-tetrahydropyridine, 3,4, 5,6- tetrahydropyridine, 4H-pyran, 4H-thiin, 1, 4-dihydropyridine, 1,4-dithiane, 1,4- dioxane, 1,4-oxathiane, 1,2-oxazolidine, 1, 2-hiazolidine, pyrazolidine, 1,3- oxazolidine, 1, 3-thiazolidine, imidazolidine, 1,2, 4-oxadiazolidine, 1,3, 4- oxadiazolidine, 1,2, 4-thiadiazolidine, 1,3, 4-thiadiazolidine, 1, 2, 4-triazolidine, 2- imidazoline, 3-imidazoline, 2-pyrazoline, 4-imidazoline, 2,3-dihydroisothiazole, 4,5-dihydroisoxazole, 4, 5-dihydroisothiazle, 2, 5-dihydroisoxazole, 2,5- dihydroisothiazole, 2, 3-dihydroisoxazle, 4, 5-dihydrooxazole, 2,3- dihydrooxazole, 2, 5-dihydrooxazole, 4, 5-dihydrothiazole, 2, 3-dihydrothiazole"
2, 5-dihydrothiazole, 1,3, 4-oxathiazolidine, 1,4, 2-oxathiazolidine, 2, 3-dihydro-1H- [1, 2,3] triazole, 2, 5-dihydro-lH- [1, 2,3] triazole, 4, 5-dihydro-lH- [1, 2,3] triazole, 2, 3-dihydro-lH-[l, 2,4] triazole, 4, 5-dihydro-lH- [1, 2,4] triazole, 2,3-dihydro- [1, 2,4] oxadiazole, 2, 5-dihydro- [1, 2,4] oxadiazole, 4, 5-dihydro- [1, 2,4] thiadiazole, 2,3-dihydro- [1, 2,4] thidiazole, 2, 5-dihydro-[1, 2,4] thiadiazole, 4, 5-dihydro-[1, 2,4] thiadiazole, 2, 5-dihydro- [1, 2,4] oxadiazole, 2, 3-dihydro- [1, 2,4] oxadiazole, 4,5- dihydro- [1, 2,4] oxadiazole, 2, 5-dihydro- [1, 2,4] thiadiazole, 2, 3-dihydro-[1, 2, 4] thiadiazole, 4, 5-dihydro-[1, 2,4] thiadiazole, 2, 3-dihydro-[1, 3,4] oxadiazole, 2,3- -dihydro-[1, 3,4] thiadiazole, [1, 4,2] oxathiazole, [1, 3,4] oxathiazole, 1,3, 5- triazaperhydroine, 1,2, 4-triazaperhydroine, 1,4, 2-dithiazaperhydroine, 1,4, 2- dioxazaperhydroine, 1,3, 5-oxadiazaperhydroine, 1,2, 5-oxadiazaperhydroine, 1,3, 4-thiadiazaperhydroine, 1,3, 5-thiadiazaperhydroine, 1, 2,5- thiadiazaperhydroine, 1,3, 4-oxadiazaperhydroine, 1,4, 3-oxathiazaperhydroine, 1,4, 2-oxathiazaperhydroine, 1,4, 5, 6-tetrahydropyridazine, 1,2, 3,4- tetrahydropyridazine, 1,2, 3,6-tetrahydropyridazine, 1,2, 5,6-tetrahydropyrimidine, 1,2, 3,4-tetrahydropyrimidine, 1,4, 5, 6-tetrahydropyrimidine, 1,2, 3,6- tetrahydropyrazine, 1, 2,3, 4-tetrahydropyrazine, 5, 6-dihydro-4H- [1, 2] oxazine, 5,6- dihydro-2H- [1, 2] oxazine, 3, 6-dihydro-2H- [1, 2] oxazine, 3,4-dihydro-2H- [1, 2] oxazine, 5, 6-dihydro-4H- [1, 2] thiazine, 5, 6-dihydro-2H- [1, 2] thiazine, 3,6- dihydro-2H- [1, 2] thiazine, 3, 4-dihydro-2H- [1, 2] thiazine, 5,6-dihydro-2H- [1, 3] oxazine, 5, 6-dihydro-4H- [1, 3] oxazine, 3, 6-dihydro-2H-[1, 3] oxazine, 3,4- dihydro-2H-[1, 3] oxazine, 3,6-dihydro-2H- [1, 4] oxazine, 3,4-dihydro-2H- [1, 4oxazine, 5, 6-dihydro-2H-[1, 3] thiazine, 5, 6-dihydro-4H- [1, 3] thiazine, 3,6- dihydro-2H- [1, 3] thiazine, 3,4-dihydro-2H- [1, 3] thiazine, 3, 6-dihydro-2H- [1, 4] thiazine, 3, 4-dihydro-2H- [1, 4] thiazine, 1, 2,3, 6-tetrahydro-[1, 2,4] triazine, 1, 2,3, 4-tetrahydro-[1, 2,4] triazine, 1, 2,3, 4-tetrahydro-[1, 3,5] triazine, 2,3, 4,5- tetrahydro- [1, 2,4] triazine, 1, 4,5, 6-tetrahydro-[1, 2, 4] triazine, 5, 6-dihydro- [1, 4,2] dioxazine, 5, 6-dihydro-[1, 4,2] dioxazine, 5, 6-dihydro-[1, 4,2] dithiazine, 2,3- dihydro-[1, 4,2] dioxazine, 3, 4-dihydro-2H- [1, 3,4] oxadiazine, 3,6-dihydro-2H- [1, 3,4] oxadiazine, 3, 4-dihydro-2H- [1, 3,5] oxadiazine, 3,6-dihydro-2H- [1, 3,5] oxadiazine, 5, 6-dihydro-2H- [1, 2,5] oxadiazine, 5,6-dihydro-4H- [1, 2,5] oxadiazine, 3, 4-dihydro-2H- [1, 3,4] thiadiazine, 3,6-dihydro-2H-
[1, 3,4] thiadiazine, 3, 4-dihydro-2H- [1, 3,5] thiadiazine, 3,6-dihydro-2H- [1, 3,5] thiadiazine, 5, 6-dihydro-2H- [1, 2,5] thiadiazine, 5,6-dihydro-4H- [1, 2,5] thiadiazine, 5, 6-dihydro-2H- [1, 2,3] oxadiazine, 3,6-dihydro-2H- [1, 2,5] oxadiazine, 5, 6-dihydro-4H- [1, 3,4] oxadiazine, 3,4-dihydro-2H- [1, 2,5] oxadiazine, 5, 6-dihydro-2H- [1, 2,3] thiadiazine, 3,6-dihydro-2H- [1, 2,5] thiadiazine, 5, 6-dihydro-4H- [1, 3,4] thiadiazine, 3,4-dihydro-2H- [1, 2,5] thiadiazine, 5, 6-dihydro- [1, 4,3] oxathiazine, 5, 6-dihydro-[1, 4,2] oxathiazine, 2, 3-dihydro- [1, 4,3] oxathiazine, 2,3-dihydro- [1, 4,2] oxathiazine, 4,5- dihydropyridine, 1, 6-dihydropyridine, 5, 6-dihydropyridine, 2H-pyran, 2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-dihydropyridazine, 4,5- dihydropyridazine, 1, 2-dihydropyridazine, 2, 3-dihydropyrimidine, 2,5- dihydropyrimidine, 5, 6-dihydropyrimidine, 3,6-dihydropyrimidine, 4,5- dihydropyrazine, 5,6-dihydropyrazine, 3,6-dihydropyrazine, 4,5-dihydropyrazine, 1, 4-dihydropyrazine, 1,4-dithiin, 1,4-dioxin, 2H-1, 2-oxazine, 6H-1, 2-oxazine, 4H- 1,2-oxazine, 2H-1, 3-oxazine, 4H-1, 3-oxazine, 6H-1, 3-oxazine, 2H-1, 4-oxazine, 4H-1, 4-oxazine, 2H-1, 3-thiazine, 2H-1, 4-thiazine, 4H-1, 2-thiazine, 6H-1, 3- thiazine, 4H-1, 4-thiazine, 2H-1, 2-thiazine, 6H-1, 2-thiazine, 1,4-oxathiin, 2H, 5H- 1,2, 3-triazine, 1H, 4H-1, 2, 3-triazine, 4, 5-dihydro-1, 2, 3-triazine, 1H, 6H-1,2, 3- triazine, 1, 2-dihydro-1, 2,3-triazine, 2, 3-dihydro-1, 2,4-triazine, 3H, 6H-1,2, 4- triazine, 1H, 6H-1, 2,4-triazine, 3, 4-dihydro-1, 2,4-triazine, 1H, 4H-1, 2,4-triazine, 5, 6-dihydro-1, 2,4-triazine, 4, 5-dihydro-1, 2,4-triazine, 2H, 5H-1, 2,4-triazine, 1,2- dihydro-l, 2,4-triazine, 1H, 4H-1, 3, 5-triazine, 1, 2-dihydro-1, 3, 5-triazine, 1,4, 2- dithiazine, 1,4, 2-dioxazine, 2H-1, 3,4-oxadiazine, 2H-1, 3,5-oxadiazine, 6H-1,2, 5- oxadiazine, 4H-1, 3,4-oxadiazine, 4H-1, 3,5-oxadiazine, 4H-1, 2,5-oxadiazine, 2H- 1,3, 5-thiadiazine, 6H-1, 2,5-thiadiazine, 4H-1, 3,4-thiadiazine, 4H-1,3, 5- thiadiazine, 4H-1, 2,5-thiadiazine, 2H-1, 3,4-thiadiazine, 6H-1, 3,4-thiadiazine, 6H- 1,3, 4-oxadiazine and 1,4, 2-oxathiazine, wherein the heterocycle is optionally vicinally fused with a saturated or unsaturated 5-, 6-or 7-membered ring containing 0, 1 or 2 atoms independently selected from N, 0 and S; R fis phenyl substituted by 0,1 or 2 groups selected from halo, Cl 4alkyl, C, 3haloalkyl,-OKd and-NRdRd ; or Rf is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently
selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0,1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents selected from halo, C1-4alkyl, C1-3haloalkyl, -ORd and -NRdRd ; Rg is hydrogen or-CH3; Rm is independently at each instance H or Rn ; R"is independently at each instance Cl 8alkyl, phenyl or benzyl; Rq is independently in each instance H, C1-4alkyl,C1-4haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C (=O) ORn,-C (=O) NRmRm,-C (=NRm) NRmRm, -ORm, -OC(=O)Rn,-OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNR'"R"\ - 6alkylORm,-SRm,-S (=O) R",-S (=0) 2Rn,-S (=O) 2NR"'R"', - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn,-S(=O)2N(Rm)C(=O)NRmRm, -NRmRm,-N(Rm) C (=O) Rn,-N (Rm) C (=O) ORn,-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, - or-NRmC26alkylORm ; and Rz is Rn substituted by 0,1, 2 or 3 substituents independently selected from Rq.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is NH.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is O.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is S.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is Cl 5alkyl, halo or Cl 4haloalkyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is a naphthyl substituted by 0,1, 2 or 3 substituents independently selected from R5.
In another embodiment, in conjunction with the novel compound embodiments above and below, R1 is Re substituted by 1,2 or 3 substituents independently selected from R5 ; In another embodiment, in conjunction with the novel compound embodiments above and below, R15 is- (CH2) nphenyl substituted by 0,1, 2 or 3 substituents independently selected from R'°.
In another embodiment, in conjunction with the novel compound embodiments above and below, Rl5 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R10.
In another embodiment, in conjunction with the novel compound embodiments above and below, Rl5 is Cl 8alkyl substituted by 0,1 or 2 substituents selected from R10.
In another embodiment, in conjunction with the novel compound embodiments above and below, Rl5 is selected from C1-8alkyl,C1-4haloalkyl, halo, cyano, nitro,-C (=O) (C, 8alkyl),-C (=O) O (Cl galkyl),-C (=O) NRdRd, - C (=NRd) NRdRd,-ORd,-OC (=O) (C,-8alkyl),-OC (=O) NRdRd, -OC(=O) N (Rd) S (=0) 2 (C, -8alkyl),-OC2-6alkylNRdRd,-OC2-6alkylORd,-SRd, -S(=O)(C1-8alkyl),-S(=O) 2 (C-8alkyl),-S (=0) 2NRdRd, -S (=0) 2N (Rd) C (=O) (C, 8alkyl),-S (=0) 2N (Rd) C (=O) O (C1-8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1-8alkyl), -N(Rd)C(=O)O(C1-8alkyl),-N(Rd)C(=O)NRdRd,-N(Rd)C(=NRd)NRdRd, -N(Rd)S(=O)2(C1-8alkyl),-N(Rd) S (=O) 2NRdRd,-NRdC2-6alkylNRdRd and -NRdC26alkylORd ; or R'° is a saturated or unsaturated 5-, 6-or 7-membered
monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6-or 7-membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from C1-8alkyl,C1-4haloalkyl,halo, cyano, nitro, -C(=O)(C1-8alkyl),-C(=O)O(C1-8alkyl),-C(=O)NRdRd,-C(=NRd)NRd Rd,-ORd, -OC (=O) (CI 8alkyl),-OC (=O) NRdRd,-OC (=O) N (Rd) S (=0) 2 (C1-8alkyl), -OC2 OC2-6alkylNRdRd,-OC2-6alkylORd,-SRd,-S(=O)(C1-8alkyl),-S(=O) 2(C1-8alkyl), -S (=0) 2NRdRd,-S (=0) 2N (Rd) C (=O) (C1-8alkyl),-S(=O)2N(Rd) C (=O) O (C1-8alkyl), -S (=0) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C1-8alkyl), -N(Rd) C (=O) O (CI 8alkyl),-N (R) C (=O) NRdRd,-N (Rd) C (=NRd)NRdRd, -N(Rd) S (=O) 2 (C1-8alkyl),-N(Rd) S (=O) 2NRdRd,-NRdC2-6alkylNRdRd and -NRdC26alkylORd ; or R10 is C1-4alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl),-C(=O)O(C1-8alkyl), -C (=O) NRdRd-C (=NRd) NRdRd,-ORd,-OC (=O) (C, 8alkyl),-OC (=O) NRdRd, -OC(=O) N (Rd) S (=0) 2 (C1-8alkyl),-OC2-6alkylNRdRd,-OC2-6alkylORd,-SRd, -S (=O) (C, 8alkyl),-S (=0) 2 (C, 8alkyl),-S (=O) 2NRdRd, -S(=O) 2N (Rd) C (=O) (C1-8alkyl),-S(=O)2N(Rd) C (=O) O (C1-8alkyl), -S (=O) 2N (Rd) C (=O) NRdRd,-NRdRd,-N (Rd) C (=O) (C,-8alkyl), -N(Rd) C (=O) O (C1-8alkyl),-N(Rd)C(=O)NRdRd,-N(Rd) C (=NRd) NRdRd, -N(Rd) S (=O) 2 (C1-8alkyl),-N(Rd) S (=O) 2NRdRd,-NRdC2-6alkylNRdRd and - C2-6alkylOR In another embodiment, in conjunction with the novel compound embodiments above and below, R is, independently, in each instance, halo, -NH2,-NHC1-3alkyl,-N(C1-3alkyl)C1-3alkyl or C1-3alkyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is an unsaturated 6-membered ring containing 0 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,
1,2 or 3 substituents independently selected from C1-8alkyl,C1-4haloalkyl,halo, cyano, nitro, -C (=O) Rn,-C(=O)ORn,-C(=O)NRmRm,-C(NRm)NRmRm,-ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2R",-OC2-6alkylNR"'Rm, -OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn,-S(=O)2N(Rm)C(=O)NRm Rm, -NR Rm,-N (Rm) C (=O) R",-N (Rm) C (=O) ORn,-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs,-C(=O)ORs, -C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs,-OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs,-OC2-6alkylORs,-SRs,-S(=O)Rs, - S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)O Rs, -S(=O)2N(Rm) C (=O) NRmRs,-NRmR',-N (Rm) C (=O) Rs,-N (Rm) C (=O) OR', -N (Rm) C (=O) NRmR',-N (Rm) C (=NRm) NRmR',-N (Rm) S (=0) 2Rs, -N(Rm) S (=O) 2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn,-C(=O)ORn,-C(=O)NRmRm,-C(=NRm)NRmRm,-ORm,-OC(=O)Rn, -OC(=O)NRmRm,-OC(=O) N (Rm) S (=0) 2R°,-OC2-6alkylNR"'R"',-OC2-6alkylORm, -SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn, - S(=O)2N(Rm)C(=O)ORn,-S(=O)2N(Rm)C(=O)NRmRm,-NRmRm, -N (Rm) C (=O) Rn,-N (Rm) C (=O) ORn,-N(Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs,-C(=O)ORs, -C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs,-OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs,-OC2-6alkylORs,-SRs,-S(=O)Rs, - S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)O Rs, - S(=O)2N(Rm)C(=O)NRmRs,-NRmRs,-N(Rm)C(=O)Rs,-N(Rm)C(=O)ORs, - N (R"') C (=O) NRmRs,-N (Rm) C (=NRm) NRmRs,-N (Rm) S (=0) 2Rs, -N (Rm) S (=O) 2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6alkylORs ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4is a saturated or unsaturated 5-or 6-membered ring containing 1, 2 or 3 atoms selected from O, N and S that is vicinally fused
with a saturated or unsaturated 3-or 4-atom bridge containing 0 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C(=O)ORn,-C(=O)NRmRm, -C(=NRm)NRmRm,-ORm,-OC(=O)Rn,-OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S(=O)Rn, - S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)O Rn, -S(=O) 2N (Rm) C (=O) NRmRm,-NRmRm,-N(Rm) C (=O) R",-N (Rm) C (=O) ORn, -N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm) S (=O) 2Rn, - N (R"') S (=0) 2NRmRm,-NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs, -C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs, -OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmRs,-OC2-6alkylORs, -SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRmRs,-NRmRs,-N(Rm) C (=O) R', -N(Rm) C (=O) ORs,-N (Rm) C (=O) NRmR',-N (Rm) C (=NRm) NR"'R', -N (Rm) S (=O) 2R',-N (Rm) S (=0) 2NRmRs,-NRmC2-6alkylNRmRs,-NRmC26alkylORs and Chalky ! substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) OR",-C (=O) NR"'Rm,-C (=NRm) NRmR"',-OR"', -OC(=O)Rn,-OC(=O)NRmRm,-OC(=O) N (Rm) S (=0) 2R°,-OC2-6alkylNRmRm, -OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn,-S(=O)2N(Rm)C(=O)NR mRm, NRmRm-N (Rm) C (=O) R",-N (Rm) C (=O) OR",-N (R"') C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs,-C(=O)ORs, -C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs,-OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmRs,-OC2-6alkylORs,-SR',-S (=O) R -S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O) ORs, -S(=O)2N(Rm) C (=O) NRmRs,-NRmRs,-N (Rm) C (=O) R',-N (Rm) C (=O) ORs, -N(Rm)C(=O)NRmRs,-N(Rm)C(=NRm)NRmRs,-N(Rm)S(=O)2Rs, -N(Rm) S (=O) 2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6alkylORs ; and the ring and
bridge carbon atoms are substituted with 0,1 or 2 =O groups; but in no instance is R4 3, 5-ditrifluoromethylphenyl or 3-trifluoromethyl-4-fluorophenyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 6-membered ring containing 0 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1,2 or 3 substituents independently selected from C1-8alkyl,C1-4haloalkyl,halo, cyano, nitro, -C (=O) Rn,-C (=O) ORn,-C (=O) NR'R',-C (=NRm) NRmRm,-ORm -OC(=O)Rn,-OC(=O)NRmRm,-OC(=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNRmRm, -OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm, -S(=O) 2N (Rm) C (=O) R',-S (=0) 2N (Rm) C (=O) OR',-S (=0) 2N (Rm) C (=O) NRmRm, - NR"'R°,-N (R"') C (=O) Rn,-N(Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs,-C(=O)ORs, -C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs,-OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs,-OC2-6alkylORs,-SRs,-S(=O)Rs, - S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)O Rs, -S(=O)2N(Rm) C (=O) NRmRs,-NRmRs,-N (Rm) C (=O) Rs,-N (Rm) C (=O) ORs, - N (R"') C (=O) NRmR',-N (Rm) C (=NR"') NRmRs,-N (Rm) S (=0) 2Rs, -N (Rm) S (=O) 2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn,-C(=O)ORn,-C(=O)NRmRm,-C(=NRm)NRmRm,-ORm,-OC(=O)Rn, -OC(=O)NRmRm,-OC(=O) N (Rm) S (=O) 2Rn,-OC2-6alkylNRmRm,-OC2-6alkylORm, -SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm) C (=O) OR",-S (=0) 2N (R"') C (=O) NRmRm,-NRmRm, - N(Rm)C(=O)Rn,-N(Rm)C(=O)ORn,-N(Rm)C(=O)NRmRm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs,-C(=O)ORs, -C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs,-OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs,-OC2-6alkylORs,-SRs,-S(=O)Rs,
- S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)O Rs, -S(=O)2N(Rm) C (=O) NRmRs,-NRmRs,-N (Rm) C (=O) R',-N (Rm) C (=O) OR', -N (Rm) C (=O) NRmR',-N (Rm) C (=NRm) NRmRs,-N (Rm) S (=0) 2Rs, -N(Rm) S (=O) 2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6alkylORs ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; but in no instance is R4 3,5-ditrifluoromethylphenyl or 3-trifluoromethyl-4-fluorophenyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 5-or 6-membered ring containing 1,2 or 3 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 1,2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C(=O)ORn,-C(=O)NRmRm, -C(=NRm)NRmRm,-ORm,-OC(=O)Rn,-OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S(=O)Rn, - S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)O Rn, -S (=O) 2N (R) C (=O) NRmRm,-NRmRm,-N(Rm) C (=O) Rn,-N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn, - N (R"') S (=O) 2NRmRm,-NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs, -C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs, -OC(=O)NRmRs,-OC(=O)N(Rm)S(=O)2Rs,-OC2-6alkylNRmRs,-OC2-6alk ylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, S(=O)2NRmRs, S(=O)2N(Rm)C(=O)Rs, - S 2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRmRs,-NRmRs,-N(Rm) C (=O) Rs, - N (R"') C (=O) ORs,-N (Rm) C (=O) NRmRs,-N (Rm) C (=NRm) NRmRs, -N(Rm) S (=0) 2Rs,-N (Rm) S (=0) 2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from C1-2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C(=O)ORn,-C(=O)NRmRm,-C(=NRm)NRmRm,-ORm, -OC(=O)Rn,-OC(=O)NRmRm,-OC(=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNRmRm, - 6alkylORm,-SRm,-S (=O) Rn,-S(=O)2Rn,-S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn,-S(=O)2N(Rm)C(=O)NRm Rm, -NRmRm,-N(Rm) C (=O) Rn,-N(Rm) C (=O) OR",-N (Rm) C (=O) NRmRm
- N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm -NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs,-C(=O)ORs, -C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs,-OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs,-OC2-6alkylORs,-SRs,-S(=O)Rs, - S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)O Rs, -S(=O)2N(Rm) C (=O) NRmR',-NR'Rs,-N (Rm) C (=O) R',-N (Rm) C (=O) ORs, -N(Rm)C(=O)NRmRs,-N(Rm)C(=NRm)NRmRs,-N(Rm)S(=O)2Rs, -N (Rm) S (=O) 2NRmRs,-NR"'C2-6alkylNRmRs,-NR"'C2-6alkylOR' ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; but in no instance is R4 3, 5-ditrifluoromethylphenyl or 3-trifluoromethyl-4-fluorophenyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R9 is H.
In another embodiment, in conjunction with the novel compound embodiments above and below, R9 is independently, at each instance, C1-8alkyl, C1-4haloalkyl, halo, nitro, cyano,-OC, 6alkyl,-OC, 4haloalkyl,-OC26alkylNRdRd, - OC2-6alkylORd,-NRdRd,-NRdC1-4haloalkyl,-NRdC2-6alkylNRdRd or - NRdCz-6alkylORd,-CO2 (C-6alkyl),-C (=O) (C, _6alkyl),-C (=O) NRd Rd, -NRdC(=O)(C1-6alkyl),-NRdC(=O)NRdRd,-NRdCO2(C1-6alkyl), -C1-8alkylORd, -C1-6alkylNRdRd,-S(=O)n(C1-6alkyl),-S(=O)2NRdRd,-NRdS(=O)2(C 1-6alkyl) or -OC(=O)NRdRd.
In another embodiment, in conjunction with the novel compound embodiments above and below, R9 is a- (CRqRq) ophenyl wherein the phenyl is substituted with 0,1, 2, or 3 substituents independently selected from Rl°.
In another embodiment, in conjunction with the novel compound embodiments above and below, R9 is- (CRqRq) oHet wherein Het is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from R'° ; or R''is a saturated or unsaturated 4-or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, Cl 2haloalkyl and C1-3alkyl.
Another aspect of the invention relates to a compound having the structure: or any pharmaceutically-acceptable salt thereof, wherein: Y is 0 or S ; n is independently, at each instance, 0,1 or 2.
Rl is or R'is a naphthyl substituted by 0,1, 2 or 3 substituents independently selected from R5 ; or R'is R'substituted by 1,2 or 3 substituents independently selected from R5; Rl5 is, independently, in each instance, Rl°, C1-8alkyl substituted by 0,1 or 2 substituents selected from R10,- phenyl substituted by 0,1, 2 or 3 substituents independently selected from R'°, or a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, the heterocycle and bridge being substituted by 0,1, 2 or 3 substituents independently selected from R'° ; R""is, independently, in each instance, H, halo,-NH2,-NHCs 3alkyl, -N(C1-3alkyl)C1-3alkyl,-OC1-3alkyl,-C1-2haloalkyl,-OC1-2halo alkyl or C1-3alkyl ;
R4 i s wherein when Rl is bromophenyl, methylphenyl or trifluoromethylphenyl, R4 is not trifluoromethylphenyl or trifluoromethylhalophenyl ; or R4 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, wherein each of the carbon atoms of the heterocycle is substituted by H, Cl galkyl, Cl 4haloalkyl, halo, cyano, oxo,-ORh,-S (=O) nCl-6alkyl, - OC1-4haloalkyl,-OC2-6alkylNRhRh,-OC2-6alkylORh,-OC1-6alkylC( =O)ORh, - NRhRh,-NRhC1-4haloalkyl,-NRhC2-6alkylNRhRh,-NRhC2-6alkylORh, -C(=O)C1-6alkyl,-C(=O)OC1-6alkyl,-OC(=O)C1-6alkyl,-C(=O)NRhC 1-6alkyl or -NRhC(=O)C1-6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and each of the available nitrogen atoms in the heterocycle are substituted by H,-C, 6alkylORh,-C1-6alkyl,-C1-6alkylNRhRh,-C1-3alkylC(=O)ORh, -C1-3alkylC(=O)NRhRh,-C1-3alkylOC(=O)C1-6alkyl,-C1-3alkylNRh C(=O)C1-6alkyl, -C(=O)Rj or -C1-3alkylRj; or R4 is an 8-, 9-, 10-or 11-membered bicyclic ring, containing 0, 1, 2,3 or 4 N atoms and 0,1 or 2 atoms selected from S and O with the remainder being carbon atoms, wherein each of the carbon atoms of the ring is substituted by H, C1-9alkyl,C1-4haloalkyl, halo, cyano, oxo,-OR, -S(=O)nC1-6alkyl,-OC1-4haloalkyl,-OC2-6alkylNRhRh,-OC2-6alky lORh, -OC1-6alkylC(=O)ORh,-NRhRh,-NRhC1-4haloalkyl,-NRhC2-6alkylNR hRh, - NRhC2-6alkylORh,-C(=O)C1-6alkyl,-C(=O)OC1-6alkyl,-OC(=O)C1-6 alkyl, -C (=O) NRhCs 6alkyl or-NRhC (=O) C, 6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any available nitrogen atoms in the ring are substituted by H,-C1-6alkylORh,-C1-6alkyl,-C1-6alkylNRhRh, -C1-3alkylC(=O)ORh,-C1-3alkylC(=O)NRhRh,-C1-3alkylOC(=O)C1-6 alkyl, - C1-3alkylNRhC(=O)C1-6alkyl,-C(=O)Rj or -C1-3alkylRj ;
R5 is independently, at each instance, H, C1-5alkyl,C1-4haloalkyl, halo, nitro, -OC1-6alkyl,-OC1-4haloalkyl,-OC2-6alkylNRhRh,-OC2-6alkylORh, -NRhRh, -NRhC, 4haloalkyl,-NRhC26alkylNRhRh,-NRhC26alkylORh, naphthyl, -CO2(C1-6alkyl), -C(=O)(C1-6alkyl),-C(=O)NRhRh,-NRhC(=O)Rh, -NRhC(=O)NRhRh,-NRhCO2(C1-6alkyl),-C1-8alkylORh,-C1-6alkylNR hRh, -S(=O)n(C1-6alkyl),-S(=O)2NRhRh,-NRhS(=O)2(C1-6alkyl),-OC(=O )NRhRh, a phenyl ring substituted with 0,1, 2, or 3 substituents independently selected from R'° ; or RS is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S, substituted with 0, 1, 2, or 3 substituents independently selected from Rl° ; R6 is independently, at each instance, H, C1-5alkyl,C1-4haloalkyl, halo, -OC1-6alkyl,-OC1-4haloalkyl,-OC2-6alkylNRhRh,-OC2-6alkylORh, -NRhRh, -NRhC, 4haloalkyl,-NRhC26alkylNRhRh or-NRhC26alkylORh,-C, 8alkylORh, -C1-6alkylNRhRh, -S(C1-6alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected from Rl° ; or R''is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from Rlo ; R7 is independently, at each instance, H, C1-8alkyl,C1-4haloalkyl, bromo,-OC, -6alkyl,-OC1-4haloalkyl,-OC2-6alkylNRhRh,-OC2-6alkylORh, - NRhRh,-NR"Ci_4haloalkyl,-NRhC2-6alkylNRhR",-NR"C2-6alkylORh, -Cl C1-8alkylORh,-C1-6alkylNRhRh or -S(C1-6alkyl) ; or R7 is a saturated or unsaturated 4-or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, Cl 2haloalkyl and Cl 3alkyl ; R8 is independently, at each instance, H, Cl 5alkyl, Cl 4haloalkyl, halo, -OC1-6alkyl,-OC1-4haloalkyl,-OC2-6alkylNRhRh,-OC2-6alkylORh, -NRhRh, - NRhC1-4haloalkyl,-NRhC2-6alkylNRhRh,-NRhC2-6alkylORh,-C1-8al kylORh, -C1-6alkylNRhRh, -S(C1-6alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from Rl°, or R8 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from Rlo
R9 is independently, at each instance, H, C1-8alkyl,C1-4haloalkyl, halo, nitro,-OC1-6alkyl,-OC1-4haloalkyl,-OC2-6alkylNRhRh, -OC2-6alkylORh,-NRhRh,-NRhC1-4haloalkyl,-NRhC2-6alkylNRhRh or -NRhC2-6alkylORh,-CO2(C1-6alkyl), -C(=O)(C1-6alkyl), -C(=O)NRhRh, -NRhC(=O)(C1-6alkyl), -NRhC(=O)NRhRh,-NRhCO2(C1-6alkyl), -C1-8alkylORh,-C1-6alkylNRhRh, -S(=O)n(C1-6alkyl),-S(=O)2NRhRh, -NRhS(=O) 2 (CI-6alkyl),-OC (=O) NRhR", a phenyl ring substituted with 0, 1,2, or 3 substituents independently selected from R10 ; or R9 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from R'° ; wherein at least one of R5,R6,R7,R8 and R9 is C1-8alkyl,C1-4haloalkyl,halo,-OC1-4haloalkyl, - OC2-6alkylNRhRh,-OC2-6alkylORh,-NRhC1-4haloalkyl, - NRhC26alkylNRhRh,-NRhC2-6alkylORh,-C1-8alkylORh,-C1-6alkylNR hRh or-S (Cl 6alkyl) ; or R9 is a saturated or unsaturated 4-or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0,1 or 2 substituents independently selected from halo, C1-2haloalkyl and Cl 3alkyl ; Rl° is independently, at each instance, selected from H, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl),-C(=O)O(C1-8alkyl), -C(=O)NRhRh,-C(=NRh)NRhRh,-ORh,-OC(=O)(C1-8alkyl),-OC(=O)NRh Rh, -OC(=O) N (Rh) S (=0) 2 (C, 8alkyl),-OC2-6alkylNRhR",-OC2-6alkylORh,-SRh, -S(=O)(C1-8alkyl),-S(=O)2(C1-8alkyl),-S(=O)2NRhRh, -S (=0) 2N (Rh) C (=O) (C, 8alkyl),-S (=0) 2N (Rh) C (=O) O (C1-8alkyl), - S (=0) 2N (R") C (=O) NR"R",-NRhRh,-N (R") C (=O) (C, 8alkyl), -N(Rh) C (=O) O (C, 8alkyl),-N (R") C (=O) NRhRh,-N (Rh) C (=NRh) NRhRh, -N(Rh) S (=O) 2 (C1-8alkyl),-N(Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC2-6alkylORh ; or Rl° is a saturated or unsaturated 5-, 6-or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1 or 2 atoms selected from N, O and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O
and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from C1-8alkyl,C1-4haloalkyl, halo, cyano, nitro, -C(=O)(C1-8alkyl),-C(=O)O(C1-8alkyl),-C(=O)NRhRh,-C(=NRh)NRh Rh,-ORh, -OC (=O) (Cl 8alkyl),-OC (=O) NRhRh,-OC (=O) N (Rh) S (=0) 2 (CI-8alkyl), -OC2 OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh,-S(=O)(C1-8alkyl),-S(=O) 2 (C1-8alkyl), -S(=O)2NRhRh,-S(=O)2N(Rh) C (=O) (C1-8alkyl),-S(=O)2N(Rh) C (=O) O (C1-8alkyl), -S(=O) 2N (R'') C (=O) NR"Rh,-NRhRh,-N (Rh) C (=O) (C1-8alkyl), -N(Rh) C (=O) O (C -8alkyl),-N(Rh) C (=O) NRhRh,-N (Rh) C (=NRh) NR''R", -N(Rh) S (=O) 2 (C1-8alkyl),-N(Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC2-6alkylORh ; or R'° is Cl 4alkyl substituted by 0,1, 2 or 3 groups selected from C, 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl),-C(=O)NRhRh, -C(=NRh)NRhRh,-ORh,-OC(=O)(C1-8alkyl),-OC(=O)NRhRh, -OC(=O) N (Rh) S (=0) 2 (C1-8alkyl),-OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh, -S(=O)(C1-8alkyl),-S(=O) 2 (C, 8alkyl),-S (=0) 2NR"Rh, - S (=0) 2N (R") C (=O) (C1-8alkyl),-S(=O)2N(Rh) C (=O) O (C1-8alkyl), -S (=0) 2N (Rh) C (=O) NRhRh,-NRhRh,-N (Rh) C (=O) (C1-8alkyl), -N(Rh) C (=O) O (C1-8alkyl),-N(Rh) C (=O) NRhRh,-N(Rh) C (=NRh) NRhRh, - N (R") S (=O) 2 (C, 8alkyl),-N (Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC2-6alkylORh; Rl l is independently, at each instance, selected from H, C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl),-C(=O)O(C1-8alkyl), - C (=O) NRhR",-C (=NR") NRhR",-OR",-OC (=O) (CI-8alkyl),-OC (=O) NRhRh, -OC(=O) N (Rh) S (=0) 2 (C, -8alkyl),-OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh, -S(=O)(C1-8alkyl),-S(=O)2(C1-8alkyl),-S(=O)2NRhRh, -S (=0) 2N (Rh) C (=O) (Cl -8alkyl),-S(=O)2N(Rh) C (=O) O (C1-8alkyl), - S (=0) 2N (R") C (=O) NR"Rh,-NR"Rh,-N (R") C (=O) (C1-8alkyl), - N (R") C (=O) O (C1-8alkyl),-N(Rh) C (=O) NRhRh,-N (Rh) C (=NRh) NRhRh, -N(Rh) S (=O) 2 (C1-8alkyl),-N(Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC2-6alkylORh ; or R"is a saturated or unsaturated 5-, 6-or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo
groups and 0 or 1 saturated or unsaturated 5-, 6-or 7-membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C(=O)(C1-8alkyl),-C(=O)O(C1-8alkyl),-C(=O)NRhRh,-C(=NRh)NRh Rh,-ORh, -OC(=O)(C1-8alkyl),-OC(=O)NRhRh,-OC(=O) N (Rh) S (=0) 2 (C1-8alkyl), - OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh,-S(=O)(C1-8alkyl),-S(=O) 2(C1-8alkyl), -S(=O)2NRhRh,-S(=O)2N(Rh) C (=O) (C1-8alkyl),-S(=O)2N(Rh) C (=O) O (C -8alkyl), - S (=0) 2N (R") C (=O) NRhRh,-NRhRh,-N (R") C (=O) (C, -8alkyl), -N(Rh) C (=O) O (Cl 8alkyl),-N (R) C (=O) NRhRh,-N(Rh) C (=NRh)NRhRh, - N (R") S (=O) 2 (C1-3alkyl),-N(Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC2-6alkylORh;orR11 is C1-4alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl),-C(=O)O(C1-8alkyl), -C(=O)NRhRh,-C(=NRh)NRhRh,-ORh,-OC(=O)(C1-8alkyl),-OC(=O)NRh Rh, -OC(=O) N (Rh) S (=0) 2 (C1 8alkyl),-OC2 6alkylNRhRh,-OC2 6alkylORh,-SRh, -S (=O) (Cl 8alkyl),-S (=0) 2 (C1-8alkyl),-S(=O)2NRhRh, -S(=O) 2N (Rh) C (=O) (C,_galkyl),-S (=0) 2N (Rh) C (=O) O (C1-8alkyl), -S(=O) 2N (Rh) C (=O) NRhRh,-NRhRh,-N (Rh) C (=O) (C, 8alkyl), -N(Rh) C (=O) O (C1-8alkyl),-N(Rh) C (=O) NRhRh,-N(Rh) C (=NRh)NRhRh, -N(Rh) S (=O) 2 (C1-8alkyl),-N(Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and - 6alkylORh ; R 12 is independently, at each instance, selected from H, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, -C (=O) O (C,_8alkyl),-C (=O) NR"Rh, -C(=NRh)NRhRh,-ORh,-OC(=O)(C1-8alkyl),-OC(=O)NRhRh, -OC(=O) N (Rh) S (=0) 2(C1-8alkyl),-OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh, -S (=O) (CI-8alkyl),-S (=0) 2 (Cl-galkyl),-S (=0) 2NR R, -S(=O) 2N (Rh) C (=O) (C, -8alkyl),-S(=O)2N(Rh) C (=O) O (C1-8alkyl), -S (=0) 2N (R h) C (=O) NR"Rh,-NRhR",-N (R") C (=O) (C1 -8alkyl), -N(Rh)C(=O)O(C1-8alkyl),-N(Rh)C(=O)NRhRh,-N(Rh)C(=NRh)NRhRh, -N(Rh) S (=O) 2 (C,-salkyl),-N (R") S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC2-6alkylORh ; or R12 is a saturated or unsaturated 5-, 6-or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1,2 or 3
atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6-or 7-membered heterocyclic ring containing 1,2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, <BR> <BR> <BR> - C (=O) (CI-8alkyl),-C (=O) O (CI_8alkyl),-C (=O) NR"Rh,-C (=NR") NRhRh,-OR", -OC(=O)(C1-8alkyl),-OC(=O)NRhRh,-OC(=O) N (Rh) S (=0) 2 (C1-8alkyl), - OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh,-S(=O)(C1-8alkyl),-S(=O) 2(C1-8alkyl), -S(=O)2NRhRh,-S(=O)2N(Rh) C (=O) (C1-8alkyl),-S(=O)2N(Rh) C (=O) O (C, 8alkyl), -S(=O)2N(Rh) C (=O) NRhRh,-NRhRh,-N(Rh) C (=O) (C1-8alkyl), -N(Rh) C (=O) O (C, 8alkyl),-N (R) C (=O) NRhRh,-N (R") C (=NRh) NRhRh, - N (R") S (=O) 2 (C1-8alkyl),-N(Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhR"and -NRhC2-6alkylORh ; or R12 is Cl 4alkyl substituted by 0,1, 2 or 3 groups selected from C1-4haloalkyl, halo, cyano, nitro, -C (=O) (C1-8alkyl),-C(=O)O(C1-8alkyl), -C(=O)NRhRh,-C(=NRh)NRhRh,-ORh,-OC(=O)(C1-8alkyl),-OC(=O)NRh Rh, -OC(=O) N (Rh) S (=O) 2 (CI_8alkyl),-OC2-6alkylNRhR",-OC2-6alkylORh,-SRh, -S(=O)(C1-8alkyl),-S(=O)2(C1-8alkyl),-S(=O)2NRhRh, -S(=O)2N(Rh) C (=O) (C1-8alkyl),-S(=O)2N(Rh) C (=O) O (C1-8alkyl), -S(=O)2N(Rh) C (=O) NRhRh,-NRhRh,-N (Rh) C (=O) (C1-8alkyl), - N (R") C (=O) O (C1-8alkyl),-N(Rh) C (=O) NR R,-N (R) C (=NRh)NRhRh, - N (R") S (=0) 2 (C1-8alkyl),-N(Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC2 6alkylORh ; R13 is independently, at each instance, selected from H, C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) (Cl 8alkyl),-C (=O) O (C1-8alkyl), -C(=O)NRhRh,-C(=NRh)NRhRh,-ORh,-OC(=O)(C1-8alkyl),-OC(=O)NRh Rh, -OC(=O) N (Rh) S (=0) 2 (Ci -8alkyl),-OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh -S(=O)(C1-8alkyl),-S(=O) 2 (C1-8alkyl),-S(=O)2NRhRh, - S (=0) 2N (R") C (=O) (C1-8alkyl),-S(=O)2N(Rh) C (=O) O (C1-8alkyl), - S (=0) 2N (R") C (=O) NRhRh,-NRhRh,-N(Rh) C (=O) (C1-8alkyl), -N(Rh)C(=O)O(C1-8alkyl),-N(Rh)C(=O)NRhRh,-N(Rh)C(=NRh)NRhRh, - N (R") S (=O) 2 (C1-8alkyl),-N(Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC26alkylORh ; or Rl3 is a saturated or unsaturated 5-, 6-or 7-membered
monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1,2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6-or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C(=O)(C1-8alkyl),-C(=O)O(C1-8alkyl),-C(=O)NRhRh,-C(=NRh)NRh Rh,-ORh, -OC(=O)(C1-8alkyl),-OC(=O)NRhRh,-OC(=O) N (Rh) S (=0) 2 (C1-8alkyl), - OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh,-S(=O)(C1-8alkyl),-S(=O) 2 (C1-8alkyl), - S(=O)2NRhRh,-S(=O)2N(Rh)C(=O)(C1-8alkyl),-S(=O)2N(Rh)C(=O)O( C1-8alkyl), -S(=O) 2N (Rh) C (=O) NRhRh,-NRhRh,-N(Rh) C (=O) (C1-8alkyl), -N(Rh)C(=O)O(C1-8alkyl),-N(Rh)C(=O)NRhRh,-N(Rh)C(=NRh)NRhRh, - N (R") S (=O) 2 (Ci-8alkyl),-N (Rh) S (=O) 2NRhRh,-NRhC26alkylNRhRh and -NRhC2-6alkylORh ; or Rl3 is Cl 4alkyl substituted by 0, 1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl),-C(=O)O(C1-8alkyl), -C(=O)NRhRh,-C(=NRh)NRhRh,-ORh,-OC(=O)(C1-8alkyl),-OC(=O)NRh Rh, -OC(=O) N (Rh) S (=0) 2 (C1-8alkyl),-OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh, -S(=P)(C1-8alkyl),-S(=O) 2 (C1-8alkyl),-S(=O)2NRhRh, -S (=0) 2N (Rh) C (=O) (C1-8alkyl),-S(=O)2N(Rh) C (=O) O (C1-8alkyl), -S(=O) 2N (Rh) C (=O) NRhRh,-NRhRh,-N (Rh) C (=O) (C, -8alkyl), -N(Rh)C(=O)O(C1-8alkyl),-N(Rh)C(=O)NRhRh,-N(Rh)C(=NRh)NRhRh, -N(Rh) S (=O) 2 (Ci- 8alkyl),-N (R") S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and - 6alkyl0Rh ; R14 is independently, at each instance, selected from H, C, 8alkyl, C, 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl),-C(=O)O(C1-8alkyl), - C (=O) NRhRh,-C (=NR") NRhRh,-ORh,-OC (=O) (C1-8alkyl),-OC (=O) NRhRh, -OC(=O) N (Rh) S (=0) 2 (C1-8alkyl),-OC2-8alkylNRhRh,-OC2-6alkylORh,-SRh, -S(=O)(C1-8alkyl),-S(=O) 2 (C1-8alkyl),-S(=O)2NRhRh, -S(=O) 2N (Rh) C (=O) (C, -8alkyl),-S(=O)2N(Rh) C (=O) O (C1-8alkyl), - S (=0) 2N (R") C (=O) NRhRh,-NRhRh,-N (Rh) C (=O) (C, -8alkyl), - N (R") C (=O) O (C1-8alkyl),-N(Rh)C(=O)NRhRh,-N(Rh)C(=NRh)NRhRh, -N(Rh) S (=O) 2 (C, 8alkyl),-N (Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC26alkylORh ; or R'4 is a saturated or unsaturated 5-, 6-or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 1 or 2 atoms selected from N, O and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 groups selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C(=O)(C1-8alkyl),-C(=O)O(C1-8alkyl),-C(O)NRhRh,-C(=NRh)NRhR h,-ORh, -OC(=O)(C1-8alkyl),-OC(=O)NRhRh,-OC(=O) N (Rh) S (=0) 2 (C1-8alkyl), - OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh,-S(=O)(C1-8alkyl),-S(=O) (C1-8alkyl), -S(=O)2NRhRh,-S(=O)2N(Rh)C(=O)(C1-8alkyl),-S(=O)2N(Rh)C(=O)O (C1-8alkyl), -S (=0) 2N (R h) C (=O) NRhRh,-NRhRh,-N (Rh) C (=O) (C _8alkyl), -N(Rh) C (=O) O (C, 8alkyl),-N (R) C (=O) NRhRh,-N(Rh) C (=NR") NRhRh, -N(Rh) S (=O) 2 (C,-8alkyl),-N (Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC2-6alkylORh ; or Rl4 is Chalky ! substituted by 0,1, 2 or 3 groups selected from C, 4haloalkyl, halo, cyano, nitro,-C (=O) (C, 8alkyl),-C (=O) NR"Rh, -C(=NRh)NRhRh,-ORh,-OC(=O)(C1-8alkyl),-OC(=O)NRhRh, -OC(=O) N (Rh) S (=0) 2 (CI_8alkyl),-OC2 6alkylNR"Rh,-OC2-6alkylORh,-SR", -S (=O) (CI 8alkyl),-S (=0) 2 (C1-8alkyl),-S(=O)2NRhRh, -S(=O)2N(Rh) C (=O) (C, 8alkyl),-S (=0) 2N (Rh) C (=O) O (C1-8alkyl), -S(=O) 2N (Rh) C (=O) NRhRh,-NRhRh,-N (Rh) C (=O) (C, -8alkyl), -N(Rh)C(=O)O(C1-8alkyl),-N(Rh)C(=O)NRhRh,-N(Rh)C(=NRh)NRhRh, - N (R") S (=O) 2 (C1-salkyl),-N (R") S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and - 6alkylORh ; Rh is independently, at each instance, H, phenyl, benzyl or C, 6alkyl, the phenyl, benzyl and Cl 6alkyl being substituted by 0, 1, 2 or 3 substituents selected from halo, C1-4alkyl,C1-3haloalkyl,-OC1 4alkyl,-NH2,-NHC1 4alkyl, -N(C1-4alkyl)C1-4alkyl ; Ri is a heterocycle selected from the group of thiophene, pyrrole, 1,3- oxazol, 1, 3-thiazol-5-yl, 1,3, 4-oxadiazole, 1, 3, 4-thiadiazole, 1,2, 3-oxadiazole, 1,2, 3-thiadiazole, IH-I, 2, 3-triazole, isothiazole, 1,2, 4-oxadiazole, 1,2, 4-
thiadiazole, 1,2, 3,4-oxatriazole, 1, 2,3, 4-thiatriazole, 1H-1, 2,3, 4-tetraazole, 1,2, 3,5-oxatriazole, 1,2, 3,5-thiatriazole, furan, imidazol-1-yl, imidazol-3-yl, imidazol-4-yl, 1,2, 4-triazole, 1,2, 4-triazole, isoxazole, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiolane, pyrrolidine, tetrahydrofuran, 4,5-dihydrothiophene, 2- pyrrole, 4,5-dihydrofuran, pyridazine, pyrimidine, pyrazine, 1,2, 3-triazine, 1,2, 4-triazine, 1, 2,4-triazine, 1, 3, 5-triazine, pyridine, 2H-3,4, 5,6-tetrahydropyran, thiane, 1,2-diazaperhydroine, 1, 3-diazaperhydroine, piperazine, 1,3- oxazaperhydroine, morpholine, 1,3-thiazaperhydroine, 1,4-thiazaperhydroine, piperidine, 2H-3,4-dihydropyran, 2,3-dihydro-4H-thiin, 1,4, 5,6- tetrahydropyridine, 2H-5,6-dihydropyran, 2,3-dihydro-6H-thiin, 1,2, 5,6- tetrahydropyridine, 3,4, 5,6-tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4- dihydropyridine, 1,4-dithiane, 1,4-dioxane, 1,4-oxathiane, 1, 2-oxazolidine, 1,2- thiazolidine, pyrazolidine, 1, 3-oxazolidine, 1, 3-thiazolidine, imidazolidine, 1,2, 4- oxadiazolidine, 1,3, 4-oxadiazolidine, 1,2, 4-thiadiazolidine, 1,3, 4-thiadiazolidine, 1,2, 4-triazolidine, 2-imidazolin-1-yl, 2-imidazolin-2-yl, 2-imidazolin-5-yl, 3- imidazoline, 2-pyrazoline, 4-imidazoline, 2,3-dihydroisothiazole, 4,5- dihydroisoxazole, 4, 5-dihydroisothiazole, 2,5-dihydroisoxazole, 2,5- dihydroisothiazole, 2,3-dihydroisoxazole, 4,5-dihydrooxazole, 2,3- dihydrooxazole, 2,5-dihydrooxazole, 4,5-dihydrothiazole, 2, 3-dihydrothiazole" 2,5-dihydrothiazole, 1,3, 4-oxathiazolidine, 1,4, 2-oxathiazolidine, 2, 3-dihydro-lH- [1, 2,3] triazole, 2, 5-dihydro-lH- [1, 2,3] triazole, 4, 5-dihydro-lH- [1, 2,3] triazol-1-yl, 4, 5-dihydro-lH- [1, 2,3] triazol-3-yl, 4, 5-dihydro-lH- [1, 2,3] triazol-5-yl, 2,3- dihydro-1H-[1, 2,4] triazole, 4, 5-dihydro-lH- [1, 2,4] triazole, 2,3-dihydro- [1, 2,4] oxadiazole, 2, 5-dihydro- [1, 2,4] oxadiazole, 4, 5-dihydro- [1, 2,4] thiadiazole, 2, 3-dihydro-[1, 2, 4] thidiazole, 2, 5-dihydro-[1, 2, 4] thiadiazole, 4, 5-dihydro- [1, 2,4] thiadiazole, 2,5-dihydro- [1, 2, 4] oxadiazole, 2, 3-dihydro- [1, 2,4] oxadiazole, 4,5- dihydro-[1, 2,4] oxadiazole, 2, 5-dihydro- [1, 2,4] thiadiazole, 2, 3-dihydro- [1, 2,4] thiadiazole, 4,5-dihydro- [1, 2,4] thiadiazole, 2, 3-dihydro- [1, 3,4] oxadiazole, 2,3- dihydro- [1, 3,4] thiadiazole, [1, 4,2] oxathiazole, [1, 3,4] oxathiazole, 1,3, 5- triazaperhydroine, 1,2, 4-triazaperhydroine, 1,4, 2-dithiazaperhydroine, 1,4, 2- dioxazaperhydroine, 1,3, 5-oxadiazaperhydroine, 1,2, 5-oxadiazaperhydroine, 1,3, 4-thiadiazaperhydroine, 1,3, 5-thiadiazaperhydroine, 1,2, 5-
thiadiazaperhydroine, 1,3, 4-oxadiazaperhydroine, 1,4, 3-oxathiazaperhydroine, 1,4, 2-oxathiazaperhydroine, 1,4, 5,6-tetrahydropyridazine, 1,2, 3,4- tetrahydropyridazine, 1,2, 3,6-tetrahydropyridazine, 1,2, 5,6-tetrahydropyrimidine, 1,2, 3, 4-tetrahydropyrimidine, 1,4, 5, 6-tetrahydropyrimidine, 1,2, 3,6- tetrahydropyrazine, 1,2, 3,4-tetrahydropyrazine, 5, 6-dihydro-4H- [1, 2] oxazine, 5,6- dihydro-2H- [1, 2] oxazine, 3,6-dihydro-2H- [1, 2] oxazine, 3,4-dihydro-2H- [1, 2] oxazine, 5, 6-dihydro-4H- [1, 2] thiazine, 5, 6-dihydro-2H- [1, 2] thiazine, 3,6- dihydro-2H- [1, 2] thiazine, 3, 4-dihydro-2H- [1, 2] thiazine, 5,6-dihydro-2H- [1, 3] oxazine, 5, 6-dihydro-4H- [1, 3] oxazine, 3, 6-dihydro-2H- [1, 3] oxazine, 3,4- dihydro-2H- [1, 3] oxazine, 3, 6-dihydro-2H- [1, 4] oxazine, 3,4-dihydro-2H- [1, 4] oxazine, 5, 6-dihydro-2H- [1, 3] thiazine, 5, 6-dihydro-4H- [1, 3] thiazine, 3,6- dihydro-2H- [1, 3] thiazine, 3,4-dihydro-2H- [1, 3] thiazine, 3,6-dihydro-2H- [1, 4] thiazine, 3, 4-dihydro-2H- [1, 4] thiazine, 1, 2,3, 6-tetrahydro-[1, 2,4] triazine, 1, 2,3, 4-tetrahydro- [1, 2,4] triazine, 1, 2,3, 4-tetrahydro-[1, 3, 5] triazine, 2,3, 4,5- tetrahydro-[1, 2,4] triazine, 1, 4,5, 6-tetrahydro-[1, 2,4] triazine, 5,6-dihydro- [1, 4,2] dioxazine, 5, 6-dihydro-[1, 4,2] dioxazine, 5, 6-dihydro-[1, 4,2] dithiazine, 2,3- dihydro-[1, 4,2] dioxazine, 3, 4-dihydro-2H- [1, 3,4] oxadiazine, 3,6-dihydro-2H- [1, 3,4] oxadiazine, 3, 4-dihydro-2H- [1, 3, 5] oxadiazine, 3,6-dihydro-2H- [1, 3,5] oxadiazine, 5, 6-dihydro-2H-[1, 2,5] oxadiazine, 5, 6-dihydro-4H- [1, 2,5] oxadiazine, 3, 4-dihydro-2H- [1, 3,4] thiadiazine, 3,6-dihydro-2H- [1, 3,4] thiadiazine, 3, 4-dihydro-2H- [1, 3,5] thiadiazine, 3,6-dihydro-2H- [1, 3,5] thiadiazine, 5, 6-dihydro-2H- [1, 2,5] thiadiazine, 5, 6-dihydro-4H- [1, 2,5] thiadiazine, 5, 6-dihydro-2H- [1, 2,3] oxadiazine, 3,6-dihydro-2H- [1, 2,5] oxadiazine, 5, 6-dihydro-4H-[1, 3,4] oxadiazine, 3,4-dihydro-2H- [1, 2,5] oxadiazine, 5, 6-dihydro-2H- [1, 2,3] thiadiazine, 3,6-dihydro-2H- [1, 2,5] thiadiazine, 5, 6-dihydro-4H- [1, 3,4] thiadiazine, 3, 4-dihydro-2H- [1, 2,5] thiadiazine, 5, 6-dihydro-[1, 4,3] oxathiazine, 5, 6-dihydro-[1, 4,2] oxathiazine, 2, 3-dihydro-[1, 4,3] oxathiazine, 2, 3-dihydro-[1, 4,2] oxathiazine, 4,5- dihydropyridine, 1, 6-dihydropyridine, 5, 6-dihydropyridine, 2H-pyran, 2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-dihydropyridazine, 4,5- dihydropyridazine, 1, 2-dihydropyridazine, 1, 4-dihydropyrimidin-1-yl, 1,4- dihydropyrimidin-4-yl, 1, 4-dihydropyrimidin-5-yl, 1, 4-dihydropyrimidin-6-yl,
2, 3-dihydropyrimidine, 2,5-dihydropyrimidine, 5, 6-dihydropyrimidine, 3,6- dihydropyrimidine, 4,5-dihydropyrazine, 5,6-dihydropyrazine, 3,6- dihydropyrazine, 4,5-dihydropyrazine, 1,4-dihydropyrazine, 1,4-dithiin, 1,4- dioxin, 2H-1, 2-oxazine, 6H-1, 2-oxazine, 4H-1, 2-oxazine, 2H-1, 3-oxazine, 4H- 1,3-oxazine, 6H-1, 3-oxazine, 2H-1, 4-oxazine, 4H-1, 4-oxazine, 2H-1, 3-thiazine, 2H-1, 4-thiazine, 4H-1, 2-thiazine, 6H-1, 3-thiazine, 4H-1, 4-thiazine, 2H-1,2- thiazine, 6H-1, 2-thiazine, 1,4-oxathiin, 2H, SH-1, 2,3-triazine, 1H, 4H-1,2, 3- triazine, 4, 5-dihydro-l,; 2, 3-triazine, 1H, 6H-1, 2,3-triazine, 1, 2-dihydro-1, 2,3- triazine, 2, 3-dihydro-1, 2, 4-triazine, 3H, 6H-1, 2,4-triazine, 1H, 6H-1, 2,4-triazine, 3, 4-dihydro-1, 2, 4-triazine, 1H, 4H-1, 2,4-triazine, 5, 6-dihydro-1, 2,4-triazine, 4,5- dihydro-1, 2,4-triazine, 2H, 5H-1, 2,4-triazine, 1, 2-dihydro-1, 2,4-triazine, 1H, 4H- 1,3, 5-triazine, 1, 2-dihydro-1, 3,5-triazine, 1,4, 2-dithiazine, 1,4, 2-dioxazine, 2H- 1,3, 4-oxadiazine, 2H-1, 3,5-oxadiazine, 6H-1, 2,5-oxadiazine, 4H-1,3, 4- oxadiazine, 4H-1, 3,5-oxadiazine, 4H-1, 2,5-oxadiazine, 2H-1, 3,5-thiadiazine, 6H- 1,2, 5-thiadiazine, 4H-1, 3,4-thiadiazine, 4H-1, 3,5-thiadiazine, 4H-1,2, 5- thiadiazine, 2H-1, 3,4-thiadiazine, 6H-1, 3,4-thiadiazine, 6H-1, 3,4-oxadiazine, and 1,4, 2-oxathiazine, wherein the heterocycle is optionally vicinally fused with a saturated or unsaturated 5-, 6-or 7-membered ring containing 0,1 or 2 atoms independently selected from N, O and S; Ri is phenyl substituted by 0,1 or 2 groups selected from halo, Cl 4alkyl, C, 3haloalkyl,-ORh and-NRhRh ; or Ri is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0,1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, Cl 4alkyl, Cl 3haloalkyl,-ORh and-NRhRh ; and Rk is hydrogen or-CH3.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is C2-6alkyl or Cl 4haloalkyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is R'substituted by 1,2 or 3 substituents independently selected from R.
In another embodiment, in conjunction with the novel compound embodiments above and below, Ri is substituted by one substituent selected from halo, Cl 4haloalkyl and C1-8alkyl, and additionally by 0,1 or 2 substituents independently selected from R.
In another embodiment, in conjunction with the novel compound embodiments above and below, Rl5 is H.
In another embodiment, in conjunction with the novel compound embodiments above and below, R 15 is R'°, C1-8alkyl, substituted by 0, 1 or 2 substituents selected from R'°, or a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, the heterocycle and bridge being substituted by 0,1, 2 or 3 substituents independently selected from Rl° ; or Rls is- phenyl substituted by 0, 1, 2 or 3 substituents independently selected from H, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl),-C(=O)O(C1-8alkyl), - C (=O) NR"R",-C (=NR") NR"R',-OC (=O) (C, _8alkyl),-OC (=O) NR"R", -OC(=O) N (Rh) S (=0) 2 (C, -8alkyl),-OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh,
-S (=O) (C, 8alkyl),-S (=0) 2 C1-8alkyl,-S(=O)2NRhRh, (=O)2N(Rh) C (=O) (C, -8alkyl),-S(=O)2N(Rh) C (=O) O (C, -8alkyl), -S(=O)2N(Rh) C (=O) NRhRh,-NRhRh,-N (Rh) C (=O) C1-8alkyl, - N (R") C (=O) O C1-8alkyl,-N(Rh) C (=O) NRhR",-N (Rh) C (=NRh)NRhRh, - N (R") S (=0) 2 (C,-8alkyl),-N (R') S (=0) 2NR"R",-NRhC2_6alkylNRhRh, -NRhC2-6alkylORh,and C1-4alkyl substituted by 0, 1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) C1-8alkyl,-C(=O)O(C1-8alkyl), -C(=O)NRhRh,-C(=NRh)NRhRh,-ORh,-OC(=O)(C1-8alkyl,)-OC(=O)NRh Rh, -OC(=O) N (Rh) S (=0) 2 (C1-8alkyl),-OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh, -S(=O)(C1-8alkyl),-S(=O) 2 (C1 -8alkyl),-S(=O)2NRhRh, -S(=O) 2N (Rh) C (=O) (C1-8alkyl),-S(=O)2N(Rh) C (=O) O (C1-8alkyl), - S(=O)2N(Rh)C(=O)NRhRh,-NRhRh,-N(Rh)C(=O)(C1-8alkyl), - N (R") C (=O) O (C1-8alkyl),-N(Rh) C (=O) NR"R",-N (R") C (NRh) NRhRh - N (R") S (=O) 2 (C1-8alkyl),-N(Rh) S (=O) 2NRhRh,-NR"C2-6alkylNRhR"and -NRhC2-6alkylORh.
In another embodiment, in conjunction with the novel compound embodiments above and below, R 16 is H.
In another embodiment, in conjunction with the novel compound embodiments above and below, R16 is halo,-NHC1-3alkyl,-N(C1-3alkyl)C1-3alkyl, -OC1-3alkyl,-C1-2haloalkyl,-OC1-2haloalkyl or C1-3alkyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is wherein at least one pf R10,R11,R12,R13 and R14 is other than Cl 4haloalkyl or halo.
In another embodiment, in conjunction with the novel compound embodiments above and below, at least one pfR10,R11,R12,R13 and Rl4 is-ORh or -NRhRh.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, wherein each of the carbon atoms of the heterocycle is substituted by H, C1-9alkyl,C1-4haloalkyl,halo, cyano, oxo,-ORh,-S(=O)nC1-6alkyl,-OC1-4haloalkyl,-OC2-6alkylNRhRh, -PC2-6alkylORh,-OC1-6alkylC(=O)Orh,NRhRh,-NRhC1-4haloalkyl, - NRhC2-6alkylNRhRh,-NRhC2-6alkylORh,-C(=O)C1-6alkyl,-C(=O)OC1 -6alkyl, -OC(=O)C1-6alkyl,-C(=O)NRhC1-6alkyl or -NRhC(=O)C1-6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any available nitrogen atoms in the heterocycle are substituted by H,-C1-6alkylORh,-C1-6alkyl, -C1-6alkylNRhRh,-C1-3alkylC(=O)ORh,-C1-3alkylC(=O)NRhRh, -C1-3alkylOC(=O)C1-6alkyl,-C1-3alkylNRhC(=O)C1-6alkyl,-C(=O) Rj or -C1-3alkylRj; In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1 or 2 atoms selected from O, N and S, wherein each of the carbon atoms of the heterocycle is substituted by H, Cl _9alkyl, C, 4haloalkyl, halo, cyano, oxo,-ORh,-S(=O)nC1-6alkyl,-OC1-4haloalkyl, - 6alkylNRhRh,-OC2 6alkylORh,-OCl 6alkylC (=O) ORh,-NRhRh, - NRhC, 4haloalkyl,-NRhC2-6alkylNRhRh,-NR"C2-6alkylORh,-C (=O) C,_6alkyl, -C (=O) OCl 6alkyl,-OC (=O) Cz 6alkyl,-C (=O) NRhCl 6alkyl or -NRhC (=O) CI 6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any available nitrogen atoms in the bridge are substituted by H, -C1-6alkylORh,-C1-6alkyl,-C1-6alkylNRhRh,-C1-3alkylC(=O)ORh, -C1-3alkylC(=O)NRhRh,-C1-3alkylOC(=O)C1-6alkyl,-C1-3alkylNRh C(=O)C1-3alkyl, -C(=O)Rj or -C1-3alkylRj, In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is an 8-, 9-, 10-or 11-membered bicyclic ring, containing 1,2, 3 or 4 N atoms and 0,1 or 2 atoms selected from S and O with the remainder being carbon atoms, wherein each of the carbon atoms of the ring is substituted by H, C_alkyl, C, 4haloalkyl, halo, cyano, oxo,-OR,
- S (=O) nC, 6alkyl,-OC, 4haloalkyl,-OC2-6alkylNR"Rh,-OC2_alkylOR", -OC1-6alkylC(=O)ORh,-NRhRh,-NRhC1-4haloalkyl,-NRhC2-6alkylNR hRh, -NRhC2-6alkylORh,-C(=O)C1-6alkyl,-C(=O)OC1-6alkyl,-OC(=O)C1- 6alkyl, -C (=O) NRhCl 6alkyl or-NRhC (=O) Cl 6alkyl ; and saturated carbon atoms may be additionally substituted by =O ; and any available nitrogen atoms in the ring are substituted by H,-C1-6alkylORh,-C1-6alkyl,-C1-6alkylNRhRh, -C1-3alkylC(=O)ORh,-C1-3alkylC(=O)NRhRh,-C1-3alkylOC(=O)C1-6 alkyl, -C1-3alkylNRhRjh(=O)C1-6alkyl,-C(=O)Rj or -C1-3alkylRj, In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is an 8-, 9-, 10-or 11-membered bicyclic ring, containing 0,1, 2,3 or 4 N atoms and 0,1 or 2 atoms selected from S and O with the remainder being carbon atoms, wherein at least one of the carbon atoms of the ring is substituted by C1-9alkyl,C1-4haloalkyl, halo, cyano, oxo,-ORh, -S(=O)nC1-6alkyl,-OC1-4haloalkyl,-OC2-6alkylNRhRh,-OC2-6alky lORh, -OC, 6alkylC (=O) ORh,-NRhRh,-NRhCI 4haloalkyl,-NRhC2 6alkylNRhRh, -NRhC2-6alkylORh,-C(=O)C1-6alkyl,-C(=O)OC1-6alkyl,-OC(=O)C1- 6alkyl, -C(=O)NRhC1-6alkyl or -NRhC(=O)C1-6alkyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R and R9 are each independently selected from H, Cl 4haloalkyl, halo, nitro,-OC1-6alkyl,-OC1-4haloalkyl,-OC2-6alkylNRhRh, - OC2_6alkylORh,-NRhRh,-NRnC, _4haloalkyl,-NR"C2-6alkylNRhR", - NRhC2-6alkylORh,-CO2(C1-6alkyl),-C(=O)(C1-6alkyl),-C(=O)NRhR h, - NR"C (=O) Rh,-NRhC (=O) NR'Rh,-NR"CO2 (CI 6alkyl),-CI-8alkylORh, -Cl C1-6alkylNRhRh,-S(=O)n(C1-6alkyl),-S(=O)2NRhRh,-NRhS(=O)2(C1 -6alkyl) and -OC(=O)NRhRh.
In another embodiment, in conjunction with the novel compound embodiments above and below, R6 and R8 are each independently selected from H, C1-5alkyl,C1-4haloalkyl,halo,-OC1-6alkyl,-OC1-4haloalkyl,-OC 2-6alkylNRhRh, - OC2_6alkylOR",-NR"Rh,-NRhC, _4haloalkyl,-NRhC2-6alkylNRhRh or -NRhC2-6alkylORh,-C1-8alkylORh,-C1-6alkylNRhRh and -S(C1-6alkyl).
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is independently, at each instance,
C1-8alkyl,C1-4haloalkyl,-OC1-4haloalkyl,-OC2-6alkylNRhRh, -OC2-6alkylORh,-NRhRh,-NRhC1-4haloalkyl,-NRhC2-6alkylNRhRh, -NRhC2-6alkylORh,-C1-8alkylORh,-C1-6alkylNRhRh or -S(C1-6alkyl).
In another embodiment, in conjunction with the novel compound embodiments above and below, Rl° and R14 are each independently selected from H, C1-8alkyl,C1-4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl), <BR> <BR> <BR> -C (=O) O (C, 8alkyl),-C (=O) NRhRh,-C (=NRh) NRhRh,-ORh-OC (=O) (CI 8alkyl) -OC(=O)NRhRh,-OC(=O) N (R h) S (=0) 2 (C, _8alkyl),-OC2-6alkylNRhRh, - OC2-6alkylORh,-SRh,-S(=O)(C1-8alkyl),-S(=O) 2 (C1-8alkyl),-S(=O)2NRhRh, - S (=0) 2N (R") C (=O) (C1-8alkyl),-S(=O)2N(Rh) C (=O) O (C1-8alkyl), -S(=O)2N(Rh) C (=O) NRhRh,-NRhRh,-N(Rh) C (=O) (C1-8alkyl), -N(Rh) C (=O) O (C1-8alkyl),-N(Rh) C (=O) NR R,-N (R) C (=NRh) NRhRh, - N (R") S (=O) 2 (C1-8alkyl),-N(Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC2-6alkylORh and C1-6alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl),-C(=O)NRhRh, - C (=NRh) NRhR",-OR",-OC (=O) (C,-8alkyl),-OC (=O) NRhRh, -OC(=O) N (Rh) S (=0) 2 (C1-8alkyl),-OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh, -S(O)(C1-8alkyl),-S(O) 2 (C1-8alkyl),-S(=O)2NRhRh, -S(=O) 2N (Rh) C (=O) (C1-8alkyl),-S(=O)2N(Rh) C (=O) O (C1-8alkyl), -S (=0) 2N (Rh) C (=O) NRhR",-NRhRh,-N (R") C (=O) (C, 8alkyl), -N(Rh) C (=O) O (Cl 8alkyl),-N (R) C (=O) NRhRh,-N(Rh) C (=NRh) NRhRh, - N (R") S (=O) 2 (C1-8alkyl),N(Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and - C2-6alkylOR In another embodiment, in conjunction with the novel compound embodiments above and below, R11 and R13 are independently, at each instance, selected from H, C1-8alkyl,C1-4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl), -C(P)O(C1-8alkyl),-C(=O)NRhRh,-C(=NRh)NRhRh,-ORh,-OC(=O)(C1- 8alkyl), -OC(=O)NRhRh,-OC(=O) N (Rh) S (=0) 2 (C, -8alkyl),-OC2-6alkylNRhRh, - OC2-6alkylORh,-SRh,-S(=O)(C1-8alkyl),-S(=O)2(C1-8alkyl),-S(= O)2NRhRh, -S (=0) 2N (Rh) C (=O) (C, 8alkyl),-S (=0) 2N (Rh) C (=O) O (C1-8alkyl), - S (=0) 2N (R") C (=O) NRhR",-NRhRh,-N (Rh) C (=O) (C, -8alkyl), -N(Rh)C(=O)O(C1-8alkyl),-N(Rh)C(=O)NRhRh,-N(Rh)C(=NRh)NRhRh,
-N(Rh) S (=0) 2 (C,-8alkyl),-N (R") S (=0) 2NRhRh,-NRhC2-6alkylNRhRh, -NRhC2-6alkylORh and C1-4alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl),-C(=O)O(C1-8alkyl), -C(=O)NRhRh,-C(=NRh)NRhRh,-ORh,-OC(=O)(C1-8alkyl),-OC(=O)NRh Rh, -OC(=O) N (Rh) S (=0) 2 (C1-8alkyl),-OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh, -S(=O)(C1-8alkyl),-S(=O) 2 (C1-8alkyl),-S(=O)2NRhRh, -S(=O)2N(Rh) C (=O) (C1-8alkyl),-S(=O)2N(Rh) C (=O) O (C, -8alkyl), - S (=0) 2N (R") C (=O) NRhRh,-NRhRh,-N(Rh) C (=O) (C1-8alkyl), -N (R h) C (=O) O (C1-8alkyl),-N(Rh) C (=O) NRhRh,-N (Rh) C (=NRh) NR"Rh, -N(Rh) S (=O) 2 (C, 8alkyl),-N (R") S (=O) 2NRhR",-NRhC2-6alky1NRhRh and -NRhC2-6alkylORh.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'2 is independently, at each instance, selected from H, C1-8alkyl,C1-4haloalkyl,halo, cyano, nitro,-C (=O) O (C1-8alkyl), -C(=O)NRhRh,-C(=NRh)NRhRh,-ORh,-OC(=O)(C1-8alkyl),-OC(=O)NRh Rh, -OC(=O) N (Rh) S (=0) 2 (C1-8alkyl),-OC2-6alkylNRhRh,-OC2 6alkylORh,-SRh, -S(=O)(C1-8alkyl),-S(=O) 2 (C1 -8alkyl),-S(=O)2NRhRh, -S(=O)2N(Rh) C (=O) (C, -8alkyl),-S(=O)2N(Rh) C (=O) O (C1-8alkyl), - S(=O)2N(Rh)C(=O)NRhRh,-NRhRh,-N(Rh)C(=O)(C1-8alkyl), -N(Rh) C (=O) O (C1-8alkyl),-N(Rh) C (=O) NR R,-N (R) C (=NRh) NR"R", -N(Rh) S (=O) 2 (c1-8alkyl),-N(Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC26alkylORh ; or R12 is Cl 4alkyl substituted by 0,1, 2 or 3 groups selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) (C1-8alkyl)n-C(=O)O(C1-8alkyl), <BR> <BR> <BR> - C (=O) NR"Rh,-C (=NR") NR"Rh,-OR",-OC (=O) (C,-salkyl),-OC (=O) NR"R, -OC(=O) N (Rh) S (=0) 2(C1-8alkyl),-OC2-6alkylNRhRh,-OC2-6alkylORh,-SRh, -S(=O)(C1-8alkyl),-S(=O) 2 (C1-8alkyl),-S(=O)2NRhRh, - S (=0) 2N (R") C (=O) (C1-8alkyl),-S(=O)2N(Rh) C (=O) O (C, -8alkyl), - S (=0) 2N (R") C (=O) NRhR",-NR"R",-N (R") C (=O) (C1-8alkyl), -N(Rh) C (=O) O (C -8alkyl),-N(Rh) C (=O) NRhRh,-N (R") C (=NR") NRhRh, - N (R") S (=O) 2 (C1-8alkyl),-N(Rh) S (=O) 2NRhRh,-NRhC2-6alkylNRhRh and -NRhC2-6alkylORh.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is O.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is S.
Another aspect of the invention relates to a compound having the structure: wherein: X is O, S or NRm; n is independently, at each instance, 0,1 or 2; o is independently, at each instance, 0,1, 2 or 3; Rm is independently at each instance H or Rn ; Rn is independently at each instance Cl 8alkyl, phenyl or benzyl; Rq is independently in each instance H, C1-4alkyl, C1-4haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C (=O) OR n,-C (=O) NR'R',-C (=NR') NR'R',-OR', -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2R°,-OC2-6alkylNR"'R"', - OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S 2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm)C(=O)NRmRm, - NR"'R"',-N (R"') C (=O) R",-N (R"') C (=O) ORn,-N (Rm) C (=O) NR"'R"', - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm - NR'R' or-NR'C2-6alkylOR' ; Rs is Rn substituted by 0,1, 2 or 3 substituents independently selected from Rq ; R3 is H or Cl 4alkyl ; Rs is H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, or-(CH2)nRc R6 is, independently at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm,
-O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; R8 is H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OC1-6alkyl, - O-C1-4haloalkyl, -O-C1 -6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; and (A) R'is R2 is H, -ORm, halo, C1-3haloalkyl or C1-6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC (=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNR"'R"',-OC2 6alkylOR"',-SRm,-S (=O) R°, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm, -NRmRm, -N (Rm) C (=O) R,-N (Rm) C (=O) OR", - N(Rm)C(=O)NRmRm, &-N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs, (Rm) C (=O) OR',-N (Rm) C (=O) NR'R',-N (Rm) C (=NRm) NRmRs, - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo,
cyano, nitro,-C (=O) Rn,-C (=O) OR",-C (=O) NR'Rm,-C (=NRm) NRmRm,-ORm -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm) C (=O) Rn,-S (=O) 2N (Rm) C (=O) OR',-S (=0) 2N (Rm) C (=O) NRmRm, - NRmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> - NRmC2-6alkylNR"'Rm,-C (=O) RS,-C (=O) ORs,-C (=O) NRmR',-C (=NRm) NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)C(=NRm)NRMRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, - NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, C 4haloalkyl, halo, cyano, nitro, -C (=O) R",-C (=O) ORn,-C (=O) NRmRm, -C (=NRm) NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn,-S(=O)2N(Rm)C(=O)NR mRm, -NR'R',-N (Rm) C (=O) Rn7-N (Rm) C (=O) OR",-N (R"') C (=O) NR"'R"', - N (R"') C (=NRm) NRmRm,-N (Rm) S (=O) 2R",-N (Rm) S (=O) 2NRmRm, - NRmC2+6alkylNRmRm or-NRmC2-6alkylORm ; and Y is 0 or NH; or (B) R'is R2 is H,-ORm, halo, Cl 3haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C (=O) ORn,-C(=O)NRmRm, -C(=NRm)NRmRm,-ORm,-OC(=O)Rn; -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2R,-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S (=O) R -S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O) ORn, -S(=O)2N(Rm) C (=O) NRmRm,-NRmRm,-N(Rm) C (=O) R,-N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm) S (=O) 2Rn, - N (R"') S (=0) 2NRmRm,-NRmC2-6alkylNRmRm,-NRm,C2-6alkylORm,-C(=O)Rs, -C (=O) ORs,-C (=O) NRmRs,-C (=NRm) NRmRs,-ORs,-OC (=O) Rs, -OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmR',-OC2-6alkylOR', -SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRmRs,-NRmRs,-N(Rm) C (=O) Rs, - N (R"') C (=O) OR',-N (Rm) C (=O) NRmRs,-N (Rm) C (=NR"') NRmRs, - N(Rm)S(=O)2Rs,-N(Rm)S(=O)2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6a lkylORs and C, 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) R",-C (=O) ORn,-C(=O)NRmRm,-C(=NRm)NRmRm,-ORm, -OC(=O)Rn,-OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNRmRm, - kylORm,-SRm,-S (=O) R",-S (=0) 2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm,-N(Rm) C (=O) R",-N (Rm) C (=O) OR°,-N (Rm) C (=O) NR"'R"',
-N (R') C (=NRm) NRmRm,-N (R"') S (=0) 2R",-N (Rm) S (=0) 2NRmRm, - NRmC2-6alkylNRmRm,-C(=O)Rs,-C(=O)ORs,-C(=O)ORs,-C(=O)NRmRs,- C(=NRm)NRmRs, -ORs,-OC(=O)Rs,-OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs, -OC2-6alkylORs,-SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRm Rs, -NRmRs,-N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs,-N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs,-NRmC2-6alkylORsand-NRmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C1-9alkyl, C1-4haloalkyl,halo, nitro, cyano,-OCl -6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm,-O-C1-6alkylORm,-NRmRm, -NRm-C1-4haloalkyl,-NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; Rp is independently at each instance C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, -C (=O) R°,-C (=O) OR",-C (=O) NRR"\-C (=NRm) NRmRm,-ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNRmRm, - OC2 6alkylORm,-SR°',-S (=O) R",-S (=0) 2R",-S (=0) 2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn,-S(=O)2N(Rm)C(=O)NRmrm, -NRmRm,-N(Rm) C (=O) rn,-N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, - N(Rm)C(NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; and Y is O or NH; or (C) R'is R2 is H, -ORm, halo, C1-3haloalkyl or C1-6 alkyl ; R4 is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or 11-membered bicyclic heterocycle containing 1,2, 3,4 or 5 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5, 6,7-tetrahydro-benzo [b] thiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo [1, 4] dioxin-6-yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from Cl 9alkyl, oxo, C1-4haloalkyl, halo, nitro, cyano,-ORm,-S (=O) -6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, - O-C1-6alkylORm,-NRmRm,-NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm,-C(=O)C1-6alkyl,-OC(=O)C1-6alkyl,-C(=O)NRm C1-6alkyl, -NRmC(=O)C1-6alkyl-C(=O)Rs,-C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NRm Rs, - ORS,-OC (=O) R',-OC (=O) NRmR',-OC (=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs, -OC2-6alkylORs,-SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRm Rs, NRmRs-N (Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs,-N(Rm)S(=O)2Rs,-N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) R n,-C (=O) NR'Rm, -C (=NRm) NRmRm,-ORm,-OC (=O) Rn,-OC (=O) NRmRm, -OC (=0) N (Rm) S (=0) 2Rn,-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S(=O)Rn, - S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)O Rn, - S(=O)2N(Rm)C(=O)NRmRm,-N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, - N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn, - N(Rm)S(=O)2NRmRm, -C(=O)R5,-C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-salkylNRmR', -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs,
-NRmRs,-N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm) S (=0) 2R',-N (R') S(=O)2NRmRs -NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and -NRmC2-6alkylORm ; wherein R4 is not 2-aminocarbonylmethyl-2, 3-dihydro-benzo [1, 4] dioxin-8-yl, 2-cyanomethyl- 2, 3-dihydro-benzo [1, 4] dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo [1, 3] dioxol-5-yl, 3, 3-dimethyl-1, 3-dihydro-indol-2-on-6-yl or 4, 4-dimethyl- 3, 4-dihydro-lH-quinolin-2-on-7-yl ; R7 is C1 8alkyl, C1 5haloalkyl, I or Br R9 is H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OC1-6alkyl,-O-C1-4haloalkyl, -O-C1-6alkylNRmRm,-O-C1-6alkylORm,-NRmRm,-NRm-C1-4haloalkyl, - NRm-C1-6alkylNRmRm,-NRm-C1-6alkylORm, or-(CH2)nR@ ; R9 is independently, at each instance, H, C1-9alkyl,C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1 6alkylNRmRm, -O-C1-6alkylORm,-NRmRm,-NRm-C1-4haloalkyl,-NRm-C1-6alkylNRmR mor -NRm-C1-6alkylORm ; Y is NH; and Z is CR8 or N; or (D) R'is R2 is Chalky ! substituted by 1, 2 or 3 substituents selected from C, 4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) ORn,-C(=O)NRmRm, - C (=NR"') NR"'R"',-OR"',-OC (=O) R",-OC (=O) NR"'R"', -OC (=0) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm,-OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm,-NRmRm,-N(Rm) C (=O) R,-N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm) S (=O) 2Rn, -N(Rm) S (=O) 2NR"'Rm,-NRmC2-6alkylNR"'Rm or-NRmC2-6alkylORm ; or
R2 is-(C (Rq) 2) 0phenyl, wherein the phenyl is substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C (=O) R",-C (=O) ORn, -C(=O)NRmRm,-C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNRmRm, -OC2-6alkylORm,-SRm,-S(=O)Rn, -S(=O)2Rn,-S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn,-S(=O) 2N (Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn7-N (Rm) C (=O) ORn, -N(Rm)C(=O)NRmRm, -N(Rm) C (=NRm) NRmRm,-N(=Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs,-C(=O)ORs, -C (=O) NRmR',-C (=NRm) NR'R',-ORs,-OC (=O) R,-OC (=O) NR'R', -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNR"'R',-OC2-6alkylORs,-SR',-S (=O) RS, - S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm) C (=O) NRmRs,-NRmR',-N (Rm) C (=O) Rs,-N (Rm) C (=O) ORs, - N(Rm)C(=O)NRmRs, -N(Rm)C(=NRm)NRmRs,-N(Rm)S(=O)2Rs, - N (R"') S (=O) 2NRmRs,-NRmC2-6alkylNRmR',-NR"'C2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C (=O) ORn,-C (=O) NRmRm,-C (=NRm) NRmRm, ORm OC (=O) Rn -OC OC(=O)NRmRm,-OC(=O)N(Rm)S(=O)2Rn,-OC2-6alkylNRmRm,-OC2-6alky lORm, -SRm,-S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn, - S(=O)2N(Rm)C(=O)ORn,-S(=O) 2N (Rm)C(=O)NRmRm,-NRmRm, -N(Rm) C (=O) R",-N (Rm) C (=O) ORn,-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - 6alkylNRmRm,-C (=O) R',-C (=O) ORs,-C (=O) NRmRs, -C (=NRm) NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - kylOR',-SR',-S (=O) Rs,-S (=0) 2R',-S (=0) 2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; or R2 is -(C(Rq)2)0R@, wherein Ru ils a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S,
wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from C, 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR', -C(=O)NRmRm,-C(=NRm)NRmRm,-ORm,-OC(=O)Rn,-OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm,-SRm,-S(=O)Rn, - S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C (=O) NR'R',-NR'R',-N (Rm) C (=O) Rn,-N(Rm) C (=O) OR', - N (R"') C (=O) NRmRm,-N (Rm) C (=NRm) NR'Rm,-N (Rm) S (=0) 2Rn, 1N(Rm) S (=0) 2NRmRm,-NRmC2-6alkylNRmRm,-NRmC2-6alkylORm, -C(=O)Rs, - C (=O) OR',-C (=O) NRmR',-C (=NR"') NR"'RS,-ORs,-OC (=O) R', -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs,-S(=O)Rs,-S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs,-NRmRs, -N(Rm) C (=O) Rs, -N (R') C (=O) ORs, -N(Rm) C (=O) NRmRs, -N (Rm) C (=NR'") NRmRs, -N(Rm) S (=0) 2Rs,-N (Rm) S (=O) 2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C (=O) OR",-C (=O) NRmRm,-C (=NRm) NRmRm,-ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm,-SRm,-S(=O)Rn, -S(=O)2Rn,-S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn,-S(=O) 2N (Rm)C(=O)NRmRm, -NRmRm,-N(Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> <BR> - NR"'C2-6alkylNR"'Rm,-C (=O) R',-C (=O) OR',-C (=O) NR"'RS,-C (=NRm) NR"'Rs, -ORs,-OC(=O)Rs,-OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs,-SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs,-N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - NRR)'C (=NRm) NR"'Rs,-N (Rm) S (=0) 2R',-N (Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and -NRmC2-6alkylORm ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected
from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) OR",-C (=O) NRmRm, -C(=NRm)NRmRm,-ORm,-OC(=O)Rn,-OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm,-S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NR'R',-NR'R',-N (Rm) C (=O) Rn,-N (Rm) C (=O) OR", -N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm,-NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O) Rs, - C (=O) OR',-C (=O) NRmRs,-C (=NR"') NR"'R',-ORs,-OC (=O) RS, -OC(=O)NRmRs,-OC(=O) N (R"') S (=0) 2Rs,-OC2-6alkylNRmRs, -OC2-6alkylORs, - SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C (=O) NRmRs,-NRmRs,-N (Rm) C (=O) Rs, -N (R') C (=O) ORs,-N(Rm) C (=O) NR'R',-N (Rm) C (=NRm) NRmRs, - (Rm) S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn,-OC2 6alkylNRmRm, -OC2-6alkylORm,-SRm,-S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, - NR"'R"',-N (R"') C (=O) Rn,-N(Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm,-C(=O)Rs, -C(=O)ORs,-C(=O)NRmRs, -C(=NRm)NRmRs, -ORs,-OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmR', -OC2-6alkylORs,-SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C 0) NRmRs, -NRmRs,-N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, - NR"C2-6alkylNR"'R',-NRmC2-6alkylORs and-NRmC2-6alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C2-8alkyl, C1-5haloalkyl, I, Br;
R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OC, -6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, - O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl,-NRm-C1-6alkylNRmRm or - NR"'-C -6alkylOR"' ; Y is NH; and Z is CR8or N ; or (E) R'is R2 is H, - ORm, Cl, C1-3haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C(=O)NRmRm,-C(=NRm)NRmRm, -ORn,-OC(=O)Rn, -OC(=O)NRmRm, -OC(=O)N(Rm)S(=O)2Rn, -OC2-6alkylORm,-SRm, -S(=O)Rn,-S(=O)2Rn, - S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NR"'R"',-NR'"R'",-N (R"') C (=O) R,-N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, - N (R'") S (=0) 2NRmRm,-NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, - OC NRmRs, -OC(=O) N R"') S (=0) 2R',-OC2-6alkylNR"'Rs,-OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R', - N (R°') C (=O) ORs, -N(Rm) C (=O) NRmRs,-N (Rm) C (=NRm) NRmRs, -N(Rm) S (=0) 2Rs-N (Rm) S (=0) 2NR"'Rs,-NR"'C2-6alkylNRmRs,-NR"'C2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm,-OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm,
-SRm, -S(=O)Rn,-S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, - S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm,-NRmRm, -N(Rm) C (=O) R",-N (Rm) C (=O) OR", -N (Rm) C (=O) NR"'Rm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm,-C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R5, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, -N(Rm) C (=NRm) NRmR',-N (Rm) S (=O) 2R',-N (Rm) S (=0) 2NRmRs, -NRmC26alkylNRmRs,-NRmC26alkylORs and-NRmC26alkylORm ; wherein R4 is not unsubstituted phenyl ; R9 is independently, at each instance, H, Cl 9alkyl, Cl 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; Y is NH; and Z is CR8 or N.
In another embodiment, in conjunction with the novel compound embodiments above and below, 80, wherein: R'is R2 is H, -ORm, halo, C1-3haloalkyl or C1-6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge
are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm,-NRmRm,-N(Rm) C (=O) R, N (R) C (=O) OR", -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2R, - N (R"') S (=O) 2NRmRm,-NRmC2-6alkylNRmRm,-NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O)N(Rm)S(=O)2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N (Rm) C (=O) ORs, -N(Rm) C (=O) NRmR',-N (Rm) C (=NR"') NRmRs, -N (Rm) S (=0) 2Rs,-N (Rm) S (=0) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) OR",-C (=O) NRmRm,-C (=NRm) NRmRm-ORm -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn,-OC2 6alkylNRmRm, -OC2-6alkylORm,-SRm,-S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn,-N (Rm) C (=O) ORn, -N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> <BR> - NR°'C2-6alkylNRmRm,-C (=O) Rs,-C (=O) ORs,-C (=O) NRmRs,-C (=NRm) NR"'R', -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O) 2N (Rm) C (=O) R',-S (=0) 2N (Rm) C (=O) OR',-S (=O) 2N (Rm) C (=O) NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm;and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C, 9alkyl, C, 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm,-O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ;
R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, -C (=O) R°,-C (=O) OR",-C (=O) NR"'Rm,-C (=NR"') NRmRm,-OR"', -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (R"') S (=O) 2Rn,-OC2 6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn7-N (Rm) C (=O) oRn7-N (Rm) C (=O) NRmRm - (Rm) C NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; and Y is O or NH.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C (=O) NRmRm, -NRmRm, -N(Rm) C (=O) R",-N (R"') C (=O) OR 1N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, -N(Rm) S (=0) 2NR"'R"',-NR"'C2-6alkylNR"'Rm,-NR"'C2-6alkylORm,-C (=O) R', -C(-O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, - OC (=O) NRmR',-OC (=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs,
- S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, -N (Rm) C (=NRm) NRmRs, -N(Rm) S (=0) 2Rs, -N (Rm) S (=0) 2NRmR',-NR"'C2-6alkylNR"'Rs,-NR"'C2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR",-C (=O) NRmRm,-C (=NR"') NRmRm,-OR"', -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2R",-OC2 6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs,-OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmR', - OC2 6alkylORs,-SR',-S (=O) Rs,-S (=0) 2R',-S (=0) 2NR"'R', - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C (=O) NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR",-C (=O) NRmRm, -C (=NRm) NRmRm,-ORm,-OC (=O) Rn,-OC (=O) NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C (=O) NRmRm, -NRmRm, -N (Rm) C (=O) Rn,-N (Rm) C (=O) OR", -N (Rm) C (=O) NRmRm, -N(Rm) C (=NRm) NRmRm,-N (Rm) S (=O) 2Rn, -N (Rm) S (=0) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs,
-OC(=O)NRmRs, -OC(=O) N (R"') S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs,-S (=O) Rs,-S (=0) 2Rs,-S (=0) 2NRmRs,-S (=0) 2N (Rm) C (=O) Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs, -N(Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs,-N (R) C (=NR"') NRmRs, - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, ni tro,-C (=O) Rn,-C (=O) ORn,-C (=O) NRmRm,-C (=NRm) NRmRm-ORm -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNR"'R"', -OC2-6alkylORm,-SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, --S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NR'Rs, -N(Rm) C (=NRm) NRmR',-N (Rm) S (=0) 2Rs,-N (Rm) S (=0) 2NRmRs -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the bridge carbon atoms are substituted with 0,1 or 2 =O groups.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is C1-9alkyl, C1-4haloalkyl, halo, -OC1-6alkyl, -O-C1-4haloalkyl, -NRmRm or -NRm-C1-4haloalkyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is C1-5alkyl, C1-4haloalkyl, I, Br or Cl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is tert-butyl or trifluoromethyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic ring containing 0,1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0,1 or 2
oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP.
In another embodiment, in conjunction with the novel compound embodiments above and below, R° is a saturated, partially-saturated or unsaturated 6-membered ring containing 0,1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from Rp.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is O.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is NH.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is R2 is H,-ORm, halo, Cl 3haloalkyl or C1-6alkyl; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, - C (=NRm) NR"'Rm,-ORm,-OC (=O) R°,-OC (=O) NR"'Rm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn,-S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, - S (=0) 2N (R"') C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) Rn,-N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2R, -N (Rm) S (=0) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs,
-C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNR"'R',-OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)1N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm) C (=O) ORs, -N(Rm) C (=O) NRmRs, -N (R) C (=NRm) NRmRs, - N (R"') S (=0) 2R',-N (Rm) S (=O) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C1-2haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn,-OC2 6alkylNRmRm, - OC2-6alkylORm,-SR"',-S (=O) R°,-S (=0) 2R",-S (=0) 2NR"'Rm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, - NR"'R"',-N (R°') C (=O) Rn, -N(Rm) C (=O) ORn, -N(Rm) C (=O) NR"'R'", - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmR5, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmR', - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =O groups; R7 is C, 9alkyl, Cl 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm,-O-C1-6alkylORm, -NRmRm, -NRm -C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; [C1-8alkyl, C1-5haloalkyl, I, Br or Cl] R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP ;
RP is independently at each instance Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C (=O) R",-C (=O) OR",-C (=O) NR"'R'",-C (=NRm) NR'R',-ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, - OC2-6alkylORm,-SRm,-S (=O) R",-S (=0) 2R°,-S (=0) 2NR"'R"', - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NR R, N (Rm) C (=O) R",-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N (R"') C (=NRm) NR"'R"',-N (Rm) S (=0) 2Rn, -N (Rm) S (=0) 2NRmRm, - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; and Y is O or NH.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR",-C (=0) NR"'R"\ -C(=NRm)NRmRm, -Orm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm, -NRmRm, -N(Rm) C (=O) R,-N (R) C (=O) OR, -N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm,-N (Rm) S (=O) 2Rn, -N(Rm) S (=O) 2NR"'R"',-NR"'C2-6alkylNR"'R"',-NRmC2-6alkylOR"',-C (=O) RS, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, - OC NRmRs, -OC(=O)N(Rm)S(=O)2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O) 2N (Rm) C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, -N (R"') C (=NR"') NR"'R', - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Chalky ! substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR",-C (=O) NR"'R"',-C (=NR"') NRmRm,-OR"', -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm,
- OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm) C (=O) R",-S (=0) 2N (Rm) C (=O) oRn7-S (=0) 2N (Rm) C (=O) NRmRm, - NR"'R°',-N (R") C (=O) Rn7-N (Rm) C (=O) oRn7-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S (=O) R',-S (=0) 2R',-S (=0) 2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, l, 2 or 3 substituents independently selected from C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm, -NRmRm, -N (Rm) C (=O) R",-N (Rm) C (=O) OR", -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N (Rm) S (=O) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNR"'RS,-OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, - N (R"') C (=O) ORs, -N(Rm) C (=O) NR'"R',-N (R"') C (=NR"') NRmRs, - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from C1-2haloalkyl, halo,
cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRmn,-C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNR"R"', -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (R"') C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> - NR"'C2-6alkylNR"'R"',-C (=O) R',-C (=O) ORS,-C (=O) NR"'RS,-C (=NRm) NR"R', -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OCz-alkylNRmR', - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C (=O) NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm) S (=0) 2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the bridge carbon atoms are substituted with 0,1 or 2 =O groups.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is C1-9alkyl, C1-4haloalkyl, halo, -OC1-6alkyl, -O-C1-4haloalkyl, -NRmRm or -NRm-C1-4haloalkyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is C1-5alkyl, C1-4haloalkyl, I, Br or Cl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is tert-butyl or trifluoromethyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic ring containing 0,1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP.
In another embodiment, in conjunction with the novel compound embodiments above and below, R° is a saturated, partially-saturated or unsaturated 6-membered ring containing 0, I, 2 or 3 N atoms, wherein the carbon
atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is O.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is NH.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is R2 is H,-ORm, halo, Cl 3haloalkyl or Chalky ! ; R4 is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or 11-membered bicyclic heterocycle containing 1,2, 3,4 or 5 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5, 6,7-tetrahydro-benzo [b] thiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo [1, 4] dioxin-6-yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C1-9alkyl, oxo, C1-4haloalkyl, halo, nitro, cyano,-ORm,-S (=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, -C(=O)C1-6alkyl, -Oc(=O)C1-6alkyl, -C(=O)NRmC1-6alkyl, -NRmC(=O)C1-6alkyl -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C (=O) NRmR -NRmRs,-N (Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)NRmRm, - C (=NR"') NR"'R"',-OR°,-OC (=O) R°,-OC (=O) NR"'R°',
-OC (=O) N (Rm) S (=O) 2Rn,-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S(=O)Rn, - S(=O)2Rn, S(=O)2NRmRm,S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn, - S(=O)2N(Rm)C(=O)NRmRm,-N(Rm)C(=O)Rn,-N(Rm)C(=O)ORn, - N (R"') C (=O) NR'"R"',-N (Rm) C (=NR"') NR"'R"',-N (Rm) S (=O) 2Rn, - N(Rm)S(=O)2NRmRm,-C(=O)Rs,-C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NRmR s, -ORs,-OC(=O)Rs,-OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmR', -OC2-6alkylORs,-SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)ORs,-S(=O) 2N (Rm) C(=O)NRmRs, - NRmRs,-N(Rm)C(=O)Rs,-N(Rm)C(=O)OR2,-N(Rm)C(=O)NRmRs, - N (R'") C (=NRm) NRmR',-N (Rm) S (=0) 2Rs, -N (Rm) S (=0) 2NRmRs, - NRn'C2-6alkylNR"'R',-NRmC2-6alkylORs and-NRmC2-6alkylOR"' ; wherein R4 is not 2-aminocarbonylmethyl-2, 3-dihydro-benzo [1, 4] dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo [1, 4] dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo [1, 3] dioxol-5-yl, 3, 3-dimethyl-1, 3-dihydro-indol-2-on-6-yl or 4,4-dimethyl- 3, 4-dihydro-1H-quinolin-2-on-7-yl ; R7 is C1-8alkyl, C1-5haloalkyl, I or Br; R9 is H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OCl-6alkyl, - OR',-NRmR', -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm; Y is NH; and Z is CR8 or N.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a heterocycle selected from indole, 3H- indole, benzo [b] furan, benzothiophene, 1H-indazole, benzimidazole, benzthiazole, 1H-benzotriazole, 7-quinoline, 8-quinoline, 1,2, 3,4- tetrahydroquinoline, isoquinoline, cinnoline, phthalazine, quinazoline and quinoxaline, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C, 9alkyl, oxo, C, 4haloalkyl, halo, nitro, cyano, -ORm, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, -C(=O)C1-6alkyl,-OC(=O)C1-6alkyl, -C(=O)NRmC1-6alkyl,-NRmC(=O)C1-6alkyl -C (=O) Rs,-C (=O) ORs,-C (=O) NRmRs,-C (=NRm) NRmRs,-ORs,-OC (=O) Rs,
-OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R', -N(Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs,-N (Rm) C (=NR"') NRmRs, -N(Rm) S (=0) 2R',-N (Rm) S (=0) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) NRmRm,-C (=NRm) NRmRm,-ORm,-OC (=O) Rn, -OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, - SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, - S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -N(Rm)C(=O)Rn, -N(Rm) C (=O) OR",-N (R"') C (=O) NRmRm,-N (R"') C (=NRm) NRmRm, - N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, - NR"'R',-N (R"') C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a heterocycle selected from 6-indole, 7- indole, 6-3H-indole, 7-3H-indole, 6-benzo [b] furan, 7-benzo [b] furan, 6- benzothiophene, 7-benzothiophene, 6-1H-indazole, 7-1H-indazole, benzimidazole, benzthiazole, 1H-benzotriazole, 7-quinoline, 8-quinoline, 7- 1,2, 3,4-tetrahydroquinoline, 8-1, 2,3, 4-tetrahydroquinoline, isoquinolin-7-yl, isoquinolin-8-yl, 7-cinnoline, 8-cinnoline, phthalazine, 7-quinazoline, 8- quinazoline and quinoxaline, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from C1-9alkyl,oxo,C1-4haloalkyl,halo, nitro, cyano,-OR'",-S (=O) -6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, -C(=O)C1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRmC1-6alkyl, -NRmC(=O)C1-6alkyl-C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs,
- OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm) C (=O) R',-S (=0) 2N (Rm) C (=O) OR',-S (=0) 2N (R"') C (=O) NRmRs, - NR"'R',-N (R"') C (=O) R',-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRMC2-6alkylNR'R',-NRMC2-6alkyl OR'and C I-4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, - S (=0) 2N (R"') C (=O) NRmRm,-N (Rm) C (=O) R",-N (Rm) C (=O) OR', -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, - N(Rm)S(=O)2NRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, - NRmC2-6alkylNRmR',-NR"'C2-6alkylORs and-NRmC2-6alkylOR"'.
In another embodiment, in conjunction with the novel compound embodiments above and below, R9 is C1-9alkyl, C1-4haloalkyl,halo, nitro, cyano, - OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, - NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm.
In another embodiment, in conjunction with the novel compound embodiments above and below, R9 is H.
In another embodiment, in conjunction with the novel compound embodiments above and below, Z is CR8.
In another embodiment, in conjunction with the novel compound embodiments above and below, Z is N.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is tert-butyl or trifluoromethyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is R2 is Cul 6alkyl substituted by 1,2 or 3 substituents selected from C, 4haloalkyl, halo, cyano, nitro,-C (=O) R n,-C (=O) OR',-C (=O) NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) Rn,-N (Rm) C (=O) OR -N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm,-N (Rm) S (=O) 2Rn, -N (Rm) S (=O) 2NRmRm, -NRmC2-6alkylNRmRm and -NRmC2-6alkylORm ; or R2 is R2 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7 ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn, -C (=O) NR""R"\ -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm,
-OC (=O) N (Rm) S (=0) 2R°,-OC2-6alkylNR"'Rm,-OC2-6alkylORm,-SRm,-S (=O) R", - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, - S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N (Rm) S (=O) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, @ (=O)2N(Rm)C(=O)ORs, -S(=O) 2N (R') C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R', -N(Rm) C (=O) ORs, -N(Rm) C (=O) NRmR',-N (R') C (=NR"') NRmRs, -N (Rm) S (=0) 2Rs,-N (Rm) S (=0) 2NR"'R',-NR"'C2-6alkylNR"'R',-NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=o) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm) C (=O) Rn, -S(=O) 2N (Rm) C (=O) ORn, -S(=O)2N(Rm) C (=O) NRmRm, -NRmRm, -N(Rm) C (=O) R",-N (Rm) C (=O) OR",-N (Rm) C (=O) NR"'R"', -N(Rm) C (=NRm) NRmRm,-N (Rm) S (=0) 2Rn, -N(Rm) S (=O) 2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, - NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C2-8alkyl, C1-5haloalkyl, I, Br; R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, - O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; Y is NH; and
Z is CR8 or N.
In another embodiment, in conjunction with the novel compound embodiments above and below, R2 is Cs 6alkyl substituted by 1,2 or 3 substituents selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR", -C (=O) NRmRm,-C (=NRm) NRmRm,-ORm,-OC (=O) Rn,-OC (=O) NRmRm -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNR"'Rm,-OC2-6alkylORm,-SR"',-S (=O) R", - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (R"') C (=O) NRmRm, -NRmRm, -N(Rm) C (=O) R,-N (Rm) C (=O) OR, -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N-(Rm)S(=O)2Rn, - N (R"') S (=O) 2NRmRm, -NRmC2-6alkylNRmRm and -NRmC2-6alkylORm ; In another embodiment, in conjunction with the novel compound embodiments above and below, R2 is -(C(Rq) 2) 0phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from Cl 8alkyl, C 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) Rn, -N(Rm) C (=O) OR", -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC (=O) NRmRs,-OC (=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, -N(Rm)C(=NRm)NRmRs, -N(Rm) S (=0) 2Rs,-N (Rm) S (=0) 2NRmRs,-NRmC2-6alkylNRmRs,-NR"'C2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, - OC (=O) R",-OC (=O) NR"'R"',-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, - OC2-6alkylORm,-SRm,-S (=O) R",-S (=0) 2R",-S (=O) 2NR"'R"', -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, - NR'"R"',-N (R"') C (=O) R",-N (Rm) C (=O) oRn7-N (Rm) C (=O) NRmRm,
-N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm.
In another embodiment, in conjunction with the novel compound embodiments above and below, R2 is -(C(Rq)2)oRr, wherein Rr is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, C1 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn,-OC2 6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) R",-N (R"') C (=O) OR",-N (R"') C (=O) NRmRm -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmRs,-OC2. 6alkylORs,-SR',-S (=O) RS, - S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C (=O) NR"'R',-NR"'R\-N (Rm) C (=O) R',-N (Rm) C (=O) OR', -N(Rm) C (=O) NRmRs, -N (Rm) C (=NR"') NRmRs, -N (Rm) S (=0) 2R', -N (Rm) S (=O) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn,
- (=0) 2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, - N (R"') C (=O) R",-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNR"'R', -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (R"') C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Ci. 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R,-OC2-6alkylNRmRm,-OC2-6alkylORm,-SR',-S (=O) R -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm-NRmRm,-N (Rm) C (=O) R,-N (Rm) C (=O) OR", -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, -N (Rm) S (=O) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C (=O) ORs,-C (=O) NRmRs,-C (=NRm) NRmRs,-ORs,-OC (=O) Rs, -OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs,-N (Rm) C (=NR"') NRmRs, - N (R'") S (=0) 2Rs,-N (Rm) S (=0) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR",-C (=O) NRmRm,-C (=NRm) NR"'Rm,-ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm,
- OC2-6alkylORm, -SRm, -S (=O) Rn, -S (=0) 2Rn, -S (=0) 2NR'R', -S(=O) 2N (R"') C (=O) R",-S (=0) 2N (Rm) C (=O) OR",-S (=0) 2N (Rm) C (=O) NR"'R'", -NRmRm, -N(Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N (R"') C (=NRm) NRmRm, -N (Rm) S (=O) 2R",-N (Rm) S (=0) 2NR'R', -NRmC2-6alkylNRmRm and -NRmC2-6alkylORm ; and the bridge carbon atoms are substituted with 0,1 or 2 =O groups.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is tert-butyl or trifluoromethyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R9 is H.
In another embodiment, in conjunction with the novel compound embodiments above and below, Z is CR8.
In another embodiment, in conjunction with the novel compound embodiments above and below, Z is N.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is R2 is H, -ORm, Cl, C1-3haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORn, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O)N(Rm)S(=O)2Rn, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, - S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm, -NRmRm,-N (Rm) C (=O) R,-N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm) S (=O) 2Rn, -N (Rm) S (=0) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs,
-C (=O) OR',-C (=O) NR'R',-C (=NR') NRmR',-ORs,-OC (=O) R', -OC OC(=O)NRmRs, -OC(=O)N(Rm)S(=O)2Rs,-OC2-6alkylNRmRs,-OC2-6alkylORs, -SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRmRs,-NRmRs,-N(Rm) C (=O) Rs, - N(Rm)C(=O)ORs,-N(Rm)C(=O)NRmRs,-N(Rm)C(=NRm)NRmRs, -N(Rm) S (=0) 2R',-N (Rm) S (=0) 2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C(=O)NRmRm,-C(=NRm)NRmRm,-ORm,-OC(=O)Rn, -OC(=O)NRmRm,-OC(=O)N(Rm)S(=O)2Rn,-OC2-6alkylNRmRm,-OC2-6alk ylORm, - SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn, - S(=O)2N(Rm)C(=O)ORn,-S(=O)2N(Rm)C(=O)NRmRm,-NRmRm, - N(Rm)C(=O)Rn,-N(Rm)C(=O)ORn,-N(Rm)C(=O)NRmRm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm and -NRmC2-6alkylORm ; wherein R4 is not unsubstituted phenyl; R is independently, at each instance, H, C1-9alkyl,C1-4haloalkyl, halo, nitro, cyano,-OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm,-NRmRm,-NRm-C1-4haloalkyl,-NRm-C1-6alkylNRmR m or -NRm-C, 6alkylORm ; Y is NH; and Z is CR8 or N.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 5-or 6-membered ring containing 1,2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) NR"'R"',-C (=NRm) NRmRm,-ORn,-OC (=O) R", -OC(=O)NRmRm,-OC(=O) N (Rm) S (=0) 2R,-OC2-6alkylORm,-SRm,-S (=O) R -S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O) ORn, -S(=O)2N(Rm) C (=O) NRmRm,-NRmRm,-N (R"') C (=O) Rn,-N(Rm) C (=O) OR -N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm) S (=O) 2R, -N(Rm) S (=0) 2NRmRm,-NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs,
-C (=O) OR',-C (=O) NR'R',-C (=NR') NR'R',-OR,-OC (=O) RF, -OC (=O) NR'R',-OC (=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmRs,-OC2-6alkylORs, -SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs,-S(=O) 2N (Rm) C(=O)NRmRs,-NRmRs,-N(Rm) C (=O) R', -N(Rm) C (=O) ORs, -N(Rm) C (=O) NRmRs,-N (Rm) C (=NRm) NRmRs, - N(Rm)S(=O)2Rs,-N(Rm)S(=O)2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6a lkylORs and C1-4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C(=O)NRmRm,-C(=NRm)NRmRm,-ORm,-OC(=O)Rn, -OC(=O)NRmRm,-OC(=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNRmRm,-OC2-6alkylORm, - SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn, - (=O)2N(Rm)C(=O)ORn,-S(=O) 2N (Rm)C(=O)NRmRm,-NRmRm, -N (Rm) C (=O) R°,-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, -N (Rm) C (=NRm) NRmRm,-N (R"') S (=0) 2R",-N (Rm) S (=0) 2NRmRm, -NRmC2-6alkylNRmRm and -NRmC2-6alkylORm ; In another embodiment, in conjunction with the novel compound embodiments above and below, Z is CR8.
In another embodiment, in conjunction with the novel compound embodiments above and below, Z is N.
Another aspect of the invention relates to a compound having the structure: wherein: X is O, S or NR°' ; n is independently, at each instance, 0, 1 or 2; o is independently, at each instance, 0,1, 2 or 3; Rm is independently at each instance H or Rn ; Rn is independently at each instance Cl 8alkyl, phenyl or benzyl ; Rq is independently in each instance H, C, _4alkyl, C, 4haloalkyl, halo, cyano, nitro,-C (=O) R°,-C (=O) OR°,-C (=O) NR"'R°',-C (=NR"') NR°R"',-OR"', -OC(=O)Rn,-OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm,
-OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm, -S(=O)2N(Rm) C (=O) R",-S (=0) 2N (Rm) C (=O) OR",-S (=0) 2N (Rm) C (=O) NR"'R"', -NRmRm,-N(Rm) C (=O) Rn,-N (Rm) C (=O) ORn,-N(Rm) C (=O) NRmRm, -N(Rm) C (=NRm) NRmRm,-N (Rm) S (=0) 2R",-N (Rm) S (=0) 2NR"'R"', - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm; Rs is R"substituted by 0, 1, 2 or 3 substituents independently selected from Rq ; R3 is H or C1-4alkyl ; Rus vis H, C1-9alkyl,C1-4haloalkyl,halo, nitro, cyano,-OC1-6alkyl, - O-C1-4haloalkyl,-O-C1-6alkylNRmRm,-O-C1-6alkylORm,-NRmRm, -NRm-C1-4haloalkyl,-NRm-C1-6alkylNRmRm,-NRm-C1-6alkylORm, or-(CH2)nRc R6 is, independently at each instance, H, Cl-galkyl, CI-4haloalkyl, halo, nitro, cyano,-OC1-6alkyl,-O-C1-4haloalkyl,-O-C1-6alkylNRmRm, -O-C1-6alkylORm,-NRmRm,-NRm-C1-4haloalkyl,-NRm-C1-6alkylNRmR m or -NRm-C1-6alkylORm; R8 is H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OC1 6alkyl, -O-C1-4haloalkyl,-O-C1-6alkylNRmRm,-O-C1-6alkylORm,-NRmRm, -NRm-C1-4haloalkyl,-NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm; and (A) R'is R2is H,-OR', halo, Cl 3haloalkyl or C 6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0, 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C, 8alkyl, C, 4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C(=O)ORn,-C(=O)NRmRm,
-C(=NRm)NRmRm,-ORm,-OC(=O)Rn,-OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn,-OC2-6alkylNRmRm,-OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)O Rn, -S(=O)2N(Rm) C (=O) NRmRm, -NRmRm, -N(Rm) C (=O) R,-N (Rm) C (=O) OR -N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm,-N (Rm) S (=O) 2R, -N(Rm)S(=O)2NRmRm,-NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O) Rs, -C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs, -OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs,-OC2-6alkylORs, - SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRmRs,-NRmRs,-N(Rm) C (=O) Rs, -N (Rm) C (=O) ORs,-N (R') C (=O) NRmRs,-N (R"') C (=NRm) NRmRs, -N(Rm) S (=0) 2R',-N (Rm) S (=0) 2NRmRs,-NRn'C2-6alkylNR"'R',-NR"'C2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C (=O) OR",-C (=O) NRmRm,-C (=NRm) NRmRm-ORm -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=O) 2Rn,-OC2 6alkylNRmRm, -OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2Rn,-S(=O)2NRmR m, - S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn,-S(=O)2N(Rm)C(=O)NRm Rm, -NRmRm,-N(Rm) C (=O) R",-N (Rm) C (=O) ORn,-N(Rm) C (=O) NRmRm -N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm,-C(=O)Rs,-C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NR mRs, -ORs,-OC(=O)Rs,-OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs, - OC2-6alkylORs,-SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRm Rs -NRmRs,-N(Rm)C(=O)Rs,-N(Rm)C(=O)ORs,-N(Rm)C(=O)NRmRs, -N(Rm) C (=NRm) NRmRs,-N (Rm) S (=0) 2R',-N (Rm) S (=O) 2NRmRs - NR"'C2-6alkylNRmR',-NR"'C2-6alkylORs and-NR"'C2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, - O-C1-4haloalkyl,-O-C1-6alkylNRmRm,-O-C1-6alkylORm,-NRmRm, -NRm-C1-4haloalkyl,-NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0, 1, 2,3 or
4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance C1-8alkyl, C1-4haloalkyl,halo, cyano, nitro, -C (=O) R",-C (=O) ORn,-C(=O)NRmRm,-C(=NRm)NRmRm,-ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R°,-OC2-6alkylNRmRm, - OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm, -S(=O)2N(Rm) C (=O) Rn,-S (=0) 2N (Rm) C (=O) OR',-S (=O) 2N (Rm) C (=O) NRmR', -NRmRm,-N(Rm) C (=O) Rn7-N (Rm) C (=O) ORn,-N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; and Y is 0 or NH; or (B) R'is R2 is H,-ORm, halo, Cl 3haloalkyl or Chalky ! ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn,-C (=O) NRmRm, -C(=NRm)NRmRm,-ORm,-OC(=O)Rn,-OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn,-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S(=O)Rn, -S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O) ORn, -S(=O)2N(Rm) C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) Rn,-N(Rm) C (=O) OR', -N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,
- N (R"') S (=O) 2NR"'Rm,-NR"'C2-6alkylNRmRm,-NR"'C2-6alkylORm,-C (=O) R', -C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs, -OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2RS,-OC2-6alkylNRmR',-OC2-6alkylORs, -SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs,-S(=O) 2N (Rm)C(=O)NRmRs,-NRmRs,-N(Rm) C (=O) R', -N(Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs,-N (R"') C (=NR"') NR"'R', -N(Rm)S(=O)2Rs,-N(Rm)S(=O)2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6 alkylORs and Cul 4alkyl substituted by 1 or 2 groups selected from Cs 2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C(=O)ORn,-C(=O)NRmRm, -C(=NRm)NRmRm,-ORm, -OC(=O)Rn,-OC(=O)NRmRm,-OC(=O) N (Rm) S (=O) 2R",-OC2-6alkylNRmR"', -OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=0)NRmRm, -NRmRm, -N(Rm) C (=O) R",-N (Rm) C (=O) ORn, -N(Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs,-OC (=O) Rs,-OC (=O) NRmRs,-OC (=O) N (Rm) S (=0) 2R5, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmR', - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C, 9alkyl, C, 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm -C1-6alkylNRmRm or -NRm -C1-6alkylORm ; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP ;
RP is independently at each instance C, 8alkyl, C, 4haloalkyl, halo, cyano, nitro, -C (=O) R",-C (=O) OR",-C (=O) NRmR"',-C (=NRm) NR"'Rm,-OR"', -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm)C(=O)NRmRm, - NR"'R"',-N (R"') C (=O) Rn, -N(Rm) C (=O) ORn, -N(Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; and Y is 0 or NH ; or (C) R'is R2isH, -ORm, halo, C1-3haloalkyl or Cl 6alkyl ; R4 is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or 11-membered bicyclic heterocycle containing 1,2, 3,4 or 5 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5, 6,7-tetrahydro-benzo [b] thiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo [1, 4] dioxin-6-yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C1-9alkyl, oxo, Cl 4haloalkyl, halo, nitro, cyano,-ORm,-S (=O) nC1 -6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkyloRm, -NRmRm, -NRm-C1-4haloalkyl, -NRm -C1-6alkylNRmRm, -NRm -C1-6alkylORm, -C(=O)C1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRmC1-6alkyl, -NRmC(=O)C1-6alkyl -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(NRm)NRmRs, -ORs,-OC (=O) Rs,-OC (=O) NRmRs,-OC (=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, S(=O)2Rs, -S(=O)2NRmRs, - S 2N C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, - NR"'Rs,-N (R"') C (=O) R',-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmR, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2
groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm,-N (Rm) C (=O) Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2R, - N(Rm)S(=O)2NRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmR', - OC2-6alkylORs, -SRs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O) 2N (Rm) C (=O) R',-S (=O) 2N (Rm) C (=O) ORs,-S (=O) 2N (Rm) C (=O) NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmR, -NRmC26alkylNRmRs,-NRmC26alkylORs and-NRmC26alkylORm ; wherein R4 is not 2-aminocarbonylmethyl-2,3-dihydro-benzo [1, 4] dioxin-8-yl, 2-cyanomethyl- 2, 3-dihydro-benzo [1, 4] dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo [1, 3] dioxol-5-yl, 3, 3-dimethyl-1, 3-dihydro-indol-2-on-6-yl or 4, 4-dimethyl- 3, 4-dihydro-lH-quinolin-2-on-7-yl ; R7 is C1-8alkyl, C1-5haloalkyl, I or Br R9 is H, C, _9alkyl, C, 4haloalkyl, halo, nitro, Cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm -C1-4haloalkyl, - Nrm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, or -(CH2)nRc, R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -OC1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm -C1-4haloalkyl, -NRm -C1-6alkylNRmRm or -NRm-C, 6alkylORm ; Y is NH; and Z is CR8or N ; or (D) R'is R2 is Cl 6alkyl substituted by 1, 2 or 3 substituents selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn,-C (=O) NR"'R"', -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (R"') S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, - S (=0) 2N (R"') C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) Rn, -N(Rm) C (=O) OR', -N(Rm)C(=O)NRmRm, -N(Rm)C(=Nrm)NRmRm, -N(Rm) S (=O) 2Rn, -N (Rm) S (=O) 2NRmRm, -NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; or R2 is -(C(Rq)2)ophenyl, wherein the phenyl is substituted by 0,1, 2 or 3 substituents independently selected from C 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C (=O) ORn,-C (=O) NRmRm,-C (=NRm) NRmRm,-ORm -OC(=O)Rn, -OC(=O)NRmR, -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNR"'R"', - OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm)C(=O)NRmRm, - (Rm) C (=O) Rn,-N (Rm) C (=O) ORn,-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmR, -NRmC2-6alkylNRmR, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)OR3, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, - S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm) C (=O) NRmRs, -NRmRs, -N (Rm) C (=O) R',-N (Rm) C (=O) OR', -N (Rm) C (=O) NRmRs,-N (Rm) C (=NRm) NRmRs, -N(Rm) S (=0) 2Rs, -N (Rm) S (=0) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4 alkl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmR, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn
- S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) R",-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmR, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(NRm) NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmR', -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; or R2 is -(C-(R9)2oR#, wherein Rr is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, C 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O)N(Rm)S(=O)2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S (=0) 2N (Rm) C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) Rn, -N(Rm) C (=O) OR", -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, - N (R"') S (=0) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs,-S (=O) Rs,-S (=0) 2Rs,-S (=0) 2NRmRs,-S (=0) 2N (Rm) C 0) Rs, - S 2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R', -N(Rm) C (=O) OR',-N (R"') C (=O) NRmRs, -N (Rm) C (=NR"') NRmRs, - N (R"') S (=O) 2R',-N (Rm) S (=0) NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C1-2haloalkyl, halo, cyano, nitro, -C (=O) R",-C (=O) OR",-C (=O) NRmRm,-C (=NR"') NR"'Rm,-OR"', -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2R",-OC2-6alkylNRmR"', - 6alkylORm,-SRm,-S (=O) R",-S (=0) 2R°,-S (=O) 2NR"'R"',
- S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn,-N (R"') C (=O) ORn,-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> - NR°'C2-6alkylNR"'Rm,-C (=O) R',-C (=O) ORs,-C (=O) NR"'R',-C (=NR"') NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmR', -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S 2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2alkylORn ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0, 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C, 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2R",-OC2-6alkylNRmRm,-OC2-6alkylOR"',-SRm,-S (=O) R°, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) Rn, -N (Rm) C (=O) OR -N(m)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, -N(Rm) S (=0) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, C(=O)R5, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmRs,-OC2_6alkylORs, -SRs, -S(=O)Rs, - S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs, - N (R"') C (=O) OR5, -N(Rm) C (=O) NRmRs, -N (R) C (=NR"') NRmRs, - (Rm) S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C1-2haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm,
-OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm) C (=O) Rn, -S (=0) 2N (Rm) C (=O) ORn, -S (=0) 2N (Rm) C (=O) NRmRm, - NR"'R"',-N (R°') C (=O) Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, - N (R"') C (=NRm) NRmRm, -N(Rm) S (=0) 2Rn, -N(Rm) S (=O) 2NR R, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs,-OC (=O) Rs,-OC (=O) NRmRs,-OC (=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRm Rs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, - NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and-NRmC2-6alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C2-8alkyl, C1-5haloalkyl, I, Br; R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalky, -O-C1-6alkylINRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm -C1-6alkylNRmRm or -NRm-C, 6alkylORm ; Y is NH; and Z is CR8 or N; or (E) R'is R2 is H, -ORm, Cl, C1-3haloalkyl or C1-6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C(=O)NRmRm, -C(=NRm)NRmRm, -OR", OC(=O)Rn, -OC(=O)NRmRm, -OC OC N(Rm)S(=O)2Rn, -OC-2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn,
-S(=O)2NRmRm, -S(=O)2NRm(Rm) C (=O) Rn, -S (=O) 2N (Rm) C (=O) OR", -S(=O)2NRm(Rm) C (=O) NRmRm-NRmRm,-N (Rm) C (=O) R,-N (Rm) C (=O) OR', -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm) S (=0) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -NRmRs, -NRmRs, -N(Rm) C (=O) Rs, -N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs,-N (R"') C (=NR"') NRmRs, - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C (=O) NRmRm,-C (=NRm) NRmRm,-ORm-OC (=O) Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, - S 2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, - N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, - N (R"') C (=NRm) NRmRm,-N (Rm) S (=0) 2R",-N (Rm) S (=O) 2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs,-C(=O)ORs, -C(=O)NRmRs,-C(NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)Rs, -N(Rm)S(=O)2NRmRs, - NR"'C2-6alkylNR"'R',-NRmC2-6alkylORs and-NR"'C2-6alkylORm ; wherein R4 is not unsubstituted phenyl ; R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1 alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm; Y is NH; and Z is CR8 or N.
In another embodiment, in conjunction with the novel compound embodiments above and below, R1 is R2 is H,-OR"', halo, C, 3haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0, 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)O Rn, -S (=0) 2N (Rm) C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) Rn,-N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm) S (=0) 2Rn, -N (Rm) S (=0) 2NRmRm,-NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs, -C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs, -OC (=O) NRmRs,-OC (=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs,-OC2-6alkylORs, -SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs, - S 2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRmRs,-NRmRs,-N(Rm) C (=O) R', -N(Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs,-N (Rm) C (=NRm) NR"'R', - (Rm) S(=O)2Rs,-N(Rm)S(=O)2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6alkylO Rs and C1-4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn,-C(=O)NRmRm,-C(=NRm)NRmRm,-ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=O) 2Rn,-OC2-6alkylNRmRm, - OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn,-S(=O) 2N (Rm)C(=O)NRmRm,
-NRmRm,-N(Rm) C (=O) Rn,-N (R"') C (=O) ORn,-N((Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm,-C(=O)Rs,-C(=O)Rs,-C(=O)ORs,-C(=O)NRmRs,- C(=NRm)NRmRs, -ORs,-OC(=O)Rs,-OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmR', - OC2-6alkylORs,-SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRm Rs, -NRmRs,-N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NR"'R\ -N(Rm)C(=NRm)NRmRs,-N(Rm)S(=O)2Rs,-N(Rm)S(=O)2NRmRs, -NRmC26alkylNRmRs,-NRmC26alkylORs and-NRmC26alkylORm ; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =O groups; R7 is C, 9alkyl, C, 4haloalkyl, halo, nitro, cyano,-OC1-6alkyl, - O-C1-4haloalkyl,-O-C1-6alkylNRmRm,-O-C1-6alkylORm,-NRmRm, -NRm-C1-4haloalkyl,-NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C(=O)ORn,-C(=O)NRmRm,-C(=NRm)NRmRm,-ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=O) 2Rn,-OC2-6alkylNRmRm, OC OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn,-S(=O)Rn,-S(=O)2N(Rm)C(=O)ORn,-S(=O) 2N (Rm)C(=O)NRmRm, -NRmRm,-N(Rm) C (=O) Rn,-N(Rm) C (=O) ORn,-N (Rm) C (=O) NRmRm -N (R) C (=NR"') NRmRm,-N(Rm) S (=O) 2Rn,-N(Rm) S (=O) 2NR"'R"', - or-NRmC26alkylORm ; and YisOorNH.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms
selected from O. N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl,halo, cyano, nitro,-C (=O) R",-C (=O) ORn,-C(=O)NRmRm, -C (=NRm) NRmRm,-ORm,-OC (=O) Rn,-OC (=O) NRmRm, -OC(=O) N (Rm) S (=0) 2Rn,-OC2alkylNRmRm,-OC2-6alkylORm,-SRm,-S(=O)Rn, -S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm) C (=O) Rn,-S (=O) 2N (Rm) C (=O) OR -S(=O)2N(Rm) C (=O) NRmRm-NRmRm,-N (Rm) C (=O) R,-N (Rm) C (=O)ORn, -N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm) S (=O) 2Rn, -N (Rm) S (=O) 2NRmRm,-NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs, -C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs, - OC (=O) NRmR',-OC (=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs,-OC2-6alkylORs, -SRs,-S(=O)Rs,-S-=O)2Rs,-S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C (=O)Rs, - S(=O)2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRmRs,-NRmRs,-N(Rm) C (=O) Rs, -N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs,-N (R) C (=NRm) NRmRs, -N (Rm) S (=0) 2R',-N (Rm) S (=0) 2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR°,-C (=O) NRmRm,-C (=NR"') NR"'Rm,-OR"', -OC(=O)Rn,-OC(=O)NRmRm,-OC(=O) N (Rm) S (=0) 2Rn,-OC2 6alkylNRmRm, - OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn,-S(=O)2N(Rm)C(=O)NR mRm, -NRmRm,-N (Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm -N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm,-C(=O)Rs,-C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NRm Rs, -ORs,-OC(=O)Rs,-OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs, -OC2-6alkylORS,-SRs,-SRs,-S(=O)RS,-S(=O)2Rs,-S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)ORS,-S(=O)2N(Rm)C(=O)NRm Rs, -NRmRs,-N(Rm) C (=O) Rs,-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs,-N(Rm)S(=O)2Rs,-N(Rm)S(=O)2NRmRs, - NR"'C2-6alkylNR"'Rs,-NRmC2-6alkylORs and-NRmC2-6alkylOR" ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C(=O)ORn,-C(=O)NRmRm, -C(=NRm)NRmRm,-ORm,-OC(=O)Rn,-OC(=O)NRmRm, -OC(=O) N (Rm) S 2R°,-OC2-6alkylNRmR"',-OC2-6alkylORm,-SRm,-S (=O) R", - S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)O Rn, -S (=O) 2N (R) C (=O) NRmRm,-NRmRm,-N(Rm) C (=O) R",-N (Rm) C (=O) OR, - N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn, -N(Rm) S (=0) 2NRmRm,-NRmC2-6alkylNRmRm,-NRmC2-6aklylORm,-C(=O)Rs, -C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs, -OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs,-OC2-6alkylORs, -SRs,-(=O)RS,-S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs,-S(=O)ORs,-S(=O),-S(=O) 2N (Rm) C (=O) NRmRs,-NRmRs,-N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs,-N(Rm) C (=O) NR'"R',-N (Rm) C (=NRm) NRmRs, -N (Rm) S (=0) 2Rs-N (Rm) S (=0) 2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C(=O)ORn,-C(=O)NRmRm,-C(=NRm)NRmRm,-ORm, -OC(=O)Rn,-OC(=O)NRmRm,-OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNRmRm, - OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn,-S(=O)1=2N(Rm)C(=O)N RmRm, -NRmRm,-N(Rm)C(=O)Rn,-N(Rm)C(=O)ORn,-N(Rm)C(=O)NRmRm, -N(Rm) C (=NRm) NRmRm,-N (Rm) S (=0) 2Rn,-N(Rm) S (=O) 2NRmRm, - NRmC2-6alkylNRmRm,-C(=O)Rs,-C(=O)ORs,-C-=O)NRmRs,-C(=NRm)NRm Rs, -ORs,-OC(=O)Rs,-OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmR', - OC2-6alkylORs,-SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)ORs,-S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs,-N(Rm)C(=O)Rs,-N(Rm)C(=O)ORs,-N(Rm)C(=O)NRmRs, - N(Rm)C(=NRm)NRmRs,-N(Rm)S(=O)2Rs,-N(Rm)C(=O)2NRmRs,
-NRmC26alkylNRmRs,-NRmC26alkylORs and-NRmC26alkylORm ; and the bridge carbon atoms are substituted with 0,1 or 2 =O groups.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is Cl 9alkyl, Cl 4haloalkyl, halo,-OCl 6alkyl, -O-C1-4haloalkyl,-NRmRm or -NRm-C1-4haloalkyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is C1_5alkyl, C1_4haloalkyl, I, Br or Cl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is tert-butyl or trifluoromethyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic ring containing 0, 1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from Rp In another embodiment, in conjunction with the novel compound embodiments above and below, R° is a saturated, partially-saturated or unsaturated 6-membered ring containing 0,1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from Rp.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is O.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is NH.
In another embodiment, in conjunction with the novel compound embodiments above and below, Rl is
R2 is H,-OR"', halo, C1-3haloalkyl or C1-6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-6alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR°,-C (=O) NRmR"', -C(=NRm)NRmRm,-ORm,-OC(=O)Rn,-OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R°,-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S (=O) R°, - S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)O Rn, -S(=O)2N(Rm) C (=O) NRmRm-NRmRm,-N (Rm) C (=O) R,-N (Rm) C (=O) OR, -N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm) S (=O) 2Rn, - N (R"') S (=0) 2NRmRm,-NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNR"'Rs,-OC2_6alkylORs, -SRs, -S(=O)Rs, -S(=O)2RS, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C (=O) NR'R',-NRmRs,-N (Rm) C (=O) Rs, -N(Rm)C(=O)ORs, -N(Rm) C (=O) NRmRs,-N (Rm) C (=NRm) NRmRs - N(Rm)S(=O)2Rs, -N(Rm=S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C1-2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) ORn,-C (=O) NRmRm,-C (=NRm) NRmRm,-ORm -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NR Rm7-N (Rm) C (=O) Rn, -N(Rm) C (=O) OR",-N (Rm) C (=O) NR"'R"', -N(Rm) C (=NRm) NRmRm, -N(Rm) S (=O) 2Rn, -N (R"') S (=O) 2NR"'R"', - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs,
- N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6aklylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkyloRm; [C1-8alkyl, C1-5haloalkyl, 1, Br or C1] R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0, 1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance C, 8alkyl, C, 4haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, - OC2-6alkylORm,-SRm,-S (=O) R",-S (=0) 2R",-S (=0) 2NR"'Rm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C (=O) NRmRm, - NR"'R"',-N (R"') C (=O) Rn7-N (Rm) C (=O) ORn, -N(Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; and Y is O or NH.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C, 4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn,
- S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm=C(=O)ORn, -S(=O) 2N (Rm) C (=O) NRmRm, -NRmRm, -N (Rm) C (=O) R",-N (Rm) C (=O) OR -N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm,-N (Rm) S (=O) 2R, -N(Rm) S (=O) 2NRmRm,-NR"C2-6alkylNRmRm,-NRmC2-6alkylORm,-C (=O) R', -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - s(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R', -N(Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, -N (R"') C (=NRm) NR"'R', -N(Rm) S (=0) 2R',-N (Rm) S (=O) 2RNmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn,-C (=O) NRmRm,-C (=NRm) NRmRm,-ORm -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, - OC2-6alkylOR",-SR"',-S (=O) R",-S (=O) 2R",-S (=0) 2NRmR"', -S(=O)2N(Rm) C (=O) Rn, -S(=O)2N(Rm) C (=O) OR, -S(=O), -S(=O)2N(Rm) C (=O) NRmRm, -NR'Rm,-N (Rm) C (=O) Rn, -N(Rm) C (=O) ORn, -N(Rm) C (=O) NRmRm -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N'Rjm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC-=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmR', -OC2-6alkylORs, SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O) 2N (Rm) C (=O) R',-S (=0) 2N (Rm) C (=O) OR',-S (=O) 2N (Rm) C (=O) NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORS and -NRmC2-6aklylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C, 4haloalkyl, halo, cyano, nitro, -C (=O) R",-C (=O) OR",-C (=O) NRmRm,
-C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRM, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C (=O) NRmRm, -NRmRm, -N (Rm) C (=O) R",-N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, -N(Rm) S (=0) 2NR"'Rm,-NR"'C2-6alkylNR"'R"',-NR"'C2-6alkylORm,-C (=O) RS, - C (=O) ORs,-C (=O) NR"'R',-C (=NR"') NRmRs,-OR',-OC (=O) RS, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmR',-OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2RS, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R', -N(Rm) C (=O) OR',-N (Rm) C (=O) NRmR',-N (R) C (=NR"') NRmRs, - N (R"') S (=0) 2Rs,-N (Rm) S (=O) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C1-2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR",-C (=O) NR"'R",-C (=NR"') NRmR"',-OR°, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRmn -S(=O)Rn, -S(=O)2Rn, -S(=O)NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs,-C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORS, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2Nr(Rm) C (=O) Rs, -S (=O) 2N (Rm) C (=O) OR',-S (=O) 2N (Rm) C (=O) NRmRs, NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmR', - N(Rm)C((=NRm)NRmRs, -N(Rm) S (=O) 2Rs,-N (R"') S (=0) 2NR"'R', -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the bridge carbon atoms are substituted with 0,1 or 2 =O groups.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is C1-9alkyl, C1-4haloalkyl, halo, -OC1-6alkyl, -O-C1-4haloalkyl, -NRmRm or -NRm-C1-4haloalkyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is C1-5alkyl, C1-4haloalkyl,I, Br or Cl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is tert-butyl or trifluoromethyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic ring containing 0,1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP.
In another embodiment, in conjunction with the novel compound embodiments above and below, R° is a saturated, partially-saturated or unsaturated 6-membered ring containing 0,1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is O.
In another embodiment, in conjunction with the novel compound embodiments above and below, Y is NH In another embodiment, in conjunction with the novel compound embodiments above and below, R'is R2is H,-OR', halo, Cl 3haloalkyl or Cl 6alkyl ; R4 is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or 11-membered bicyclic heterocycle containing 1, 2,3, 4 or 5 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5, 6,7-tetrahydro-benzo [b] thiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo [1, 4] dioxin-6-yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from Cl 9alkyl, oxo, Cl 4haloalkyl,
halo, nitro, cyano,-OR',-S (=O) nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, -C(=O)C1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRmC1-6alkyl, -NRmC(=O)C1-6alkyl-C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNR"R', -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)NRmRm, -C (=NRm) NRmRm,-ORm,-OC (=O) Rn,-OC (=O) NRmRm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2NRm)C(=O)ORn, - (=0) 2N (R') C (=O) NR'Rm,-N (Rm) C (=O) R",-N (Rm) C (=O) OR', - N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, - N(Rm)S(=O)2NRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rjm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C (=O) NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkyNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; wherein R4 is not 2-aminocarbonylmethyl-2, 3-dihydro-benzo [1, 4] dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo [1, 4] dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo [1, 3] dioxol-5-yl, 3, 3-dimenthyl-1,3-dihydro-indol-2-on-6-yl or 4, 4-dimethyl- 3, 4-dihydro-1H-quinolin-2-on-7-yl ; R7 is C1-8alkyl, C1-5haloalkyl, I or Br; R9 is H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, - kylORm,-NR'Rm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; Y is NH; and
Z is CR8 or N.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a heterocycle selected from indole, 3H- indole, benzo [b] furan, benzothiophene, 1H-indazole, benzimidazole, benzthiazole, 1H-benzotriazole, 7-quinoline, 8-quinoline, 1,2, 3,4- tetrahydroquinoline, isoquinoline, cinnoline, phthalazine, quinazoline and quinoxaline, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C1-9alkyl, oxo, C1-4haloalkyl, halo, nitro, cyano, -ORm, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, - NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, <BR> <BR> <BR> <BR> -C (=O) C, 6alkyl,-OC (=O) CI 6alkyl,-C (=O) NRmC, 6alkyl,-NRmC (=O) CI 6alkyl -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R', -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, -N(Rm) C (=NRm) NRmRs, - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Chalky ! substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)NRmRm, -C(=NRm)NRmRm, ORm, -OC(=O)Rn, -OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn - S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -N(Rm)C(=O)Rn, - N (R"') C (=O) OR,-N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRm m -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRMRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm) C (=O) Rs,-S (=0) 2N (Rm) C (=O) ORs, -S (=0) 2N (Rm) C (=O) NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N (R"') C (=NRm) NRmRs, -N (Rm) S (=0) 2Rs,-N (Rm) S (=0) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a heterocycle selected from 6-indole, 7-
indole, 6-3H-indole, 7-3H-indole, 6-benzo [b] furan, 7-benzo [b] furan, 6- benzothiophene, 7-benzothiophene, 6-1H-indazole, 7-1H-indazole, benzimidazole, benzthiazole, IH-benzotriazole, 7-quinoline, 8-quinoline, 7- 1,2, 3,4-tetrahydroquinoline, 8-1,2, 3,4-tetrahydroquinoline, isoquinolin-7-yl, isoquinolin-8-yl, 7-cinnoline, 8-cinnoline, phthalazine, 7-quinazoline, 8- quinazoline and quinoxaline, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C1-9alkyl, oxo, C1-4haloalkyl, halo, nitro, cyano,-ORm,-S (=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, -C(=O)C1-6alkyl, -OC(=O)1-6alkyl, -C(=O)NRmC1-6alkyl, -NRmC(=O)C1-6alkyl -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm) S (=0) 2Rs, -N (Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6aklylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) R,-C (=O) NRmRm, - C (=NR°') NR"'R"',-ORm,-OC (=O) R",-OC (=O) NRmRm, -Oc(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NrmRm, -N (Rm) C (=O) Rn, -N(Rm) C (=O) OR', -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, - N(Rm)S(=O)2NRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmR', -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S 2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, - NRmC2-6alkylNRmR',-NRmC2-6alkylORs and-NR"'C2-6alkylORm.
In another embodiment, in conjunction with the novel compound embodiments above and below, R9 is C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,
-OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, - NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm.
In another embodiment, in conjunction with the novel compound embodiments above and below, R9 is H.
In another embodiment, in conjunction with the novel compound embodiments above and below, Z is CR.
In another embodiment, in conjunction with the novel compound embodiments above and below, Z is N.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is tert-butyl or trifluoromethyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, Rl is R2 is C1-6aklyl substituted by 1,2 or 3 substituents selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) OR,, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S (=O) 2N (R) C (=O) NRmRm, -NRmRm, -N(Rm) C (=O) Rn,-N (Rm) C (=O) OR -N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm,-N (Rm) S (=O) 2Rn, -N(Rm) S (=O) 2NRmRm, -NRmC2-6alkylNRmRm and -NRmC2-6alkylORm ; or R2 is
R2 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7 ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm,-ORm,-OC(=O)Rn,-OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S(=O)Rn, - S(=O)2Rn,-S(=O)2NRmRm,-S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)O Rn, -S(=O) 2N (R') C (=O) NRmRm,-NRmRm,-N(Rm) C (=O) R,-N (R) C (=O) OR', -N(Rm)C(=O)NRmRm,-N(Rm)C(=NRm)NRmRm,-N(Rm) S (=O) 2R, - N (R"') S (=0) 2NRmRm,-NRmC2-6alkylNRmRm,-NRmC2-6alkylORm,-C(=O)Rs, -C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NRmRs,-ORs,-OC(=O)Rs, -OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNR"'R',-OC2_6alkylORs, -SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs,-S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRmRs,-NRmRs,-N(Rm) C (=O) Rs, -N(Rm)C(=O)ORs,-N(Rm) C (=O) NRmRs,-N (Rm) C (=NRm) NR"'R', -N(Rm) S (=O) 2Rs,-N (Rm) S (=0) 2NRmRs,-NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C(=O)ORn,-C(=O)NRmRm,-C(=NRm)NRmRm,-ORm, -OC(=O)Rn,-OC(=O)NRmRm,-OC(=O) N (Rm) S (=O) 2R°,-OC2-6alkylNRmR"', OC OC2-6alkylORm,-SRm,-S(=O)Rn,-S(=O)2Rn,-S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn,-S(=O)2N(Rm) C (=O) NRmRm, - NR"'R"',-N (R"') C (=O) R",-N (Rm) C (=O) ORn,-N(Rm)C(=O)NRmRm, - N(Rm)C(=NRm)NRmRm,-N(Rm)S(=O)2Rn,-N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm,-C(=O)Rs,-C(=O)ORs,-C(=O)NRmRs,-C(=NRm)NR mRs,
-ORs,-OC(=O)Rs,-OC(=O)NRmRs,-OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNR"'Rs, - OC2-6alkylORs,-SRs,-S(=O)Rs,-S(=O)2Rs,-S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs,-S(=O)2N(Rm)C(=O)ORs,-S(=O)2N(Rm)C(=O)NRm Rs, -NRmRs,-N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs,-N(Rm)S(=O)2Rs,-N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and -NRmC2-6alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C2-8alkyl, C1-shaloalkyl, I, Br; R9 is independently, at each instance, H, C1-9alkyl,C1-4haloalkyl, halo, nitro, cyano,-OC1-6alkyl,-O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm,-NRmRm,-NRm-C1-4haloalkyl,-NRm-C1-6alkylNRmR m or -NRm-C1-6alkylORm; Y is NH; and Z is CR8 or N.
In another embodiment, in conjunction with the novel compound embodiments above and below, R2 is C1-6alkyl substituted by 1, 2 or 3 substituents selected from C, 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C (=O) OR, - C (=O) NR"'Rm,-C (=NR"') NR"'R"',-ORm,-OC (=O) R",-OC (=O) NR"'R"', -OC(=O) N (Rm) S (=0) 2R,-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S (=O) R -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm, -NRmRm, -N (Rm) C (=O) R",-N (Rm) C (=O) OR -N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm,-N (Rm) S (=O) 2Rn, - N (R"') S (=O) 2NRmRm, -NRmC2-6alkylNRmRm and -NRmC2-6alkylORm ; In another embodiment, in conjunction with the novel compound embodiments above and below, R2 is- (C (Rq) 2) ophenyl, wherein the phenyl is substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1- 4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) OR",-C (=O) NRmRm, - C (=NRm) NRmRm,-OR"',-OC (=O) R",-OC (=O) NR"'R"', -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, - S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C (=O) NRmRm,-NRmR',-N (Rm) C (=O) R",-N (Rm) C (=O) OR -N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm,-N (Rm) S (=O) 2R,
- N (R"') S (=0) 2NRmRm, -NRmC2-6alkylNRmRm, - NRmC2-6alkylORm, -C(=O)Rs, -C (=O) ORs,-C (=O) NRmRs,-C (=NRm) NRmRs,-ORs,-OC (=O) Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C (0) NRmRs,-NRmRs,-N (Rm) C (=O) R', - N (R"') C (=O) OR',-N (R'") C (=O) NRmRs,-N (R"') C (=NR"') NR'"R', - N (R"') S (=0) 2Rs,-N (Rm) S (=0) 2NRmRs, -NRmC2-6alkylNRmRs, - NRmC2-6alkylORs and Chalky ! substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR",-C (=O) NRmRm,-C (=NRm) NR"'Rm,-OR°, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn,-OC2 6alkylNRmRm, - OC2-6alkylORm, - SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, - NRmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, - N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> <BR> - NR"'C2-6alkylNR"'R°',-C (=O) R',-C (=O) OR',-C (=O) NR"'Rs,-C (=NRm) NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRMRs, -OC2 6alkylORs,-SRs,-S (=O) Rs,-S (=0) 2Rs,-S (=0) 2NRmR -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)OR8, -S(=O)2N(Rm)C(=O)NRmRs, -NRmR8, -N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, -N(Rm) C (=NRm) NRmRs, -N (Rm) S (=0) 2Rs, -N (Rm) S (=0) 2NRmrs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm.
In another embodiment, in conjunction with the novel compound embodiments above and below, R2 is -(C(Rq)2)0Rr, wherein Ru ils a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm,
-NRmRm, -N(Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NR'R - NRR)'C (=NRn') NRmRm,-N (Rm) S (=0) 2Rn, -N (Rm) S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORS, - C (=O) NRmRs,-C (=NR"') NRmR',-ORs,-OC (=O) Rs,-OC (=O) NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNR"'Rs,-OC2_6alkylORs,-SRs,-S (=O) Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm) C (=O) Rs, -S (=0) 2N (Rm) C (=O) ORs, -S(=O)2N(Rm) C (=O) NRmRs,-NRmRs,-N (Rm) C (=O) Rs,-N (Rm) C (=O) ORs, -N(Rm) C (=O) NRmRs,-N (Rm) C (=NRm) NRmRs, -N(Rm) S (=0) 2Rs, -N (Rm) S (=O) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, - S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm)C(=O)Rn, -N(Rm) C (=O) ORn,-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> - NR"'C2-6alkylNRmRm,-C (=O) Rs,-C (=O) OR',-C (=O) NRmR',-C (=NR"') NR"'Rs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmR', -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmrs, -N(Rm) S (=0) 2Rs,-N (Rm)S(=O)2NRmRs, -NRmC26alkylNRmRs,-NRmC26alkylORs and-NRmC26alkylORm ; In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn, -C(=O)NRmRm, C(=NRm)NRmRm, ORm, OC(=O)Rn, OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2R",-OC2-6alkylNR"'Rm,-OC2-6alkylORn',-SRm,-S (=O) R",
-S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) R,-N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, -N (Rm) S (=O) 2NRmRm, -NRmC2-6alkylNRmRm, - NRmC2-6alkylORm, -C(=O)Rs, -C (=O) ORs,-C (=O) NRmRs,-C (=NRm) NRmRs,-ORs,-OC (=O) Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNR"'R',-OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs, - N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, -N(Rm)C(=NRm)NRmRs, - N (R"') S (=0) 2Rs,-N (Rm) S (=0) 2NR"'R',-NR"'C2-6alkylNRmR',-NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, - OC2-6alkylOR"',-SR"',-S (=O) R",-S (=O) 2R",-S (=O) 2NR"'R"', - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, - NR"'R"',-N (Rm) C (=O) Rn, -N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm and -NRmC2-6alkylORm ; and the bridge carbon atoms are substituted with 0,1 or 2 =O groups.
In another embodiment, in conjunction with the novel compound embodiments above and below, R7 is tert-butyl or trifluoromethyl.
In another embodiment, in conjunction with the novel compound embodiments above and below, R9 is H.
In another embodiment, in conjunction with the novel compound embodiments above and below, Z is CR8.
In another embodiment, in conjunction with the novel compound embodiments above and below, Z is N.
In another embodiment, in conjunction with the novel compound embodiments above and below, R'is
R2 is H, -ORm, Cl, C1-3haloalkyl or C1-6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C, 8alkyl, C, 4haloalkyl, halo, cyano, nitro, -CF(=O)NRmRm, -C(=NRm)NRmRm, -ORn, -OC(=O)Rn, -OC(=O)NRmRm, -OC OC N(Rm)S(=O)2Rn, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, - S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm-NRmRm,-N (Rm) C (=O) R,-N (Rm) C (=O) OR -N (Rm) C (=O) NRmRm, -N (Rm) C (=NRm) NRmRm, -N (Rm) S (=O) 2Rn, -N (Rm) S (=0) 2NRmRm, -NRmC2-6alkylRmRm, -NRmC2-6alkylORm, -C(=O)Rs, - C (=0) ORs,-C (=O) NRmRs,-C (=NR") N"'Rs,-ORs,-OC (=0) RS, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)OR3, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs, - N (R"') C (=O) OR',-N (Rm) C (=O) NRmR',-N (Rm) C (=NRm) NRmRs, -N(Rm) S (=0) 2R',-N (R"') S (=0) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORS and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) NRmRm,-C (=NRm) NRmRm,-ORm,-OC (=O) R -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, - S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C (=O) NRmRm,-NRmRm - N (Rm) C (=O) R",-N (Rm) C (=O) ORn, -N(Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm and -NRmC2-6alkylORm ; wherein R4 is not unsubstituted phenyl ;
R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; Y is NH ; and Z is CR8 or N.
In another embodiment, in conjunction with the novel compound embodiments above and below, R4 is a saturated or unsaturated 5-or 6-membered ring containing 1, 2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) NRmRm,-C (=NRm) NRmRm,-OR",-OC (=O) R, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylORm, -SRm, -S(=O)Rn, - (=O) 2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm, -NRmRm, -N (Rm) C (=O) R",-N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, -N(Rm) S (=O) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmR',-OC2_6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - (=0) 2NR(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, - N (R°') C (=O) ORs,-N (Rm) C (=O) NRmR',-N (R) C (=NRm) NR"'R', - (Rm) S 2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C1-2haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC (=O) NRmR',-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, - S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm -N (Rm) C (=O) Rn, -N(Rm) C (=O) ORn,-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm and -NRmC2-6alkylORm ;
In another embodiment, in conjunction with the novel compound embodiments above and below, Z is CR In another embodiment, in conjunction with the novel compound embodiments above and below, Z is N.
Another aspect of the invention relates to a method of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, bums, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, comprising the step of administering a compound having the structure: or a naphthyl or saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein
no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7 ; R2 is H, hydroxy, halo, Chalky ! substituted by 0,1 or 2 substituents selected from R'°, or a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7 ; or R'and Rz together are R3 is H or C1-4alkyl ; or R1 and R3 together are
R4 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0,1, 2 or 3 substituents independently selected from Cl galkyl, Cl 4haloalkyl, halo, nitro, cyano,-ORa, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloaklyl, -NRa-C1-6alkylNRaRa, - 6alkylORa,-C (=O) C1 6alkyl,-C (=O) OCI 6alkyl,-OC (=O) C, 6alkyl, -C (=O) NRaCl 6alkyl and-NRaC (=O) Cl 6alkyl ; or R4 is 10-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2,3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORa, NRaRa, C1-6alkyl and Cl 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =O ; R5 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, - 4haloalkyl,-NRa-CI 6alkylNRaRa or-NRa-C, 6alkylORa ; or Rs is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S; R6 is independently, at each instance, H, Cl oalkyl, C, 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, - NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkyNRaRa or -NRa-C1-6alkylORa; or R5 and R6 together are a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the
carbon atoms of the bridge are substituted by 0,1, 2 or 3 substituents selected from halo, C1-6alkyl, (=O), -OC1-6alkyl, -NRaC1-6alkyl, -C1-6alkylORa and CI-6alkylNR aR', and the available N atoms of the bridge are substituted by Ra, -C1-6alkylORa or C1-6alkylNRaRa ; R7 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OCl 6alkyl,-O-C, 4haloalkyl,-O-C, 6alkylNRaRa,-O-Cs 6alkylORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa or -Nra-C1-6alkylORa ; R8 is independently, at each instance, H, C, _9alkyl, C, 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, - NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa or -NRa-C1-6alkylORa ; or R7 and R8 together are a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0,1, 2 or 3 substituents selected from halo, C1-6alkyl, (=O), -O-C1-6alkyl, -NRaC1-6alkyl, -C1-6alkylORa and Cl 6alkylNRaRa, and the available N atoms of the bridge are substituted by Ra, -C1-6alkylORa or C1-6alkylNRaRa ; R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OC, -6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa or -NRa-C1-6alkylORa ; Rl°is independently, at each instance, H, Chalky -9alkyl, -C1-3alkylORa, C, 4haloalkyl, halo, nitro, cyano, -ORa, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl, - O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, - NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C (=O) OC, 6alkyl,-OC (=O) C, 6alkyl,-C (=O) NRaC, 6alkyl or -NRaC (=O) CI 6alkyl ; R"is independently, at each instance, H, C1-9alkyl, -C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, -ORa, -S(=O),C1-6alkyl, -O-C1-4haloalkyl, - O-C1-6alkylNRaRa, -O-C1-6alkylRc, -O-C1-6lkylORa, -O-C1-6alkylC(=O)ORa, - NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C (=O) Cl 6alkyl,-C (=O) OC, 6alkyl,-OC (=O) C 6alkyl,-C (=O) NRaCl 6alkyl or - NRaC (=O) C, 6alkyl ; or Rl° and Together are a saturated or unsaturated 3-or
4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, -ORa, -C1-6alkylORa, -C1-6alkyl, -NRaRa, -C1-6alkylNRaRa, -C(=O)ORa, <BR> <BR> <BR> <BR> -C (=O) NRaRa,-CI 3alkylC (=O) ORa,-Cl 3alkylC (=O) NRaRa,-OC (=O) CI 6alkyl, -NRaC(=O)C1-6alkyl, -C1-3alkylOC(=O)C1-6alkyl or -C1-3alkylNRaC(=O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, -C1-6alkylORa, -C1-6alkyl, -C1-6alkylNRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, - C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRaC(=O)C1-6alkyl, -C(=O)Rc or -C1-3alkylRc ; wherein if R10, R12, R13 and R14 are all H, then R"is not -O-C1-6alkylNRaRa or -O-C1-6alkylORa ; R is independently, at each instance, H, C, galkyl,-Cl 3alkylORa, Cz 4haloalkyl, halo, nitro, cyano,-ORa,-S (=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, - 4haloalkyl,-NRa-C, 6alkylNRaRa,-NRa-C, 6alkylORa,-C (=O) Cl 6alkyl, -C (=O) OC, 6alkyl,-OC (=O) C, 6alkyl,-C (=O) NRaCl 6alkyl or -NRaC (=O) Cl 6alkyl ; or R 11 and R12 together are a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, -ORa, -C1-6alkylORa, -C1-6alkyl, -NRaRa, -C1-6alkylNRaRa, -C(=O)ORa, <BR> <BR> <BR> <BR> -C (=O) NRaRa,-C, 3alkylC (=O) ORa,-C, 3alkylC (=O) NRaRa,-OC (=O) C, 6alkyl, -NRaC(=O)C1-6alkyl, -C1-3alkylOC(=O)C1-6alkyl or -C1-3alkylNRaC(=O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, -C1-6alkylORa, -C1-6alkyl, -C1-6alkylNRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRaC(=O)C1-6alkyl, -C(=O)Rc or -C1-3alkylRc; R'3 is independently, at each instance, H, C1-9alkyl, -C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, -ORa, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl,
-C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl or -NRaC (=O) C1 6alkyl ; R14 is independently, at each instance, H, C1-9alkyl, -C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, -ORa, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl, - 6alkylNRaRa,-O-Cl 6alkylORa,-O-Ct 6alkylC (=O) ORa,-NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl or -NRaC (=O) C, 6alkyl ; Ra is independently, at each instance, H, phenyl, benzyl or Chalky ! ; Rc is phenyl substituted by 0,1 or 2 groups selected from halo, C1-3haloalkyl, -ORa and -NRaRa; or Rc is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0,1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, C1-3haloalkyl, -ORa and -NRaRa ; Ll is a bond, -CH2CH2- or -CH=CH-; L is NRa, O, S (=O) a_,-CH=N-or-NRaCH2- ; X is O, S or NRa ; or X and R2 together are =N-CH=CH-, =C-O-, =C-S-, or = Yis NHorO ; and n is independently, at each instance, 0,1 or 2; with the proviso that when R'is 4-chlorophenyl, then R4 is not 3-methoxyphenyl.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R'is
or a naphthyl or saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7 ; R is H, hydroxy, halo, Cl 6alkyl substituted by 0,1 or 2 substituents selected from Rl°,
or a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7 ; and R3 is H or C, 4alkyl.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R'is
In another embodiment, in conjunction with the method of treatment embodiments above and below, R7 is independently, at each instance, C29alkyl or Cl 4haloalkyl.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R'is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the
heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R5, R6 and R.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R2 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R6 and R7.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R2 is or a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from R5, R and R.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R2 is
In another embodiment, in conjunction with the method of treatment embodiments above and below, R2 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R5, R6 and R In another embodiment, in conjunction with the method of treatment embodiments above and below, R'and RZ together are In another embodiment, in conjunction with the method of treatment embodiments above and below, R'and R3 together are In another embodiment, in conjunction with the method of treatment embodiments above and below, X and R together are =N-CH=CH-, =C-O-, =C-S-, or =C-NRa-.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R4 is
Rb is H, C, 6alkyl,-C (=O) C, 6alkyl, Cl 6alkyl-O-Ra ; and y2 is -NRa- or -O-.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R4 is L3 is a 2-or 3-atom, saturated or unsaturated, bridge containing 1,2 or 3 carbon atoms and 0 or 1 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, =0,-OR, -C1-6alkylORa, -C1-6alkyl, -NRaRa, -C1-6alkylNRaRa, -C(=O)ORa, -C(=O)NRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -OC(=O)C1-6alkyl, -NRaC(=O)C1-6alkyl, -C1-3alkylOC(=O)C1-6alkyl or -C1-3alkylNRaC(=O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, -C1-6alkylORa, - C1-6alkyl, -C1-6alkylNRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRaC(=O)C1-6alkyl, -C(=O)Rc or -C1-3alkylRc ; Rb is H, C, 6alkyl,-C (=O) C, 6alkyl, Cl 6alkyl-O-Ra ; and y2 is-NRb-or-O-.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R4 is
L3 is a 2-or 3-atom, saturated or unsaturated, bridge containing 1,2 or 3 carbon atoms and 0,1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, =0,-OR, - C1-6alkylORa, -C1-6alkyl, -NRaRa, -C1-6alkylNRaRa, -C(=O)ORa, -C(=O)NRaRa, - 3alkylC (=O) ORa,-C, 3alkylC (=O) NRaRa,-OC (=O) CI 6alkyl, -NRaC(=O)C1-6alkyl, -C1-3alkylOC(=O)C1-6alkyl or -C1-3alkylNRaC(=O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H,-Cl 6alkylORa, -C1-6alkyl, -C1-6alkylNRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -C1-3alkylOC(O)C1-6alkyl, -C1-3alkylNRaC(=O)C1-6alkyl, -C(=O)Rc or -C1-3alkylRc ; Rb is H, C-16alkyl, -C(=O)C1-6alkyl, C1-6alkyl-O-Ra ; and y2 is-NRb-or-O-.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R4 is L3 is a 2-or 3-atom, saturated or unsaturated, bridge containing 1,2 or 3 carbon atoms and 0,1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, =0,-OR, -C1-6alkylORa, -C1-6alkyl, -NRaRa, -C1-6alkylNRaRa, -C(=O)ORa, -C(=O)NRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa, -OC(=O)C1-6alkyl, -NRaC(=O)C1-6alkyl, -C1-3alkylOC(=O)C1-6alkyl or -C1-3alkylNRaC(=O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H,-Cl 6alkylORa, -C1-6alkyl, -C1-6alkylNRaRa, -C1-3alkylC(=O)ORa, -C1-3alkylC(=O)NRaRa,
-C1-3alkylOC(=O)C1-6alkyl, -C1-3alkylNRaC(=O)C1-6alkyl, -C(=O)Rc or -Cl 3alkylRC ; Rb is H, C 6alkyl,-C (=O) CI 6alkyl, Cl 6alkyl-O-Ra ; and y2 is-NRb-or-O-.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R4 is
Rb is H, Cl -6alkyl, -C(=O)C1-6alkyl, C1-6alkyl-O-Ra ; and Y2 is -NRa - or -O-.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R4 is 10-membered bicyclic ring comprising fused 6-membered rings, containing 0,1, 2,3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORa, NRaRa, Cl 6alkyl and Cs 3haloalkyl ; and saturated carbon atoms may be additionally substituted by =O.
In another embodiment, in conjunction with the method of treatment embodiments above and below, R4 is
R'° is independently, at each instance, H, C1-9alkyl, -C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano,-ORa,-S (=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C (=O) OC, 6alkyl,-OC (=O) C, 6alkyl,-C (=O) NRaCl 6alkyl or -NRaC (=O) CI 6alkyl ;
R"is independently, at each instance, H, C19alkyl, -C1-3alkylORa, C, 4haloalkyl, halo, nitro, cyano,-ORa,-S (=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylRc, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, -NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C (=O) C, 6alkyl,-C (=O) OC, 6alkyl,-OC (=O) C, 6alkyl,-C (=O) NRaCs 6alkyl or -NRaC(=O)C1-6alkyl ; C, 6alkylNRaRa ; R is independently, at each instance, H, C1-9alkyl, -C1-3alkylORa, Cl 4haloalkyl, halo, nitro, cyano, -ORa, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkyl(=O)ORa, -NRaRa, - NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl or -NRaC(=O)C1-6alkyl ; R is independently, at each instance, H, C1-9alkyl, -C1-3alkylORa, Cl 4haloalkyl, halo, nitro, cyano,-ORa,-S (=O)C1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa; - NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl or -NRaC (=O) Cs 6alkyl ; and Rl4 is independently, at each instance, H, Chalky kylOR a, C, 4haloalkyl, halo, nitro, cyano,-ORa,-S (=O) nC, 6alkyl,-O-C, 4haloalkyl, -O-C1-6alkylNRaRa, -O-C1-6alkylORa, -O-C1-6alkylC(=O)ORa, -NRaRa, - NRa-C1-4haloalkyl, -NRa-C1-6alkylNRaRa, -NRa-C1-6alkylORa, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRaC1-6alkyl or -NRaC (=O) CI 6alkyl ; wherein one of R° and R 12 is not H.
In another embodiment, in conjunction with the method of treatment embodiments above, R4 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents selected from halo, C1-4haloalkyl, -ORa and -NRaRa.
Another aspect of the invention relates to a method of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, comprising the step of administering a compound according to compound description embodiments above--each seperately and alternatively.
Another aspect of the invention involves a method of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, comprising the step of administering a compound having the structure:
wherein: X is O, S or NRm ; n is independently, at each instance, 0,1 or 2; o is independently, at each instance, 0,1, 2 or 3; Rm is independently at each instance H or Rn ; Rn is independently at each instance Cl 8alkyl, phenyl or benzyl; Rq is independently in each instance H, Cl 4alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, - OC2-6alkylOR"',-SR"',-S (=O) R°,-S (=0) 2R",-S (=O) 2NR"'R"', - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm -NRmR',-N (Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NR'R', -N(Rm) C (=NRm) NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; Rs is Rn substituted by 0,1, 2 or 3 substituents independently selected from Rq ; R3 is H or C1-4alkyl ; Rus ils H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OC, 6alkyl, -O-C14-haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, or -(CH2)nRc R6 is, independently at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1 -6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; R8 is H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OC, 6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; and (A) R'is
* is H, -ORm, halo, C1-3haloalkyl or C1-6alkyl; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2R",-OC2_6alkylNRmRm,-OC2-6alkylOR"',-SRm,-S (=O) R", - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NR'Rm,-NRmRm,-N (Rm) C (=O) R",-N (Rm) C (=O) OR -N (Rm) C (=O) NRmRm, -N(Rm) C (=NRm) NRmR"',-N (Rn') S (=O) 2Rn, -N (Rm) S (=0) 2NRmRm,-NRmC2-6alkylNR"'R"',-NR"'C2-6alkylOR"',-C (=O) RS, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, -N (R"') C (=NR"') NR"'R', -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, - 6alkylORm-SRm,-S (=O) Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NR R, N (Rm) C (=O) Rn, -N(Rm) C (=O) ORn, -N (Rm) C (=O) NRmRm
-N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, -N(Rm) C (=NRm) NRmRs, -N (Rm) S (=0) 2R',-N (Rm) S (=0) 2NRmR', -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C, 9alkyl, C, 4haloalkyl, halo, nitro, cyano,-OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, - NR"'-C, 4haloalkyl,-NR"'-C, 6alkylNR"'Rm or-NR"'-C, 6aalkylORm ; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=O) 2Rn,-OC2 6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm; and Y is O or NH ; or (B) R'is
R2 is H,-OR"', halo, Cl 3haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC (=0) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, - N (R"') S (=O) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, - C (=0) OR',-C (=0) NR"'R',-C (=NR"') NR"'R',-OR',-OC (=0) R', -OC(=O)NRmRs, -OC(=O)N(Rm)S(=O)2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, - N (R"') C (=O) ORs, -N(Rm) C (=O) NRmRs, -N (R"') C (=NR"') NRmRs, -N(Rm) S (=0) 2R',-N (R"') S (=0) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, - OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm,
- NR"'C2-6alkylNR"'R"',-C (=O) R',-C (=O) OR',-C (=O) NRmRs,-C (=NR"') NR"'Rs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC26-alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C, 9alkyl, Cl 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, - NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNR"'Rm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O) 2N (Rm) C (=O) R",-S (=0) 2N (R"') C (=O) OR",-S (=0) 2N (Rm) C (=O) NRmRm, -NRmRm,-N (Rm) C (=O) Rn, -N(Rm) C (=O) OR",-N (R"') C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn,- N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; and Y is O or NH; or (C) R'is
R2 is H, -ORm, halo, C1-3 haloalkyl or C1-6alkyl ; R4 is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or 11-membered bicyclic heterocycle containing 1,2, 3,4 or 5 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5, 6,7-tetrahydro-benzo [b] thiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo [1, 4] dioxin-6-yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C1-9alkyl, oxo, C1-4haloalkyl, halo, nitro, cyano, -ORm, -S(=O)nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, - kylOR',-NRmRm,-NRm-CI-4haloalkyl,-NRm-CI-6alkylNRmRm, -NRm-C1-6alkylORm, -C(=O)C1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRmC1-6alkyl, -NRmC(=O)C1-6alkyl -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, - NRmRs,-N (R"') C (=O) R',-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N (R"') C (=NRm) NR'R',-N (Rm) S(=O)2Rs, -N(Rm)S(=O)2NRmRs, - NR"'C2-6alkylNRmR',-NR"'C2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm,-N (Rm) C (=O) R",-N (R"') C (=O) OR, -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, -N(Rm)S(=O)2NRmRm, -C(=O)Rs, -C(=O)ORs, -S(=O)NRmRs, -C(=NRm)NRmRs, - ORS,-OC (=O) Rs,-OC (=O) NRmR',-OC (=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNR"'R', - kylOR',-SRs,-S (=O) Rs,-S (=0) 2Rs, -S (=0) 2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - (Rm) C (=NRm) NR'R',-N (Rm) S (=0) 2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; wherein R4 is not 2-aminocarbonylmethyl-2,3-dihydro-benzo[l, 4] dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo [1, 4] dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl,
benzo [1, 3] dioxol-5-yl, 3, 3-dimethyl-1,3-dihydro-indol-2-on-6-yl or 4, 4-dimethyl- 3, 4-dihydro-lH-quinolin-2-on-7-yl ; R7 is C1-8alkyl, C1-5haloalkyl, I or Br R9 is H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1 6alkyl,-O-Cl 4haloalkyl, - O-C1-6alkylNRmRm, -OC1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, - NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, or -(CH2)nRc ; R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1 -6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, - or -NRm-C1-6alkylORm ; Y is NH ; and Z is CR8 or N ; or (D) R'is R2 is Cul 6alkyl substituted by 1, 2 or 3 substituents selected from C, 4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR",-C (=O) NR"'Rm, -C (=NRm) NRmRm,-ORm,-OC (=O) Rn,-OC (=O) NRmRm, -OC(=O)N(Rm)S(=O)2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, - S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, - N (R"') S (=O) 2NRmRm, -NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; or R2 is-(C (Rq) 2) phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) R°,-C (=O) OR°,-C (=O) NR"'R"',-C (=NRm) NRmRm,-ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn,-OC2 6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm)C(=O)NRmRm,
-NRmRm, -N(Rm) C (=O) R",-N (Rm) C (=O) ORn,-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C (=O) NRmR',-C (=NR') NR'R',-OR',-OC (=O) R,-OC (=O) NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, - S (=0) 2Rs,-S (=O) 2NR"'R',-S (=0) 2N (Rn') C (=O) R',-S (=0) 2N (Rm) C (=O) OR', -S(=O)2N(Rm) C (=O) NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N (Rm) C (=O) NRmR',-N (Rm) C (=NRm) NRmR',-N (R"') S (=0) 2R', -N (Rm) S (=O) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC OC(=O)NRmRm, -OC(=O)N(Rm)S(=O)2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, - S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N (Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNR°'R', -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRm C2-6alkylORm; or R2 is -(C(Rq)2)0Rr, wherein Ru ils a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, - C (=O) NRmRm,-C (=NRm) NR"'Rm,-ORm,-OC (=O) R",-OC (=O) NRmRm, -OC(=O) N (Rm) S (=O) 2R",-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S (=O) R -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn,
- S (=0) 2N (R"') C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) R",-N (Rm) C (=O) OR", -N (Rm) C (=O) NRmRm, -N (Rm) C (=NRm) NR'Rm,-N (Rm) S (=O) 2R", - N (R"') S (=O) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S 2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -NRmRs, -N(Rm)C(=O)Rs, - N (R"') C (=O) ORs, -N(Rm) C (=O) NRmR',-N (Rm) C (=NRm) NRmRs, - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C (=O) OR",-C (=O) NRmRm, -C (=NRm) NRmRm,-ORm -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, - OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, - NR"'R"',-N (R"') C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, -N(Rm) C (=NRm) NRmRm,-N (Rm) S (=O)2Rn, -N(Rm) S (=0) 2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2_6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) ORs, -N (Rm) C (=O) NRmR', - (Rm) C C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0, 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C, 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O)N(Rm)S(=O)2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn,
-S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) R",-N (Rm) C (=O) OR", -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, -N(Rm) S (=0) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O)N(Rm)S(=O)2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R', - N (R"') C (=O) OR',-N (R"') C (=O) NRmRs,-N (R) C (=NR"') NRmRs, -N(Rm) S (=0) 2R5, -N (Rm) S (=0) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn, -C(=O)NRmRs, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNRmRm, - OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm) C (=O) Rn,-s (=0) 2N (Rm) C (=O) OR',-S (=O) 2N (Rm) C (=O) NRmRm, -NRmRm,-N (Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (R"') C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmR', -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm) C (=O) R',-S (=0) 2N (Rm) C (=O) OR',-S (=0) 2N (Rm) C (=O) NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, - NRmC2-6alkylNRmRs,-NRmC2-6alkylORs and-NRmC2-6alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C2-8alkyl, C1-5haloalkyl, I, Br; R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, - O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; Y is NH; and Z is CR8 or N; or (E) R'is
R2 is H, -ORm, Cl, C1-3haloakyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, - C (=O) NRmRm,-C (=NR"') NRmRm,-OR",-OC (=O) R°,-OC (=O) NR"'R"', -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, - S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) Rn, -N (Rm) C (=O) OR -N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NR'R',-N (Rm) S (=O) 2Rn, - N (R"') S (=0) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylOR, -C(=O)R5, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, - OC (=O) NRmR',-OC (=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs,-OC2_6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs, -N(Rm) C (=O) OR',-N (R"') C (=O) NRmR',-N (R"') C (=NR"') NRmRs, - N(Rm)S(=O)2R5, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) NRmRm, -C (=NRm) NRmRm, -ORm, -OC (=O) Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, - SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, - N (R"') C (=O) Rn, -N(Rm) C (=O) OR",-N (Rm) C (=O) NR"'R"', - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> <BR> - NRmC2-6alkylNRmR"',-C (=O) R',-C (=O) ORs,-C (=O) NR"'Rs,-C (=NRm) NR"'Rs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs,
- OCz_6alkylORs,-SR',-S (=O) R',-S (=0) 2R',-S (=0) 2NR"R', -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, -N(Rm) C (=NRm) NRmRs,-N (Rm) S (=0) 2Rs, -N (Rm)S(=O)2NRmRs, - 6alkylNRmRs,-NRmC26alkylORs and-NRmC26alkylORm ; wherein R4 is not unsubstituted phenyl ; R7 is C2-6alkyl, C, 5haloalkyl, I or Br; R9 is independently, at each instance, H, C, 9alkyl, C, 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, - or -NRm-C1-6alkylORm; Y is NH; and Z is CR8 or N.
Another aspect of the invention involves a method of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, comprising the step of administering a compound having the structure:
wherein: X is O, S or NR"' ; n is independently, at each instance, 0,1 or 2; o is independently, at each instance, 0,1, 2 or 3; Rm is independently at each instance H or Rn ; Rn is independently at each instance C, 8alkyl, phenyl or benzyl ; Rq is independently in each instance H, C1-4alkyl, C1-4haloalkyl, halo, cyano, nitro, -C (=O) R n,-C (=O) OR',-C (=O) NR'R',-C (=NR') NR'R',-OR', -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn, -N(Rm) C (=O) OR",-N (R"') C (=O) NR'R', - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; Rs is R"substituted by 0,1, 2 or 3 substituents independently selected from Rq ; R3 is H or Cl 4alkyl ; Rs is H, Cl 9alkyl, Cl 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, or -(CH2)nRc R6 is, independently at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; R8 is H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -Nrm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm; and (A) R'is
R2is H,-OR', halo, Cl 3haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from CI-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NR'R',-NRmRm,-N (Rm) C (=O) Rn, -N (Rm) C (=O) OR -N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm,-N (Rm) S (=O) 2Rn, - N (R"') S (=0) 2NRmRm,-NR"'C2-6alkylNRmRm,-NR°'C2-6alkylORm,-C (=O) R', -C (=O) OR',-C (=O) NRmR',-C (=NRm) NRmR',-OR',-OC (=O) Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm) C (=O) ORs, -N(Rm) C (=O) NRmRs,-N (R"') C (=NR"') NRmRs, -N(Rm)S(=O)2Rs, -N(Rm) S (=O) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2R°,-OC2-6alkylNRmR"', - 6alkylORm,-SRm,-S (=O) Rn,-S (=0) 2Rn,-S (=0) 2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm,
- NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-GalkylNRmR', - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is Cl 9alkyl, C 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4halolakyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance C, 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C (=O) OR",-C (=O) NRmR"',-C (=NR"') NR"'R"',-OR", -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, - OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) R",-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N (R"') C (=NRm) NRmRm, -N (Rm) S (=0) 2Rn, -N(Rm) S (=0) 2NRmRm, - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; and Y is O or NH ; or (B) R'is
R2 is H,-ORm, halo, C, 3haloalkyl or C1-6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn,-C (=O) NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm, -NRmRm, -N (Rm) C (=O) Rn, -N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N (Rm) S (=0) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmRS,-OC2-6alkylORs, - SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm) C (=O) OR',-N (R"') C (=O) NRmRs, -N (R"') C (=NRm) NR"'R', - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, - OC (=O) R",-OC (=O) NR"'R"',-OC (=O) N (Rm) S (=O) 2R°,-OC2-6alkylNRmR"', -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm,-N (Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (R"') S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs,
-N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OC, 6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, C, 4haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2R",-OC2-6alkylNR"'R°', - OC2-6alkylORm,-SRm,-S (=O) R",-S (=O) 2R",-S (=O) 2NR"'R"', -S(=O)2N(Rm) C (=O) R°,-S (=O) 2N (R"') C (=O) OR",-S (=0) 2N (Rm) C (=O) NRmRm, -NRmRm, -N(Rm) C (=O) R",-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - or-NRmC2-6alkylORm ; and Y is O or NH ; or (C) R'is R2 is H, -ORm, halo, C1-3haloalkyl or Cl 6alkyl ; R4 is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or 11-membered bicyclic heterocycle containing 1, 2,3, 4 or 5 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5, 6,7-tetrahydro-benzo [b] thiophen-2-yl, benzothiazol-
2-yl, 2,3-dihydro-benzo [1, 4] dioxin-6-yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C1-9alkyl, oxo, C1-4haloalkyl, halo, nitro, cyano,-ORm,-S (=O) nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, - 6alkylORm,-NRmRm,-NRm-C, 4haloalkyl,-NRm-C, 6alkylNRmRm, - NRm-C1-6alkylORm, -C(=O)C1-6alkyl, -OC(=O)C1-6alkyl, -(=O)NRmC1-6alkyl, -NRmC(=O)C1-6alkyl -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2RmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmR', -N(Rm) C (=NRm) NRmRs,-N (Rm) S (=0) 2R',-N (Rm) S (=0) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) NRmRm, - C (=NRm) NRmRm,-ORm,-OC (=O) R",-OC (=O) NR"'R"', -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C (=O) NRmRm-N (Rm) C (=O) R',-N (Rm) C (=O) OR', -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2R, - N(Rm)S(=O)2NRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)2NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SR, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NrmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) ORs, -N (Rm) C (=O) NRmRS, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NrmC2-6alkylORm ; wherein R4 is not 2-aminocarbonylmethyl-2, 3-dihydro-benzo [1, 4] dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo [1, 4] dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo [1, 3] dioxol-5-yl, 3, 3-dimethyl-1,3-dihydro-indol-2-on-6-yl or 4, 4-dimethyl- 3, 4-dihydro-1H-quinolin-2-on-7-yl ; R'is C, 8alkyl, C, 5haloalkyl, I or Br
R9 is H, Cl. 9alkyl, C 4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, or -(CH2)nRc; R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, - nor' or -NRm-C1-6alkylORm ; Y is NH; and Z is CRs or N; or (D) RI is R2 is Ci 6alkyl substituted by 1,2 or 3 substituents selected from C, 4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) ORn, -C(=O)NRmRm, -C (=NRm) NRmRm,-ORm,-OC (=O) Rn,-OC (=O) NRmRm, S-OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S (=O) R°, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -SC(=O)2N(Rm) C (=O) NRmR',-NRmRm,-N (Rm) C (=O) Rn,-N (Rm) C (=O) OR', -N(Rm)C(=O)2NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, - N (R"') S (=O) 2NRmRm, -NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; or R2 is-(C (Rq) 2) Ophenyl, wherein the phenyl is substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC (=O) R",-OC (=O) NR'Rm,-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NR3R3, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, - NRmRm, - N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NrmRm, - -N(Rm)C(=O)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs,
-C(=O), -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)Rs, -OC(=O)NRmRs, - OC (=O) N (Rm) S (=0) 2R',-OC2-6alkylNR"'R',-OC2-6alkylORs,-SR',-S (=O) R', - S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, - S(=O)2N(Rm)C(=O)NRmRs, NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, -N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N (Rm) S (=O) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC (=O) NR'R',-OC (=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SR, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O) 2N (Rm)C(=O)Rn, - S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, - N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, -N(Rm) C (=NRm) NRmR',-N (Rm) S (=0) 2Rn, -N(Rm) S (=0) 2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmR', - OC2-6alkylORs,-SR',-S (=O) R',-S (=0) 2R',-S (=0) 2NRmR', -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C (=O) NRmRs, -NRmRs,-N (Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, -N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, - NRmC2-6alkylNRmRs,-NR"'C2-6alkylORs and-NRmC2-6alkylORm ; or R2 is- (C (Rq) 2) oR', wherein Rr is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, - C (=O) NRmRm,-C (=NR"') NR"'Rm,-OR"',-OC (=O) R",-OC (=O) NR"'Rm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NR"'R"',-NR"'Rm,-N (Rm) C (=O) Rn, -N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm, -N(Rm)C(=NR)NRmRm, -N(Rm) S (=O) 2Rn, -N (Rm) S (=0) 2NRmRm,-NR"'C2-6alkylNR"'R"',-NRmC2-6alkylORm,-C (=O) Rs,
- C (=O) OR',-C (=O) NR"'R',-C (=NR"') NR"'R',-OR',-OC (=O) RS, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNR"Rs,-OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N (R') C (=O) OR',-N (R"') C (=O) NR'R',-N (Rm) C (=NR"') NRmRs, -N(Rm) S (=0) 2Rs,-N (Rm) S (=0) 2NR'R',-NR'C2-6alkylNR'R',-NR'C2-6alkylOR' and Cl 4alkyl substituted by 1 or 2 groups selected from C1-2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) ORn,-C (=O) NRmR',-C (=NRm) NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, - NR"'R"',-N (R"') C (=O) R",-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRRs, -N(Rm)C(=O)Rs, -NR(m)C(=O)ORs, -N(Rm)C(=O)NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, - NR"'C2-6alkylNR"'RS,-NR"'C2-6alkylORs and-NRmC2-6alkylOR"' ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1 8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R°,-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S (=O) R", - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, - S (=0) 2N (R"') C (=O) NRmR',-NR'Rm,-N (Rm) C (=O) R",-N (Rm) C (=O) OR -N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm, -N(Rm)S(=O)2Rn,
- N (R"') S (=O) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmR',-OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm) C (=O) NRmRs, -N (Rm) C (=NRm) NRmRs, - (Rm) S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from C1-2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR",-C (=O) NRmRm,-C (=NRm) NR"'R"',-OR"', -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNR"'Rm, - OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NR'Rm,-N (Rm) C (=O) Rn, -N (Rm) C (=O) OR",-N (Rm) C (=O) NRmR -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, -N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC26alkylNRmRs,-NRmC26alkylORs and-NRmC26alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C2-8alkyl, C1-5haloalkyl, I, Br; R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm -C1-6alkylNRmRm or -NRm-C1-6alkylORm ; Y is NH; and Z is CR8 or N; or (E) R'is
R2 is H, -ORm, Cl, Cl 3haloalkyl or C1-6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORn, -OC(=O)Rn, -OC(=O)NRmRm, - OC N(Rm)S(=O)2Rn, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm) C (=O) Rn, -S (=0) 2N (Rm) C (=O) OR, -S(=O)2N(Rm) C (=O) NRmRm, -NRmRm, -N (R"') C (=O) Rn, -N (Rm) C (=O) OR -N (Rm) C (=O) NR'R',-N (Rm) C (=NRm) NRmRm, -N(Rm) S (=0) 2R, -N(Rm) S (=0) 2NR"'Rm,-NR"'C2-6alkylNRmR"',-NR°'C2-6alkylORm,-C (=O) R', -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R', - N (R"') C (=O) OR',-N (Rm) C (=O) NRmR',-N (R"') C (=NRm) NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C (=O) NRmRm,-C (=NRm) NRmRm,-ORm,-OC (=O) Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, - S 2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N (Rm) C (=O) Rn, -N(Rm) C (=O) OR",-N (R"') C (=O) NRmRm, - N (R"') C (=NRm) NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=O) 2Rs, -OC2-6alkylNRmRs, - OR',-SR',-S (=O) R',-S (=0) 2R',-S (=0) 2NRmRs,
- S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, NRmRs,-N (Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, -N(Rm) C (=NRm) NRmRs, -N (Rm) S (=0) 2Rs, -N(Rm)S(=O)2NR3Rs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; wherein R4 is not unsubstituted phenyl; R7 is C26alkyl, C1-5haloalkyl, I or Br; R9 is independently, at each instance, H, C_9alkyl, C, 4haloalkyl, halo, nitro, cyano,-OC, 6alkyl,-O-Cl 4haloalkyl,-O-CI 6alkylNRmRm, - kylNRmR' or -NR-C1-6alkylORm; Y is NH; and Z is CR8 or N.
Another aspect of the invention involves a pharmaceutical composition comprising a compound according to any of the above embodiments and a pharmaceutically-acceptable diluent or carrier.
Another aspect of the invention involves the use of any of the above compound embodiments as a medicament.
Another aspect of the invention relates to the use of a compound according the any one of the above embodiments in the manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration,
duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.
Another aspect of the invention relates to the manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non- vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, wherein the medicament contains a compound having the structure: wherein: X is O, S or NRm; n is independently, at each instance, 0,1 or 2; o is independently, at each instance, 0,1, 2 or 3; Rm is independently at each instance H or Rn ; Rn is independently at each instance Cl 8alkyl, phenyl or benzyl; Rq is independently in each instance H, Cl 4alkyl, C 4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn,-C (=O) NR'R',-C (=NRm) NRmRm,-ORm -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (R"') S (=0) 2R",-OC2-6alkylNR"'Rm, - 6alkyl0Rm,-SRm,-S (=O) Rn,-S (=0) 2Rn,-s (=0) 2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm,
-NRmRm,-N (Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NR3R3, - or-NR"'C2-6alkylORm ; Rs is R"substituted by 0,1, 2 or 3 substituents independently selected from Rq ; R3 is H or C1-4alkyl ; Rus ils H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, or -(CH2)nRc R6 is, independently at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNR3Rm, - O-C1-6alkylORm, -NRmRm, -NR3-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; R8 is H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, - O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; and (A) R'is R2 is H,-OR"', halo, C1-3haloalkyl or C1-6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) ORn, -C(=O)NRmRm, -C (=NRm) NRmRm,-ORm,-OC (=O) Rn,-OC (=O) NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rm,
-S(=O)2Rn, -S(=O)2NRmRm, -S(=O) 2N (Rm) C (=O) Rn,-S (=0) 2N (Rm) C (=O) OR', - S (=0) 2N (R"') C (=O) NRmRm, -NRmRm, -N (Rm) C (=O) R,-N (Rm) C (=O) OR -N(Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm,-N (Rm) S (=0) 2Rn, -N (Rm) S (=0) 2NRmR"',-NR"'C2-6alkylNR"'R"',-NR"'C2-6alkylOR"',-C (=O) R', -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, -N(Rm)C(=NRm)NRmRs, - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) ORn,-C (=O) NRmRm, -C (=NRm) NRmRm, -ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -jS(=O)2Rn, -S(=O=2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O2)N(Rm)C((=O)ORn, -S(=O)2N(Rm) C (=o) NRmRm, NRmRm,-N (Rm) C (=O) Rn,-N (Rm) C (=O) ORn, -N(Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(RM)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)Ors, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) Rs-N (Rm) C (=O) ORs, -N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OCl 6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or
2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (R"') S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2 6alkylORm,-SRm,-S (=O) Rn,-S (=0) 2Rn,-S (=0) 2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -Z(=O)2N(Rm)C(=O)2N(Rm)C(=O)NRmRm - NRmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)S(=O)2NRmRm, - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; and Y is O or NH; or (B) R'is R2 is H, -ORm, halo, Cl 3haloalkyl or Cul 6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn,-N (Rm) C (=O) OR -N (R') C (=O) NRmRm,-N (R') C (=NRm) NRmRm,-N (R') S (=O) 2Rn, -N(Rm) S (=0) 2NRmR"',-NRmC2-6alkylNRmR"',-NR"'C2-6alkylOR",-C (=O) Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs,
-OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNR"'R',-OC2-6alkylORs, -SRs, -S(=O)Rs, -S(O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs - S(=O)2N(Rm)C(=O)ORS, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, - N (R"') C (=O) ORs, -N(Rm) C (=O) NRmR',-N (R) C (=NRm) NRmRs, - N(Rm)S(=O)2R2, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, ni tro,-C (=O) Rn,-C (=O) ORn,-C (=O) NRmRm,-C (=NRm) NRmRm,-ORm -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, - OC2-6alkylORm,-SRm,-S (=O) R",-S (=O) 2R",-S (=0) 2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmrm, -NRmrm, -N(Rm) C (=O) R",-N (Rm) C (=O) ORn,-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRùRù; -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -CO(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=O) 2Rs,-OC2-6alkylNRmR', - 6alkylORs,-SRs,-S (=O) Rs,-S (=0) 2Rsx-S (=0) 2NRmR - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)Rs, N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, -N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6AlkylNRmRs, -NRmC2-6alkylORS and -NRmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is Cl-galkyl, C, 4haloalkyl, halo, nitro, cyano, -OC1 -6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, -C (=O) R°,-C (=O) OR",-C (=O) NRmRm,-C (=NRm) NRmRm,-ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm,
- OR',-SRm,-S (=O) Rn, -S(=O)2Rn, -S(=O)2NrmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn,-N (Rm) C (=O) ORn, -N(Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm or -NRmC2-6alkylORm ; and Y is O or NH ; or (C) R'is R2 is H, -ORm, halo, Cl 3haloalkyl or Cl 6alkyl ; R4 is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or 11-membered bicyclic heterocycle containing 1,2, 3,4 or 5 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5, 6,7-tetrahydro-benzo [b] thiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo [1, 4] dioxin-6-yl, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from C1-9alkyl, oxo, C1-4haloalkyl, halo, nitro, cyano,-OR"',-S (=O) -6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, - O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm, -Nrm-C1-6alkylORm, -C(=O)C1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRmC1-6alkyl, -NRmC(=O)C1-6alkyl -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, ORs-OC (=O) Rs,-OC (=O) NRmRs,-OC (=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmR', -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(rm)C(=O)ORs, -S(=O) 2N (Rm) C (=O) NRmR -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmR', - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) NR"'R"', -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O)N(Rm)S(=O)2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn,
-S(=O)2Rn, -S(=O)2NrmRm, -S(=O)2N(Rm) C (=O) Rn,-S (=0) 2N (Rm) C (=O) OR', - S (=0) 2N (R"') C (=O) NR"'R'",-N (R°') C (=O) Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NrmRm, -N(Rm) S (=0) 2R, - N(Rm)S(=O)2NRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs,-SR',-S (=O) Rs,-S (=0) 2RS,-S (=0) 2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NrmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmR', - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm; wherein R4 is not 2-aminocarbonylmethyl-2, 3-dihydro-benzo [1, 4] dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo [1, 4] dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo [1, 3] dioxol-5-yl, 3, 3-dimethyl-1, 3-dihydro-indol-2-on-6-yl or 4, 4-dimethyl- 3, 4-dihydro-1H-quinolin-2-on-7-yl ; R7 is C1-8alkyl, C1-5haloalkyl, I or Br R9 is H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -Nrm-C1-4haloalkyl, - NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, or -(CH2)nRc; R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -Nrm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C, 6alkylORm ; Y is NH ; and Z is CR8or N ; or (D) R'is R2 is C1-6alkyl substituted by 1,2 or 3 substituents selected from
C, 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C (=NRm) NRmRm,-ORm,-OC (=O) Rn,-OC (=O) NRmRm, -OC(=O) N (Rm) S (=0) 2R,-OC2-6alkylNRmRm,-OC2-6alkylORm,-SRm,-S (=O) R - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) Rn, -N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm) S (=O) 2NR"'R"',-NR"'C2-6alkylNRmR"or-NRmC2-6alkylOR"' ; or R2 is- (C (Rq) 2) ophenyl, wherein the phenyl is substituted by 0,1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C (=O) Rn,-C (=O) ORn, -C(=O)NRmRm, -(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNRmRm, - 6alkyl ORm,-SRm,-S (=O) Rn,-S (=O) 2Rn,-S (=O) 2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn,-N (Rm) C (=O) ORn,-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm -NRmC2-6alkylNRmRm, -NrmC2-6alkylOrm, -C(=O)Rs, -C(=O)ORs, -C (=O) NRmRs,-C (=NRm) NRmRs,-ORs,-OC (=O) Rs,-OC (=O) NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmR',-OC2-6alkylORs,-SR',-S (=O) R', - S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C (=O) NR"'R',-NR"'R',-N (Rm) C (=O) Rs,-N (Rm) C (=O) OR', -N(Rm)C(=O)NRmRs, -N(Rm)C(=NRm)NRmRs, -N(Rm) S (=0) 2Rs, -N (Rm) S (=O) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NrmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, - (=0) 2N(Rm)C(=O)ORn, -S(=O) 2N (Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=Nrm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, <BR> <BR> <BR> - NR"'C2-6alkylNRmRm,-C (=O) R',-C (=O) ORs,-C (=O) NRmR',-C (=NRm) NRmRS, -ORs, -OC(=O)Rs, -OC(=O)NrmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs,
-S (=0) 2N (R"') C (=O) R',-S (=0) 2N (Rm) C (=O) OR',-S (=0) 2N (Rm) C (=O) NRmR - NRmR',-N (R"') C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylOrm ; or R2 is-(C (Rq) 2) oRr wherein Rr is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0,1, 2 or 3 substituents independently selected from C1-8alklyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C (=O) OR, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -Oc(=O) N (Rm) S (=O) 2R",-OC2-6alkylNRmRm,-OC2 6alkylORm,-SRm,-S (=O) R°, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) R",-N (Rm) C (=O) OR', -(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, - N (R"') S (=0) 2NR"'R"',-NR"'C2 6alkylNRmR"',-NR"'C2-6alkylOR"',-C (=O) R', -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, -N(Rm)C(=NRm)NRmRs, -(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR",-C (=O) NR"'R"',-C (=NR°') NRmRm,-OR"', -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNR"'Rm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C (=O) NRmRm, -NRmRm,-N (Rm) C (=O) R",-N (Rm) C (=O) OR",-N (Rm) C (=O) NR'R', - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)NRmRm, <BR> <BR> <BR> - NRmC2-6alkylNRmRm,-C (=O) Rs,-C (=O) ORS,-C (=O) NR"'Rs,-C (=NR"') NRmR', -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (R"') S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs,
- S(=O)2N(Rm)C(=O)Rs, -S(=O)2N((Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, - NR"'R',-N (R"') C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C1-8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn,-C (=O) NRmR"', -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2R",-OC2-6alkylNR"'Rm,-OC2-6alkylORm,-SRm,-S (=O) R", -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm,-NRmRm,-N (Rm) C (=O) Rn, -N (Rm) C (=O) OR -N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm,-N (Rm) S (=O) 2Rn, -N(Rm) S (=O) 2NRmRm, -NRmC2-6alkylNRmRm, -NrmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, - OC (=O) NRmR',-OC (=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O) 2N (Rm) C (=O) R', - S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, -N (Rm) C (=NR"') NR"'R', - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NrmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, OC(=O) N (Rm) S (=O) 2R",-OC2-6alkylNR"'R"', - OC2-6alkylORm, -SRm, -S(=O)Rn, -X(=O)2Rn, -S(=O)2NrmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn, -N(Rm) C (=O) OR",-N (Rm) C (=O) NrmRm, - N (R"') C (=NRm) NrmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NrmRm, - NrmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=Nrm)NrmRs, )ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmRs,
-OC2-6alkylORs, -SRs, -S(O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NrmRs, -N(Rm) C (=O) R',-N (R"') C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NrmRs, - NR"'C2-6alkylNRmRs,-NRmC2-6alkylORs and-NR"'C2-6alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C2-8alkyl, C1-5haloalkyl, 1, Br; R9 is independently, at each instance, H, Cl 9alkyl, Cl 4haloalkyl, halo, nitro, cyano, -OC1 kylNR'Rm, - or -NRm-C1-6allkylORm ; Y is NH; and Z is CR8 or N; or (E) R'is R2 is H, -ORm, Cl, C1-3haloalklyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C1-8alklyl, C1-4haloalkyl, halo, cyano, nitro, -C(=O)NRmRm, -C(=NRm)NrmRm, -ORn, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R,-OC2-6alkylORm,-SRm,-S (=O) R,-S (=0) 2R -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, - S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N (Rm) C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm,-N (Rm) S (=O) 2R, -N(Rm) S (=0) 2NR"'Rm,-NRmC2-6alkylNRmR"',-NRmC2-6alkylOR"',-C (=O) R', -C(=O)ORs, -C(=O)NRmRs, -C(=Nrm)NrmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNR"'R',-OC2_6alkylORs,
-SRs,-S SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NrmRs, -S(=O)2N(Rm)C(=O)Rs, - S 2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NrmRs, -N(Rm)C(=O)Rs, -N(Rm) C (=O) ORs, -N(Rm) C (=O) NRmRs,-N (Rm) C (=NRm) NrmRs, - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NrmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) NRmRm, -C (=NRm) NRmRm,-ORm,-OC (=O) R', -OC(=O)NRmRm, -Oc(=O)N(Rm)S(=O),Rn, -OC2-6alklylNrmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, - S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C (=O) NRmRm,-NRmRm, -N(Rm) C (=O) R°,-N (Rm) C (=O) OR",-N (Rm) C (=O) NrmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NrmRm, -NrmC2-6allkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=Nrm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NrmRs, -OC(=O) N (Rm) S (=O) 2Rs,-OC2-6alkylNRmR', - OC2-6alkylPRs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NrmRs, -N(Rm) C (=O) Rs-N (Rm) C (=O) ORs, -N (Rm) C (=O) NRmRs -N(Rm)C(-NRm)NrmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NrmRs, -NrmC2-6alkylNRmRs, -NrmC2-6allkylORs and -NRmC2-6alklylORm ; wherein R4 is not unsubstituted phenyl ; R7 is C2-6alkyl, C1-5haloalkyl, I or Br; R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -Nrm-C1-4haloalkyl, -Nrm-C1-6alkylNRmRm or -Nrm-C1-6alkylORm ; Y is NH; and Z is CR8 or N.
Another aspect of the invention relates to the manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non- vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints
with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, wherein the medicament contains a compound having the structure: wherein: X is O, S or NRm ; n is independently, at each instance, 0,1 or 2; o is independently, at each instance, 0,1, 2 or 3; Rm is independently at each instance H or R" ; R"is independently at each instance C, 8alkyl, phenyl or benzyl ; Rq is independently in each instance H, Cl 4alkyl, Cz 4haloalkyl, halo, cyano, nitro, -C (=O) R",-C (=0) OR",-C (=0) NR"'R"',-C (=NR"') NR"'R'",-OR"', -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNR°'R"', - OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (R') C(=O)NrmRm, -NrmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NrmRm, - N(Rm)C(=NRm)NrmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NrmC2-6alkylNRmRm or -NRmC2-6alkylOrm ; R'is R"substituted by 0,1, 2 or 3 substituents independently selected from Rq ; R3 is H or C1-4alkyl;
R5 is H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OC, 6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -Nrm-C1-4haloalkyl, -Nrm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, or -(CH2)nRc R6 is, independently at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano,-OC, 6alkyl,-O-Cl 4haloalkyl,-O-CI 6alkylNRmRm, -O-C1-6alkylOrm, -NRmRm, -NRm-C1-4haloalkyl, -Nrm-C1-6alkylNrmRm or -Nrm-C1-6alkylORm ; R is H, Cl galkyl, C, 4haloalkyl, halo, nitro, cyano,-OCl 6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or -NRm-C1-6alkylORm ; and (A) R'is R2 is H, -Orm, halo, C1-3haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from Chalky -8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) R°,-C (=O) OR",-C (=O) NR"'R"', -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -X(=O)Rn, - S(=O)2Rn, -S(=O)2NrmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, - S (=0) 2N (R"') C (=O) NRmR"',-NR"'Rm,-N (R"') C (=O) Rn, -N(Rm) C (=O) OR", -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NrmRm, -N(Rm) S (=O) 2Rn, -N (Rm) S (=0) 2NRmRm,-NRmC2-6alkylNR"'R"',-NR"'C2-6alkylORm,-C (=O) RS, - C (=O) OR',-C (=O) NRmR',-C (=NR"') NRmR',-ORs,-OC (=O) RS, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmRs,-OC2-6alkylORs,
- SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NrmRs, -NrmRs, -N(Rm)C()O)Rs, - N (R"') C (=O) ORs,-N (Rm) C (=O) NRmR',-N (Rm) C (=NR"') NrmRs, - N(Rm)S(=O)Rs, -N(Rm)S(=O)S(=O)2NrmRs, -NrmC2-6alklylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) ORn,-C (=O) NRmRm,-C (=NRm) NrmRm, -ORm, -OC(=O)Rn, -OC(=O)NrmRm, -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNR"'R"', -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NrmRm, - NR"'R"',-N (R"') C (=O) Rn, -N(Rm) C (=O) OR",-N (R"') C (=O) NR"'R"', - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NrmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=Nrm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NrmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNR"'R', - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NrmRs, -NrmRs, -N(Rm) C (=O) Rs,-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmR', - NRR)') (=N"') NRmR',-N (Rm) S (=0) 2Rs,-N (Rm) S (=0) 2NR"'R', -NRmC2-6alkylNRmRs, -NNNRmC2-6alkylORs and -NrmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C1-9alklyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alklylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -Nrm-C1-6alkylNRmRm or -Nrm-C1-6alkylOrm ; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0,1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance C, 8alkyl, C, 4haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C(=O)ORn, -C(=O)NrmRm, -C(=NRm)NrmRm, -Orm, -OC(=O)Rn, -OC(=O)NrmRm, -OC(=O) N (Rm) S (=0) 2R°,-OC2-6alkylNR"'Rm, -OC2-6alklylOrm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm,
- S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NR'R',-N (R') C (=O) R",-N (Rm) C (=O) OR",-N (Rm) C (=O) NR'R', - N(Rm)C(=NRm)NrmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm or -NrmC2-6alkylORm ; and Y is O or NH ; or (B) R'is R2 is H, -ORm, halo, C1-3haloalkyl or Cl 6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-8alkyl, C, 4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) ORn, -C(=O)NRmRm, -C(=NRm)NrmRm, -Orm, -Oc(=O)Rn, -Oc(=O)NrmRm, -OC(=O)N(Rm)S(=O)2Rn, -OC2-6alkylNrmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, - S(=O)2N(Rm)C(=O)NrmRm, -NrmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NrmRm, -N(Rm)C(=NRm)NrmRm, -N(Rm) S (=O) 2Rn, - N (R"') S (=O) 2NR"'Rm,-NRmC2-6alkylNR"'Rm,-NR"'C2-6alkylORm,-C (=O) R', -C(=O)ORs, -C(=O)NrmRs, -C(=NRm)NrmRs, -ORs, -OC(=O)Rs, -OC (=O) NR'R',-OC (=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmRs,-OC2-6alkylOR', -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm) C (=O) Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NrmRs, -NrmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm) C (=O) NRmRs, -N (R"') C (=NR"') NR'"R', -N (Rm) S (=0) 2Rs,-N (Rm) S (=O) 2NRmRs, -NRmC2-6alklylNRmRs, -NrmC2-6alklylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo,
cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, - OC (=O) R",-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2R",-OC2-6alkylNRmR°', -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm, -N(Rm) C (=O) Rn,-N (Rm) C (=O) ORn, -N(Rm) C (=O) NRmRm, -N(Rm) C (=NRm) NRmRm,-N (Rm) S (=0) 2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmR', - OC2-6alkylORs, -S(=O), -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs,-N (Rm) C (=O) Rs,-N (Rm) C (=O) ORs,-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRms, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloakyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRm or-NRm-C1-6alkylORm; R° is a saturated, partially-saturated or unsaturated 5-, 6-or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0, 1, 2,3 or 4 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0,1 or 2 oxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from RP ; RP is independently at each instance Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=O) 2Rn,-OC2-6alkylNRmRm, - OC2-6alkylORm,-SRm,-S (=O) R",-S (=O) 2R",-S (=0) 2NRmRm, -S(=O)2N(Rm) C (=O) R",-S (=0) 2N (Rm) C (=O) OR",-S (=0) 2N (R"') C (=O) NRmRm, -NRmRm, -N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm) S (=0) 2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm or-NRmC2-6alkylORm ; and Y is O or NH; or (C) R'is
R2 is H,-ORm, halo, C, 3haloalkyl or C1-6alkyl ; R4 is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or 11-membered bicyclic heterocycle containing 1,2, 3,4 or 5 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5, 6,7-tetrahydro-benzo [b] thiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo [1, 4] dioxin-6-yl, wherein the heterocycle is substituted by 0,1, 2 or 3 substituents independently selected from C1-9alkyl, oxo, C1-4haloalkyl, halo, nitro, cyano,-ORm,-S (=O) nC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, - O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloakyl, -NRm-C1-6akylNRmRm, -NRm-C1-6alkylORm, -C(=O)C1-6alkyl, -OC(=O)C1-6alkyl, -C(=O)NRmC1-6alkyl, -NRmC(=O)C1-6alkyl -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2RS,-OC2-6aIkylNR"'R', -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NR'R', - N(Rm)C(=NRm)NRmRs,-N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C(=O)NRmRm, C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=O) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O) 2N (Rm) C (=O) NRmRm, -N (Rm) C (=O) R',-N (Rm) C (=O) OR', - N (R"') C (=O) NRmRm,-N (Rm) C (=NRm) NRmRm,-N (Rm) S (=O) 2Rn, - N(Rm)S(=O)2NRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs,
-S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm) C (=O) OR',-S (=0) 2N (Rm) C (=O) NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; wherein R4 is not 2-aminocarbonylmethyl-2, 3-dihydro-benzo [1, 4] dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo [1, 4] dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo [1, 3] dioxol-5-yl, 3, 3-dimethyl-1, 3-dihydro-indol-2-on-6-yl or 4, 4-dimethyl- 3, 4-dihydro-1H-quinolin-2-on-7-yl ; R7 is C1-8alkyl, C1-5haloalkyl, I or Br R9 is H, C1-9alkyl, C1-4haloakly, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloakyl, - O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloakyl, -NRm-C1-6alkylNRmRm, -NRm-C1-6alkylORm, or -(CH2)nRc; R9 is independently, at each instance, H, C1-9alkyl, C1-4haloakyl, halo, nitro, cyano,-OC, -6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloakyl, -NRm-C1-6alkylNRmRmor -NRm-C1-6alkylORm ; Y is NH; and Z is CR8or N ; or (D) R'is R2 is Cl 6alkyl substituted by 1,2 or 3 substituents selected from Cl 4haloalkyl, halo, cyano, nitro,-C (=O) Rn,-C (=O) OR",-C (=O) NRmR"', C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R°,-OC2-6alkylNRmRm,-OC2 6alkylOR'",-SR"',-S (=O) R", - S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(RmRm, -S(=O)2N(Rm)C(=O)Rn,-S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NR3Rm, -NRmRm, -N (Rm) C (=O) Rn,-N (Rm) C (=O) OR', -N (Rm) C (=O) NRmRm, -N(Rm) C (=NRm) NRmRm, -N(Rm) S (=O) 2Rn, - N (R"') S (=O) 2NRmRm,-NRn'C2-6alkylNRmRm or -NRmC2-6alkylORm ; or
R2 is -(C(Rq)2)ophenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) ORn,-C (=O) NR"'R"',-C (=NRm) NR'"R"',-OR'", - OC (=O) R",-OC (=O) NR"'Rm,-OC (=O) N (Rm) S (=0) 2Rn,-OC2-6alkylNRmRm, - OC2-6alkylOR"',-SRm,-S (=O) R",-S (=O) 2R",-S (=0) 2NRmRm, - S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, - NRmRm,-N (R"') C (=O) Rn, -N(Rm) C (=O) ORn, -N(Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)Rs, -C(=O)ORS, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2R',-OC2-6alkylNRmR',-OC2-6alkylORs,-SRs,-S (=O) Rs, - S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, - S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, -N(Rm)C(=NRm)NRmRs, -N(Rm) S (=O) 2Rs, - N (R"') S (=0) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and C1-4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro, -C(=O)Rn, -C(=O)ORn, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORm, -OC(=O)Rn, -OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SR, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O) 2N (Rm) C (=O) OR",-S (=0) 2N (Rm) C (=O) NRmRm, -NRmRm, - N(Rm)C(=O)Rn, -N(Rm)C(=O)ORn, -N(Rm)C(=O)NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORS, -OC(=O)Rs,-OC(=O)NRmRs, -OC(=O N (Rm) S (=0) 2R',-OC2-6alkyINRmRS, - OC2-6alkylORs, -SRs,-S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O) 2N (Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm; or R2 is-(C (Rq) 2) Rr, wherein Ru ils a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S,
wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from Cl 8alkyl, Cl 4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR', -C (=O) NRmRm,-C (=NRm) NRmRm,-ORm,-OC (=O) Rn,-OC (=O) NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C()O)ORn, -S(=O)2N(Rm) C (=O) NRmRm-NRmRm,-N (Rm) C (=O) Rn,-N (Rm) C (=O) OR', -N(Rm)C(=O)NRmRm, -N(Rm)C()NRm)NRmRm, -N(Rm) S (=O) 2R -N (Rm) S (=0) 2NRmRm,-NRmC2-6alkylNR"'Rm,-NR"'C2-6alkylORm,-C (=O) Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2RS,-OC2-6alkylNRmRs,-OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2N(Rm)C(=O)Rs, - S 2N(Rm)C(=O)ORs, -S(=O) 2N (Rm) C (=O) NRmRs,-NRmR',-N (Rm) C (=O) R', -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, -N(Rm) C (=NRm) NR"'R', - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from C1-2haloalkyl, halo, cyano, nitro,-C (=O) Rn, -C (=O) OR,-C (=O) NRmRm,-C (=NRm) NRmRm,-OR -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2 6alkylORm,-SRm,-S (=O) Rn,-S (=0) 2Rn,-S (=0) 2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRmRm, -NRmRm,-N (Rm) C (=O) R",-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NR)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, - NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm) C (=O) R',-N (Rm) C (=O) OR',-N (Rm) C (=O) NRmR', - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkyNRmRs, -NRmC2-6alkylORs and -NRmC2-6alkylORm ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3-or 4-atom bridge containing 0, 1, 2 or 3 atoms selected
from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C, 8alkyl, C1-4haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR",-C (=O) NR"'Rm, -C(=NRm)NRmRm, -ORm, -OC()O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2Rn, -OC2-6alkylNRmRm, -OC2-6alkylORm, -SRm, -S(=O)Rn, - S 2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm, -NRmRm, -N (Rm) C (=O) Rn, -N (Rm) C (=O) OR -N(Rm)C(=O)NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm) S (=O) 2Rn, -N (Rm) S (=0) 2NRmR"',-NR"'C2-6alkylNRmRm,-NRmC2-6alkylORm,-C (=O) R', -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, -N(Rm)C(=NRm)NRlRs, -N(Rm) S (=0) 2Rs-N (Rm) S (=0) 2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORs and Cl 4alkyl substituted by 1 or 2 groups selected from Cl 2haloalkyl, halo, cyano, nitro,-C (=O) R",-C (=O) OR",-C (=O) NR"'Rm,-C (=NR"') NRmRm,-OR"', -OC (=O) Rn,-OC (=O) NRmRm,-OC (=O) N (Rm) S (=0) 2R",-OC2-6alkylNR"'Rm, - OC2-6alkylORm, -SRm, -S(=O)Rn, -S(=O)2Rn, -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm)C(=O)NRlRm, -NRmRm, -N(Rm) C (=O) R",-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, -N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -C()O)Rs, -C()O)ORs, -C()O)NRmRs, -C(=NRm)NRmRs, - ORS,-OC (=O) Rs,-OC (=O) NR"'R',-OC (=O) N (Rm) S (=0) 2Rs,-OC2-6alkylNRmR', - OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2NRmRs, - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, -N(Rm) C (=NRm) NRmR',-N (Rm) S (=0) 2Rs,-N (Rm) S (=O) 2NRmRs, -NRmC26alkylNRmRs,-NRmC26alkylORs and-NRmC26alkylORm, and the ring and bridge carbon atoms are substituted with 0,1 or 2 =O groups; R7 is C2-8alkyl, C1-5haloalkyl, I, Br;
R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, -O-C1-6alkylORm, -NRmRm, -NRm-C1-4haloalkyl, -NRm-C1-6alkylNRmRmor -NRm-C1-6alkylORm ; Y is NH; and Z is CR8 or N ; or (E) R'is R2 is H, -ORm, Cl, C1-3haloalkyl or C1-6alkyl ; R4 is a saturated or unsaturated 5-or 6-membered ring containing 0,1, 2 or 3 atoms selected from O, N and S, so long as the combination of O and S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from Cul 8alkyl, Cl 4haloalkyl, halo, cyano, nitro, -C(=O)NRmRm, -C(=NRm)NRmRm, -ORn, -OC(=O)Rn, -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R,-OC2-6alkylOR',-SRm,-S (=O) R,-S (=0) 2R -S(=O)2NRmRm, -S(=O)2N(Rm)C(=O)Rn, -S(=O)2N(Rm)C(=O)ORn, -S(=O)2N(Rm) C (=O) NRmRm-NRmRm,-N (Rm) C (=O) Rn, -N (Rm) C (=O) OR - N (R"') C (=O) NR"'R"',-N (R"') C (=NR"') NR"'R"',-N (R"') S (=O) 2R", - N (R"') S (=O) 2NRmRm, -NRmC2-6alkylNRmRm, -NRmC2-6alkylORm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC()O)Rs, -OC(=O)NRmRs, -OC(=O)N(Rm)S(=O)2Rs, -OC2-6alkylNRmRs, -OC2-6alkylORs, -SRs, -S(=O)Rs, -S(=O)2Rs, -S(=O)2NRmRs, -S(=O)2N(Rm)C(=O)Rs, - (=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, -N(Rm) C (=O) Rs - N (R"') C (=O) ORs,-N (Rm) C (=O) NRmRs,-N (Rm) C (=NRm) NRmRs, - N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkymORs and C1-4alkyl substituted by 1 or 2 groups selected from C, 2haloalkyl, halo, cyano, nitro, -C (=O) Rn, -C (=O) NRmRm,-C (=NRm) NRmRm,-ORm,-OC (=O) R", -OC(=O)NRmRm, -OC(=O) N (Rm) S (=0) 2R",-OC2-6alkylNRmR"',-OC2-6alkylOR°',
- SRm, -S(=O)Rn, -S(=O)2Rn, -S (=0) 2NRmRm, -S(=O) 2N (R') C (=O) Rn, - S (=0) 2N (R"') C (=O) OR',-S (=0) 2N (Rm) C (=O) NRmRm, -NRmRm, - N (R"') C (=O) Rn,-N (Rm) C (=O) OR",-N (Rm) C (=O) NRmRm, - N(Rm)C(=NRm)NRmRm, -N(Rm)S(=O)2Rn, -N(Rm)S(=O)2NRmRm, -NRmC2-6alkylNRmRm, -C(=O)Rs, -C(=O)ORs, -C(=O)NRmRs, -C(=NRm)NRmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, -OC(=O) N (Rm) S (=0) 2Rs, -OC2-6alkylNRmRs, - OC2-6alkylORs,-SRS,-S (=O) R',-S (=0) 2R',-S (=O) 2NRmR', - S(=O)2N(Rm)C(=O)Rs, -S(=O)2N(Rm)C(=O)ORs, -S(=O)2N(Rm)C(=O)NRmRs, - NRmRs, -N(Rm)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rm)C(=O)NRmRs, - N(Rm)C(=NRm)NRmRs, -N(Rm)S(=O)2Rs, -N(Rm)S(=O)2NRmRs, -NRmC2-6alkylNRmRs, -NRmC2-6alkylORsand -NRmC2-6alkylORm ; wherein R4 is not unsubstituted phenyl; R7 is C2-6alkyl, Cl-5haloalkyl, I or Br; R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, -OC1-6alkyl, -O-C1-4haloalkyl, -O-C1-6alkylNRmRm, - or -NRm-C1-6alkylORm ; Y is NH; and Z is CR8 or N.
The compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers.
Unless otherwise specified, the following definitions apply to terms found in the specification and claims: "C&alph -ßalkyl" means an alkyl group comprising from a to ß carbon atoms in a branched, cyclical or linear relationship or any combination of the three. The alkyl groups described in this section may also contain a double or triple bond.
Examples of C1-6alkyl include, but are not limited to the following:
"Halo"means a halogen atoms selected from F, Cl, Br and I.
"Ca phaloalkyl"means an alkyl group, as described above, wherein any number-- at least one--of the hydrogen atoms attached to the alkyl chain are replaced by F, Cl, Br or I.
"Heterocycle"means a ring comprising at least one carbon atom and at least one other atom selected from N, O and S. Examples of heterocycles that may be found in the claims include, but are not limited to, the following:
"Pharmaceutically-acceptable salt"means a salt prepared by conventional means, and are well known by those skilled in the art. The"pharmacologically acceptable salts"include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. When compounds of the invention include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. For additional examples of"pharmacologically acceptable salts,"see infra and Berge et al. , J. Pharm. Sci.
66: 1 (1977).
"Leaving group"generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
"Protecting group"generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho- methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9- (9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals, preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl
methyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloro acetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1, 2-bis (methylene) benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di-or tri- substituted, such as nitrophthalimidyl. Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like. Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkyl groups are also suitable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl, tert- butyldimethylsilyl, dimethylphenylsilyl, 1, 2-bis (dimethylsilyl) benzene, 1, 2-bis (dimethylsilyl) ethane and diphenylmethylsilyl. Silylation of an amino groups provide mono-or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a N, N, O-tri-silyl derivative. Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art.
Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled
in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t- butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HCI or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine. Carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydroylsis and hydrogenolysis conditions well known to those skilled in the art.
It should be noted that compounds of the invention may contain groups that may exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, heteroatom substituted heteroaryl groups (Y'= O, S, NR), and the like, which are illustrated in the following examples:
and though one form is named, described, displayed and/or claimed herein, all the tautomeric forms are intended to be inherently included in such name, description, display and/or claim.
Prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989) ). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985) ).
Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
Experimental General Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures.
Melting points were determined on a Buchi apparatus and are uncorrected. Mass spectral data was determined by electrospray ionization technique. All examples were purified to >95% purity as determined by high-performance liquid chromatography (HPLC). Unless otherwise stated, reactions were run at room temperature.
The following abbreviations are used: aq.-aqueous cond-concentrated DMF-N, N-dimethylformamide Et20-diethyl ether EtOAc-ethyl acetate EtOH-ethyl alcohol h-hour min-minutes MeOH-methyl alcohol satd-saturated THF-tetrahydrofuran Example 1 (2E)-3- [4- (tert-Butyl) phenyl]-N-phenylprop-2-enamide. To a 10 mL glass vial was added 4-tert-butyl-trans-cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) followed by CH2Cl2 (5 mL), 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (225 mg, 1.17 mmol, Bachem) and aniline (98 uL, 100 mg,
1.08 mmol, Aldrich). The reaction mixture was magnetically stirred at 25 °C for 24 h. EtOAc was added (60 mL) and the mixture washed successively with 1 N NaOH (2 x 20 mL), 1 N HO (20 mL), water (20 mL) and satd NaCl (20 mL), dried over MgS04, filtered and concentrated. Recrystallization from hexane and CH2Cl2 provided the title product as white crystals. MP 141 °C. MS (ESI, pos. ion) m/z : 280 (M+1).
Example 2 (2E)-N- (3, 4-Dimethoxyphenyl)-3- [4- (tert-butyl) phenyl] prop-2-enamide. To a 20 mL round-bottomed flask equipped with reflux condenser and drying tube was added 4-tert-butyl-trans-cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) followed by CH2CI2 (5 mL), oxalyl chloride (90 uL, 130 mg, 1.03 mmol, Aldrich) and DMF (1 uL). The reaction mixture was magnetically stirred and heated at reflux for 30 min. The reaction mixture was concentrated in vacuo and the residue dissolved in acetone (2 mL). The solution was added to a mixture of 3,4- dimethoxyaniline (180 mg, 1.17 mmol, Aldrich), potassium carbonate (200 mg), water (2 mL) and acetone (2 mL), magnetically stirred at 25 °C in a 10 mL glass vial. The reaction mixture was stirred at 25 °C for 16 h then diluted with EtOAc (60 mL) and washed successively with 1 N HCl (20 mL), 1 N NaOH (20 mL), water (20 mL) and satd NaCI (20 mL), dried over MgS04, filtered and concentrated. Recrystallization from hexane and CH2CI2 provided the title product as a yellow solid. MP 115-116 °C. MS (ESI, pos. ion) m/z : 340 (M+1).
Example 3 (2E)-3- [4- (tert-Butyl) phenyl]-N- (4-hydroxy-3-methoxyphenyl) prop-2- enamide.
(a). 4-Amino-2-methoxyphenol. To a round-bottomed flask was added 4- nitroguaiacol (500 mg, 3.0 mmol, Aldrich) and anhydrous EtOH (50 mL). The solution was stirred magnetically under N2 and treated with 10% Pd on carbon (200 mg, Aldrich). The suspension was purged with H2 and then stirred at 25 °C under 1 atm H2 for 16 h. The suspension was purged with N2, filtered through Celite and concentrated in vacuo to provide a dark solid. The solid was washed with 1: 1 CH2Cl2 : hexane and dried in vacuo to provide the title product as pale brown crystals. MS (ESI, pos. ion) m/z : 140 (M+1).
(b). (2E)-3- [4- (tert-Butyl) phenyl]-N- (4-hydroxy-3-methoxyphenyl) prop-2- enamide. Analogous to the procedure used to prepare Example 2,4-amino-2- methoxyphenol, Example 3 (a), (164 mg, 1.18 mmol) and 4-t-butyl-trans- cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) provided, after recrystallization of the crude product from CH2C ! 2 and hexane, the title product as brown crystals. MP 203-204 °C. MS (ESI, pos. ion) m/z : 326 (M+1).
Example 4
(2E)-3- [4- (tert-Butyl) phenyl]-N- (2-5, 6,7, 8-tetrahydronaphthyl) prop-2- enamide.
(a). 2-5,6, 7, 8-Tetrahydronaphthylamine. To a round-bottomed flask was added 6-amino-1, 2,3, 4-tetrahydronaphthalene (500 mg, 3.10 mmol, Maybridge), triethylsilane (2.50 mL, 15.5 mmol, Aldrich) and trifluoroacetic acid (5.0 mL, 66 mmol, Aldrich). The reaction mixture was magnetically stirred vigorously, at 25 °C, for 2 h. The solvents were removed in vacuo and the residue dissolved in EtOAc (50 mL) and extracted with 1 N HCI (100 mL, then 50 mL). The combined aqueous acidic extract was washed with EtOAc (50 mL) then basified with 5 N NaOH, at 0 °C, to pH 10. The mixture was extracted with CH2Cl2 (3 x 50 mL), the combined organic extract washed with water (50 mL), satd NaCI (50 mL), dried over Na2S04, filtered and concentrated in vacuo to provide the title product as a brown oil. MS (ESI, pos. ion) m/z : 148 (M+1).
(b). (2E)-3- [4- (tert-Butyl) phenyl]-N- (2-5, 6,7, 8-tetrahydronaphthyl) prop-2- enamide. Analogous to the procedure used to prepare Example 2,2-5, 6,7, 8- tetrahydronaphthylamine, Example 4 (a), (173 mg, 1.18 mmol) and 4-t-butyl- trans-cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (4: 1 hexane: EtOAc) followed by re- crystallization from CH2CI2 and hexane, the title product as white crystals. MP 198-199 °C. MS (ESI, pos. ion) m/z : 334 (M+1).
Example 5 (2E)-N- (2H, 3H, 4H-Benzo [3,4-e] 1, 4-oxazaperhydroin-6-yl)-3- [4- (tert- butyl) phenyl] prop-2-enamide.
(a) 2H, 3H, 4H-Benzo [e] 1, 4-oxazaperhydroine-6-ylamine. To a round- bottomed flask was added 2-amino-4-nitrophenol (1.0 g, 6.5 mmol, Aldrich), potassium carbonate (1.8 g, 13 mmol), DMF (5 mL) and 1,2-dibromoethane (0.59 mL, 6.9 mmol, Aldrich). The mixture was magnetically stirred and heated in a 125 °C oil bath, under N2, for 2.5 h. After allowing to cool to 25 °C, the reaction mixture was diluted with EtOAc (100 mL), washed with 1 N NaOH (3 x 50 mL), water (50 mL), satd NaCL (50 mL), dried over Na2SO4, filtered and concentrated to provide a dark residue [MS (ESI, pos. ion) nzlz : 181 (M+1)]. The crude product was dissolved in EtOH (100 mL), the solution was purged with N2, treated with 10% Pd on carbon (450 mg, Aldrich), purged with H2 then magnetically stirred under 1 atm H2 for 2 h. After purging again with N2, the suspension was filtered through Celite and concentrated in vacuo. Purification by silica gel chromatography (95: 5 CH2CI2 : 2 M NH3 in EtOH) provided the title product as a viscous brown oil. MS (ESI, pos. ion) m/z : 151 (M+1).
(b) (2E)-N- (2H, 3H, 4H-Benzo [3,4-e] 1, 4-oxazaperhydroin-6-yl)-3- [4- (tert- butyl) phenyl] prop-2-enamide. Analogous to the procedure used to prepare Example 2,2H, 3H, 4H-benzo [e] 1, 4-oxazaperhydroine-6-ylamine, Example 5 (a), (176 mg, 1.18 mmol) and 4-t-butyl-trans-cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (step gradient, 6: 3: 1 CH2CI2 : hexane: EtOAc then 9: 1 hexane: EtOAc) the title product as a yellow solid. MP 108-114 °C. MS (ESI, pos. ion) m/z : 337 (M+1).
Example 6 (2E)-3- [4- (tert-Butyl) phenyl]-N- (3-oxo (2H, 4H-benzo [3, 4-tell, 4- oxazaperhydroin-6-yl)) prop-2-enamide.
(a) 6-Nitro-2H, 4H-benzo [e] 1, 4-oxazaperhydroin-3-one. A mixture of 4-nitro- 2-aminophenol (4.6 g, 30 mmol, Aldrich), benzyltrimethylammonium chloride (6.8 g, 30 mmol, Aldrich) and solid NaHC03 (12.6 g, 150 mmol) in chloroform (100 mL) was magnetically stirred at 0 °C in a round-bottomed flask and treated dropwise with chloroacetyl chloride (2.9 mL, 33 mmol, Aldrich) over a period of 30 min. After the addition was complete, the reaction mixture was stirred at 0 °C for 1 h, then at 50 °C overnight. The solvent was removed in vacuo and the residue treated with water (50 mL), collected by filtration and washed with water.
The solid was recrystallized from EtOH to provide 6-nitro-2H, 4H-benzo [e] 1, 4- oxazaperhydroin-3-one. MS (ESI, neg. ion) m/z : 193 (M-1). (b) 6-Amino-2H, 4H-benzo [e] 1, 4-oxazaperhydroin-3-one. To a suspension of 6-nitro-2H, 4H-benzo [e] 1, 4-oxazaperhydroin-3-one, Example 6 (a), (0.50 g, 2.6 mmol) and CuCl (0.77 g, 7.8 mmol, Aldrich) in anhydrous MeOH (25 mL), magnetically stirred at 25 °C in a round-bottomed flask, was added potassium borohydride (0.98 g, 18 mmol, Aldrich) in portions. The reaction mixture was stirred at 25 °C for 0.5 h, then the solvent was removed in vacuo and the residue suspended in water (30 mL) and extracted with EtOAc (5 x 20 mL). The combined organic extracts were washed with satd NaCI, dried over Na2S04,
filtered and concentrated in vacuo to provide the title product as a brown solid.
MS (ESI, pos. ion) nilz : 165 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N- (3-oxo (2H, 4H-benzo [3,4-e] 1, 4- oxazaperhydroin-6-yl)) prop-2-enamide. Analogous to the procedure used to prepare Example 1,6-amino-2H, 4H-benzo [e] 1, 4-oxazaperhydroin-3-one, Example 6 (b), (207 mg, 1.26 mmol) and 4-tert-butyl-trans-cinnamic acid (258 mg, 1.26 mmol EMKA-Chemie) provided, after recrystallization from EtOAc and hexane, the title compound as a pale yellow solid. MP > 280 °C. MS (ESI, pos. ion) m/z : 351 (M+1).
Example 7 (2E)-3- [4- (tert-Butyl) phenyl]-N- (4-methyl-3-oxo (2H-benzo [3, 4-tell, 4- oxazaperhydroin-6-yl)) prop-2-enamide.
(a) 4-Methyl-6-nitro-2H-benzo [e] 1, 4-oxazaperhydroin-3-one. A mixture of 6- nitro-2H, 4H-benzo [e] 1, 4-oxazaperhydroin-3-one, Example 6 (a), (970 mg, 25 mmol), benzyltrimethylammonium chloride (114 mg, 0.50 mmol, Aldrich) and iodomethane (0.47 mL, 7.5 mmol, Aldrich) in CH2CI2 (20 mL) was stirred magnetically in a 100 mL round-bottomed flask and treated with CsOH monohydrate (4.2 g, 25 mmol, Aldrich). The reaction mixture was stirred at 25 °C for 1 h, treated with water (5 mL) and extracted with CH2CI2 (3 x 50 mL).
The combined organic extract was washed with water (5 mL), satd NaCl (5 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (9: 1 hexane: EtOAc) to provide the title product.
MS (ESI, pos. ion) m/z : 209 (M+1).
(b) 6-Amino-4-methyl-2H-benzo [e] 1, 4-oxazaperhydroin-3-one. To a solution of 4-methyl-6-nitro-2H-benzo [e] 1, 4-oxazaperhydroin-3-one, Example 7 (a), (700 mg, 3.4 mmol) and NiCI2 6H2O (400 mg, 1.7 mmol, Aldrich) in MeOH (10 mL), magnetically stirred in a 100 mL round-bottomed flask at 25 °C, was added NaBH4 (190 mg, 5.1 mmol, Aldrich) in portions. The reaction mixture was stirred for 30 min then concentrated in vacuo. Purification by silica gel chromatography (CH2CI2/EtOAc) provided the title product. MS (ESI, pos. ion) m/z : 179 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N- (4-methyl-3-oxo (2H-benzo [3, 4-tell, 4- oxazaperhydroin-6-yl)) prop-2-enamide. Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA- Chemie) and 6-amino-4-methyl-2H-benzo [e] 1, 4-oxazaperhydroin-3-one, Example 7 (b), (180 mg, 1.0 mmol) provided, after purification by silica gel chromatography (4: 1 CH2CI2 : EtOAc), the title product as a pale yellow solid. MP 201-203 °C. MS (ESI, pos. ion) mlz : 365 (M+1).
Example 8 (2E)-3- [4- (tert-Butyl) phenyl]-N- (4-methyl (2H, 3H-benzo [3,4-e] 1, 4- oxazaperhydroin-6-yl)) prop-2-enamide.
To a solution of lithium aluminum hydride (2.0 mL, 2.0 mmol, 1.0 M in THF, Aldrich), magnetically stirred at 0 °C in a round-bottomed flask under N2, was added 6-amino-4-methyl-2H-benzo [e] 1, 4-oxazaperhydroin-3-one, Example 7b, (180 mg, 1.0 mmol). The reaction mixture was allowed to warm to 25 °C and stirred at that temperature for 1 h. The reaction was quenched by the dropwise addition of 20% HzO/THF (1.2 mL), followed by 5 N NaOH (0.2 mL). The mixture was stirred at 25 °C for 30 min, then filtered and washed with EtOAc.
The filtrate was dried over Na2SO4, filtered and concentrated in vacuo [MS (ESI, pos. ion) m/z : 165 (M+1)]. Analogous to the procedure used to prepare Example 1, the crude product and 4-tert-butyl-trans-cinnamic acid provided the title compound as a pale yellow solid. MP 186-188 °C. MS (ESI, pos. ion)/ : 351 (M+1).
Example 9 (2E)-3- [4- (tert-Butyl) phenyl]-N- (3-oxo (2H, 4H-benzo [e] 1, 4-oxazaperhydroin- 7-yl)) prop-2-enamide.
(a) 7-Nitro-2H, 4H-benzo [e] 1, 4-oxazaperhydroin-3-one. Analogous to the procedure used for the preparation of 6-nitro-2H, 4H-benzo [e] 1, 4- oxazaperhydroin-3-one, Example 6 (a), 5-nitro-2-aminophenol (4.6 g, 30 mmol, Aldrich) and chloroacetyl chloride (2.9 mL, 33 mmol, Aldrich) provided, after recrystallization from EtOH, 7-nitro-2H, 4H-benzo [e] 1, 4-oxazaperhydroin-3-one.
MS (ESI, neg. ion) m/z : 193 (M-l).
(b) 7-Amino-2H, 4H-benzo [e] 1, 4-oxazaperhydroin-3-one. A mixture of 7- nitro-2H, 4H-benzo [e] 1, 4-oxazaperhydroin-3-one, Example 9 (a), (970 mg, 5.0 mmol) and 10% Pd on carbon (100 mg, Aldrich) in MeOH (20 mL) was magnetically stirred in a round-bottomed flask under 1 atm H2 for 2 h. The mixture was purged with N2 and filtered through a pad of Celite. Concentration in vacuo provided the title product. MS (ESI, pos. ion) m/z : 165 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N- (3-oxo (2H, 4H-benzo [e] 1,4- oxazaperhydroin-7-yl)) prop-2-enamide. Analogous to the procedure used to
prepare Example 1, 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA- Chemie) and 7-amino-2H, 4H-benzo [e] 1, 4-oxazaperhydroin-3-one, Example 9 (b), (164 mg, 1.0 mmol) provided, after purification by silica gel chromatography (4: 1 CH2CI2 : EtOAc), the title product as a pale yellow solid. MP 226-227 °C. MS (ESI, pos. ion) m/z : 351 (M+1).
Example 10 (2E)-N- (2H, 3H, 4H-Benzo [e] 1, 4-oxazaperhydroin-7-yl)-3- [4- (tert- butyl) phenyl] prop-2-enamide.
To a solution of borane-THF complex (2.5 mL, 2.5 mmol, 1.0 M in THF, Aldrich), magnetically stirred at 0 °C under N2 in a round-bottomed flask equipped with a reflux condenser, was added 7-amino-2H, 4H-benzo [e] 1, 4- oxazaperhydroin-3-one, Example 9 (b), (160 mg, 1. 0 mmol). The reaction mixture was stirred at reflux for 2 h, then treated with EtOH (0.5 mL) and reflux continued for an additional 1 h. The mixture was treated with cond HCI (0.5 mL) and reflux continued for an additional 1 h. The solvent was removed in vacuo and the residue treated with 1 N NaOH (5 mL) and extracted with CH2CI2 (3 x 20 mL). The combined organic extracts were washed with satd NaCI, dried over Na2SO4, filtered and concentrated in vacuo to provide the crude aniline [MS (ESI, pos. ion) m/z : 151 (M+1)]. Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) and the crude aniline, after purification by silica gel chromatography (85: 15 CH2CI2 : EtOAc), provided the title product as a pale yellow solid. MP 186-188 °C. MS (ESI, pos. ion) m/z : 337 (M+1).
Example 11 (2E)-3- [4- (tert-Butyl) phenyl]-N- (4-methyl-3-oxo (2H-benzo [e] 1, 4- oxazaperhydroin-7-yl) ) prop-2-enamide.
(a) 4-Methyl-7-nitro-2H-benzo [e] 1, 4-oxazaperhydroin-3-one. Analogous to the procedure used to prepare Example 7 (a), 7-nitro-2H, 4H-benzo [e] 1, 4- oxazaperhydroin-3-one, Example 9 (a), (970 mg, 25 mmol), benzyltrimethyl- ammonium chloride (110 mg, 0.50 mmol, Aldrich), iodomethane (0.47 mL, 7.5 mmol, Aldrich) and CsOH hydrate (4.2 g, 25 mmol, Aldrich), after purification by silica gel chromatography (9: 1 hexane: EtOAc), provided the title product. MS (ESI, neg. ion) m/z : 207 (M-1).
(b) 7-Amino-4-methyl-2H-benzo [e] 1, 4-oxazaperhydroin-3-one. Analogous to the procedure used to prepare Example 3 (a), 4-methyl-7-nitro-2H-benzo [e] 1, 4- oxazaperhydroin-3-one, Example 11 (a), (1.0 g, 5. 0 mmol) provided, after recrystallization from EtOH, the title product. MS (ESI, pos. ion) m/z : 179 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N- (4-methyl-3-oxo (2H-benzo [e] 1, 4- oxazaperhydroin-7-yl)) prop-2-enamide. Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA- Chemie) and 7-amino-4-methyl-2H-benzo [e] 1, 4-oxazaperhydroin-3-one, Example lib, (164 mg, 1.0 mmol) provided, after purification by silica gel chromatography (85: 15 CH2CI2 : EtOAc), the title product as a pale yellow solid.
MP 194-195 °C. MS (ESI, pos. ion) m/z : 365 (M+1).
Example 12
(2E)-3- [4- (tert-Butyl) phenyl]-N- (4-methyl (2H, 3H-benzo [e] 1, 4- oxazaperhydroin-7-yl)) prop-2-enamide.
Analogous to the procedure used for the preparation of Example 10,7-amino-4- methyl-2H-benzo [e] 1, 4-oxazaperhydroin-3-one, Example 11 (b), (180 mg, 1.0 mmol) and 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA- Chemie) provided, after purification by silica gel chromatography (85: 15 CH2CI2 : EtOAc), the title product as a pale yellow solid. MP 232-233 °C. MS (ESI, pos. ion) m/z : 351 (M+1).
Example 13 Ethyl 6- { (2E)-3- [4- (tert-butyl) phenyl] prop-2-enoylamino}-2H, 3H, 4H- benzo [e] 1, 4-oxazaperhydroine-2-carboxylate. (a) Ethyl 6-nitro-2H, 3H, 4H-benzo [e] 1, 4-oxazaperhydroine-2-carboxylate. A solution of ethyl 2,3-dibromopropionate (4.8 mL, 33 mmol, Aldrich) in acetone (10 mL, Aldrich) was added to a mixture of 2-amino-4-nitrophenol (4.6 g, 30 mmol, Aldrich) in 80 mL of acetone in a 150 mL round-bottomed flask at 25 °C. After the addition, the mixture was stirred at 60 °C for 48 h. The solvent was removed in vacuo, and the residue was treated with water (30 mL) and extracted with CH2CI2 (3 x 50 mL). The combined organic phases were washed with satd NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (9: 1 CH2CI2 : EtOAc) to give the title product. MS (ESI, pos. ion) m/z : 253 (M+1).
(b) Ethyl 6-amino-2H, 3H, 4H-benzo [e] 1, 4-oxazaperhydroine-2-carboxylate.
Analogous to the procedure used to prepare Example 3 (a), ethyl 6-nitro- 2H, 3H, 4H-benzo [e] 1, 4-oxazaperhydroine-2-carboxylate, Example 13 (a), (1.3 g, 5.0 mmol) provided the title product. MS (ESI, pos. ion) m/z : 223 (M+1).
(c). Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans- cinnamic acid (1.3 g, 6.4 mmol, EMKA-Chemie) and ethyl 6-amino-2H, 3H, 4H- benzo [e] 1, 4-oxazaperhydroine-2-carboxylate, Example 13 (b), (1.4 g, 6.4 mmol) provided, after purification by silica gel chromatography (85: 15 CH2CI2 : EtOAc), the title product as a pale yellow solid. MP 207-208 °C. MS (ESI, pos. ion) m/z : 409 (M+1).
Example 14 (2E)-3- [4- (tert-Butyl) phenyl]-N- [2- (hydroxymethyl) (2H, 3H, 4H-benzo [3,4- e] 1, 4-oxazaperhydroin-6-yl)] prop-2-enamide.
A solution of ethyl 6- { (2E)-3- [4- (tert-butyl) phenyl] prop-2-enoylamino}- 2H, 3H, 4H-benzo [e] 1, 4-oxazaperhydroine-2-carboxylate, Example 13, (410 mg, 1.0 mmol) in THF (5 mL, Aldrich), magnetically stirred in a round-bottomed flask under N2 at 0 °C, was treated with lithium borohydride (1.5 mL, 3.0 mmol, 2.0 M in THF, Aldrich). The reaction mixture was allowed to warm to 25 °C, and stirred at that temperature for 3 h. The reaction was quenched by the addition of satd NH4CI (5 mL), stirred for 30 min at 25 °C and extracted with EtOAc (2 x 15 mL).
The combined organic extract was washed with satd NaCI, dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (1: 1 CH2Cl2 : EtOAc) provided the title product as a pale yellow solid. MP 165- 167 °C. MS (ESI, pos. ion) m/z : 367 (M+1).
Example 15
(2E)-N- [ (3S)-3- (Hydroxymethyl) (2H, 3H-benzo [e] 1, 4-dioxan-6-yl)]-3- [4- (tert- butyl) phenyl] prop-2-enamide.
(a) 2-[((2R)Oxiran-2-yl)methoxy]-5-nitrobenzaldehyde. A mixture of (R)- glycidyl tosylate (1.1 g, 5 mmol, Aldrich), 2-hydroxy-5-nitrobenzaldehyde (840 mg, 5.0 mmol, Aldrich) and solid K2CO3 (1.4 g, 10 mmol) in DMF (5 mL, Aldrich) was magnetically stirred in a round-bottomed flask at 100 °C under N2 for 30 min. The reaction mixture was allowed to cool to 25 °C, water (20 mL) was added, and the mixture was extracted with EtOAc (3 x 30 mL). The combined extracts were washed with water (2 x 20 mL), satd NaC ! (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (4: 1 hexane : EtOAc) provided the title product. MS (ESI, pos. ion) m/z : 224 (M+1).
(b) ( (2S)-7-Nitro-2H, 3H-benzo [e] 1, 4-dioxan-2-yl) methan-1-ol. To a solution of 2-[((2R)oxiran-2-yl)methoxyl]-5-nitrobenzaldehyde, Example 15 (a), (670 mg, 3.0 mmol) in CH2CI2 (10 mL), magnetically stirred in a round-bottomed flask at 0 °C, was added 86% m-chloroperbenzoic acid (350 mg, 2.0 mmol, Aldrich). The reaction mixture was allowed to warm to 25 °C and stirred at that temperature for 18 h. The mixture was then diluted with CH2Cl2 (20 mL), washed with 10% Na2S203 (3 mL), NaHCO3 (3 x 5 mL), satd NaCI (3 mL), dried over Na2SO4,
filtered and concentrated in vacuo. The resulting residue was treated with MeOH (20 mL) and 1 N NaOH (6 mL) and stirred at 25 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL).
The combined organic extracts were washed with satd NaCl, dried over NaSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (3: 2 hexane: EtOAc) provided the product. MS (ESI, pos. ion) m/z : 212 (M+1).
(c) (2E)-N- [ (3S)-3- (Hydroxymethyl) (2H, 3H-benzo [e] 1, 4-dioxan-6-yl)]-3- [4- (tert-butyl) phenyl] prop-2-enamide. A mixture of ( (2S)-7-nitro-2H, 3H- benzo [e] 1, 4-dioxan-2-yl) methan-1-ol, Example 15 (b), (110 mg, 0.5 mmol) and 10% Pd on carbon (20 mg, Aldrich) in MeOH (5 mL), in a round-bottomed flask, was magnetically stirred under 1 atm H2 for 2 h. The mixture was purged with N2, filtered through a pad of Celite and concentrated in vacuo to provide the crude aniline [MS (ESI, pos. ion) m/z : 182 (M+1)]. Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (102 mg, 0.5 mmol, EMKA Chemie) and the crude aniline, provided the title product as a white solid. MP 169-171 °C. MS (ESI, pos. ion) m/z : 368 (M+1).
Example 16 (2E)-N- [ (3R)-3- (Hydroxymethyl) (2H, 3H-benzo [e] 1, 4-dioxan-6-yl)]-3- [4- (tert- butyl) phenyl] prop-2-enamide.
Analogous to the procedure described for Example 15, the title product was prepared starting from (S)-glycidyl tosylate (Aldrich), 2-hydroxy-5- nitrobenzaldehyde (Aldrich) and 4-tert-butyl-trans-cinnamic acid (EMKA Chemie). MP 170-171 °C. MS (ESI, pos. ion) m/z : 368 (M+1).
Example 17
(2E)-N-[(2R)-2-(Hydroxymethyl) (2H, 3H-benzo [3,4-e] 1, 4-dioxan-6-yl)]-3- [4- (tert-butyl) phenyl] prop-2-enamide.
(a) (2-Methoxy-4-nitrophenyl) methan-1-ol. To a solution of 2-methoxy-4- nitrobenzoic acid (2.0 g, 10 mmol, Aldrich) in THF (30 mL), magnetically stirred at 0 °C under N2 in a round-bottomed flask equipped with a reflux condenser, was added borane-THF complex (30 mL, 30 mmol, 1.0 M in THF, Aldrich). The reaction mixture was stirred at reflux overnight. The reaction was quenched by the careful addition of MeOH (5 mL), followed by 1 N NaOH (30 mL). The mixture was extracted with EtOAc (2 x 50 mL), the combined organic extracts were washed with satd NaCI, dried over Na2SO4, filtered and concentrated in vacuo to give the product. MS (ESI, neg. ion) m/z : 182 (M-1).
(b) 2-Methoxy-4-nitrobenzaldehyde. A mixture of (2-methoxy-4- nitrophenyl) methan-1-ol, Example 17 (a), (1.6 g, 8.9 mmol) and Mn02 (15 g, 180 mmol, Aldrich) in 1: 1 hexane: CH2CI2 (60 mL) was magnetically stirred at 40 °C for 3 h. The solid was removed by filtration and washed with CH2CI2. The filtrate was concentrated in vacuo and the residue was recrystallized from EtOAc and hexane to give the title product. MS (ESI, neg. ion) m/z : 180 (M-l).
(c) 2-Hydroxy-4-nitrobenzaldehyde. To a solution of 2-methoxy-4- nitrobenzaldehyde, Example 17 (b), (190 mg, 1.0 mmol) in CH2Cl2 (5 mL), magnetically stirred at-78 °C in a round-bottomed flask, was added BBr3 (0.19 mL, 2.0 mmol, Aldrich). The reaction mixture was allowed to warm to 25 °C and stirred at that temperature for 2 h. The reaction mixture was then cooled to - 78 °C, and treated with MeOH (5 mL). The mixture was allowed to warm to 25 °C, stirred at that temperature for 30 min, then concentrated in vacuo. Purification
by silica gel chromatography (3: 2 hexane: EtOAc) provided 2-hydroxy-4- nitrobenzaldehyde. MS (ESI, neg. ion) m/z : 166 (M-1).
(d) (2E)-N-[(2R)-2-(Hydroxymethyl) (2H, 3H-benzo [3,4-e] 1, 4-dioxan-6-yl)]-3- [4-(tert-butyl) phenyl] prop-2-enamide. Analogous to the procedure described for Example 15, the title product was obtained as a white solid from 2-hydroxy-4- nitrobenzaldehyde, Example 17 (c), (S)-glycidyl tosylate (Aldrich) and 4-tert- butyl-trans-cinnamic acid (EMKA-Chemie). MP 159-160 °C. MS (ESI, pos. ion) m/z : 368 (M+1).
Example 18 (2E)-N-[(2S)-2-(Hydroxymethyl) (2H, 3H-benzo [3,4-e] 1, 4-dioxan-6-yl)]-3- [4- (tert-butyl) phenyl] prop-2-enamide.
Analogous to the procedure described for Example 15, the title product was prepared starting from 2-hydroxy-4-nitrobenzaldehyde, Example 17 (c), (R)- glycidyl tosylate (Aldrich) and 4-tert-butyl-trans-cinnamic acid (EMKA Chemie).
MP 169-170 °C. MS (ESI, pos. ion) m/z : 368 (M+1).
Example 19 (2E)-3- [4- (tert-Butyl) phenyl]-N- (7-1, 2,3, 4-tetrahydroquinolyl) prop-2- enamide.
(a) 7-Nitro-1, 2,3, 4-tetrahydroquinoline. To a round-bottomed flask equipped with magnetic stirring was added 1,2, 3, 4-tetrahydroquinoline (6.3 mL, 50 mmol,
Aldrich) and 96% H2SO4 (42 mL). The mixture was stirred until all of the amine had dissolved, then cooled to 0 °C and treated with KNO3 (5. 9 g, 59 mmol) in portions. The reaction mixture was allowed to warm to 25 °C and stirred overnight at that temperature. The mixture was then cooled to 0 °C and neutralized with solid NaOH followed by 5 N NaOH until pH 11 was reached.
The mixture was extracted with CH2CI2 and the extract was dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (8: 1 hexane: EtOAc) provided 7-nitro-1, 2,3, 4-tetrahydroquinoline as an orange solid.
MS (ESI, pos. ion) m/z 179 (M+1).
(b) 7-1, 2,3, 4-Tetrahydroquinolylamine. Analogous to the procedure used to prepare Example 3 (a), 7-nitro-1, 2,3, 4-tetrahydroquinoline, Example 19 (a), (0.35 g, 2.0 mmol) provided the aniline as a pale gray oil. MS (ESI, pos. ion) m/z : 149 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N- (7-1, 2,3, 4-tetrahydroquinolyl) prop-2- enamide. Analogous to the procedure used to prepare Example 1,7-1, 2,3, 4- tetrahydroquinolylamine, Example 19 (b), (280 mg, 1.9 mmol) and 4-tert-butyl- trans-cinnamic acid (0.33 g, 1.6 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (3: 1 hexane: EtOAc) then recrystallization from EtOAc and hexane, the title product as a yellow solid. MP 225-227 °C. MS (ESI, pos. ion) m/z : 335 (M+1).
Example 20 (2E)-3- [4- (tert-Butyl) phenyl]-N- (1-methyl (7-1, 2,3, 4-tetrahydroquinolyl))- prop-2-enamide.
(a) 1-methyl-7-nitro-1, 2,3, 4-tetrahydroquinoline. To a solution of 7-nitro- 1,2, 3,4-tetrahydro-quinoline, Example 19 (a), (0.36 g, 2 mmol) in DMF (10 mL), magnetically stirred under N2 at 0 °C in a 15 mL round-bottomed flask, was added sodium hydride (0.12 g, 3 mmol, 60% dispersion in mineral oil, Aldrich). After stirring for 10 min, the reaction mixture was treated with iodomethane (0.24 mL, 4 mmol, Aldrich) dropwise. The reaction mixture was stirred at 0 °C for 1 h, at 25 °C for an additional 1 h, then partitioned between EtOAc and satd NaCI. The aqueous layer was extracted with EtOAc (40 mL) and the combined organic extract was dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (7: 1 hexane: EtOAc) provided the product as an orange oil. MS (ESI, pos. ion) m/z : 193 (M+1).
(b) (2E)-3- [4- (tert-Butyl) phenyl]-N- (1-methyl (7-1, 2,3, 4-tetrahydroquinolyl))- prop-2-enamide. Analogous to the procedure described for Example 19, steps (b)- (c), 1-methyl-7-nitro-1, 2,3, 4-tetrahydroquinoline, Example 20 (a), (240 mg, 1.3 mmol) and 4-tert-butyl-trans-cinnamic acid (0.23 g, 1.1 mmol, EMKA- Chemie) provided, after purification by silica gel chromatography (4: 1 hexane: EtOAc) then recrystallization from EtOAc and hexane, the title product as a yellow solid. MP 200-202 °C. MS (ESI, pos. ion)/ : 349 (M+1).
Example 21 (2E)-3- [4- (tert-Butyl) phenyl]-N- (2-oxo (6-1, 3, 4-trihydroquinolyl)) prop-2- enamide.
(a) 6-Nitro-1, 3, 4-trihydroquinolin-2-one. To a round-bottomed flask equipped with magnetic stirring was added 3,4-dihydro-2 (1H)-quinolinone (1.47 g, 10 mmol, Aldrich) and 96% H2SO4 (8.3 mL). The mixture was stirred until all of the material was dissolved, then cooled to 0 °C and treated with KN03 (1.2 g, 11.7 mmol) in portions. The reaction mixture was allowed to warm to 25 °C and stirred at that temperature overnight. The mixture was basified to pH 9 with 35% NaOH, resulting in a precipitate. The solid was collected by filtration, washed with water and dried in vacuo at 50 °C to provide the title product as a yellow solid. MS (ESI, pos. ion) m/z : 193 (M+1).
(b) 6-Amino-1, 3, 4-trihydroquinolin-2-one. Analogous to the procedure used to prepare Example 3 (a), 6-nitro-1, 3, 4-trihydroquinolin-2-one, Example 21 (a), (1.7 g, 8.9 mmol) was converted to the title product as a tan solid. MS (ESI, pos. ion) m/z : 163 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N- (2-oxo (6-1, 3, 4-trihydroquinolyl)) prop-2- enamide. Analogous to the procedure used to prepare Example 1,6-amino- 1, 3, 4-trihydroquinolin-2-one, Example 21 (b), (0.68 g, 4.2 mmol) and 4-tert- butyl-trans-cinnamic acid (0.86 g, 4.2 mmol, EMKA-Chemie) provided, after recrystallization from MeOH, the title product as a pale yellow solid. MP 275- 276 °C. MS (ESI, pos. ion) m/z : 349 (M+1).
Example 22 (2E)-3- [4- (tert-Butyl) phenyl]-N- (2-oxo (7-1, 3, 4-trihydroquinolyl)) prop-2- enamide.
(a) Ethyl 3- (2, 4-dinitrophenyl) prop-2-enoate. A suspension of sodium hydride (2.0 g, 50 mmol, 60% dispersion in mineral oil, Aldrich) in anhydrous THF (100 mL) was magnetically stirred under N2 at 25 °C and treated dropwise with triethyl phosphonoacetate (10 mL, 11 g, 51 mmol, Aldrich). The reaction mixture was stirred for 1 h at 25 °C then treated with 2,4-dinitrobenzaldehyde (9.0 g, 46 mmol, Aldrich) in portions. After stirring overnight at 25 °C, the reaction was quenched by the addition of water (50 mL) and concentrated in vacuo to remove the THF. The remaining aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic extract was washed with water (4 x 100 mL), satd NaCI (75 mL), dried over Na2SO4, filtered and concentrated in vacuo.
Purification by silica gel chromatography (1: 4 hexane: EtOAc) provided the title product as a dark oil.
(b) 7-Amino-1, 3, 4-trihydroquinolin-2-one. Ethyl 3- (2, 4-dinitrophenyl) prop-2- enoate, Example 22 (a), (3.0 g, 11 mmol) was dissolved in glacial acetic acid (240 mL), treated with 10% Pd on carbon (2.4 g, Aldrich) and hydrogenated on a Parr shaker apparatus at 65 °C, under 60 psi H2, for 3 h. The reaction mixture was allowed to cool to 25 °C, purged with N2, filtered through Celite and the filtercake washed with acetic acid (200 mL) and EtOH (200 mL). The combined filtrate was concentrated in vacuo, then treated with 1 N NaOH (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extract was washed with satd
NaCI (50 mL), dried over Na2SO4, filtered and concentrated in vacuo.
Purification by silica gel chromatography (EtOAc) provided the title product as a pale yellow solid. MS (ESI, pos. ion) m/z : 163 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N- (2-oxo (7-1, 3, 4-trihydroquinolyl)) prop-2- enamide. Analogous to the procedure used to prepare Example 1,7-amino- 1, 3,4-trihydroquinolin-2-one, Example 22 (b), (300 mg, 1.8 mmol) and 4-tert- butyl-trans-cinnamic acid (370 mg, 1.8 mmol, EMKA-Chemie) provided the title product as white crystals. MP 288-290 °C. MS (ESI, pos. ion) m/z : 349 (M+1).
Example 23 (2E)-3- [4- (tert-Butyl) phenyl]-N- (3-hydroxyphenyl) prop-2-enamide. To a round-bottomed flask equipped with magnetic stirring was added 4-tert-butyl- trans-cinnamic acid (530 mg, 2.43 mmol, EMKA-Chemie), CH2CI2 (10 mL), and DMF (10 uL, Aldrich) under N2. The solution was treated dropwise with oxalyl chloride (3.0 mL, 6.0 mmol, 2.0 M in CH2CI2, Aldrich) then stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo and treated with 3- aminophenol (265 mg, 2.43 mmol, Aldrich), THF (20 mL) and satd K2CO3 (15 mL). The reaction mixture was stirred at 25'C overnight, then acidified to pH-4. 5 with 1 N HCI. The mixture was extracted with EtOAc (2 x 30 mL), the combined organic extract was dried and concentrated in vacuo. Purification by silica gel chromatography (2: 1 hexane: EtOAc) provided the title product as an oil.
MS (ESI, pos. ion) m/z: 296 (M+1).
Example 24
2- (3- { (2E)-3- [4- (tert-Butyl) phenyl] prop-2-enoylamino} phenoxy) acetic acid.
To a round-bottomed flask equipped with magnetic stirring was added (2E)-3- [4- (tert-butyl) phenyl]-N- (3-hydroxyphenyl) prop-2-enamide, Example 23, (120 mg, 0.407 mmol), THF (10 mL), tert-butyl bromoacetate (60 uL, 0.407 mmol, Aldrich) and 5 N NaOH (10 mL). The reaction mixture was stirred at 25 °C overnight. The mixture was extracted with EtOAc (20 mL), the organic extract washed with water (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was treated with trifluoroacetic acid (10 mL), stirred at 25 °C for 2 h, then concentrated in vacuo. Purification by silica gel chromatography (1: 2 hexane: EtOAc) provided the title product as an off-white solid. MP 166-172 °C. MS (ESI, pos. ion) m/z: 354 (M+1).
Example 25 (2E)-3- [4- (tert-Butyl) phenyl]-N- [3- (2-hydroxyethoxy) phenyl] prop-2-enamide.
To a round-bottomed flask, equipped with magnetic stirring and reflux condenser, was added (2E)-3- [4- (tert-butyl) phenyl]-N- (3-hydroxyphenyl) prop-2-enamide, Example 23, (200 mg, 0.68 mmol), THF (10 mL), 2-bromoethanol (200 uL, 2.80 mmol, Aldrich) and 5 N NaOH (10 mL). The reaction mixture was stirred at reflux for 5 h. After allowing to cool to 25 °C, the mixture was extracted with EtOAc (20 mL). The organic extract was washed with water (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (2: 1 hexane: EtOAc) provided the title product as a colorless oil.
MS (ESI, pos. ion) m/z: 340 (M+1).
Example 26
(2E)-3- [4- (tert-Butyl) phenyl]-N- [3- (2-methoxyethoxy) phenyl] prop-2- enamide.
(a) 3- (2-Methoxyethoxy) phenylamine. To a round-bottomed flask equipped with magnetic stirring was added 3-aminophenol (1.2 g, 11 mmol, Aldrich), THF (15 mL) and sodium hydride (440 mg, 11 mmol, 60% in mineral oil, Aldrich) at 0 °C. The reaction mixture was allowed to stir at 0 °C for 30 min, then 2- bromoethyl methyl ether (1.0 mL, 11 mmol, Aldrich) was added dropwise. The reaction mixture was stirred at 25 °C overnight, then cooled to 0 °C and quenched with satd NaCl (10 mL). The mixture was extracted with EtOAc (20 mL) and the organic phase was washed with water (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide the title product. MS (ESI, pos. ion) m/z : 168 (M+1).
(b) (2E)-3- [4- (tert-Butyl) phenyl]-N- [3- (2-methoxyethoxy) phenyl] prop-2- enamide. Analogous to the procedure used to prepare Example 2, 3- (2- methoxyethoxy) phenylamine, Example 26 (a), (350 mg, 2.45 mmol) and 4-tert- butyl-trans-cinnamic acid (500 mg, 2.45 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (5: 1 hexane: EtOAc), the title product as a colorless oil. MS (ESI, pos. ion) m/z: 354 (M+1).
Example 27 (2E)-3- [4- (tert-Butyl) phenyl]-N- {3- [2- (1, 3-dioxobenzo [c] azolin-2- yl) ethoxy] phenyl} prop-2-enamide.
(a) 2- [2- (3-Nitrophenoxy) ethyl] benzo [c] azoline-1, 3-dione. To a round- bottomed flask, equipped with magnetic stirring, an addition funnel and a reflux condenser, was added 3-nitrophenol (2.0 g, 14 mmol, Fluka), triphenylphosphine (4.9 g, 19 mmol, Aldrich) and DMF (20 mL). A solution of N- [2-hydroxyethyl] phthalimide (2.7 mg, 14 mmol, Aldrich) and diethyl azodicarboxylate (3.3 g, 19 mmol, Aldrich) in DMF (20 mL) was added dropwise through the addition funnel at 25 °C. The reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc (55 mL), and washed with satd NaCI (20 mL) and water (20 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (2: 1 hexane: EtOAc) provided the title product. MS (ESI, pos. ion) m/z: 313 (M+1).
(b) 2- [2- (3-Aminophenoxy) ethyl] benzo [c] azoline-1, 3-dione. In a round- bottomed flask, equipped with magnetic stirring, a solution of 2- [2- (3- nitrophenoxy) ethyl] benzo [c] azoline-1, 3-dione, Example 27 (a), (1.9 g, 6.1 mmol) in 0.5% acetic acid in EtOAc (10 mL), under N2, was treated with 10% Pd on carbon (500 mg, Aldrich). The suspension was purged with H2 and stirred under 1 atm H2 at 25 °C overnight. The suspension was purged with N2 and filtered
through a pad of Celite. The solvent was removed in vacuo to provide the title product.
(c) (2E)-3- [4- (tert-Butyl) phenylJ-N- {3- [2- (1, 3-dioxobenzo [c] azolin-2- yl) ethoxy] phenyl} prop-2-enamide. Analogous to the procedure used to prepare Example 2, 2- [2- (3-aminophenoxy) ethyl] benzo [c] azoline-1, 3-dione, Example 27 (b), (1.7 g, 6.1 mmol) and 4-tert-butyl-trans-cinnamic acid (1.2 g, 6.0 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (3: 1 hexane: EtOAc), the title product as an off-white film. MS (ESI, pos. ion) m/z : 469 (M+1).
Example 28 (2E)-N- [3- (2-Aminoethoxy) phenyl]-3- [4- (tert-butyl) phenyl] prop-2-enamide.
To a round-bottomed flask equipped with magnetic stirring was added Example 27, (2E)-3- [4- (tert-butyl) phenyl]-N- {3- [2- (1, 3-dioxobenzo [c] azolin-2- yl) ethoxy] phenyl} prop-2-enamide, (856 mg, 1.83 mmol), EtOH (15 mL) and hydrazine (574 uL, 18.3 mmol, Aldrich). The reaction mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo, the residue dissolved in EtOAc (40 mL), washed with 10% K2CO3 (15 mL), water (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (step gradient, EtOAc followed by 1: 1 EtOAc: EtOH) provided the title product as an oil. MS (ESI, pos. ion) m/z: 339 (M+1).
Example 29 (2E) -3- [4-(tert-Butyl) phenyl]-N-indolin-6-ylprop-2-enamide.
(a) tert-Butyl 6- (1-aza-2, 2-diphenylvinyl) indolinecarboxylate. To a solution of benzophenone imine (0.91 g, 5.0 mmol, Aldrich) in CH2CI2 (35 mL), magnetically stirred at 25 °C in a round-bottomed flask, was added a solution of 6-aminoindoline dihydrochloride (1.04 g, 5.0 mmol, Biosynth AG) in CH2C12 (40 mL). The reaction mixture was stirred at 25 °C for 12 h, then diluted with CH2Cl2 (30 mL), washed with water (30 mL), satd NaCI (30 mL), dried over MgS04, filtered and concentrated in vacuo. The crude product [MS (ESI, pos. ion) milz : 299 (M+1)] was dissolved in 1,4-dioxane and treated with di-tert- butyl dicarbonate (8.0 mL, 8.0 mmol, 1.0 M in THF, Aldrich) and 5 N aq. Na2CO3 (5 mL). The reaction mixture was magnetically stirred at 25 °C until complete, then diluted with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic extract was washed with satd NaCI (30 mL), dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel chromatography (4: 1 hexane EtOAc) provided the title product. MS (ESI, pos. ion) dz : 399 (M+1).
(b) tert-Butyl 6-aminoindolinecarboxylate. In a round-bottomed flask, a solution of tert-butyl 6- (1-aza-2, 2-diphenylvinyl) indolinecarboxylate, Example 29 (a), (0.80 g, 2.0 mmol) in 1,4-dioxane (10 mL) was treated with 1 N aq. HCl (10 mL). The reaction mixture was magnetically stirred overnight at 25 °C, then
diluted with water (20 mL) and extracted with ethyl ether (30 mL). The aqueous phase was treated with 5 N NaOH (10 mL) and extracted with ethyl ether (3 x 30 mL). The combined organic extracts were dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel chromatography (3: 2 hexane EtOAc) provided the title product. MS (ESI, pos. ion) m/z : 235 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N-indolin-6-ylprop-2-enamide. Analogous to the procedure used to prepare Example 1, tert-butyl 6-aminoindoline- carboxylate, Example 29 (b), (230 mg, 1.0 mmol) and 4-tert-butyl cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (7: 3 hexane EtOAc), a crude product which was dissolved in CH2Cl2 (5 mL) and treated with 4 N HCl in dioxane (5 mL, Aldrich). The reaction mixture was magnetically stirred at 25 °C for 1 h, then washed with 5 N NaOH (15 mL), satd NaCI (15 mL), dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel chromatography (55: 45 hexane EtOAc) provided the title product. MP 153-167 °C. MS (ESI, pos. ion) m/z : 321 (M+1).
Example 30 (2E)-3- [4- (tert-Butyl) phenyl]-N- (1-methylindolin-6-yl) prop-2-enamide.
(a) 1-Methylindoline-6-ylamine. To a round-bottomed flask was added 6- nitroindoline (1.64 g, 10.0 mmol, Aldrich), 37% aq. formaldehyde (2.35 g, 30.0 mmol, Aldrich) and THF (40 mL). The reaction mixture was magnetically stirred at 25 °C and treated with sodium cyanoborohydride (1.89 g, 30.0 mmol, Aldrich). The reaction mixture was allowed to stir at 25 °C for 30 min, then washed with satd Na2CO3. The aqueous phase was extracted with ethyl ether, the organic phases combined and concentrated in vacuo to a residue. Analogous to the procedure of Goswami, P.; Chowdhury, P.; Indian J Chem, Sect B, 1997,36
(2), 185-186, the crude residue was dissolved in tetrahydrofuran (60 mL) and added to Zn dust (0.43 g, 6.6 mmol, Aldrich) and AlCl3. 6H2O (9.6 g, 40 mmol, Aldrich) in water (2 mL), magnetically stirred at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, then filtered. The filtrate was added to cold water (300 mL) and extracted with CH2CI2 (3 x 100 mL). The combined organic extract was concentrated in vacuo to provide the title product as a brown solid. MS (ESI, pos. ion) m/z : 149 (M+1).
(b) (2E)-3- [4- (tert-Butyl) phenyl]-N- (l-methylindolin-6-yl) prop-2-enamide.
Analogous to the procedure used to prepare Example 1, 1-methylindoline-6- ylamine, Example 30 (a), (150 mg, 1.0 mmol) and 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) provided the title product as an amorphous yellow solid. MS (ESI, pos. ion) m/z: 335 (M+1).
Example 31 (2E)-N- (1-Acetyl-3, 3-dimethylindolin-6-yl)-3- [4- (tert-butyl) phenyl] prop-2- enamide.
(a) N- (2-Bromo-5-nitrophenyl) acetamide. A solution of 2-bromo-5- nitroaniline (43 g, 0.20 mol, Aldrich) in glacial acetic acid (1.3 L), magnetically stirred at 25 °C, was treated with acetic anhydride (20 mL, 0.21 mol). The reaction mixture was allowed to stir at 25 °C overnight, then quenched by pouring into water (6 L). The precipitate was collected by filtration, washed with water, and dried in vacuo to provide the title product as an off white solid. MS (ESI, pos. ion) m/z : 259,262 (M+1, M+3).
(b) N- (2-Bromo-5-nitrophenyl)-N- (2-methylprop-2-enyl) acetamide. To a flame-dried round-bottomed flask, equipped with magnetic stirring and an addition funnel, was added N- (2-bromo-5-nitrophenyl) acetamide, Example 31 (a), (48 g, 0.19 mol), solid potassium carbonate (103 g, 744 mmol) and anhydrous DMF (830 mL). The resulting solution was stirred at 25 °C and treated dropwise, through the addition funnel, with a solution of 3-bromo-2-methylpropene (38 mL, 380 mmol, Aldrich) in anhydrous DMF (100 mL) over 45 min. The reaction mixture was stirred at 25 °C overnight, then filtered and treated with satd NaHCO3. The organic layer was removed and the aqueous layer was extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with water (4 x 70 mL), satd NaCl (70 mL), dried over MgS04, filtered and concentrated in vacuo to provide the title product as a golden solid. MS (ESI, pos. ion) m/z : 313,315 (M+1, M+3).
(c). 1-Acetyl-3, 3-dimethyl-6-nitroindoline. To a flame-dried round-bottomed flask, equipped with magnetic stirring, was added N- (2-bromo-5-nitrophenyl)-N- (2-methylprop-2-enyl) acetamide, Example 31 (b), (55 g, 0. 18 mol), tetraethylammonium chloride hydrate (30.8 g, 186 mmol, Aldrich), sodium formate (14.4 g, 212 mmol, Aldrich), sodium acetate (36.3 g, 443 mmol) and anhydrous DMF (443 mL). The resulting solution was purged with N2 and treated with palladium (II) acetate (3.97 g, 17.7 mmol, Aldrich). The reaction mixture was stirred in an oil bath at 80 °C for 15 h, then allowed to cool to 25 °C and filtered through a pad of Celite. The Celite was washed with EtOAc and the combined filtrate was washed with satd NaHC03 (500 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic extract was washed with water (4 x 100 mL), satd NaC ! (2 x 100 mL), dried over MgS04,
filtered and concentrated in vacuo to provide 1-acetyl-3, 3-dimethyl-6- nitroindoline as a brown solid. MS (ESI, pos. ion) m/z : 235 (M+1).
(d) (2E)-N- (1-Acetyl-3, 3-dimethylindolin-6-yl)-3- [4- (tert-butyl) phenyl] prop- 2-enamide. To a solution of 1-acetyl-3, 3-dimethyl-6-nitroindoline, Example 31 (c), (110 mg, 0.47 mmol) in ethyl ether (3 mL), magnetically stirred in a round- bottomed flask at 0 °C, was added tin (II) chloride dihydrate (0.67 g, 2.96 mmol, Aldrich) and cond HCI (0.3 mL). The reaction mixture was stirred at 0 °C for 10 min, allowed to warm to 25 °C then stirred at that temperature overnight. The reaction mixture was washed with 10 N NaOH (10 mL), extracted with EtOAc and concentrated in vacuo. Analogous to the procedure used to prepare Example 1, the crude product and 4-tert-butyl-trans-cinnamic acid (92 mg, 0.45 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (2: 3 hexane: EtOAc), the title product. MP 121 °C. MS (ESI, pos. ion) mlz : 391 (M+1).
Example 32 (2E)-3- [4- (tert-Butyl) phenyl]-N- (1, 3, 3-trimethylindolin-6-yl) prop-2-enamide.
(a) 3, 3-Dimethyl-6-nitroindoline. To a round-bottomed flask, equipped with magnetic stirring and a reflux condenser, was added 1-acetyl-3, 3-dimethyl-6- nitroindoline, Example 31 (c), (1.73 g, 7.39 mmol) and EtOH (20 mL). The solution was treated with 12 N HCl (20 mL) then stirred and heated at reflux for 2 h. The reaction mixture was cooled to 0 °C, providing a precipitate which was collected by filtration and dried in vacuo to afford the title product as an off-white solid. MS (ESI, pos. ion) m/z : 193 (M+1).
(b) 1, 3, 3-Trimethylindoline-6-ylamine. A solution of 3, 3-dimethyl-6- nitroindoline, Example 32 (a), (0.23 g, 1.2 mmol) in anhydrous DMF (15 mL) was magnetically stirred at 25 °C and treated with sodium hydride (0.14 g, 3.6 mmol, 60% dispersion in mineral oil, Aldrich), followed by iodomethane (0.17, 1.3 mmol, Aldrich). The reaction mixture was stirred at 25 °C for 3 h, then quenched with water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined extract was concentrated in vacuo to provide a residue [MS (ESI, pos. ion) m/z : 207 (M+1)] which was immediately dissolved in ethyl ether (5 mL), magnetically stirred at 0 °C, and treated with tin (II) chloride dihydrate (1.7 g, 7.5 mmol, Aldrich) and cond HCl (0.8 mL). The reaction mixture was stirred at 0 °C for 10 min, allowed to warm to 25 °C, then stirred at that temperature overnight. The reaction mixture was washed with 10 N NaOH (20 mL) and extracted with EtOAc (3 x 50 mL). The combined extracts were concentrated in vacuo and purified by silica gel chromatography to provide the title product. MS (ESI, pos. ion) mlz : 177 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N- (1, 3, 3-trimethylindolin-6-yl) prop-2- enamide. Analogous to the procedure used to prepare Example 1,1, 3,3- trimethylindoline-6-ylamine, Example 32 (b), (176 mg, 1.0 mmol) and 4-tert- butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (3: 2 hexane: EtOAc), the title product.
MP 90-101 °C. MS (ESI, pos. ion) m/z : 363 (M+1).
Example 33 (2E)-3- [4- (tert-Butyl) phenyl]-N- (1-methylindol-6-yl) prop-2-enamide.
(a) 1-Methylindole-6-ylamine. To a round-bottomed flask was added 6- nitroindole (0.81 g, 5.0 mmol, Aldrich) and anhydrous DMF (40 mL). The solution was stirred magnetically and treated with sodium hydride (0.40 g, 10 mmol, 60% dispersion in mineral oil, Aldrich) followed by iodomethane (0.71 gm 10 mmol, Aldrich). Stirring was continued at 25 °C for 30 min, then the reaction mixture was quenched by the addition of water (75 mL) and extracted with EtOAc. The organic extract was concentrated in vacuo to provide a residue which was dissolved in EtOH (40 mL), treated with 10% Pd on carbon (400 mg, Aldrich), purged with H2 and magnetically stirred under 1 atm H2 for 4 h. The suspension was purged with N2, filtered through a pad of Celite and concentrated in vacuo. Purification by silica gel chromatography (50: 50 hexane: EtOAc) provided the aniline. MS (ESI, pos. ion) m/z : 147 (M+1).
(b) (2E)-3- [4- (tert-Butyl) phenyl]-N- (l-methylindol-6-yl) prop-2-enamide.
Analogous to the procedure used to prepare Example 1, 1-methylindole-6- ylamine, Example 33 (a), (150 mg, 1.0 mmol) and 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol), after purification by silica gel chromatography (65: 35 hexane: EtOAc), provided the title product as a yellow solid. MP 95 °C. MS (ESI, pos. ion) niz : 333 (M+1).
Example 34 (2E)-3- [4- (tert-Butyl) phenyl]-N- (l-methylindol-5-yl) prop-2-enamide.
(a) 1-Methylindole-5-ylamine. To a round-bottomed flask was added 5- nitroindole (0.81 g, 5.0 mmol, Aldrich) and anhydrous DMF (40 mL). The solution was stirred magnetically and treated with sodium hydride (0.40 g, 10 mmol, 60% dispersion in mineral oil, Aldrich) followed by iodomethane (0.71 gm 10 mmol, Aldrich). Stirring was continued at 25 °C for 30 min, then the reaction mixture was quenched by the addition of water (75 mL) and extracted with EtOAc. The organic extract was concentrated in vacuo to provide a crude residue. Analogous to the procedure of Goswami, P.; Chowdhury, P.; Indian J Chem, Sect B, 1997,36 (2), 185-186, the crude residue was dissolved in THF (40 mL) and added to Zn dust (0.22 g, 3.3 mmol, Aldrich) and AIC13-6H20 (4.78 g, 19.8 mmol, Aldrich) in water (1 mL), magnetically stirred at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, then filtered. The filtrate was added to cold water (300 mL) and extracted with CH2CI2 (3 x 100 mL). The combined organic extract was concentrated in vacuo to provide the title product.
MS (ESI, pos. ion) m/z : 147 (M+1).
(b) (2E)-3- [4- (tert-Butyl) phenyl]-N- (1-methylindol-5-yl) prop-2-enamide.
Analogous to the procedure used to prepare Example 1, 1-methylindole-5- ylamine, Example 34 (a), (150 mg, 1.0 mmol) and 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (65: 35 hexane: EtOAc), the title product as a crystalline yellow solid. MP 171 °C. MS (ESI, pos. ion) m/z : 333 (M+1).
Example 35 (2E)-3- [4- (tert-Butyl) phenyl]-N- (l-methylindolin-5-yl) prop-2-enamide.
(a) 1-Methyl-5-nitroindoline. To a round-bottomed flask equipped with magnetic stirring was added 5-nitroindoline (0.82, 5.0 mmol, Aldrich), iodomethane (0.71g, 5.0 mmol, Aldrich), sodium hydroxide (0.24, 6 mmol) and DMF (20 mL). The reaction mixture was stirred at 25 °C for 3 h, diluted with water (50 mL), extracted with EtOAc (3 x 40 mL) and the combined extracts were concentrated in vacuo. Purification by silica gel chromatography 97: 3 hexane: EtOAc) provided the title product. MS (ESI, pos. ion) m/z : 179 (M+1).
(b) 1-Methylindoline-5-ylamine. To a solution of 1-methyl-5-nitroindoline, Example 35 (a), (0.55 g, 3.1 mmol) in ethyl ether (20 mL), magnetically stirred in a round-bottomed flask at 0 °C, was added tin (II) chloride dihydrate (4.5 g, 20 mmol, Aldrich) and cond HO (2.5 mL). The reaction mixture was stirred at 0 °C for 10 min, allowed to warm to 25 °C then stirred at that temperature overnight. The reaction mixture was washed with ION NaOH (30 mL) and the aqueous phase extracted with EtOAc (3 x 20 mL). The combined organic extracts were concentrated in vacuo. Purification by silica gel chromatography (55: 45 hexane: EtOAc) provided the aniline. MS (ESI, pos. ion) m/z : 149 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N- (1-methytindolin-5-yl) prop-2-enamide.
Analogous to the procedure used to prepare Example 1, 1-methylindoline-5- ylamine, Example 35 (b), (150,1. 0 mmol) and 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (60: 40 hexane: EtOAc), the title product as a crystalline yellow solid. MP 194 °C. MS (ESI, pos. ion) m/z : 335 (M+1).
Example 36
(2E)-N-Benzoxazol-5-yl-3- [4- (tert-butyl) phenyl] prop-2-enamide.
(a) 5-Nitrobenzoxazole. Following the procedure of A. R. Katritzky et al.
Heterocycles 1995, 41, 345, to a round-bottomed flask was added 2-amino-4- nitrophenol (5.0 g, 32 mmol, Aldrich), trimethyl orthoformate (20 mL, 180 mmol, Aldrich) and p-toluenesulfonic acid monohydrate (300 mg, 1.6 mmol, Aldrich).
The reaction mixture was magnetically stirred in a 95 °C oil bath for 1 h, and then allowed to cool to 25 °C. The mixture was cooled to 0 °C to provide a precipitate which was collected by filtration, washed with cold toluene, pentane, then dried in vacuo to afford the title product as a dark brown powder.
(b) Benzoxazole-5-ylamine. Analogous to the procedure used to prepare Example 3 (a), 5-nitrobenzoxazole, Example 36 (a), (2.4 g, 15 mmol) provided, after purification by silica gel chromatography (step gradient, 7: 3 then 4.5 : 5.5 then 3: 7 hexane: EtOAc), the title product. MS (ESI, pos. ion) m/z : 135 (M+1).
(c) (2E)-N-Benzoxazol-5-yl-3- [4- (tert-butyl) phenyl] prop-2-enamide.
Analogous to the procedure used to prepare Example 1, benzoxazole-5-ylamine, Example 36 (b), (530 mg, 4.0 mmol) and 4-tert-butyl-trans-cinnamic acid (820 mg, 4.0 mmol, EMKA-Chemie) provided, after twice being purified by silica gel chromatography (7: 3 hexane: EtOAc then 1.25% MeOH in CH2Cl2), the title product as white crystals. MP 177 °C. MS (ESI, pos. ion) m/z : 321 (M+1).
Example 37
(2E)-N-Benzoxazol-6-yl-3- [4- (tert-butyl) phenyl] prop-2-enamide.
(a) Benzoxazole-6-ylamine. Analogous to the procedure described for the preparation of Example 36, steps (a)- (b), 2-amino-5-nitrophenol (5.0 g, 32 mmol, Aldrich) provided the title product as a pale tan solid. MS (ESI, pos. ion) m/z : 135 (M+1).
(b) (2E)-N-Benzoxazol-6-yl-3- [4- (tert-butyl) phenyl] prop-2-enamide.
Analogous to the procedure used to prepare Example 1, benzoxazole-6-ylamine, Example 37 (a), (1.8 g, 13 mmol) and 4-tert-butyl-trans-cinnamic acid (2.7 g, 13 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (6: 4: 0.2 CH2Cl2 : hexane: MeOH), the title product as a tan solid.
MP 147-148 °C. MS (ESI, pos. ion) m/z : 321 (M+1).
Example 38 (2E) -N-Benzo [b] furan-5-yl-3- [4- (tert-butyl) phenyl] prop-2-enamide.
(a) Methyl 2- (2-formyl-4-nitrophenoxy) acetate. To a round-bottomed flask was added a suspension of 2-hydroxy-5-nitrobenzaldehyde (10 g, 60 mmol, Aldrich) in anhydrous EtOH (180 mL). The suspension was treated with KOH (4.4 g, 66 mmol) and heated under N2 with magnetic stirring in a 65'C oil bath for 45 min. The reaction mixture was allowed to cool to 25 °C and concentrated in vacuo. Anhydrous DMF (180 mL) was added, and the reaction flask was
cooled in an ice bath and charged with methyl bromoacetate (10 mL, 110 mL, Aldrich). The reaction mixture was stirred for 3.5 h at 25 °C, then the solvent was removed in vacuo. Water (200 mL) was added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic extract was washed with 1 M H3PO4, satd NaHC03, and satd NaCI. After drying over MgS04, the organic layer was filtered and concentrated in vacuo. The residue was recrystallized from CH2CIz and hexane to afford the title product as a pale yellow solid. MS (ESI, pos. ion) nVz : 240 (M+1).
(b) Ethyl 5-nitrobenzo [d] furan-2-carboxylate. To a 250 mL round-bottomed flask was added methyl 2- (2-formyl-4-nitrophenoxy) acetate, Example 38 (a), (5.3 g, 22 mmol), EtOH (110 mL) and 1, 8-diazabicyclo [5.4. 0] undec-7-ene (3.7 g, 24 mmol, Aldrich). The reaction mixture was magnetically stirred at 25 °C for 20 h, then concentrated to approximately half of its volume in vacuo. After cooling the mixture in an ice bath for 20 min, a precipitate formed which was collected by filtration and washed with ice cold EtOH. The resulting pale yellow solid was dried in vacuo to provide the title product. MS (ESI, pos. ion) m/z : 253 (M+H20).
(c) 5-Nitrobenzo [b] furan-2-carboxylic acid. To a 250 mL round-bottomed flask was added ethyl 5-nitrobenzo [d] furan-2-carboxylate, Example 38 (b), (1.0 g, 4.3 mmol), EtOH (10 mL), and KOH (610 mg, 11 mmol) in 10 mL of H2O. The reaction mixture was stirred at 25 °C for 24 h, then treated with 1 M H3PO4 (200 mL) and saturated with solid NaCl. The aqueous layer was extracted with EtOAc (3 x 70 mL), and the combined organic extracts were washed with satd NaCl, dried over MgS04, filtered and concentrated in vacuo to provide the title product as a yellowish-white powder. MS (ESI, pos. ion) m/z : 225 (M+H2O).
(d). 5-Nitrobenzofuran. To a 100 mL round-bottomed flask was added 5- nitrobenzo [b] furan-2-carboxylic acid, Example 38 (c), (860 mg, 4.2 mmol), copper (830 mg, 13 mmol, Aldrich), and quinoline (38 mL, Aldrich). The reaction flask was placed in a 185 °C oil bath and magnetically stirred for 20 min under N2. After allowing to cool to 25 °C, the mixture was filtered through a 1" pad of Celite. To the filtrate was added 10% aq. HCI (300 mL) and the aqueous layer was extracted with EtzO (3 x 100 mL). The combined ethereal layers were washed with 10% HCl (4 x 200 mL, 1 x 100 mL), satd NaHC03 (200 mL), and satd NaCt (100 mL), dried over MgS04, filtered and concentrated in vacuo.
Purification by silica gel chromatography (10: 0.25 hexanes: EtOAc) provided 5- nitrobenzofuran as a white solid.
(e) Benzo [b] furan-5-ylamine. To a 150 mL round-bottomed flask was added 5- nitrobenzofuran, Example 38 (d), (270 mg, 1.7 mmol) and ethyl ether (16 mL).
The mixture was magnetically stirred at 0 °C under N2 and treated with a solution of tin (II) chloride dihydrate (3.4 g, 15 mmol, Aldrich) in 12 M aq. HCI (2 mL).
The reaction mixture was stirred at 0 °C for 10 min, then allowed to warm to 25 °C and stirred at that temperature for 20 h. Water and 2 N NaOH (pH > 10) were added followed by Celite (10 g). The mixture was filtered through a pad of Celite and the filtrate extracted with EtOAc. The organic extract was washed with 2 N NaOH, satd NaCI, dried over K2CO3, filtered and concentrated in vacuo to provide the title product as a pale yellow oil. MS (ESI, pos. ion) m/z : 134 (M+1).
(f) (2E) -N-Benzo [b] furan-5-yl-3- [4- (tert-butyl) phenyl] prop-2-enamide.
Analogous to the procedure used to prepare Example 1, benzo [b] furan-5-ylamine, Example 38 (e), (230 mg, 1.7 mmol) and 4-tert-butyl-trans-cinnamic acid (350 mg, 1.7 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (9: 1 hexane: EtOAc), the title product as white crystals. MP 149- 150 °C. MS (ESI, pos. ion) ? z/Z : 320 (M+1).
Example 39
(2E)-3- [4- (tert-Butyl) phenyl]-N- (2, 3-dihydrobenzo [b] furan-5-yl) prop-2- enamide.
(a) 2,3-Dihydrobenzo [b] furan-5-ylamine. To a 150 mL round-bottomed flask was added 5-nitrobenzofuran, Example 38 (d), (250 mg, 1.5 mmol), EtOAc (16 mL) and 10% Pd on carbon (33 mg, Aldrich). The suspension was stirred at 25 °C under 1 atm H2 for 24 h, then purged with N2, filtered through Celite and concentrated in vacuo to provide the aniline as a red-brown solid. MS (ESI, pos. ion) nVz : 136 (M+1).
(b) (2E)-3- [4- (tert-Butyl) phenyl]-N- (2, 3-dihydrobenzo [b] furan-5-yl) prop-2- enamide. Analogous to the procedure used to prepare Example 1,2, 3- dihydrobenzo [b] furan-5-ylamine, Example 39 (a), (240 mg, 1.8 mmol) and 4-tert- butyl-trans-cinnamic acid (370 mg, 1.8 mmol, EMKA-Chemie) provided the crude title product. The product was purified by silica gel chromatography (9: 1: 0.25 hexane: EtOAc: MeOH) to provide 45 mg of the title product and additional impure fractions. The impure fractions were combined and concentrated in vacuo. The residue was dissolved in MeOH (25 mL), treated with 5 N NaOH (10 mL) and stirred for 1 h. The mixture was diluted with 5 N NaOH (100 mL) and extracted with EtOAc. The organic phase was washed with 5 N NaOH (2 x), 5% citric acid, satd NaCI, dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel chromatography (8: 1: 0.5 hexane: EtOAc: 2 M NH3 in MeOH) provided an additional the title product as a white solid. MP 175-176 °C. MS (ESI, pos. ion) m/z : 322 (M+1).
Example 40 N- (2H, 3H-Benzo [3, 4-e] 1, 4-dioxan-6-yl)-3, 3-bis (4-methylphenyl) prop-2- enamide.
(a) 3,3-Bis (4-methylphenyl) prop-2-enoic acid. Triethyl phosphonoacetate (2.0 mL, 10 mmol, Aldrich) was added dropwise to a suspension of NaH (0.44 g, 11 mmol, 60% dispersion in mineral oil, Aldrich) in anhydrous THF (16 mL), magnetically stirred at 0 °C under Ar, in a round-bottomed flask equipped with a reflux condenser. The reaction mixture was allowed to warm to 25 °C then stirred at that temperature for 0.5 h. 4, 4'-Dimethylbenzophenone (2.1 g, 10 mmol, Aldrich) was added in one portion and the reaction mixture stirred and heated at reflux for 48 h. After allowing to cool to 25 °C, the reaction mixture was quenched with H20 (30 mL) and extracted with Et20 (4 x 10 mL). The combined organic extract was washed with H2O (5 mL), dried over MgS04, filtered and concentrated in vacuo to an oily residue. The residue was dissolved in 1,4- dioxane (2.5 mL), treated with H20 (7 mL) and KOH (1. 1 g, 20 mmol), then stirred and heated at reflux under Ar for 18 h. The reaction mixture was allowed to cool to 25 °C, diluted with H20 (50 mL) and washed with Et20 (10 mL). The aqueous phase was acidified with 1 N HCI and extracted with chloroform. The combined chloroform extracts were washed with satd NaCl, dried over MgS04, filtered and concentrated in vacuo to provide the acid as a white solid. MS (ESI, pos. ion) m/z : 253 (M+1).
(b) N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3, 3-bis (4-methylphenyl) prop-2- enamide. Analogous to the procedure used to prepare Example 1,3, 3-bis (4- methylphenyl) prop-2-enoic acid, Example 40 (a), (0.50 g, 2.0 mmol) and 1,4- benzodioxan-6-amine (0.33 g, 2.2 mmol, Aldrich) provided, after purification by silica gel chromatography (chloroform), the title product as a yellow solid. MP 163-164 °C. MS (ESI, pos. ion) m/z : 386 (M+1).
Example 41 (2E)-N- (2H, 3H-Benzo [3, 4-e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-2- methylprop-2-enamide.
(a) (2E)-3- [4- (tert-Butyl) phenyl]-2-methylprop-2-enoic acid. Analogous to the procedure described for the preparation of Example 40, step (a), triethyl 2- phosphonopropionate (2.4 g, 10 mmol, Aldrich) and 4-tert-butylbenzaldehyde (1.6 g, 10 mmol, Aldrich) provided the title product as a yellow solid. MS (ESI, pos. ion) m/z : 219 (M+1).
(b) (2E)-N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-2- methylprop-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3- [4- (tert-butyl) phenyl]-2-methylprop-2-enoic acid, Example 41 (a), (0.44 g, 2.0 mmol) and 1, 4-benzodioxan-6-amine (0.33 g, 2.2 mmol, Aldrich) provided, after purification by silica gel chromatography (chloroform), the title product as an off-white solid. MP 157-158 °C. MS (ESI, pos. ion) m/z : 352 (M+1).
Example 42 (2E)-N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-2- ethylprop-2-enamide.
(a) (2E)-3- [4- (tert-Butyl) phenyl]-2-ethylprop-2-enoic acid. Analogous to the procedure described for the preparation of Example 40, step (a), triethyl 2- phosphonobutyrate (2.5 g, 10 mmol, Aldrich) and 4-tert-butylbenzaldehyde (1.6 g, 10 mmol, Aldrich) provided the title product as a white solid. MS (ESI, pos. ion) m/z : 233 (M+1).
(b) (2E)-N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-2- ethylprop-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3- [4- (tert-butyl) phenyl]-2-ethylprop-2-enoic acid, Example 42 (a), (0.46 g, 2.0 mmol) and 1, 4-benzodioxan-6-amine (0.33 g, 2.2 mmol, Aldrich) provided, after purification by silica gel chromatography (chloroform), the title product as a white solid. MP 133-134 °C. MS (ESI, pos. ion) m/z : 366 (M+1).
Example 43 (2E)-N- (2H, 3H-Benzo [3, 4-e] 1, 4-dioxan-6-yl)-3-(4-cyclopropylphenyl) prop-2- enamide.
(a) Ethyl 4-cyclopropylbenzoate. To a round-bottomed flask under N2 was added zinc dust (0.80 g, 12.5 mmol, Aldrich), cuprous chloride (1.23 g, 12.5 mmol, Aldrich) and Et20 (2 mL). The mixture was magnetically stirred and heated at reflux for 30 min. The suspension was treated with ethyl 4- vinylbenzoate (0.85 g, 4.82 mmol, Apin) followed by methylene diiodide (1.68 g, 6.27 mmol, Aldrich) and reflux was continued for 24 h. The reaction mixture was allowed to cool to 25 °C, filtered, concentrated in vacuo and purified by silica gel chromatography (9: 1 hexane: EtOAc) to provide the title product. MS (ESI, pos. ion) m/z : 191 (M+1).
(b) 4-Cyclopropylbenzaldehyde. Ethyl 4-cyclopropylbenzoate, Example 43 (a), (316 mg, 1.66 mmol) was transferred to a round-bottomed flask and treated with lithium aluminum hydride (0.30 mL, 3.0 mmol, 1.0 M in THF, Aldrich) under N2.
The reaction mixture was magnetically stirred at 25 °C for 1 h, then quenched by the dropwise addition of H20 (0.5 mL) followed by 20% aq. KOH (3 mL). The suspension was filtered and the aqueous phase extracted with EtOAc. The organic extract was concentrated in vacuo and the crude alcohol was redissolved in anhydrous CH2CI2 (2 mL). In a separate round-bottomed flask, a solution of oxalyl chloride (2.0 mL, 4.0 mmol, 2.0 M in CH2CI2, Aldrich) was magnetically stirred under N2 at-78 °C and treated dropwise with a solution of anhydrous
dimethyl sulfoxide (4.0 mL, 56 mmol, Aldrich) in anhydrous CH2Cl2 (2 mL). The reaction mixture was stirred at-78 °C for 5 min then treated dropwise with the solution of crude alcohol in CH2Cl2. The reaction mixture was stirred an additional 5 min at-78 °C, treated with triethylamine (2.0 mL, 14 mmol), allowed to warm to 25 °C and stirred at that temperature for 1 h. The reaction was quenched by the addition of H20 and the mixture was extracted with Et20. The organic extract was concentrated in vacuo to provide 230 mg (95% over two steps) of the title product.
(c) (2E)-3- (4-Cyclopropylphenyl) prop-2-enoic acid. Analogous to the procedure described for Example 40, step (a), 4-cyclopropylbenzaldehyde, Example 43 (b), (0.23 g, 1.6 mmol) and triethyl phosphonoacetate (0.35 g, 1.6 mmol, Aldrich) provided the title product. MS (ESI, pos. ion) m/z : 189 (M+1).
(d) (2E)-N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3- (4- cyclopropylphenyl) prop-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3- (4-cyclopropylphenyl) prop-2-enoic acid, Example 43 (c), (130 mg, 0.69 mmol) and 1, 4-benzodioxan-6-amine (104 mg, 0.69 mmol, Aldrich) provided, after purification by silica gel chromatography (65: 35 hexane: EtOAc), the title product as a clear glass. MS (ESI, pos. ion) m/z : 322 (M+1).
Example 44 (2E)-N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3- [6- (tert-butyl) (3-pyridyl)]- prop-2-enamide.
(a) 6- (tert-Butyl) pyridine-3-carbaldehyde. Analogous to the procedure of Rybakova, et al. Zh. Org. Khim. 1995, 31 (5), 670-673, pyridine-3-methanol (2.18 g, 20.0 mmol, Aldrich), trimethylacetic acid (10.2 g, 100 mmol, Aldrich), silver nitrate (0.68 gm 4.0 mmol, Aldrich), and 10% aq. sulfuric acid (20 mL) were combined in a round-bottomed flask. The reaction mixture was magnetically stirred and treated with a solution of ammonium persulfate (9.1 g, 40 mmol, Aldrich) in H2O (40 mL). Evolution of gas was observed and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was basified to pH 9 by the addition of aq. ammonium hydroxide then extracted with EtOAc.
The organic extract was washed with H20, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the crude product by silica gel chromatography (70: 30 hexane: EtOAc) provided the title product. MS (ESI, pos. ion) m/z : 164 (M+1).
(b) (2E)-3-[6-(tert-Butyl) (3-pyridyl)] prop-2-enoic acid. Analogous to the procedure described for Example 40, step (a), 6- (tert-butyl) pyridine-3- carbaldehyde, Example 44 (a), (0.55 g, 3.4 mmol) and triethyl phosphonoacetate (0.76 g, 3.4 mmol, Aldrich) provided the title product. MS (ESI, pos. ion) m/z : 206 (M+1).
(c) (2E)-N- (2H, 3H-Benzo [3, 4-e] 1, 4-dioxan-6-yl)-3-[6-(tert-butyl) (3- pyridyl) prop-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl) (3-pyridyl)] prop-2-enoic acid, Example 44 (b), (200 mg, 1.0 mmol) and 1, 4-benzodioxan-6-amine (150 mg, 1.0 mmol, Aldrich) provided, after purification by silica gel chromatography (60: 40 hexane: EtOAc), the title product as a clear glass. MS (ESI, pos. ion) m/z : 339 (M+1).
Example 45 (2E)-N- (2H, 3H-Benzo [3, 4-e] 1, 4-dioxan-6-yl)-3- [3- (tert-butyl) phenyl] prop-2- enamide.
(a) 3- (tert-Butyl) benzaldehyde. To a round-bottomed flask equipped with magnetic stirring was added 1-tert-butyl-3-methylbenzene (1 g, 6.8 mmol, Wiley), ammonium cerium (IV) nitrate (17.5 g, 29.7 mmol, Aldrich) and 50% aq. acetic acid (150 mL). The reaction mixture was stirred and heated at 90 °C for 1.5 h.
The reaction mixture was allowed to cool to 25 °C and extracted with 10% EtOAc in hexane. The organic extract was concentrated in vacuo to provide the crude aldehyde.
(b) (2E)-3- [3- (tert-Butyl) phenyl] prop-2-enoic acid. Analogous to the procedure described for Example 40, step (a), 3- (tert-butyl) benzaldehyde, Example 45 (a), (320 mg, 2.0 mmol) and triethyl phosphonoacetate (250 mg, 2.0 mmol, Aldrich) provided the title product. MS (ESI, pos. ion) m/z : 205 (M+1).
(c) (2E)-N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3- [3- (tert-butyl) phenyl] prop- 2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3- [3-
(tert-butyl) phenyl] prop-2-enoic acid, Example 45 (b), (200 mg, 1.0 mmol) and 1, 4-benzodioxan-6-amine (150 mg, 1.0 mmol, Aldrich) provided, after purification by silica gel chromatography (60: 40 hexane: EtOAc), the title product.
MP 168 °C. MS (ESI, pos. ion) m/z : 338 (M+1).
Example 46 (2E)-N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3-[2-fluoro-4-(trifluoromethyl)- phenyl] prop-2-enamide.
(a) [2-Fluoro-4-(trifluoromethyl) phenyl] methan-1-ol. Toaround-bottomed flask, equipped with magnetic stirring and a reflux condenser, was added 2- fluoro-4- (trifluoromethyl) benzoic acid (5.0 g, 24 mmol, ABCR) and borane-THF complex (72 mL, 72 mmol, 1.0 M in THF, Aldrich) at 0 °C under N2. The reaction mixture was warmed to 65 °C and stirred at that temperature for 2 h.
The reaction mixture was allowed to cool to 25 °C and the solvent was removed in vacuo. The resulting residue was dissolved in CH2Cl2 (100 mL) and washed with satd Na2CO3 (100 mL). The aqueous phase was back-extracted with CH2CI2 (4 x 80 mL). The combined organic extract was washed with satd NaCI (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-10% EtOAc in hexane) provided the title product as a colorless oil.
(b) 2-Fluoro-4-(trifluoromethyl) benzaldehyde. To a solution of [2-fluoro-4- (trifluoromethyl) phenyl] methan-1-ol, Example 46 (a), (4. 4 g, 23 mmol) in CH2C12
(100 mL) was added ground pyridinium dichromate (38.4 g, 102 mmol, Fluka).
The reaction mixture was stirred at 25 °C overnight, then filtered through Celite.
The Celite pad was washed with CH2CI2 (2 x 50 mL) and the combined filtrate was concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-5% EtOAc in hexane) provided the title product as a white slurry.
(c) Methyl (2E)-3- [2-fluoro-4- (trifluoromethyl) phenyl] prop-2-enoate. 2- Fluoro-4- (trifluoromethyl) benzaldehyde, Example 46 (b), (900 mg, 4.7 mmol) in CH2CI2 (5 mL) was added via cannula to a solution of carbomethoxymethylene triphenylphosphorane (2.0 g, 6.1 mmol, Aldrich) in CH2C12 (15 mL), magnetically stirred in a round-bottomed flask at 0 °C. The reaction mixture was allowed to warm to 25 °C and stirred at this temperature under N2 overnight. The solvent was removed in vacuo and the crude material purified by silica gel chromato- graphy (gradient: 0-5% EtOAc in hexane) to provide the title product as a white solid.
(d) (2E)-3-[2-Fluoro-4-(trifluoromethyl) phenyl] prop-2-enoic acid. Methyl (2E)-3-[2-fluoro-4-(trifluoromethyl) phenyl] prop-2-enoate, Example 46 (c), (1.6 g, 6.3 mmol) was treated with lithium hydroxide monohydrate (530 mg, 12.6 mmol, Aldrich) in wet EtOH (15 mL) and magnetically stirred in a round-bottomed flask at 25 °C overnight. The reaction mixture was acidified to pH < 2 with 10% aq.
HCl and extracted with EtOAc (3 x 50 mL). The combined extracts were washed with satd NaCI (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide the acid as a white solid.
(e) (2E)-N- (2H, 3H-Benzo [3, 4-e] 1, 4-dioxan-6-yl)-3- [2-fluoro-4- (trifluoromethyl) phenyl] prop-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3- [2-fluoro-4- (trifluoromethyl) phenyl] prop-2-enoic
acid, Example 46 (d), (200 mg, 0.85 mmol) and 1, 4-benzodioxan-6-amine (193 mg, 1.28 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-20% EtOAc in hexane) and recrystallization from EtOAc and hexane, the title product as a yellow crystalline solid. MP 174-175 °C.
MS (ESI, pos. ion) m/z : 368 (M+1).
Example 47 (2E)-N- (2H, 3H-Benzo [3, 4-e] 1, 4-dioxan-6-yl)-3-[2, 3-difluoro-4-(trifluoro- methyl) phenyl] prop-2-enamide. Analogous to the procedure used to prepare Example 46, steps (b)- (e), the title product was obtained from 2,3-difluoro-4- (trifluoromethyl) benzyl alcohol (ABCR) and 1, 4-benzodioxan-6-amine (Aldrich) as a crystalline yellow solid. MP 169-170 °C. MS (ESI, pos. ion) m/z: 386 (M+1).
Example 48 (2E)-N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3- [2, 4-bis (trifluoromethyl)- phenyl] prop-2-enamide. Analogous to the procedure used to prepare Example 46, steps (b)- (e), the title product was obtained from 2,4- bis (trifluoromethyl) benzyl alcohol (Avocado) and 1, 4-benzodioxan-6-amine (Aldrich) as a crystalline yellow solid. MP 204-205 °C. MS (ESI, pos. ion) m/z: 418 (M+1).
Example 49
(2E)-3-[2-Fluoro-4-(trifluoromethyl) phenyl]-N-indol-5-ylprop-2-enamide.
Analogous to the procedure used to prepare Example 46, steps (a)- (e), the title product was obtained from 2-fluoro-4- (trifluoromethyl) benzoic acid (ABCR) and 5-aminoindole (Aldrich) as a crystalline yellow solid. MP 203-205 °C. MS (ESI, pos. ion) m/z: 349 (M+1).
Example 50 (2E)-3-[2, 3-Difluoro-4-(trifluoromethyl) phenyl]-N-indol-5-ylprop-2-enamide.
Analogous to the procedure used to prepare Example 46, steps (b)- (e), the title product was obtained from 2, 3-difluoro-4-(trifluoromethyl) benzyl alcohol (ABCR) and 5-aminoindole (Aldrich) as a crystalline yellow solid. MP 220-222 °C. MS (ESI, pos. ion) m/z: 367 (M+1).
Example 51 (2E) -3- [2,4-Bis (trifluoromethyl) phenyl]-N-indol-5-ylprop-2-enamide.
Analogous to the procedure used to prepare Example 46, steps (b)- (e), the title product was obtained from 2,4-bis (trifluoromethyl) benzyl alcohol (Avocado) and 5-aminoindole (Aldrich) as a crystalline yellow solid. MP 207-209 °C. MS (ESI, pos. ion) m/z: 399 (M+1).
Example 52 N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyl]-3- [4- (trifluoromethyl) phenyl] prop-2-enamide.
(a). Ethyl 3- [4- (tert-butyl) phenyl] prop-2-ynoate. To a 1 L round-bottomed flask was added (4-tert-butyl) phenylacetylene (33.8 g, 214 mmol, GFS Chemicals) and anhydrous THF (220 mL). The solution was magnetically stirred, purged with N2 and cooled to-78 °C, then n-butyllithium (136 mL, 2.5 M in hexanes, Aldrich) was added slowly. After the addition was complete, the mixture was gradually warmed to 0 °C and stirred magnetically for 30 min. The reaction mixture was cooled to-78 °C again and ethyl chloroformate (28.6 mL, 299.2 mmol, Aldrich) was added. After allowing to warm to 25 °C and stirring overnight, the reaction was quenched with 1 : 1 satd NaHC03 : satd NH4C1 (200 mL) and extracted with Et20 (1000 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford a yellow oil. Purification by silica gel chromatography (gradient: 0.5%-3% EtOAc/hexane) provided ethyl 3- [4-(tert-butyl) phenyl] prop-2-ynoate as a pale yellow oil. MS (ESI, pos. ion) m/z : 231 (M+1).
(b). Ethyl (2Z)-3- [4- (tert-butyl) phenyl]-3-iodoprop-2-enoate.
According to the procedure of E. Piers et al., Can. J. Chem. 1994,72, 1816, to a 150 mL round-bottomed flask equipped with a reflux condenser and magnetic stirring was added ethyl 3- [4- (tert-butyl) phenyl] prop-2-ynoate, Example 52 (a), (15 g, 65 mmol), sodium iodide (31 g, 209 mmol, Aldrich) and glacial acetic acid (48 mL, 830 mmol). The reaction mixture was purged with N2 and the flask immersed in a pre-heated 115 °C oil bath. The reaction mixture was magnetically stirred at 115 °C for 4 h, then allowed to cool to 25 °C and treated with H20 (200 mL). The aqueous phase was extracted with Et20 (500 mL). The organic layer was washed with satd Na2CO3 until the evolution of CO2 ceased, then washed with 1 M Na2S203 (100 mL), satd NaCI, dried over Na2SO4, filtered, and concentrated in vacuo to provide ethyl (2Z)-3- [4- (tert-butyl) phenyl] -3-iodoprop- 2-enoate as a yellow oil. MS (ESI, pos. ion) m/z : 359 (M+1).
(c) Ethyl (2Z)-3- [4- (tert-butyl) phenyl]-3- [4- (trifluoromethyl) phenyl] prop-2- enoate. To a 100 mL round-bottomed flask equipped with a reflux condenser and magnetic stirring was added ethyl (2Z)-3- [4- (tert-butyl) phenyl]-3-iodoprop-2- enoate, Example 52 (b), (0.75 g, 2.1 mmol), 4-trifluoromethylphenylboronic acid (0.60 g, 3.1 mmol, Aldrich), tetrakis (triphenylphosphine) palladium (0) (0.24 g, 0.21 mmol, Aldrich), toluene (10 mL), EtOH (2 mL), and 2 M aq. Na2CO3 (2 mL). The reaction mixture was magnetically stirred at 80 °C under N2 overnight, allowed to cool to 25 °C and diluted with EtOAc (50 mL). The organic layer was separated, washed with H20, satd NaCI (50 mL), dried over Na2SO4, filtered and concentrated to afford a brown oil. Purification by silica gel chromatography (gradient: 1.5%-2% EtOAc/hexane) provided the title product as a white solid. MS (ESI, pos. ion) mlz : 377 (M+1).
(d) (2Z)-3- [4- (tert-Butyl) phenyl]-3- [4- (trifluoromethyl) phenyl] prop-2-enoic acid. To a 50 mL round-bottomed flask equipped with a reflux condenser was added ethyl (2Z)-3- [4- (tert-butyl) phenyl]-3- [4- (trifluoromethyl) phenyl] prop-2- enoate, Example 52 (c), (0.74 g, 2.0 mmol), 1,4-dioxane (3 mL), KOH (0.66 g, 12 mmol) and H20 (1.5 mL). The reaction mixture was heated and magnetically stirred under reflux overnight then diluted with H20 (20 mL) and acidified with 1 N HCI. The aqueous mixture was extracted with CH2C12 (3 x 100 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to provide the title product as a white solid. MS (ESI, pos. ion) mlz : 349 (M+1).
(e) N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyl]-3- [4- (trifluoromethyl) phenyl] prop-2-enamide. Analogous to the procedure used to prepare Example 1, (2Z)-3- [4- (tert-butyl) phenyl]-3- [4- (trifluoromethyl) phenyl] prop-2-enoic acid, Example 52 (d), (0.15 g, 0.43 mmol) and 1, 4-benzodioxan-6-amine (0.07 g, 0.43 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 10%-18% EtOAc/hexane), the title product as a pale yellow solid. MP 150-151 °C. MS (ESI, pos. ion) m/z : 482 (M+1).
Example 53 (2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-4- phenylbut-2-enamide.
(a) Ethyl (2E)-3- [4- (tert-butyl) phenyl]-4-phenylbut-2-enoate. A solution of ethyl (2Z)-3- [4- (tert-butyl) phenyl]-3-iodoprop-2-enoate, Example 52 (b), (710 mg, 2.0 mmol) in anhydrous DMF (4 mL) was added dropwise to benzylzinc bromide (12 mL, 6.0 mmol, 0.5 M solution in THF, Aldrich) magnetically stirred under Ar at 0 °C in a round-bottomed flask. The mixture was treated with bis (acetonitrile) dichloropalladium (II) (78 mg, 0.30 mmol, Aldrich) in one portion. The reaction mixture was then magnetically stirred for 16 h at 25 °C, diluted with Et20 (100 mL) and washed with IN HCI (25 mL) and satd NaCl (25 mL). The organic phase was dried over MgS04, filtered and concentrated in vacuo and the residue purified by silica gel chromatography (49: 1 hexane: EtOAc) to provide the title product as a colorless oil. MS (ESI, pos. ion) aVz : 323 (M+1).
(b) (2E)-3- [4- (tert-Butyl) phenyl]-4-phenylbut-2-enoic acid. Ethyl (2E)-3- [4- (tert-butyl) phenyl]-4-phenylbut-2-enoate, Example 53 (a), (530 mg, 1.8 mmol) was treated with KOH (0.22 g, 4.0 mmol), H20 (4 mL) and 1,4-dioxane (2 mL),
then magnetically stirred under reflux for 16 h. The reaction mixture was diluted with H20 (50 mL), acidified with 1 N HCl and extracted with chloroform. The combined organic extract was washed with satd NaCI, dried over MgS04, filtered and concentrated in vacuo. The resulting residue was crystallized from EtOAc and hexane to provide the title product as a white solid.
(c) (2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-4- phenylbut-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3- [4- (tert-butyl) phenyl]-4-phenylbut-2-enoic acid, Example 53 (b), (250 mg, 0.85 mmol) and 1, 4-benzodioxan-6-amine (140 mg, 0.93 mmol, Aldrich) provided, after purification by silica gel chromatography (chloroform), the title product as off-white needles. MP 97-99 °C. MS (ESI, pos. ion) m/z : 428 (M+1).
Example 54 (2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-5- methylhex-2-enamide.
Analogous to the procedure used to prepare Example 53, starting from 3- methylbutylzinc bromide (Aldrich), ethyl (2Z)-3- [4- (tert-butyl) phenyl]-3- iodoprop-2-enoate, Example 52 (b), and 1, 4-benzodioxan-6-amine (Aldrich), the title product was obtained as an off-white solid. MP 123 °C. MS (ESI, pos. ion) nilz : 394 (M+1).
Example 55 N- (2H, 3H-Benzo [ell, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyll-3-iodoprop- 2-enamide.
(a) 3- [4- (tert-Butyl) phenyl] prop-2-ynoic acid. To a round-bottomed flask equipped with magnetic stirring and a reflux condenser was added a solution of ethyl 3- [4- (tert-butyl) phenyl] prop-2-ynoate, Example 52 (a), (4.6 g, 20 mmol) in 1,4-dioxane (5 mL). The solution was treated with H20 (15 mL) and KOH (2.2 g, 40 mmol) then stirred and heated at reflux under Ar for 18 h. After allowing to cool to 25 °C, the mixture was diluted with H20 (200 mL) and washed with Et20 (50 mL). The aqueous phase was separated, acidified with 1 N HCI and extracted with chloroform. The chloroform extract was washed with satd NaCI, dried over MgS04, filtered and concentrated in vacuo. Crystallization from EtOAc and hexane provided the title product as white needles. MS (ESI, pos. ion) m/z : 203 (M+1).
(b) N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl] prop-2- ynamide. Analogous to the procedure used to prepare Example 1, 3- [4- (tert- butyl) phenyl] prop-2-ynoic acid, Example 55 (a), (404 mg, 2.0 mmol) and 1,4- benzodioxan-6-amine (330 mg, 2.2 mmol, Aldrich) provided the title product as a white solid. MP 199 °C. MS (ESI, pos. ion) m/z : 336 (M+1).
(c) N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyl]-3- iodoprop-2-enamide. Analogous to the procedure described for the preparation
of Example 52 (b), N- (2H, 3H-benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert- butyl) phenyl] prop-2-ynamide, Example 55 (b), (0.335 g, 1.0 mmol), sodium iodide (0.48 g, 3.2 mmol, Aldrich) and glacial acetic acid (0.73 mL) provided, after purification by silica gel chromatography (chloroform), the title product as yellow crystals. MP 164 °C. MS (ESI, pos. ion) m/z : 464 (M+1).
Example 56 (2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- (3-aminophenyl)-3- [4- (tert- butyl) phenyl] prop-2-enamide.
Analogous to the procedure used to prepare Example 52, step (c), 3- aminophenylboronic acid (0.23 g, 1.5 mmol, Avocado) and N- (2H, 3H- benzo [e] 1, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyl]-3-iodoprop-2-enamide, Example 55, (0.46 g, 1.0 mmol) provided the title product as off-white crystals.
MP 140 °C. MS (ESI, pos. ion) m/z : 429 (M+1).
Example 57 Ethyl (4E)-5- (N- (2H, 3H-benzo [e] 1, 4-dioxan-6-yl) carbamoyl)-4- [4- (tert- butyl) phenyl] pent-4-enoate.
Analogously to the procedure used to prepare Example 53, step (a), 3-ethoxy-3- oxopropylzinc bromide (6.0 mL, 3.0 mmol, 0.5 M in THF, Aldrich) and N- (2H, 3H-benzo [e] 1, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyl]-3-iodoprop-2- enamide, Example 55, (0.46 g, 1.0 mmol) provided the title product as a pale yellow solid. MP 104-105 °C. MS (ESI, pos. ion) m/z : 438 (M+1).
Example 58
3-Methoxyphenyl (2E)-3- [4- (tert-butyl) phenyl] prop-2-enoate. To a 100 mL round-bottomed flask equipped with magnetic stirring was added 4-tert-butyl- trans-cinnamic acid (500 mg, 2.45 mmol, EMKA-Chemie), CH2Cl2 (10 mL), and DMF (10 uL) under N2. The solution was treated dropwise with oxalyl chloride (4.0 mL, 8.0 mmol, 2.0 M in CH2Cl27 Aldrich) then stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo and the residue treated with 3- methoxyphenol (269 uL, 2.45 mmol, Aldrich), THF (20 mL) and satd K2CO3 (15 mL). The reaction mixture was stirred at 25 °C overnight, then acidified to pH 4.5 with 1 N HCI. The mixture was extracted with EtOAc (2 x 30 mL), the combined organic extract was dried and concentrated in vacuo. Purification by silica gel chromatography (5: 1 hexane: EtOAc) provided the title product as a white solid. MP 83 °C. MS (ESI, pos. ion) m/z: 311 (M+1).
Example 60 N- (2H, 3H-Benzo [3, 4-e] 1, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyl]-3- hydroxyprop-2-enamide.
(a) tert-Butyl 3- [4- (tert-butyl) phenyl]-3-hydroxypropanoate. To a round- bottomed flask equipped with magnetic stirring was added N, N-diisopropylamine (10.4 mL, 74.0 mmol, Aldrich) and anhydrous THF (20 mL). The solution was stirred at-78 °C under N2 and treated dropwise with n-butyllithium (30.0 mL,
75.0 mmol, 2.5 M in hexane, Aldrich). After stirring for 10 min at-78 °C, the reaction mixture was treated with t-butyl acetate (10.8 mL, 80.1 mmol, Aldrich).
After stirring 30 min at-78 °C, the enolate was added via cannula to a solution of 4-t-butylbenzaldehyde (10.0 g, 61.6 mmol, Fluka) in anhydrous THF (100 mL), stirred under N2 at-78 °C. The reaction mixture was allowed to warm to 0 °C with stirring over 3 h, then quenched with satd NH4CI and concentrated in vacuo to remove the THF. The resulting mixture was diluted with satd NH4Cl (100 mL) and extracted with Et20 (200 mL). The organic extract was washed with H20 (100 mL), satd NaCI (50 mL), dried over MgS04, filtered and concentrated in vacuo to provide the title product as a white solid. MS (ESI, pos. ion) m/z : 261 (M+1-H20).
(b) tert-butyl 3- [4- (tert-butyl) phenyl]-3-oxopropanoate. tert-Butyl 3- [4- (tert- butyl) phenyl]-3-hydroxypropanoate, Example 60 (a), (5.0 g, 18 mmol) was dissolved in CH2Cl2 (100 mL), magnetically stirred in a round-bottomed flask at 0 °C, and treated with pyridinium chlorochromate (5.8 g, 27 mmol, Aldrich) in portions. The reaction mixture was allowed to warm to 25 °C and stirred at that temperature for 5 h. The mixture was filtered through a pad of Celite, the filtercake washed with CH2Cl2 (3 x 100 mL) and the combined filtrate was concentrated in vacuo. Purification by silica gel chromatography (1: 1 hexane: EtOAc) provided the title product as a dark oil. MS (ESI, pos. ion) m/z : 277 (M+1).
(c) N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyl]-3- hydroxyprop-2-enamide. According to the procedure of Wiseman et al., J. Org.
Chem. 1991, 56, 1713-1718, to a round-bottomed flask equipped with magnetic stirring and a reflux condenser was added tert-butyl 3- [4- (tert-butyl) phenyl]-3- oxopropanoate, Example 60 (b), (640 mg, 2.3 mmol), 1, 4-benzodioxan-6-amine (350 mg, 2.3 mmol, Aldrich) and anhydrous toluene (20 mL). The mixture was stirred and heated at 130 °C for 2 h. Upon allowing to cool to 25 °C, a precipitate
was observed. Hexane (20 mL) was added to the suspension and the precipitate collected by filtration, washed with hexane (20 mL) and dried in vacuo at 60 °C to provide the title product as a pale grey solid. MP 161 °C. MS (ESI, pos. ion) m/z: 354 (M+1).
Example 61 N- (2H, 3H-Benzo [3, 4-e] 1, 4-dioxan-6-yl) [7-(tert-butyl) (3-isoquinolyl)]- carboxamide.
(a) 2-[(tert-Butyl) oxycarbonyl]-7-(tert-butyl)-1, 2,3, 4-tetrahydroisoquinoline- 3-carboxylic acid. According to the procedure of D. Ma, et al., Bioorg. Med.
Chem. Lett. 1998, 8 (18), 2447-2450, to a 250 mL round-bottomed flask, equipped with magnetic stirring and reflux condenser, was added N-Boc-(p-tert-butyl)-S- phenylalanine (5.0 g, 15.6 mmol, Bachem), formaldehyde (50 mL, 37 wt. % in H20, Aldrich) and cond HO (30 mL). The reaction mixture was stirred and heated at 90 °C for 4 h. The solvents were removed in vacuo to provide 3.6 g of a residue [MS (ESI, pos. ion) m/z: 234 (M+1)] which was dissolved in THF (140 mL) and treated with 5% aq. K2CO3 (140 mL) and di-t-butyl dicarbonate (4.8 g, 22 mmol, Aldrich). The reaction mixture was stirred at 25 °C overnight, then acidified to pH 5 with 1 N HCI. The mixture was extracted with EtOAc (300 mL), the organic phase washed with satd NaCl (100 mL) and H20 (120 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (2: 1 hexane: EtOAc) provided the title product. MS (ESI, pos. ion) m/z: 334 (M+1).
(b) N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl) [7- (tert-butyl) (3-1, 2,3, 4- tetrahydroisoquinolyl)] carboxamide hydrochloride. To a 250 mL round- bottomed flask equipped with magnetic stirring was added 2-[(tert- butyl) oxycarbonyl]-7- (tert-butyl)-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid, Example 61 (a), (1.5 g, 4.65 mmol), DMF (15 mL), 1, 4-benzodioxan-6- amine (700 mg, 4.65 mmol, Aldrich), dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (1.25 g, 6.5 mmol, Aldrich) and N, N-diisopropylethylamine (2.5 mL, 13.95 mmol, Aldrich). The reaction mixture was stirred at 25 °C overnight then concentrated in vacuo. The residue was dissolved in EtOAc (35 mL), washed with H20 (2x15 mL), dried over Na2S04, filtered and concentrated in vacuo. Purification by silica gel chromatography (3: 1 hexane: EtOAc) provided a product [MS (ESI, pos. ion) m/z: 467 (M+1)] which was treated with 4.0 N HCl in 1,4 dioxane (10 mL, Aldrich) and stirred at 25 °C for 1 h. The solvent was removed in vacuo to provide the title product as the hydrochloride salt. MP 134 °C. MS (ESI, pos. ion) m/z: 367 (M+l).
(c) N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl) [7- (tert-butyl) (3-isoquinolyl)]- carboxamide. Analogous to the procedure of E. D. Cox; T. J. Hagen; R. M.
McKernan ; J. M. Cook, Med. Chem. Rest. 1995,5 (9), 710-718, N- (2H, 3H- benzo [3,4-e] 1, 4-dioxan-6-yl) [7- (tert-butyl) (3-1, 2,3, 4- tetrahydroisoquinolyl)] carboxamide hydrochloride, Example 61 (b), was suspended in EtOAc (55 mL), washed with 10% NaHCO3 (20 mL) and H20 (10 mL), dried over Na2S04, filtered and concentrated in vacuo. The resulting residue (80 mg, 0.22 mmol) was dissolved in toluene (10 mL) and treated with manganese dioxide (110 mg, 1.1 mmol). The reaction mixture was magnetically stirred at 70 °C under N2 for 1.5 h, filtered through Celite and concentrated in vacuo. Purification by silica gel chromatography (8: 1 hexane: EtOAc) provided the title product as a yellow solid. MP 154-157 °C. MS (ESI, pos. ion) m/z: 363 (M+1).
Example 63 N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyl] prop-2- enamide.
(a) (2Z)-3- [4- (tert-Butyl) phenyl] prop-2-enoic acid. Potassium bis (trimethylsilyl) amide (6.1 mL, 3.05 mmol, 0.5 M in toluene, Aldrich) was added dropwise with stirring to a mixture of diphenylphosphonoacetic acid ethyl ester (0.98 g, 3.05 mmol, TCI-US) and 18-crown-6 (3.35 g, 12.7 mmol, Aldrich) in anhydrous THF (20 mL), magnetically stirred at-78 °C under Ar. The reaction mixture was stirred at-78 °C for 0.5 h then treated dropwise with a solution of 4- tert-butylbenzaldehyde (0.42 mL, 2.54 mmol, Aldrich) in anhydrous THF (5 mL).
The mixture was stirred at-78 °C for 1 h, quenched with satd NH4Cl (5 mL), warmed to 25 °C, diluted with H20 (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with satd NaCI, dried over MgS04, filtered and concentrated in vacuo to provide a brown viscous oil.
[MS (ESI, pos. ion) m/z : 233 (M+1)] The oil (0.83 g) was dissolved in THF (5 mL) and MeOH (5 mL), magnetically stirred in a round-bottomed flask at 25 °C, and treated with 1 N LiOH (10 mL). The reaction mixture was stirred at 25 °C for 18 h, the organic solvents removed in vacuo, and the aqueous phase was washed with Et20, acidified with 10% citric acid and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over MgS04, filtered and concentrated in vacuo to provide the title product as a white solid. MS (ESI, pos. ion) mlz : 205 (M+1).
(b) N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyl] prop- 2-enamide. Analogous to the procedure used to prepare Example 1, (2Z)-3- [4- (tert-butyl) phenyl] prop-2-enoic acid, Example 63 (a), (0.46 g, 2.3 mmol) and 1,4- benzodioxan-6-amine (0.38 g, 2.58 mmol, Aldrich) provided the title product as a white solid. MP 114-116 °C. MS (ESI, pos. ion) m/z : 338 (M+1).
Example 64 N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyl]-3- phenylprop-2-enamide.
N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl] prop-2-ynamide, Example 55 (b), (0.34 g, 1.0 mmol) was dissolved in anhydrous EtOAc (50 mL) in a 100 mL round-bottomed flask equipped with reflux condenser and magnetic stirring under dry nitrogen atmosphere. To this solution was added iodobenzene (0.20 g, 1.0 mmol, Aldrich) and bis (dibenzylideneacetone) palladium (0.080 g, 0.14 mmol, Acros), followed by diethylamine (0.34 mL, 3.3 mmol, Aldrich) and formic acid (0.098 mL, 2.6 mmol, Aldrich). The reaction mixture was heated under reflux for 20 h, cooled to room temperature, washed with 1 N HCI (2 x 5 mL), 1 N NaOH (2 x 5 mL), satd NaCl (5 mL) and dried over Na2SO4. The organic solution was filtered and concentrated to afford a brown oil which was purified by silica gel chromatography (20 % EtOAc/hexane) to give the title compound as a pale yellow solid. MP 80-82 °C. MS (ESI, pos. ion)/ : 414 (M+1).
Example 65
(2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-3- phenylprop-2-enamide.
(a). N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3-phenylprop-2-ynamide. Analogous to the procedure used to prepare Example 1, phenylpropiolic acid (5.8 g, 140 mmol, Aldrich) and 1, 4-benzodioxan-6-amine (6.65 g, 44 mmol, Aldrich) provided, after recrystallization from EtOAc and hexane, the title compound as a white solid. MP 132 °C. MS (ESI, pos. ion) m/z : 280 (M+1).
(b). (2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-3- phenylprop-2-enamide. Analogous to the procedure used to prepare Example 64, 1-tert-butyl-4-iodobenzene (0.26 g, 1.0 mmol, Aldrich) and N- (2H, 3H- benzo [e] 1, 4-dioxan-6-yl)-3-phenylprop-2-ynamide, Example 65 (a), (0.28 g, 1.0 mmol) provided, after recrystallization from EtOAc and hexane, the title compound as an off-white solid. MP 139 °C. MS (ESI, pos. ion) m/z : 414 (M+1).
Example 66 (2E)-3- [4- (tert-Butyl) phenyl]-N- [l- (N-methylcarbamoyl) (lH-indazol-6- yl)] prop-2-enamide. To a round-bottomed flask, equipped with a magnetic stir bar, was added (2E)-N- (1H-indazol-6-yl)-3- [4- (tert-butyl) phenyl] prop-2-enamide, Example 155, (61 mg, 0.19 mmol), THF (8 mL) and isocyanatomethane (54 mg, 0.96 mmol, Carbolabs). The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water
(8 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (40: 20: 1 hexane: EtOAc: MeOH) provided the title product as an off-white solid. MP 208-209 °C. MS (ESI, pos. ion) m/z : 377 (M+1).
Example 67 (2E)-3- [4- (tert-Butyl) phenyl]-N- {4-chloro-3- [ (methylamino) carbonylamino]-<BR> <BR> phenyl} prop-2-enamide.
(a) (2E)-N- (3-Amino-4-chlorophenyl)-3- [4- (tert-butyl) phenyl] prop-2- enamide. To a round-bottomed flask equipped with a magnetic stir bar, was added (2E)-3- [4- (tert-butyl) phenyl]-N- (4-chloro-3-nitrophenyl) prop-2-enamide, Example 156, (250 mg, 0.69 mmol), EtOH (8 mL), indium (800 mg, 6.9 mmol, Aldrich) and satd NH4Cl (10 mL). The reaction mixture was stirred at reflux for 5 h. The solvents were removed in vacuo, the residue was dissolved in EtOAc (20 mL), washed with water (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to yield the title product. MS (ESI, pos. ion) m/z : 329 (M+1).
(b) (2E)-3- [4- (tert-Butyl) phenyl]-N- {4-chloro-3- [ (methylamino)- carbonylamino]phenyl} prop-2-enamide. According to the procedure used to prepare Example 66, (2E)-N- (3-amino-4-chlorophenyl)-3- [4- (tert- butyl) phenyl] prop-2-enamide, Example 67 (a), (90 mg, 0.27 mmol) and isocyanatomethane (156 mg, 2.7 mmol, Carbolabs) provided, after purification by silica gel chromatography (2: 1 hexane: EtOAc), the title product as an off-white solid. MP 120-122 °C. MS (ESI, pos. ion) m/z: 386 (M+1).
Example 68
(2E)-3- [4- (tert-Butyl) phenyl]-N-quinoxalin-6-ylprop-2-enamide.
(a) Quinoxaline-6-ylamine. To a round-bottomed flask equipped with magnetic stirring was added 4-nitro-1, 2-phenylenediamine (1.0 g, 6.5 mmol, Aldrich), acetonitrile (10 mL) and glyoxal (2.2 mL, 19 mmol, 40 wt. % in water, Aldrich).
The reaction mixture was allowed to stir at 50 °C for 12 h, then concentrated in vacuo to yield 1. 1 g crude 6-nitro-quinoxaline. The crude product was dissolved in methanol, treated with 10% Pd/C (10 mg, Aldrich) and stirred under H2 (1 atm) at 25 °C overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to provide the title product. MS (ESI, pos. ion) rn/z : 146 (M+1).
(b) (2E)-3- [4- (tert-Butyl) phenyl]-N-quinoxalin-6-ylprop-2-enamide.
Analogous to the procedure used to prepare Example 2, 4-tert-butyl-trans- cinnamic acid (100 mg, 0.40 mmol, EMKA-Chemie) and quinoxaline-6-ylamine, Example 68 (a), (71 mg, 0.40 mmol) provided, after purification by silica gel chromatography (1: 2 hexane: EtOAc), the title product as a yellow solid. MP 229- 230 °C. MS (ESI, pos. ion) m/z : 332 (M+1).
Example 69 (2E)-N- (l-acetyl (7-1, 2,3, 4-tetrahydroquinolyl))-3- [4- (tert-butyl) phenyl] prop- 2-enamide.
(a) 1-Acetyl-7-nitro-1, 2,3, 4-tetrahydroquinoline. A mixture of 7-nitro-1, 2,3, 4- tetrahydroquinoline, Example 19 (a), (0.36 g, 2.0 mmol) and acetic anhydride (3.5 mL, 37 mmol, Aldrich) in a 15 mL round-bottomed flask, was heated at reflux for 1.5 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 30% ammonium hydroxide. The aqueous layer was extracted with EtOAc (10 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellow solid. MS (ESI, pos. ion) m/z : 221 (M+1).
(b) 1-Acetyl-7-amino-1, 2,3, 4-tetrahydroquinoline. Analogous to the procedure used to prepare Example 3, step (a), 1-acetyl-7-nitro-1, 2,3, 4-tetrahydroquinoline, Example 69 (a), (0.44 g, 2.0 mmol) was converted to the title product. MS (ESI, pos. ion) m/z : 191 (M+1).
(c) (2E)-N- (l-acetyl (7-1, 2,3, 4-tetrahydroquinolyl))-3- [4- (tert- butyl) phenyl] prop-2-enamide. According to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (0.41 g, 2.0 mmol, EMKA Chemie) and 1-acetyl-7-amino-1, 2,3, 4-tetrahydroquinoline, Example 69 (b), (370 mg, 2.0 mmol) provided, after purification by silica gel chromatography (1: 1 hexane: EtOAc), the title compound as an amorphous white solid. MS (ESI, pos. ion) m/z : 377 (M+1).
Example 70
(2E)-3- [4- (tert-Butyl) phenyl]-N- [1- (2-methoxyethyl) indol-6-yl] prop-2- enamide.
To a round-bottomed flask was added, (2E)-3- [4- (tert-butyl) phenyl]-N-indol-6- ylprop-2-enamide, Example 189, (320 mg, 1.0 mmol) and anhydrous DMF (20 mL). The solution was stirred magnetically and treated with sodium hydride (0.10 g, 2.5 mmol, 60% dispersion in mineral oil, Aldrich) followed by 2- bromoethyl methyl ether (140 mg, 1.0 mmol, Aldrich). Stirring was continued at 25 °C for 2 h, then the reaction mixture was quenched by the addition of water (50 mL) and extracted with EtOAc. The organic extract was concentrated in vacuo. Purification by silica gel chromatography (60: 40 hexane: EtOAc) provided the title compound as a yellow solid. MP 133 °C. MS (ESI, pos. ion) m/z : 377 (M+1).
Example 71 (2E)-3- [4- (tert-Butyl) phenyl]-N- [l- (2-methoxyethyl) indol-5-yl] prop-2- enamide.
Analogous to the procedure used to prepare Example 70, 2-bromoethyl methyl ether (140 mg, 1.0 mmol, Aldrich) and (2E)-3- [4- (tert-butyl) phenyl]-N-indol-5- ylprop-2-enamide, Example 161, (320 mg,. 01 mmol) provided, after purification by silica gel chromatography (65: 35 hexane: EtOAc), the title compound as a pale yellow solid. MP 138 °C. MS (ESI, pos. ion) m/z : 377 (M+1).
Example 72 (2E)-3- [4- (tert-Butyl) phenyl]-N- [1- (2-hydroxyethyl) indol-6-yl] prop-2- enamide.
(a) 1- [2- (1, 1, 2, 2-Tetramethyl-1-silapropoxy) ethyl]indole-6-ylamine.
Analogous to the procedure used to prepare Example 33, step (a), 6-nitroindole (0.49 g, 3.0 mmol, Aldrich) and (2-bromoethoxy)-tert-butyldimethylsilane (0.72 g, 3.0 mmol, Aldrich) provided the title product. MS (ESI, pos. ion) m/z : 291 (M+1).
(b) (2E)-3- [4- (tert-Butyl) phenyl]-N- {1- [2- (1, 1, 2, 2-tetramethyl-1- silapropoxy) ethyl] indol-6-yl} prop-2-enamide. Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) and 1- [2- (1, 1, 2, 2-tetramethyl-1-silapropoxy)ethyl]indole-6- ylamine, Example 72 (a), (290 mg, 1.0 mmol) provided the title product. MS (ESI, pos. ion) m/z : 477 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N- [1- (2-hydroxyethyl) indol-6-yl] prop-2- enamide. (2E)-3- [4- (tert-Butyl) phenyl]-N- { 1- [2- (1, 1, 2, 2-tetramethyl-1- silapropoxy) ethyl] indol-6-yl} prop-2-enamide, Example 72 (b), (420 mg,
0.88 mmol) was transferred to a round-bottomed flask and treated with tetrabutylammonium fluoride (2.0 mL, 2.0 mmol, 1.0 M in THF, Aldrich) under N2. The reaction mixture was magnetically stirred at 25 °C for 2 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc. The organic extract was concentrated in vacuo. Purification by silica gel chromatography (30: 70 hexane: EtOAc) provided the title compound as a yellow solid. MP 178 °C. MS (ESI, pos. ion) m/z : 363 (M+1).
Example 73 (2E)-3- [4- (tert-Butyl) phenyt]-N- [1- (2-hydroxyethyl) indol-5-yl] prop-2- enamide.
(a) 1- [2- (1, 1, 2, 2-Tetramethyl-1-silapropoxy) ethyl] indole-5-ylamine.
According to the procedure used to prepare Example 33, step (a), 5-nitroindole (0.49 g, 3.0 mmol, Aldrich) and (2-bromoethoxy)-tert-butyldimethylsilane (0.72 g, 3.0 mmol, Aldrich) provided the title product. MS (ESI, pos. ion) m/z : 291 (M+1).
(b) (2E)-3- [4- (tert-Butyl) phenyt]-N- {1- [2- (1, 1, 2, 2-tetramethyl-1- silapropoxy) ethyl] indol-5-yl} prop-2-enamide. According to the procedure used
to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (100 mg, 0.50 mmol, EMKA-Chemie) and 1- [2- (1, 1, 2, 2-tetramethyl-1-silapropoxy) ethyl] indole-5- ylamine, Example 73 (a), (145 mg, 0.50 mmol) provided the title product. MS (ESI, pos. ion) mlz : 477 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N- [l- (2-hydroxyethyl) indol-5-yl] prop-2- enamide. According to the procedure used to prepare Example 72, step (c), (2E)- 3- [4- (tert-butyl) phenyl]-N-1 1- [2- (1, 1, 2, 2-tetramethyl-1-silapropoxy) ethyl] indol- 5-yl} prop-2-enamide, Example 73 (b), (130 mg, 0.27 mmol) and tetrabutylammonium fluoride (1. 0 mL, 1.0 mmol, 1.0 M in THF, Aldrich) provided, after purification by silica gel chromatography (30: 70 hexane: EtOAc), the title compound as a pale yellow solid. MP 182 °C. MS (ESI, pos. ion) m/z : 363 (M+1).
Example 74
(2E)-3- [4- (tert-Butyl) phenyl]-N- [2- (hydroxymethyl) indol-5-yl] prop-2- enamide.
(a) Ethyl 5-aminoindote-2-carboxylate. Analogous to the procedure used to prepare Example 3, step (a), ethyl 5-nitroindole-2-carboxylate (2.3 g, 9.9 mmol, Acros) provided the title product. MS (ESI, pos. ion) m/z : 205 (M+1).
(b) (5-Aminoindol-2-yl) methan-1-ol. Ethyl 5-aminoindole-2-carboxylate, Example 74 (a), (1.5 g, 7.3 mmol) was transferred to a round-bottomed flask and treated with lithium aluminum hydride (10 mL, 10 mmol, 1.0 M in THF, Aldrich) under N2. The reaction mixture was magnetically stirred at 25 °C for 1 h, then
quenched by the dropwise addition of H20 (0.5 mL) followed by 20% aq. KOH (30 mL). The suspension was filtered and the aqueous phase extracted with EtOAc. The organic extract was concentrated in vacuo. Purification of the crude product by silica gel chromatography (20: 80 hexane: EtOAc) provided the title product. MS (ESI, pos. ion) m/z : 163 (M+1).
(c) (2E)-3- [4- (tert-Butyl) phenyl]-N- [2- (hydroxymethyl) indol-5-yl] prop-2- enamide. Analogous to the procedure used to prepare Example 1, 4-tert-butyl- trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) and (5-aminoindol-2- yl) methan-1-ol, Example 74 (b), (160 mg, 1.0 mmol) provided, after purification by silica gel chromatography (40: 60 hexane: EtOAc), the title product as a pale tan amorphous solid. MS (ESI, pos. ion) m/z : 349 (M+1).
Example 75 (2E)-N- (2H, 3H-Benzo [3, 4-e] 1, 4-dioxan-6-yl)-3- [6- (tert-butyl)-2-methyl (3- pyridyl) prop-2-enamide.
(a) Ethyl 6- (tert-butyl)-2-methylpyridine-3-carboxylate. Analogous to the procedure used to prepare Example 44, step (a), ethyl 2-methylnicotinate (8.3 g, 50 mmol, Aldrich), trimethylacetic acid (26 g, 250 mmol, Aldrich), silver nitrate (1.7 g, 10 mmol, Aldrich), 10% aq. sulfuric acid (50 mL) and ammonium persulfate (23 g, 100 mmol, Aldrich) provided, after purification by silica gel chromatography (80: 20 hexane: EtOAc), the title product. MS (ESI, pos. ion) m/z : 222 (M+1).
(b) 6- (tert-Butyl)-2-methylpyridine-3-carbaldehyde. Analogous to the procedure used to prepare Example 43, step (b), ethyl 6- (tert-butyl)-2- methylpyridine-3-carboxylate, Example 75 (a), (5.2 g, 23 mmol) provided the title product. MS (ESI, pos. ion) m/z : 178 (M+1).
(c) (2E)-3-[6-(tert-Butyl)-2-methyl(3-pyridyl)prop-2-enoic acid. Analogous to the procedure used to prepare Example 40, step (a), 6-(tert-butyl)-2- methylpyridine-3-carbaldehyde, Example 75 (b), (3.0 g, 17 mmol) and triethyl phosphonoacetate (4.0 g, 18 mmol, Aldrich) provided the title product. MS (ESI, pos. ion) n ? lz : 220 (M+1).
(d) (2E)-N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3-[6-(tert-butyl)-2-methyl (3- pyridyl) prop-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)] prop-2-enoic acid, Example 75 (c), (110 mg, 0.50 mmol) and 1, 4-benzodioxan-6-amine (76 mg, 0.50 mmol, Aldrich) provided, after purification by silica gel chromatography (55: 45 hexane: EtOAc), the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z : 353 (M+1).
Example 76 (2E)-3- [6- (tert-Butyl)-2-methyl (3-pyridyl)]-N-indol-6-ylprop-2-enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-nutyl)-2- methyl (3-pyridyl)] prop-2-enoic acid, Example 75 (c), (220 mg, 1.0 mmol) and 6- aminoindole (130 mg, 1.0 mmol, Lancaster) provided, after purification by silica gel chromatography (55: 45 hexane: EtOAc), the title compound as a yellow solid.
MP 182 °C. MS (ESI, pos. ion) m/z : 334 (M+1).
Example 77
(2E)-N-Benzothiazol-6-yl-3- [6- (tert-butyl)-2-methyl (3-pyridyl)] prop-2- enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3- [6- (tert-butyl)-2- methyl (3-pyridyl)] prop-2-enoic acid, Example 75 (c), (220 mg, 1.0 mmol) and 6- aminobenzothiazole (150 mg, 1.0 mmol, Lancaster) provided, after purification by silica gel chromatography (55: 45 hexane: EtOAc), the title compound as a pale yellow amorphous solid. MS (ESI, pos. ion) m/z : 352 (M+1).
Example 78 (2E)-3- [6- (tert-Butyl)-2-methyl (3-pyridyl)]-N-indol-5-ylprop-2-enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3- [6- (tert-butyl)-2- methyl (3-pyridyl) ] prop-2-enoic acid, Example 75 (c), (0.88 g, 4.0 mmol) and 5- aminoindole (0.53 g, 4.0 mmol, Lancaster) provided, after purification by silica gel chromatography (55: 45 hexane: EtOAc), the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 334 (M+1).
Example 79 (2E)-3- [6- (tert-Butyl)-2-methyl (3-pyridyl)]-N- [2- (hydroxymethyl) indol-5- yl] prop-2-enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3- [6- (tert-butyl)-2- methyl (3-pyridyl)] prop-2-enoic acid, Example 75 (c), (110 mg, 0.50 mmol) and
(5-aminoindol-2-yl) methan-1-ol, Example 74 (b), (81,0. 50 mmol) provided, after purification by silica gel chromatography (25: 75 hexane: EtOAc), the title compound as a pale yellow solid. MP 213 °C. MS (ESI, pos. ion) m/z : 364 (M+1).
Example 80 (2E)-3-[6-(tert-Butyl) (3-pyridyl)]-N-[2-(hydroxymethyl) indol-5-yl] prop-2- enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3- [6- (tert-butyl) (3- pyridyl)] prop-2-enoic acid, Example 44 (b), (41 mg, 0.20 mmol) and (5- aminoindol-2-yl) methan-1-ol, Example 74 (b), (32 mg, 0.20 mmol) provided, after purification by silica gel chromatography (20: 80 hexane: EtOAc), the title compound as a yellow amorphous solid. MS (ESI, pos. ion) n1Jz : 350 (M+1).
Example 81 (2E)-3- [6- (tert-Butyl) (3-pyridyl)]-N- [1- (2-hydroxyethyl) indol-5-yl] prop-2- enamide.
(a) (2E)-3-[6-(tert-butyl)(3-pyridyl)]-N-{1-[2-(1,1 2, 2-tetramethyl-1- silapropoxy) ethyl]indol-5-yl]prop-2-enamide. Analogous to the procedure used
to prepare Example 1, (2E)-3-[6-(tert-butyl) (3-pyridyl)] prop-2-enoic acid, Example 44 (b), (41 mg, 0.20 mmol) and 1- [2- (1, 1, 2, 2-tetramethyl-1- silapropoxy) ethyl] indole-5-ylamine, Example 73 (a), (60 mg, 0.20 mmol) provided the title product. MS (ESI, pos. ion) m/z : 478 (M+1).
(b) (2E)-3- [6- (tert-Butyl) (3-pyridyl)]-N- [1- (2-hydroxyethyl) indol-5-yl] prop- 2-enamide. Analogous to the procedure used to prepare Example 72, step (c), (2E)-3-[6-(tert-butyl) (3-pyridyl)]-N- {1-[2-(1, 1, 2, 2-tetramethyl-1- silapropoxy) ethyl] indol-5-yl} prop-2-enamide, Example 81 (a), (75 mg, 0.16 mmol) and tetrabutylammonium fluoride (0.50 mL, 0.50 mmol, 1.0 M in THF, Aldrich) provided, after purification by silica gel chromatography (20: 80 hexane: EtOAc), the title compound as a yellow amorphous solid. MS (ESI, pos. ion) nilz : 364 (M+1).
Example 82 (2E)-N-Indol-6-yl-3-[2-methyl-6-(trifluoromethyl) (3-pyridyl)] prop-2- enamide.
(a) 2-Methyl-6-(trifluoromethyl)pyridine-3-carbaldehyde. Analogous to the procedure used to prepare Example 43, step (b), 2-methyl-6- (trifluoromethyl) pyridine-3-carboxylic acid (5.0 g, 24 mmol, Oakwood) provided the title product. MS (ESI, pos. ion) m/z : 190 (M+1).
(b) (2E)-3-[2-Methyl-6-(trifluoromethyl)(3-pyridyl)prop-2-enoic acid.
Analogous to the procedure used to prepare Example 40, step (a), 2-methyl-6- (trifluoromethyl) pyridine-3-carbaldehyde, Example 82 (a), (3.7 g, 20 mmol) and triethyl phosphonoacetate (4.5 g, 20 mmol, Aldrich) provided the title product.
MS (ESI, pos. ion) nez : 232 (M+1).
(c) (2E)-N-Indol-6-yl-3-[2-methyl-6-(trifluoromethyl) (3-pyridyl)] prop-2- enamide. Analogous to the procedure used to prepare Example 1, (2E)-3- [2- methyl-6-(trifluoromethyl) (3-pyridyl)] prop-2-enoic acid, Example 82 (b), (58 mg, 0.25 mmol) and 6-aminoindole (33 mg, 0.25 mmol, Lancaster) provided, after purification by silica gel chromatography (55: 45 hexane: EtOAc), the title compound as a yellow solid. MP 223 °C. MS (ESI, pos. ion) m/z : 346 (M+1).
Example 83 (2E)-N-Indol-5-yl-3- [2-methyl-6- (trifluoromethyl) (3-pyridyl)] prop-2- enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3- [2-methyl-6- (trifluoromethyl) (3-pyridyl)] prop-2-enoic acid, Example 82 (b), (120 mg, 0.50 mmol) and 5-aminoindole (66 mg, 0.50 mmol, Aldrich) provided, after purification by silica gel chromatography (55: 45 hexane: EtOAc), the title compound as a yellow solid. MP 231 °C. MS (ESI, pos. ion) m/z : 346 (M+1).
Example 84
(2E)-N-Benzothiazol-6-yl-3-[2-methyl-6-(trifluoromethyl) (3-pyridyl)] prop-2- enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3- [2-methyl-6- (trifluoromethyl) (3-pyridyl) ] prop-2-enoic acid, Example 82 (b), (120 mg, 0.50 mmol) and 6-aminobenzothiazole (75 mg, 0.50 mmol, Lancaster) provided, after purification by silica gel chromatography (55: 45 hexane: EtOAc), the title compound as a white solid. MP 196 °C. MS (ESI, pos. ion) m/z : 364 (M+1).
Example 85
(2E)-N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3- [2-methyl-6- (trifluoromethyl)- (3-pyridyl) prop-2-enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3- [2-methyl-6- (trifluoromethyl) (3-pyridyl) ] prop-2-enoic acid, Example 82 (b), (120 mg, 0.50 mmol) and 1, 4-benzodioxan-6-amine (76 mg, 0.50 mmol, Aldrich) provided, after purification by silica gel chromatography (55: 45 hexane: EtOAc), the title compound as a yellow solid. MP 186 °C. MS (ESI, pos. ion) m/z : 365 (M+1).
Example 86
(2E)-3- [4- (tert-butyl) phenyl]-N- [3- (hydroxymethyl)-2-oxo (7-1, 3,4- trihydroquinolyl)] prop-2-enamide.
(a) (2-Amino-4-nitrophenyl) methan-1-ol. To a solution of 4-nitroanthranilic acid (910 mg, 5.0 mmol, Aldrich) in THF (15 mL), magnetically stirred at 0 °C, was added borane-tetrahydrofuran complex (15 mL, 15 mmol, 1.0 M in THF,
Aldrich) dropwise. The reaction mixture was heated to reflux overnight. The mixture was then cooled to 0 °C and treated dropwise with MeOH (5 mL) followed by 1 N NaOH (30 mL). After stirring for 30 min at room temperature, the mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with satd NaCI (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (50% EtOAc/hexane) followed by recrystallization from EtOAc/hexane provided the title product. MS (ESI, pos. ion) m/z: 169 (M+1).
(b) 2-Amino-4-nitrobenzaldehyde. A mixture of 2-amino-4- nitrophenyl) methan-1-ol, Example 86 (a), (336 mg, 2.0 mmol) and Mn02 (3.48 g, 40.0 mmol, Aldrich) in CH2Cl2/hexane (1: 1,10 mL) was stirred at room temperature for 1 h. The suspension was filtered and washed with CH2Cl2. The filtrate was concentrated in vacuo to give the crude product. MS (ESI, pos. ion) m/z : 167 (M+1).
(c) Methyl 7-nitro-2-oxo-1, 3, 4-trihydroquinoline-3-carboxylate. A mixture of 2-amino-4-nitrobenzaldehyde, Example 86 (b), (1.66 g, 10.0 mmol), dimethyl malonate (1.37 mL, 12.0 mmol, Aldrich), copper (II) acetate (100 mg, 0.5 mmol, Aldrich) and potassium acetate (99 mg, 1.0 mmol, Bayer) in acetic acid (20 mL) was stirred at 110 °C for 48 h. Most of the solvent was removed in vacuo and the resulting precipitate was collected by filtration, washed with EtOAc and dried in vacuo to give the title product. MS (ESI, pos. ion) m/z: 248 (M+1) (d) 3- (Hydroxymethyl)-7-nitro-1, 3, 4-trihydroquinolin-2-one and (7-nitro-3- 1, 2,3, 4-tetrahydroquinolyl) methan-1-ol. To a solution of methyl 7-nitro-2-oxo- 1, 3, 4-trihydroquinoline-3-carboxylate, Example 86 (c), (1.23 g, 5.0 mmol) in THF
(50 mL) was added LiBH4 (12.5 mL, 25.0 mmol, 2.0 M in THF, Aldrich). The reaction mixture was stirred at 40 °C for 18 h, then quenched by the careful addition of satd NH4CI (20 mL). The mixture was stirred at room temperature for 30 min, then extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with satd NaCI (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (50% EtOAc/CH2CI2) provided 3- (hydroxymethyl)-7-nitro-1, 3,4-trihydroquinolin-2-one [MS (ESI, pos. ion) m/z: 223 (M+1)] and (7-nitro-3-1, 2,3, 4- tetrahydroquinolyl) methan-1-ol [MS (ESI, pos. ion) m/z: 209 (M+1)].
(e) 7-Amino-3- (hydroxymethyl)-1, 3, 4-trihydroquinolin-2-one. Analogous to the procedure used to prepare Example 3, step (a), 3- (hydroxymethyl)-7-nitro- 1, 3, 4-trihydroquinolin-2-one, Example 86 (d), (66 mg, 0.30 mmol) provided, after purification by silica gel chromatography (10% MeOH/CH2CI2), the title compound. MS (ESI, pos. ion) m/z: 193 (M+1).
(f) (2E)-3- [4- (tert-Butyl) phenyl]-N- [3- (hydroxymethyl)-2-oxo (7-1, 3,4- trihydroquinolyl)] prop-2-enamide. Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (67 mg, 0.33 mmol, EMKA- Chemie) and 7-amino-3- (hydroxymethyl)-1, 3, 4-trihydroquinolin-2-one, Example 86 (e), (52 mg, 0.27 mmol) provided, after purification by silica gel chromatography (10% MeOH/EtOAc), the title compound as a pale yellow solid.
MP 201-203 °C. MS (ESI, pos. ion) m/z: 379 (M+1).
Example 87 (2E)-N- [3- (Hydroxymethyl) (7-1, 2,3, 4-tetrahydroquinolyl)]-3- [4- (trifluoromethyl)phenyl]prop-2-enamide.
(a) (7-Amino-3-1, 2,3, 4-tetrahydroquinolyl) methan-1-ol. Analogous to the procedure used to prepare Example 3, step (a), (7-nitro-3-1,2, 3,4- tetrahydroquinolyl) methan-1-ol, Example 86 (d), (140 mg, 0.68 mmol) provided, after purification by silica gel chromatography (10% MeOH/CH2Cl2), the title compound. MS (ESI, pos. ion) m/z: 179 (M+1).
(b) (2E)-N- [3- (Hydroxymethyl) (7-1, 2,3, 4-tetrahydroquinolyl)]-3- [4- (trifluoromethyl) phenyl] prop-2-enamide. Analogous to the procedure used to prepare Example 1, trans-4- (trifluoromethyl) cinnamic acid (120 mg, 0.55 mmol, Aldrich) and (7-amino-3-1, 2,3, 4-tetrahydroquinolyl) methan-1-ol, Example 87 (a), (98 mg, 0.55 mmol) provided, after purification by silica gel chromatography (10% MeOH/EtOAc), the title compound as a pale yellow solid. MP 176-179 °C.
MS (ESI, pos. ion) m/z: 377 (M+1).
Example 88 (2E)-N- [3- (hydroxymethyl)-l-methyl (7-1, 2,3, 4-tetrahydroquinolyl)]-3- [4- (trifluoromethyl) phenyl]prop-2-enamide A mixture of (2E)-N- [3- (hydroxymethyl) (7-1, 2,3, 4-tetrahydroquinolyl)]-3- [4- (trifluoromethyl) phenyl] prop-2-enamide, Example 87, (75 mg, 0.20 mmol), iodomethane (0.014 mL, 0.22 mmol, Aldrich) and NaHC03 (84 mg, 1.0 mmol) in
DMF (1.0 mL, Aldrich) was stirred for 4 h at room temperature. Water (5 mL) was added and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with water (5 mL), satd NaCI (SmL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (60% EtOAc/CH2CI2) provided the title product as a white solid.
MP 167-169 °C. MS (ESI, pos. ion) m/z: 391 (M+1).
Example 89
(2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-5- (1, 3- dioxolan-2-yl) pent-2-enamide.
Analogous to the procedure used to prepare Example 53 (a), (1, 3-dioxolan-2- ylethyl) zinc bromide (3.0 mL, 1.5 mmol, 0.5 M THF solution, Rieke) and N- (2H, 3H-benzo [e] 1, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyl]-3-iodoprop-2- enamide, Example 55, (0.23 g, 0.50 mmol) provided, after purification by silica gel chromatography (gradient: 30%-35% EtOAc/hexane), the title product as an amorphous white solid. MS (ESI, pos. ion) m/z : 438 (M+1).
Example 90 (2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-4- (3- pyridyl) but-2-enamide.
(a). 3- (Tributylstannanylmethyl) pyridine. Analogous to the procedure of Kaiser, E. M. and Petty, J. D. Synthesis 1975,705-706, to a 50 mL round- bottomed flask equipped with magnetic stirring was added lithium diisopropylamide (5.2 mL, 10 mmol, 2.0 M in heptane/THF/ethylbenzene, Aldrich) at 0 °C under nitrogen, followed by hexamethylphosphoramide (1.8 mL, 10 mmol, Aldrich). The mixture was stirred for 15 min, then treated with a solution of 3-picoline (1.0 mL, 10 mmol, Aldrich) in THF (4 mL) over 5 min. The reaction mixture was stirred for 30 min, then a solution of tributyltin chloride (2.8 mL, 10 mmol, Aldrich) in THF (6 mL) was added. The resulting solution was gradually warmed to room temperature and concentrated in vacuo. Purification by silica gel chromatography (gradient: 2%-5% EtOAc/hexane) provided the title product as a colorless oil. MS (ESI, pos. ion) m/z : 382 (M+1).
(b) (2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-4- (3- pyridyl) but-2-enamide. To a 50 mL round-bottomed flask, equipped with magnetic stirring, was added 3-(tributylstannanylmethyl) pyridine, Example 90 (a), (0.37 g, 0.97 mmol), N- (2H, 3H-benzo [e] 1, 4-dioxan-6-yl) (2Z)-3- [4- (tert- butyl) phenyl]-3-iodoprop-2-enamide, Example 55, (0.30 g, 0.65 mmol), 1- methyl-2-pyrrolidinone (2.5 mL, Aldrich), and tetrakis (triphenylphosphine)- palladium (0) (75 mg, 0.06 mmol, Aldrich). The reaction mixture was stirred at 110 °C overnight, then diluted with EtOAc (100 mL), washed with satd NaHC03, water and satd NaCI. The organic phase was dried over Na2SO4, filtered and
concentrated in vacuo. Purification by silica gel chromatography (25%-45% EtOAc/hexane) was followed by reverse phase preparative HPLC (CH3CN/H20 with 0. 1% TFA). The fractions containing desired product were neutralized with NaHC03. The mixture was extracted with CH2CI2 and the organic phase concentrated in vacuo to provide the title product as an amorphous white solid.
MS (ESI, pos. ion) mlz : 429 (M+1).
Example 91 N- (2H, 3H-Benzo [ell, 4-dioxan-6-yl) (2Z)-3- [4- (tert-butyl) phenyll-4- pyrrolidinylbut-2-enamide.
(a). Methyl (2E)-3- [4- (tert-butyl) phenyl] but-2-enoate. To a 100 mL round- bottomed flask purged with N2 was added 1-bromo-4-tert-butylbenzene (2.34 g, 11.0 mmol, Aldrich), methyl crotonate (1.08 mL, 10 mmol, Aldrich), N- methyldicyclohexylamine (3.31 mL, 15 mmol, Aldrich), palladium acetate (0.045 g, 0.20 mmol, Aldrich), tetraethylammonium chloride (1.66 g, 10.0 mmol, Fluka), and N, N-dimethylacetamide (40 mL, Aldrich). The reaction mixture was magnetically stirred at 100 °C overnight, then allowed to cool to 25 °C, diluted with EtzO, and filtered through Celite. The solution was washed with H20 (3 x), dried over MgS04, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0.5%-3% dichloromethane in hexane) provided the title product as a colorless oil. MS (ESI, pos. ion) milz : 233 (M+1).
(b) Methyl (2Z)-3- [4- (tert-butyl) phenyl]-4-pyrrolidinylbut-2-enoate. A solution of methyl (2E)-3- [4- (tert-butyl) phenyl] but-2-enoate, Example 91 (a), (0.37 g, 1.6 mmol) in CC14 (15 mL), magnetically stirred in a 50 mL round- bottomed flask under N2, was treated with N-bromosuccinimide (0.31 g, 1.75 mmol, Aldrich) and 2,2'-azobisisobutyronitrile (5 mg, 0.03 mmol, Aldrich).
The reaction mixture was magnetically stirred under reflux overnight, then allowed to cool to 25 °C. The solid was filtered. The filtrate was concentrated in vacuo to afford a yellow oil [MS (ESI, pos. ion) m/z : 311,313 (M+l, M+3) ]. To a solution of the yellow oil in THF (5 mL), was added pyrrolidine (0.16 mL, 1.9 mmol, Aldrich) and N, N-diisopropylethylamine (0.33 mL, 1.9 mmol, Aldrich).
The reaction mixture was magnetically stirred at room temperature overnight, then concentrated in vacuo. The residue was treated with water and extracted with dichloromethane (3 x). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford a yellow oil. Purification by silica gel chromatography (gradient: 4%-20% EtOAc/hexane) provided the title product as a pale yellow oil. MS (ESI, pos. ion) m/z : 302 (M+1).
(c). N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yi) (2Z)-3- [4- (tert-butyl) phenyl]-4- pyrrolidinylbut-2-enamide. To a 50 mL round-bottomed flask charged with methyl (2Z)-3- [4- (tert-butyl) phenyl]-4-pyrrolidinylbut-2-enoate, Example 91 (b), (188 mg, 0.62 mmol) was added THF (2 mL), MeOH (0.2 mL), H20 (1 mL), and lithium hydroxide monohydrate (54 mg, 1.25 mmol, Aldrich). The reaction mixture was magnetically stirred at room temperature overnight. The excess lithium hydroxide was removed by filtration. The mixture was purified by reverse phase preparative HPLC (CH3CN/H20 with 0. 1% TFA), concentrated in vacuo, then treated with an excess of HCl in Et20. Concentration in vacuo provided a pale yellow solid 0.15 g [MS (ESI, pos. ion) m/z : 288 (M+1)]. Analogous to the procedure used to prepare Example 1, the solid (77 mg) and 1, 4-benzodioxan-6- amine (61 mg, 0.40 mmol, Aldrich) provided the crude title product. Purification by silica gel chromatography (gradient: 1-5% MeOH in CH2CI2) was followed by reverse phase preparative HPLC (CH3CN/H20 with 0. 1% TFA). The fractions containing desired product were neutralized with NaHC03. The mixture was extracted with CH2Cl2 and the organic phase concentrated in vacuo to provide the title product as a pale yellow oil. MS (ESI, pos. ion) nilz : 421 (M+1).
Example 92
(2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-6- imidazolylhex-2-enamide.
(a). Ethyl (2E)-3- [4- (tert-butyl) phenyl]-5- (1, 3-dioxolan-2-yl) pent-2-enoate.
Analogous to the procedure used to prepare Example 53 (a), starting from (1,3- dioxolan-2-ylethyl) zinc bromide (0.5 M THF solution, 40 mL, 20mmol, Rieke) and ethyl (2Z)-3- [4- (tert-butyl) phenyl]-3-iodoprop-2-enoate, Example 52 (b), (3.58 g, 10.0 mmol), the title product was obtained as a colorless oil. MS (ESI, pos. ion) m/z : 333 (M+1).
(b). Ethyl (2E)-3- [4- (tert-butyl) phenyl]-6-oxohex-2-enoate. To a round- bottomed flask was added ethyl (2E)-3- [4- (tert-butyl) phenyl]-5- (1, 3-dioxolan-2- yl) pent-2-enoate, Example 92 (a), (2.7 g, 8.1 mmol), THF (3 mL), and 5 N HCI (12 mL). The reaction mixture was initially stirred at room temperature for 24 h,
then heated to 40 °C overnight. The pH was adjusted to-5-6 by the addition of NaHCO3 and the mixture was extracted with EtOAc. The combined organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (5% EtOAc/hexane) provided the title product as a white solid. MS (ESI, pos. ion) m/z : 289 (M+1).
(c). Ethyl (2E)-3- [4- (tert-butyl) phenyl]-6-hydroxyhex-2-enoate. To solution of ethyl (2E)-3- [4- (tert-butyl) phenyl] -6-oxohex-2-enoate, Example 92 (b), (1.5 g, 5.3 mmol) in MeOH (18 mL), magnetically stirred at 0°C in a 100 mL round- bottomed flask, was added sodium borohydride (0.40 g, 11 mmol, Aldrich). The mixture was allowed to gradually warm up to room temperature over 2 h, then quenched with water (20 mL) and extracted with EtOAc (4 x). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (15% EtOAc/hexane) provided the title product as a colorless oil in quantitative yield. MS (ESI, pos. ion) m/z : 291 (M+1).
(d). Ethyl (2E)-3- [4- (tert-butyl) phenyl]-6-iodohex-2-enoate. To a 100 mL round-bottomed flask charged with ethyl (2E)-3- [4- (tert-butyl) phenyl]-6- hydroxyhex-2-enoate, Example 92 (c), (0.80 g, 2.7 mmol) and CH2CI2 (10 mL) at room temperature, was added triphenylphosphine (0.87 g, 3.3 mmol, Aldrich), imidazole (0.22 g, 3.3 mmol, Aldrich), and 12 (1.2 g, 4.7 mmol, Aldrich). The reaction mixture was stirred for 2 h, filtered and concentrated in vacuo.
Purification by silica gel chromatography (3% EtOAc/hexane) provided the title product as a white semi-solid in quantitative yield. MS (ESI, pos. ion) m/z : 401 (M+1).
(e) Ethyl (2E)-3- [4- (tert-butyl) phenyl]-6-imidazolylhex-2-enoate. To a 100 mL round-bottomed flask charged with ethyl (2E)-3- [4- (tert-butyl) phenyl] -6- iodohex-2-enoate, Example 92 (d), (1. 1 g, 2.7 mmol), imidazole (0.20 g, 3.0 mmol, Aldrich), benzyltriethylammonium chloride (63 mg, 0.30 mmol, Aldrich), and CH2C12 (15 mL), stirred magnetically at room temperature, was added potassium hydroxide (50% aqueous solution, 1.5 mL). The reaction mixture was stirred at 50 °C overnight, then diluted with water. The reaction mixture was extracted with CH2CI2. The organic solution was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (50% EtOAc/hexane) provided the title product as a pale yellow oil. MS (ESI, pos. ion) m/z : 341 (M+1).
(f) (2E)-3- [4- (tert-Butyl) phenyl]-6-imidazolylhex-2-enoic acid. To a 50 mL round-bottomed flask equipped with a reflux condenser was added ethyl (2E) -3- [4- (tert-butyl) phenyl] -6-imidazolylhex-2-enoate, Example 92 (e), (0.35 g, 1.0 mmol), THF (6 mL) and KOH (50% aqueous solution, 1.5 mL). The reaction mixture was heated and magnetically stirred under reflux overnight, then concentrated in vacuo and acidified with glacial acetic acid to pH-4-5. The aqueous mixture was extracted with CH2CI2 and the organic phase was dried over
Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (5%-10% MeOH/CH2Cl2) provided the title product as a white solid. MS (ESI, pos. ion) m/z : 313 (M+1).
(g) (2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]-6- imidazolylhex-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3- [4- (tert-butyl) phenyl]-6-imidazolylhex-2-enoic acid, Example 92 (f), (76 mg, 0.24 mmol) and 1, 4-benzodioxan-6-amine (36 mg, 0.24 mmol, Aldrich) provided, after purification by silica gel chromatography (3%-5% MeOH/CH2CI2), the title product as an amorphous off-white solid. MS (ESI, pos. ion) m/z : 446 (M+1).
Example 93
3- (4-tert-Butyl-phenyl)-6-imidazot-1-yl-hex-2-enoic acid benzothiazol-6- ylamide. Analogous to the procedure used to prepare Example 1, (2E)-3- [4- (tert- butyl) phenyl]-6-imidazolylhex-2-enoic acid, Example 92 (f), (76 mg, 0.24 mmol) and 6-aminobenzothiazole (36 mg, 0.24 mmol, Lancaster) provided, after purification by silica gel chromatography (3%-5% MeOH/CFC), the title compound as a white solid. MS (ESI, pos. ion) m/z : 445 (M+1).
Example 94 (2E)-N- (2H, 3H-benzo [e] 1, 4-dioxan-6-yl)-3-[2-morpholin-4-yl-6- (trifluoromethyl) (3-pyridyl)] prop-2-enamide.
(a) 2-Morpholin-4-yl-6- (trifluoromethyl) pyridine-3-carboxylic acid. To a round-bottomed flask was added 2-chloro-6-trifluoromethylnicotinic acid (2.0 g, 8.9 mmol, Matrix) and morpholine (5.0 g, 57 mmol, Aldrich). The reaction mixture was magnetically stirred at 25 °C for 48 h, then diluted with 1 N HCl (100 mL) and extracted with EtOAc (100 mL). The aqueous phase was saturated with NaCI and extracted again with EtOAc (50 mL). The combined EtOAc extracts were washed with 1 N HCI (50 mL), satd NaCI (50 mL), dried over MgS04, filtered and concentrated in vacuo to afford the title product as an off-white waxy solid. MS (ESI, pos. ion) m/z: 277 (M+1).
(b) [2-Morpholin-4-yl-6-(trifluoromethyl)-3-pyridyl] methan-1-ol. A solution of 2-morpholin-4-yl-6-(trifluoromethyl) pyridine-3-carboxylic acid, Example 94 (a), (2.1 g, 7.6 mmol) in anhydrous TUF (20 mL) was treated dropwise with lithium aluminum hydride (15 mL, 15 mmol, 1.0 M in THF, Aldrich) with stirring under N2 at 25 °C. The reaction mixture was stirred at 25 °C for 1.5 h, then quenched by the dropwise addition of a 10% aqueous solution of Rocelle salt
(50 mL, potassium sodium tartrate, Aldrich). EtOAc (50 mL) was added and the bi-phasic mixture stirred vigorously for 2 h at 25 °C. The mixture was diluted with water (100 mL) and the phases separated. The aqueous phase was extracted with EtOAc (2 x 75 mL), the organic phases were combined and washed with 1 N NaOH (2 x 75 mL), satd NaCI (75 mL), dried over MgS04, filtered and concentrated in vacuo to afford the title product as a viscous yellow oil. MS (ESI, pos. ion) m/z: 263 (M+1).
(c) 2-Morpholin-4-yl-6- (trifluoromethyl) pyridine-3-carbaldehyde. A solution of oxalyl chloride (3.6 mL, 7.2 mmol, 2.0 M in CH2CI2, Aldrich) in anhydrous CH2CI2 (20 mL) was magnetically stirred under N2, in an oven-dried round- bottomed flask, at-60 °C. The solution was treated dropwise with methyl sulfoxide (1.1 mL, 15 mmol, Aldrich) then stirred for 10 min. A solution of [2- morpholin-4-yl-6-(trifluoromethyl)-3-pyridyl] methan-1-ol, Example 94 (b), (1.7 g, 6.5 mmol) in anhydrous CH2CI2 (20 mL) was added via cannula, and the reaction mixture stirred at-60 °C for 15 min. Triethylamine (4.5 mL, 32 mmol, Aldrich) was added, the cooling bath was removed, and the reaction mixture allowed to warm to 25 °C and stirred at that temperature for 1 h. The mixture was washed with water (30 mL) and the aqueous wash was back-extracted with CH2CI2 (2 x 20 mL). The combined organic phase was washed with water (30 mL), satd NaCI (30 mL), dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel chromatography (9: 1 hexane: EtOAc) provided the title product as a viscous yellow oil. MS (ESI, pos. ion) m/z: 261 (M+1).
(d) (2E)-3- [2-Morpholin-4-yl-6- (trifluoromethyl) (3-pyridyl)] prop-2-enoic acid. Analogous to the procedure described for Example 40, step (a), 2- morpholin-4-yl-6-(trifluoromethyl) pyridine-3-carbaldehyde, Example 94 (c), (1.2 g, 4.6 mmol) provided the title product as a yellow solid. MS (ESI, pos. ion) m/z : 303 (M+1).
(e) (2E)-N- (2H, 3H-benzo [e] 1, 4-dioxan-6-yl)-3-[2-morpholin-4-yl-6- (trifluoromethyl) (3-pyridyl) ] prop-2-enamide. (2E)-3- [2-Morpholin-4-yl-6- (trifluoromethyl) (3-pyridyl)] prop-2-enoic acid, Example 94 (d), (200 mg, 0.66 mmol) was dissolved in anhydrous CH2Cl2 (10 mL) and treated with oxalyl chloride (0.36 mL, 0.72 mmol, 2.0 M in CH2CI2, Aldrich) and anhydrous DMF (2 uL). The reaction mixture was stirred at reflux for 30 min, then concentrated in vacuo. The residue was dissolved in anhydrous CH2CI2 (10 mL), treated with pyridine (0.27 mL, 3.5 mmol, Aldrich) and 1, 4-benzodioxan-6-amine (120 mg, 0.79 mmol, Aldrich) and stirred at reflux for 15 min. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (75 mL). The mixture was washed with 1 N HCI (2 x 50 mL), 1 N NaOH (50 mL), water (50 mL), satd NaCI (50 mL), dried over MgS04, filtered and concentrated in vacuo.
Recrystallization from EtOAc and hexane provided the title product as pale tan crystals. MP 200-201 °C. MS (ESI, pos. ion) m/z: 436 (M+1).
Example 95 (2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl)-2- bromophenyl] prop-2-enamide.
(a) 4-(tert-Butyl)-2-bromo-1-(bromomethyl) benzene. According to the procedure of Kikuchi, D. et al, J. Org. Chem. 1998, 63, 6023-6026, to a solution of sodium bromate (22 g, 145 mmol, Aldrich) in water (75 mL), magnetically stirred in an Erlenmeyer flask at 25 °C, was added a solution of 4-t-butyltoluene (5.0 mL, 29 mmol, Aldrich) in acetonitrile (60 mL). The bi-phasic mixture was vigorously stirred while a solution of sodium bisulfite (15 g, 145 mmol, Baker) in water (150 mL) was added dropwise, via addition funnel, over 20 min. The reaction mixture was stirred for 6 h, then extracted with Et20 (300 mL). The organic phase was washed with satd aq. Na2S203 (2 x 100 mL), satd NaCI (50 mL), dried over MgS04, filtered and concentrated in vacuo to afford of the title product as a pale orange oil.
(b) 4- (tert-Butyl)-2-bromobenzaldehyde. According to the procedure of Mallory, et al, Tetrahedron 2001, 57,3715-3724, a solution of sodium ethoxide (12 mL, 32 mmol, 21% in EtOH, Aldrich) in absolute EtOH (100 mL) was magnetically stirred under N2 at 25 °C and treated with 2-nitropropane (2.9 mL, 32 mmol, Aldrich) followed by 4- (tert-butyl)-2-bromo-1- (bromomethyl) benzene, Example 95 (a), (9.0 g, 29 mmol). The reaction mixture was stirred at 25 °C for 5 h, then concentrated in vacuo to an orange solid. The solid was partitioned between Et20 (150 mL) and water (100 mL). The layers were separated and the organic phase was washed with water (100 mL), 1 N NaOH (2 x 75 mL), satd NaCI (50 mL), dried over MgS04, filtered and concentrated in vacuo to afford the title product as an orange oil.
(c) (2E)-3- [4- (tert-Butyl)-2-bromophenyl] prop-2-enoic acid. Analogous to the procedure described for Example 40, step (a), 4- (tert-butyl)-2- bromobenzaldehyde, Example 95 (b), (6.5 g, 27 mmol) provided the title product as a white solid. MS (ESI, pos. ion) m/z: 283,285 (M, M+2).
(d) (2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl)-2- bromophenyl] prop-2-enamide. Analogous to the procedure described for Example 94, step (e), (2E)-3- [4- (tert-butyl)-2-bromophenyl] prop-2-enoic acid, Example 95 (c), (3.0 g, 11 mmol) and 1, 4-benzodioxan-6-amine (1.9 g, 13 mmol, Aldrich) provided, after recrystallization from CH2CI2 and hexane, the title product as off-white crystals. MP 206-210 °C. MS (ESI, pos. ion) m/z : 416, 418 (M, M+2).
Example 96 Ethyl 2-[(lE)-2-(N-(2H, 3H-benzo [e] 1, 4-dioxan-6-yl) carbamoyl) vinyl]-5- (tert- butyl) benzoate.
According to the procedure of Ma, et al, J. Org. Chem. 1999, 64, 120-125, a solution of (2E)-N- (2H, 3H-benzo [e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl)-2- bromophenyl] prop-2-enamide, Example 95, (200 mg, 0.48 mmol) in anhydrous EtOH (5 mL) and methyl sulfoxide (5 mL) was treated with triethylamine (0.67 mL, 0.48 mmol, Aldrich) and 1, 3-bis (diphenylphosphino) propane (50 mg, 0.12 mmol, Aldrich). The mixture was purged with a stream of carbon monoxide, then treated with palladium acetate (22 mg, 0.10 mmol, Aldrich), and stirred
under a balloon of carbon monoxide in a 70 °C oil bath for 3 h. The reaction mixture was allowed to cool to 25 °C and partitioned between EtOAc (50 mL) and water (20 mL). The organic phase was washed with water (10 mL), satd NaCI (10 mL), dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel chromatography (step gradient, 4: 1 then 3: 1, hexane: EtOAc), followed by recrystallization from EtOAc and hexane, provided the title product as white crystals. MP 155 °C. MS (ESI, pos. ion) m/z: 410 (M+1).
Example 97 (2E)-3-[2-Bromo-4-(trifluoromethyl) phenyl]-N-indol-5-ylprop-2-enamide.
(a) 2-Bromo-4- (trifluoromethyl) benzoic acid. To a solution of 2-brom-1- methyl-4-trifluoromethylbenzene (7.6 g, 32 mmol, ABCR) in pyridine (75 mL) was added tetraethylammonium permanganate (24 g, 96 mmol, prepared according to the procedure of Sala, et al. J. Chem. Soc., Chem. Comm. 1978,253).
The reaction mixture was warmed to 70 °C and stirred at that temperature for 30 h. The reaction mixture was allowed to cool to 25 °C and poured into an ice bath containing cond HO (150 mL) and NaHS03 (150 g). The mixture turned to a clear aqueous solution and was extracted with EtOAc (4 x 200 mL). The combined extracts were washed with satd NaCI (200 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide the title product as a white solid.
MS (ESI, neg. ion) m/z : 267 (M-1). (b) [2-Bromo-4-(trifluoromethyl) phenyl] methan-1-ol. Analogous to the procedure used to prepare Example 46, step (a), 2-bromo-4- (trifluoromethyl) benzoic acid, Example 97 (a), (5.4 g, 20 mmol) provided, after purificaton by silica gel chromatography (gradient: 0-10% EtOAc in hexane), the title product as a white solid. MS (ESI, neg. ion) m/z : 313 (M+acetate).
(c) 2-Bromo-4-(trifluoromethyl) benzaldehyde. Analogous to the procedure used to prepare Example 46, step (b), [2-bromo-4- (trifluoromethyl) phenyl] methan-1-ol, Example 97 (b), (4.6 g, 18 mmol) provided, after purificaton by silica gel chromatography (gradient: 0-4% EtOAc in hexane), the title product as a colorless oil.
(d) Methyl (2E)-3-[2-bromo-4-(trifluoromethyl) phenyl] prop-2-enoate.
Analogous to the procedure used to prepare Example 46, step (c), 2-bromo-4- (trifluoromethyl) benzaldehyde, Example 97 (c), (2.3 g, 8.9 mmol) and carbomethoxymethylene triphenylphosphorane (4.2 g, 12.5 mmol, Aldrich) provided, after purificaton by silica gel chromatography (gradient: 0-3% EtOAc in hexane), the title product as a white solid.
(e) (2E)-3-[2-Bromo-4-(trifluoromethyl) phenyl] prop-2-enoicacid. Analogous to the procedure used to prepare Example 46, step (d), methyl (2E)-3- [2-bromo- 4-(trifluoromethyl) phenyl] prop-2-enoate, Example 97 (d), (2.25 g, 8.9 mmol) provided the title product.
(f) (2E)-3-[2-Bromo-4-(trifluoromethyl) phenyl]-N-indol-5-ylprop-2-enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3- [2-bromo-4- (trifluoromethyl) phenyl] prop-2-enoic acid, Example 97 (e), (140 mg, 0.48 mmol) and 5-aminoindole (75 mg, 0.57 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-25% EtOAc in hexane), the title compound as a yellow solid. MP 205-207 °C. MS (ESI, pos. ion) m/z : 409 (M+1).
Example 98
(2E)-N-Benzothiazol-6-yl-3-[2-bromo-4-(trifluoromethyl) phenyl] prop-2- enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3- [2-bromo-4- (trifluoromethyl) phenyl] prop-2-enoic acid, Example 97 (e), (140 mg, 0.47 mmol) and 6-aminobenzothiazole (86 mg, 0.57 mmol, Lancaster) provided, after purification by silica gel chromatography (gradient: 0-30 % EtOAc in hexane), the title product as an off-white solid. MP 214-215 °C. MS (ESI, pos. ion) m/z : 427 (M+1).
Example 99 (2E)-N- (2H, 3H-Benzo [e] 1, 4-dioxan-6-yl)-3- [2-bromo-4- (trifluoromethyl)- phenyl] prop-2-enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3- [2-bromo-4- (trifluoromethyl) phenyl] prop-2-enoic acid, Example 97 (e), (140 mg, 0.47 mmol) and 1, 4-benzodioxan-6-amine (86 mg, 0.57 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-18 % EtOAc in hexane), the title product as an off-white solid. MP 212-213 °C. MS (ESI, pos. ion) dz : 428 (M+1).
Example 100
(2E)-N-indol-5-yl-3-[2-(6-methoxy (3-pyridyl))-4-(trifluoromethyl) phenyl]-<BR> <BR> <BR> <BR> <BR> <BR> <BR> prop-2-enamide.
A mixture of (2E)-3- [2-bromo-4- (trifluoromethyl) phenyl]-N-indol-5-ylprop-2- enamide, Example 97, (100 mg, 0.24 mmol), 2-methoxy-5-pyridineboronic acid (60 mg, 0.39 mmol, Digital Specialty Chemicals), tris (dibenzylideneacetone)- dipalladium (0) (22 mg, 0.024 mmol, Aldrich) and triphenylphosphine (26 mg, 0.098 mmol, Aldrich) in toluene (1.2 mL), 2. 0M aqueous Na2CO3 (0.4 mL) and ethanol (0.4 mL) was stirred at 120 °C overnight. The reaction mixture was filtered through a pad of Celite and diluted with water (50 mL). The aqueous phase was extracted with EtOAc (3 x 60 mL). The combined extracts were washed with satd NaCI (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-20% EtOAc in hexane) provided the title product as a yellow solid. MP 219-221 °C. MS (ESI, pos. ion) m/z : 438 (M+1).
Example 101 (2E)-N-Indol-5-yl-3- [2- (4-pyridyl)-4- (trifluoromethyl) phenyl] prop-2- enamide.
Analogous to the procedure used to prepare Example 100, (2E)-3- [2-bromo-4- (trifluoromethyl) phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (120 mg, 0.29 mmol) and pyridine-4-boronic acid (72 mg, 0.59 mmol, Frontier Scientific) provided, after purification by silica gel chromatography (gradient: 0-60 % EtOAc in hexane), the title product as a yellow solid. MP 229-234 °C. MS (ESI, pos. ion) m/z : 408 (M+1).
Example 102
(2E)-N-Indol-5-yl-3- [2- (3-pyridyl)-4- (trifluoromethyl) phenyl] prop-2- enamide.
Analogous to the procedure used to prepare Example 100, (2E)-3- [2-bromo-4- (trifluoromethyl) phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (120 mg, 0.29 mmol) and pyridine-3-boronic acid (58 mg, 0.47 mmol, Frontier Scientific) provided, after purification by silica gel chromatography (gradient: 0-20 % EtOAc in hexane), the title product as a yellow solid. MP 196-197 °C. MS (ESI, pos. ion) m/z : 408 (M+1).
Example 103 tert-Butyl 4-{2-[(lE)-2-(N-indol-5-ylcarbamoyl) vinyl]-5- (trifluoromethyl) phenyl}-1, 2,5, 6-tetrahydropyridinecarboxylate.
Analogous to the procedure used to prepare Example 100, (2E)-3- [2-bromo-4- (trifluoromethyl) phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (100 mg, 0.24 mmol) and 4- (4, 4,5, 5-tetramethyl- [1, 3,2] dioxaborolan-2-yl)-3, 6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (130 mg, 0.42 mmol, prepared according to the procedures of Wustrow, D. J. et al, Synthesis 1991,993 and Ishiyama, T. et al, J. Org. Chem. 1995, 60, 7508) provided, after purification by silica gel chromatography (gradient: 0-35 % EtOAc in hexane), the title product as an amorphous yellow solid. MS (ESI, pos. ion) m/z : 512 (M+1).
Example 104
(2E)-N-Indol-5-yl-3- [2- (1, 3-thiazol-2-yl)-4- (trifluoromethyl) phenyl] prop-2- enamide.
Analogous to the procedure used to prepare Example 100, (2E)-3- [2-bromo-4- (trifluoromethyl) phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (100 mg, 0.24 mmol) and 2-tributylstannylthiazole (155 mg, 0.42 mmol, Frontier Scientific) provided, after purification by silica gel chromatography (gradient: 0-35 % EtOAc in hexane), the title product as an orange solid. MP 203-204 °C. MS (ESI, pos. ion) m/z : 414 (M+1).
Example 105 (2E)-N-Indol-5-yl-3- [2- (3-pyridylmethyl)-4- (trifluoromethyl) phenyl] prop-2- enamide.
A mixture of (2E)-3- [2-bromo-4- (trifluoromethyl) phenyl]-N-indol-5-ylprop-2- enamide, Example 97, (110 mg, 0.27 mmol), 3- (tributylstannanylmethyl) pyridine, Example 90 (a), (160 mg, 0.43 mmol), tris (dibenzylideneacetone) dipalladium (0) (24 mg, 0.027 mmol, Aldrich) and triphenylphosphine (28 mg, 0.11 mmol, Aldrich) in 1-methyl-2-pyrrolidinone (1.5 mL) was stirred at 100 °C overnight. The reaction mixture was filtered through a pad of Celite and diluted with water (50 mL). The aqueous phase was extracted with EtOAc (3 x 60 mL). The combined organic extracts were washed with satd NaCI (100 mL), dried over Na2SO4, filtered and concentrated in vacuo.
Purification by silica gel chromatography (gradient: 0-70 % EtOAc in hexane) provided the title compound as an orange solid. MP 202-203 °C. MS (ESI, neg. ion) m/z : 420 (M-1).
Example 106
(2E)-3- [2- (3-Pyridyl)-4- (trifluoromethyl) phenyl]-N- (7-quinolyl) prop-2- enamide.
(a) Methyl (2E)-3- [2- (3-pyridyl)-4- (trifluoromethyl) phenyl] prop-2-enoate. A mixture of methyl (2E)-3- [2-bromo-4- (trifluoromethyl) phenyl] prop-2-enoate, Example 97 (d), (585 mg, 1.89 mmol), pyridine-3-boronic acid (950 mg, 2.8 mmol, Frontier Scientific), tris (dibenzylideneacetone) dipalladium (0) (170 mg, 0.19 mmol, Aldrich) and triphenylphosphine (200 mg, 0.76 mmol, Aldrich) in toluene (5 mL), 1.0 M aqueous Na2CO3 (2 mL) and ethanol (2 mL) was stirred at 80 °C under N2 overnight. The reaction mixture was filtered through a pad of Celite and diluted with water (60 mL). The aqueous phase was extracted with EtOAc (3 x 60 mL). The combined organic extracts were washed with satd NaCI (100 mL), dried over Na2SO4, filtered and concentrated in vacuo.
Purification by silica gel chromatography (gradient: 0-35% EtOAc in hexane) provided the title product as a yellow solid. MS (ESI, pos. ion) zn/z : 308 (M+1).
(b) (2E)-3- [2- (3-Pyridyl)-4- (trifluoromethyl) phenyl] prop-2-enoic acid. A mixture of methyl (2E)-3- [2- (3-pyridyl)-4- (trifluoromethyl) phenyl] prop-2-enoate,
Example 106 (a), (540 mg, 1.8 mmol) and Li OH monohydrate (370 mg, 8.8 mmol) in wet ethanol (5 mL) was stirred at room temperature overnight. The reaction mixture was neutralized with aqueous HCI (2.0 M, 4.4 mL, 8.8 mmol) and concentrated under reduced pressure. The material was dried under vacuum at 60 °C for 4 h to provide 955 mg of the crude material, which contained LiCl as a byproduct. MS (ESI, pos. ion)/ : 294 (M+1).
(c) (2E)-3- [2- (3-Pyridyl)-4- (trifluoromethyl) phenyl]-N- (7-quinolyl) prop-2- enamide. Analogous to the procedure used to prepare Example 1, (2E)-3- [2- (3- pyridyl)-4- (trifluoromethyl) phenyl] prop-2-enoic acid, Example 106 (b), (185 mg) and 7-aminoquinoline (64 mg, 0.44 mmol, Specs) provided, after purification by silica gel chromatography (gradient: 0-75% EtOAc in hexane), the title compound as an amorphous off-white solid. MS (ESI, pos. ion) m/z : 420 (M+1).
Example 107 (2E)-3- [2- (3-Pyridyl)-4- (trifluoromethyl) phenyl]-N- (3-quinolyl) prop-2- enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3- [2- (3-pyridyl)-4- (trifluoromethyl) phenyl] prop-2-enoic acid, Example 106 (b), (185 mg) and 3- aminoquinoline (64 mg, 0.44 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-45% EtOAc in hexane), the title compound as a white solid. MP 196-199 °C. MS (ESI, pos. ion) m/z : 420 (M+1).
Example 108
(2E)-N-Indol-6-yl-3- [2- (3-pyridyl)-4- (trifluoromethyl) phenyl] prop-2- enamide.
Analogous to the procedure used to prepare Example 1, (2E)-3- [2- (3-pyridyl)-4- (trifluoromethyl) phenyl] prop-2-enoic acid, Example 106 (b), (185 mg) and 6- aminoindole (59 mg, 0.44 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-50% EtOAc in hexane), the title compound as an amorphous orange solid. MS (ESI, pos. ion) m/z : 408 (M+1).
Example 109 N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl] propanamide.
(a) (2E)-N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3- [4- (tert-butyl) phenyl]- prop-2-enamide. A solution of 4-t-butyl-trans-cinnamic acid (500 mg, 2.45 mmol, EMKA-Chemie) in anhydrous CH2CI2 (10 mL) was magnetically stirred and treated with oxalyl chloride (0.22 mL, 2.5 mmol, Aldrich) and DMF (0.005 mL). The reaction mixture was stirred at reflux for 30 min, then concentrated in vacuo. The residue was dissolved in acetone (1 mL) and added to a mixture of 1, 4-benzodioxan-6-amine (370 mg, 2.45 mmol, Aldrich) and K2CO3 (500 mg) in acetone (2 mL) and water (4 mL), stirred at 0 °C. The reaction mixture was vigorously stirred at 0 °C for 30 min, then diluted with ice water (50 mL). The resulting solid precipitate was collected by filtration and dissolved
in CH2CI2 (20 mL) and Et20 (150 mL). The organic solution was washed with 1 N HCI (3 x 75 mL), satd NaCI (50 mL), dried over MgS04, filtered and concentrated to afford the title product as an off-white foam. MS (ESI, pos. ion) m/z: 338 (M+1).
(b) N- (2H, 3H-Benzo [3,4-e] 1, 4-dioxan-6-yl)-3- [4- (tert- <butyl)phenyl]propanamide. (2E)-N-(2H, 3H-Benzo [3, 4-e]1,4-dioxan-6-yl)-3-14- (tert-butyl) phenyl] prop-2-enamide, Example 109 (a), (200 mg, 0.59 mmol) was dissolved in EtOH (25 mL), purged with N2, treated with 10% Pd on carbon (50 mg, Aldrich) then purged with H2 and the suspension stirred at 25 °C, under 1 atm H2, for 16 hr. The suspension was purged with N2, filtered through a pad of Celite, and concentrated in vacuo to a white foam. Purification by silica gel chromatography (45: 45: 10 hexane: CH2CI2 : EtOAc) provided the title product as a clear glass. MS (ESI, pos. ion) m/z : 340 (M+1).
General Scheme I R1_M R3 M = B (OH) 2, SnBu3, R3 ZnCI, BF3-, MgBr Br Rr58N transition metal R15J+N R16 coupling R16 oxidation R4-NCO, DMF, 150 °C R3 Rs Rs bromi at o3 15 Nt bromination 15 N R-NH2 Rl N, R4 115 N R1sX O-46 aminoarylation R1sJiN R16 R R3 R R3 R3 Chichibabin R NH2 I R 15 N Reaction R15 aminoarylation . Dl6 R16 R16 1. diazotization 2. dehydrohalogenation R3 R3 Br I NH2 Ri gr a transition metal I R-NH2 coupling R15 N aminoarylation R R16 R3 R3 H R3 P-O N. R4 HO N_ . Tf20, CH2CI2 deprotection R4 s N--- 2. Ri-M R16 R'5 R16 transition metal coupling Ris Ris R4-NH2 aminoarylation R3 R3 dehydro-PW, O '* halogenation Rl* Ris P = ArylCH2- General Scheme II Br R'-B (OH) 2 R'CH3ReO3 Ri \ H202, CH2CI2 N ; _ Pd (PPh3) 4, Na2CO3 (aq.), 1, 2-dimethoxyethane reflux, 16 h 4 H Ph3P, Br2, CH2CI2 ; R R4-NH2 Rt, NsR4 NEt3 N Pd (OAc) 2, BINAP NaOf-Bu, toluene 90 °C Example 110
(a) 4- [4- (tert-Butyl) phenyl] pyridine.
To 4-bromopyridine hydrochloride (Aldrich) (8.9 g, 46 mmol) and tetrakis (triphenylphosphine) palladium (0) (Aldrich) (1.6 g, 1.4 mmol) was added 1,2-dimethoxyethane (250 mL) with stirring under nitrogen. After 20 min, a solution of Na2CO3 (9.7 g in 70 mL of water) and 4-tert-butylbenzeneboronic acid (9.8 g, 55 mmol) were added sequentially to the mixture. The reaction was stirred at reflux overnight. The reaction mixture was concentrated in vacuo to approximately 1/3 its original volume, and the mixture was extracted with EtOAc (2 x 100 mL). The combined EtOAc layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography (1: 5 EtOAc/hexanes) gave the title compound as a white solid. MS (ESI, pos. ion) m/z : 212 (M+1).
(b) 4- [4- (tert-Butyl) phenyl] pyridine 1-oxide.
To the mixture of 4- [4- (tert-butyl) phenyl] pyridine (8.7 g, 41 mmol) and methyltrioxorhenium (VII) (Aldrich) (170 mg, 0.7 mmol) in a 100-mL round-
bottomed flask was added CH2CI2 (18 mL). The mixture was then treated with 12 mL of hydrogen peroxide (Aldrich) dropwise. The reaction was stirred at room temperature under nitrogen overnight. Methylene chloride and brine were then added, and the aqueous layer was extracted with CH2CI2 (40 mL). The organic layer was dried over Na2SO4, concentrated in vacuo to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z : 228 (M+1).
(c) 4- [4- (tert-Butyl) phenyl]-2-bromopyridine.
To triphenylphosphine (Aldrich) (2.4 g, 9.1 mmol) dissolved in 10 mL of CH2CI2 in a 50-mL round-bottomed flask was added bromine (Aldrich) (0.43 mL, 8.5 mmol). After stirring at 0° C for 10 min, 4- [4- (tert-butyl) phenyl] pyridine 1- oxide (1.5 g, 6.5 mmol) was added dropwise, followed by Et3N (1.2 mL, 8.5 mmol). The reaction mixture was stirred at 0° C for 1 h and then at room temperature overnight. Methylene chloride and brine were added, and the aqueous layer was extracted with CH2CI2. The organic layer was collected and dried over Na2SO4, filtered and concentrated in vacuo. Following purification by silica gel chromatography (10: 1 hexane: EtOAc), the title compound was obtained as a pale yellow oil. MS (ESI, pos. ion) m/z : 293 (M+1).
(d) 2H, 3H-Benzo [e] 1, 4-dioxan-6-yl {4- [4- (tert-butyl) phenyl] (2- pyridyl)} amine.
To an oven-dried 50-mL round-bottomed flask were added 4- [4- (tert- butyl) phenyl] -2-bromopyridine (180 mg, 0.63 mmol) and 1, 4-benzodioxan-6- amine (Aldrich) (191 mg, 1.3 mmol), followed by anhydrous toluene (60 mL) and DMF (6 mL). Nitrogen was bubbled through the above solution via a needle for 1 h. Then palladium acetate (Aldrich) (21 mg, 0.01 mmol) and BINAP (Aldrich)
(59 mg, 0.01 mmol) were introduced to the reaction followed by sodium tert- butoxide (Aldrich) (170 mg, 1.8 mmol). The reaction mixture was heated in a 90 C oil bath overnight. After cooling to room temperature, the reaction mixture was dissolved in ether, washed with brine, dried over Na2SO4 and concentrated in vacuo. Following purification by silica gel chromatography (3: 1 hexane: EtOAc), the title compound was obtained as a pale tan solid. MS (ESI, pos. ion) m/z : 361 (M+1). MP: 162-163°C.
Table A. The following compounds were prepared according to General Schemes I and II: MS Melting Example Structure (ESI, pos. ion) Point'C < 111 N 303 (M+1) 157 N N 112 H 333 (M+1) amorphous N , N N 0 347 (M+l) 156 w w I N I H 114 N CH3 331 (M+l) 133 ZIZI L/na MS Melting Example Structure (ESI, pos. ion) Poins'C wiz H 115 X, N°CH3 393 (M+l) amorphous N OCH3 OCH3 / 342 (M+1) 106 N H / N s 360 (M+l) 154 N N 118 N N 354 (M+1) 214 F3C/ H 119 X N C s> 372 (M+ 1) 203 Ion/ N C N Foc 120 N N 366 (M+1) 206 Zizi N FOC 121 N 0 373 (M+I) 114 N 0 MS Melting Example Structure (ESI, pos. ion) Point'C niez Buzz H 383, 385 122 N 0 124 N (M, M+2) FOC F3C, 123 N N ? (M +1) N Example 124
(a) N2- (2, 3-Dihydro-benzo [1, 4] dioxin-6-yl)-pyridine-2, 4-diamine.
In a 5-mL vial was added 4-amino-2-chloropyridine (Aldrich Chemical Company) (1.1 g, 8.7 mmol), 1, 4-benzodioxane-6-amine (Aldrich Chemical Company) (5.3 g, 35 mmol) and copper (I) iodide (Aldrich Chemical Company) (0.17 g, 0.87 mmol). The content was sonicated at room temperature for 5min and then heated in the Smith Microwave Synthesizer at 200 °C for 10 min. The residue was purified by flash chromatography (95: 5 dichloromethane: 2N NH3 in MeOH) to give the title compound as a dark solid. MS (ESI, pos. ion) m/z : 244 (M+1).
(b) (2,3-Dihydro-benzo [1, 4] dioxin-6-yl)- (4-iodo-pyridin-2-yl)-amine.
Isopentyl nitrile (Aldrich Chemical Company) (3.9 mL, 29 mmol) was added to a mixture of N2- (2, 3-dihydro-benzo [1, 4] dioxin-6-yl)-pyridine-2, 4-diamine (Example 2 (a), 2.4 g, 9.8 mmol), potassium iodide (Aldrich Chemical Company) (1.6 g, 9.8 mmol), iodine (Aldrich Chemical Company) (1.2 g, 4.9 mmol) and copper (I) iodide (Aldrich Chemical Company) (1.9 g, 9.8 mmol) in 1,2- dimethoxyethane (60 mL). The reaction mixture was heated at 60-65 °C for lhr.
After cooling to room temperature, the insoluble materials were removed by filtration and the filtrate was diluted with EtOAc, washed with 25% aqueous NH40H, 5% aqueous sodium bisulfite and then brine. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified on a Biotage 40 M column (2.5 : 1 hexane: EtOAc) to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z : 355 (M+1).
(c) (4-Benzo [1, 3] dioxol-5-yl-pyridin-2-yl)- (2, 3-dihydro-benzo [1, 4] dioxin-6-yl)- amine.
In a 5 mL vial were added (2,3-dihydro-benzo [1, 4] dioxin-6-yl)- (4-iodo-pyridin-2- yl)-amine (Example 2 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol) and 1,2- dimethoxyethane (2 mL). After stirring under nitrogen for 10 min, aqueous Na2CO3 (22 mg in 0.5 mL of water) and 3, 4- (methylenedioxy) phenylboronic acid (Aldrich Chemical Company) (42 mg, 0.25 mmol) were introduced. The reaction was heated in the Smith Microwave Synthesizer at 150 °C for 10 min. The residue was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined EtOAc layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification on a Biotage 40 S column (4: 1 hexane: EtOAc) gave the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z : 349 (M+1). Mp: 116.0-118. 0 °C.
Example 125
(2,3-Dihydro-benzo [1, 4] dioxin-6-yi)- [4- (4-dimethylamino-phenyl)-pyridin-2- yl]-amine.
Following the same procedure described for Example 401 (c), the mixture of (2,3- dihydro-benzo [1, 4] dioxin-6-yl)- (4-iodo-pyridin-2-yl)-amine (Example 401 (b),
75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), N, N-dimethylaminobenzeneboronic acid (Aldrich Chemical Company) (41 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150 °C for 10 min and purification on a Biotage 40S column (1.5 : 1 hexane: EtOAc), the title compound as a tan solid. MS (ESI, pos. ion) m/z : 348 (M+1). Mp: 154.0-155. 5 °C.
Example 126
(2,3-Dihydro-benzo [1, 4] dioxin-6-yl)- [4- (4-fluoro-phenyl)-pyridin-2-yl]-amine.
Following the same procedure described for Example 401 (c), the mixture of (2,3- dihydro-benzo [1, 4] dioxin-6-yl)- (4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 4-fluorobenzeneboronic acid (Avocado Chemical Company) (35 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150 °C for 10 min and purification on a Biotage 40S column (3: 1 hexane: EtOAc), the title compound as an off-white solid. MS (ESI, pos. ion) m/z : 323 (M+1). Mp: 134.5-135. 0 °C.
Example 127
(2,3-Dihydro-benzo [1, 4] dioxin-6-yl)- [4- (3-trifluoromethyl-phenyl)-pyridin-2- yl]-amine.
Following the same procedure described for Example 401 (c), the mixture of (2,3- dihydro-benzo [1, 4] dioxin-6-yl)- (4-iodo-pyiidin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 3- (trifluoromethyl) phenylboronic acid (Aldrich Chemical Company) (47 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150 °C for 10 min and purification on a Biotage 40S column (4: 1 hexane: EtOAc), the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z : 373 (M+1). Mp: 138.9-140. 5 °C.
Example 128
(4-Benzo [b] thiophen-2-yl-pyridin-2-yl)- (2, 3-dihydro-benzo [1, 4] dioxin-6-yl)- amine.
Following the same procedure described for Example 401 (c), the mixture of (2,3- dihydro-benzo [1, 4] dioxin-6-yl)- (4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), benzothiophene-2-boronic acid (Frontier Scientific, Inc. ) (45 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150 °C for 10 min and purification on a Biotage 40S column (4: 1 hexane: EtOAc), the title compound as a light- yellow solid. MS (ESI, pos. ion)/ : 361 (M+1). Mp: 154.0-154. 1 °C.
Example 129 1- {4- [2- (2, 3-Dihydro-benzo [1, 4] dioxin-6-ylamino)-pyridin-4-yl]-phenyl}- ethanone.
Following the similar procedure described for Example 401 (c), the mixture of (2,3-dihydro-benzo [1, 4] dioxin-6-yi)- (4-iodo-pyridin-2-yi)-amine (Example 401 (b), 0.73 g, 2.1 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (0.12 g, 0.11 mmol), 4-actylphenylboronic acid (Aldrich Chemical Company) (0.41 g, 2.5 mmol) and 1,2-dimethoxyethane (20 mL) gave, after heated at 90 °C overnight and purification on a Biotage 40M column (3: 1 hexane: EtOAc), the title compound as a light-orange solid. MS (ESI, pos. ion) m/z : 347 (M+1). Mp: 178.0-180. 5 °C.
Example 130
1-14- [2- (2, 3-Dihydro-benzo [1, 4] dioxin-6-ylamino)-pyridin-4-yl]-phenyl}- ethanol.
To the suspension of 1- {4-[2-(2, 3-dihydro-benzo [1, 4] dioxin-6-ylamino)-pyridin- 4-yl]-phenyl}-ethanone (Example 7,0. 19 g, 0.55 mmol) in 2 mL of MeOH was added a solution of methylamine in MeOH (Aldrich Chemical Company) (2N, 0. 55mL, 1.1 mmol). The reaction was stirred at room temperature under nitrogen overnight. NaBH4 (Aldrich Chemical Company) (25 mg, 0.66 mmol) was then added to the reaction and it was stirred for another 5 hrs. The solvent was evaporated the residue was purified on a Biotage 40M column (97: 3 dichloromethane : 2N NH3 in MeOH) to give the title compound as an off-white foam. MS (ESI, pos. ion) m/z : 349 (M+1). Mp: 55. 9- 61. 5 °C.
Example 131 [4- (3, 5-Bis-trifluoromethyl-phenyl)-pyridin-2-yl]- (2, 3-dihydro-benzo [1, 4] - dioxin-6-yl)-amine.
Following the same procedure described for Example 401 (c), the mixture of (2,3- dihydro-benzo [1, 4] dioxin-6-yi)- (4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 3,5-bis (trifluoromethyl) phenylboronic acid (Aldrich Chemical Company) (64 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150 °C for 10 min and purification on a Biotage 40S column (4: 1 hexane: EtOAc), the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z : 441 (M+1). Mp: 130.0- 131.5 °C.
Example 132
(2,3-Dihydro-benzo [1, 4] dioxin-6-yl)- [4- (4-trifluoromethoxy-phenyl)-pyridin- 2-yl]-amine.
Following the same procedure described for Example 401 (c), the mixture of (2,3- dihydro-benzo [1, 4] dioxin-6-yl)- (4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 4- (trifluoromethoxy) phenylboronic acid (Lancaster Synthesis Ltd. ) (51 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150 °C for 10 min and purification on a Biotage 40S column (4: 1 hexane: EtOAc), the title compound as an orange glass. MS (ESI, pos. ion) m/z : 389 (M+1).
Example 133 (a) 4- (4-Trifluoromethyl-phenyl)-pyridine.
In a 250-mL, round-bottomed flask were added 4-bromopyridine hydrochloride (Aldrich) (4.7 g, 24 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich) (1.4 g, 1.2 mmol) and 1,2-dimethoxyethane (120 mL). After stirring under nitrogen for 10 min, a solution of Na2CO3 (5.2 g in 30 mL of water) and 4- trifluoromethylbenzeneboronic acid (5.1 g, 27 mmol) were added sequentially to the mixture. The reaction was stirred in a 90 °C oil bath overnight. The 1,2- dimethoxyethane was evaporated in vacuo, and EtOAc was added to the residue.
The aqueous layer was separated and extracted with EtOAc (2 x 50 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by silica gel flash chromatography using 1: 5 EtOAc/hexanes as eluent gave the title compound as a light-tan solid. MS (ESI, pos. ion) m/z : 224 (M+1).
(b) 4- (4-Trifluoromethyl-phenyl)-pyridine 1-oxide.
To a mixture of 4- (4-trifluoromethyl-phenyl)-pyridine (5.0 g, 22 mmol) and methyltrioxorhenium (VII) (Aldrich) (110 mg, 0.45 mmol) in a 100-mL, round- bottomed flask was added CH2CI2 (10 mL). Hydrogen peroxide (5 mL, Aldrich) was added drop-wise, and the reaction was stirred at room temperature under N2 for 48 h. The mixture was partitioned between CH2CI2 and brine, and the aqueous layer was extracted with CH2CI2 (40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z : 240 (M+1).
(c) 2-Chloro-4- (4-trifluoromethyl-phenyl)-pyridine.
To 4- (4-trifluoromethyl-phenyl)-pyridine 1-oxide (2.4 g, 10 mmol) was added phosphorous oxychloride (12 mL) at room temperature. The reaction mixture was heated at reflux for 5 h. POC13 was removed under reduced pressure, and the residue was partitioned between EtOAc and aqueous ammonium hydroxide. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography on a Biotage 40 M column (8: 1 hexanes: EtOAc) to give the title compound as a white solid. MS (ESI, pos. ion) m/z : 258.5 (M+1).
(d) Quinolin-3-yl- [4- (4-trifluoromethyl-phenyl)-pyridin-2-yl]-amine.
To an oven-dried 50 mL round-bottomed flask were added 2-chloro-4- (4- trifluoromethyl-phenyl)-pyridine (138 mg, 0.54 mmol) and 3-aminoquinoline (Aldrich Chemical Company) (93 mg, 0.64 mmol), followed by anhydrous toluene (45 mL). Nitrogen was bubbled through the above solution via a needle for lh. Then palladium acetate (Aldrich Chemical Company) (18 mg, 0.08 mmol) and BINAP (Aldrich Chemical Company) (50 mg, 0.08 mmol) were added to the reaction in one portion, followed by sodium tert-butoxide (Aldrich Chemical Company) (145 mg, 1.5 mmol). The reaction mixture was heated at 90 °C overnight. After cooling to room temperature, the reaction mixture was taken up to ether, and washed with brine. The aqueous layer was extracted with ether (2x) and the combined ether layer was dried over Na2SO4 and concentrated. The residue was purified on a Biotage 40 S column (2.5 : 1 hexane: EtOAc) to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z : 366 (M+1). Mp: 207.4-207. 5 °C.
General Scheme III. a R3 Ri-M R3 R3 Ber i transition metal R oxidation R'5 N coupling R15 N R'5 N+10- 15 M = B (OH) 2, SnBu3, R ZnCI, BF3-, MgBr, etc. R3 R3 y chlorination WCI R4-YH R9fYsR4 - R N I 15 R R16 R16 halogen-I exchange R3 R3 R15 N R'6 R16 Scheme lII. b R3 R3 R4-YH H2N I YR4 ll I 1. diazotization R'5 N-R15 N 2. dehydrohalogenation R16 R16 R3 Br>fuR4 R1-M transition metal N coupling Rus Scheme III. c R3 R3 Dey 1 O dehydro-p_O l Cl halogenation R Y R16 R16 P = ArylCH2- R3 R3 P-O Y HO Y 1. Tf20, CH2CI2 h N I N 2 R,-M i R15 ; R15 N transition metal coupling R16 R16
Example 134 7- [4- (4-Trifluoromethyl-phenyl)-pyridin-2-yloxy]-quinoline.
To an oven-dried, 50-mL, round-bottomed flask were added 7-hydroxyquinoline (Aldrich) (87 mg, 0.6 mmol) and DMF (1 mL). The solution was place under nitrogen, and NaH (24 mg, 0.6 mmol) was added in one portion. After stirring for 10 min, 2-chloro-4- (4-trifluoromethylphenyl) pyridine (Example 410 (c), 129 mg, 0.5 mmol) was added. The reaction mixture was heated in a 155 °C oil bath for
72 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, concentrated in vacuo. The crude material was purified on a Biotage 40 S column (3: 1 hexanes: EtOAc) to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z : 367 (M+1).
Mp: 156.5-158. 5 °C.
Example 135
2- (3-Methoxy-phenoxy)-4- (4-trifluoromethyl-phenyl)-pyridine.
This material was prepared according to the method described in Example 2 (d) using 2-chloro-4- (4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 129 mg, 0.5 mmol), 3-methoxyphenol (66 uL, 0.6 mmol), and sodium hydride (24 mg, 0.6 mmol) in DMF (1 mL). Purification on a Biotage 40S column (8: 1 hexanes: EtOAc), provided the title compound as a white solid. MS (ESI, pos. ion) m/z : 346 (M+1). Mp: 77. 5- 79. 6 °C.
Example 136
8- [4- (4-Trifluoromethyl-phenyl)-pyridin-2-yloxy]-quinolin-2-ylami ne.
A mixture of 2-azido-quinolin-8-ol (0.28 g, 1.5 mmol), 2-chloro-4- (4- trifluoromethyl-phenyl)-pyridine (Example 410 (c), 0.26 g, 1 mmol), and sodium hydride (64 mg, 1.6 mmol) in DMF (2 mL) was heated in a 180 °C oil bath for 48 h. The reaction mixture was then transferred to a 5-mL tube, and irradiated in the Microwave Smith Synthesizer at 250 °C for 10 min. EtOAc and brine were added, and the aqueous layer was extracted with EtOAc. Combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The compound was purified on a Biotage 40S column (98: 2 dichloromethane: MeOH)
followed by recrystallization from EtOAc/hexanes to give the title compound as a light-yellow shiny crystal. MS (ESI, pos. ion) m/z : 382 (M+1). Mp: 196.5- 199.5 °C. Anal. Calcd for C2lHl4F3N30 : C, 66.14 ; H, 3. 70; N, 11.02. Found: C, 66.18 ; H, 3.69 ; N, 11.08.
Example 137
8- [4- (4-Trifluoromethyl-phenyl)-pyridin-2-yloxy]-quinoline.
This material was prepared according to the method described in Example 413 using 2-chloro-4- (4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 0.16 g, 0.6 mmol), 8-hydroxyquinoline (0.1 g, 0.7 mmol), sodium hydride (38 mg, 1.0 mmol) and copper (I) iodide (12 mg, 0.06 mmol) in DMF (3 mL).
Purification on a Biotage 40S column (3: 1 hexanes: EtOAc), provided the title compound as a white solid. MS (ESI, pos. ion) m/z : 367 (M+1). Anal. Calcd for C2lHl3F3N20 : C, 68.85 ; H, 3.58 ; N, 7.65. Found: C, 68.88 ; H, 3.59 ; N, 7.51.
Example 138
2-Methyl-5- [4- (4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazole.
This material was prepared according to the method described in Example 413 using 2-chloro-4- (4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 0.16 g, 0.6 mmol), 2-methyl-5-benzothiazolol (0.12 g, 0.7 mmol), sodium hydride (38 mg, 1.0 mmol) and copper (I) iodide (12 mg, 0.06 mmol) in DMF (3 mL).
Purification on a Biotage 40S column (3: 1 hexanes: EtOAc), provided the title compound as a white solid. MS (ESI, pos. ion) m/z : 367 (M+1). Mp: 160.5-163. 5 °C. Anal. Calcd for C20Hl3F3N2OS. 0. 25 H20 : C, 61.45 ; H, 3.48 ; N, 7.17 ; S, 8.20.
Found: C, 61.45 ; H, 3.39 ; N, 7.17 ; S, 8.31. Table B. The following compounds were prepared according to General Schemes III. a, III. b and III. c: MS Melting Example Structure (ESI, pos. ion) Point C m/z F F NH2 139 F , N-S 388 (M+1) 246. 3- 0 s 247. 5 N F 0 F F HN-- 140F N-- 428 (M-1) 0 s 430 (M+1) N Additional Examples Following the procedures described above, or with slight modifications thereof, and following procedures familiar to one of ordinary skill in the art, the following examples were prepared from commercially available reagents:
Example Melting Point Mass Spec. number Structure (°C) (ESI) m/z <","" N N 142 N N 244 343 (M+1) 0 Br W N t 354 143 231 (M, M+2) Hic H3C _. ! _-= O v @ (M, M+2) 0". CH, H 44 F-Nsa _ 3 M+l) 145 k N\2N) COH >300 361 (M+1) o Example Melting Point Mass Spec. number Structure (°C) (ESI) m/z ARM , H C' t : i Q 59-61 310 (M+1) 146 'H3C II, CH3"e ° H-C') CH- ! < H M ? w, : 147 HN 174-175 310 (M+I) o, CH3 CH3 H3 t > NH 0--^3 //N 0_a' 148 97-102 340 (M+l) -H3C 0 ,. :. Hc'° c 148-152 337 (M+I) 0 N t r v = kL g N'~~ ~ ~ :' 1 I 'ji 4I 150 h. 233-237 453 (M+1) s ° a r _ ?- OH 151 + (Nt oil 296 (M+1) o 0 Example Structure Melting Point Mass Spec. number Structure (ESI) m/z l52 m l0G ltl'2 Mtl) j 1f,. * v, nu Ik x. a, n t . i va 5 :. : >-a y i 153 -< Ht, NS 98-102 295 (M+1) ' :. C'"3. _ N. ,. ° TiH3 154-< 171-173 323 (M+1) o : zu H3Ct-H _ 155 +rNoX 257 320 (M+1) 0 fuzz fol1 H3C, 156 v I' -' £ po 187-190 359 (M+1) 0 ci jl ffi 157 203 339 (M+1) H t, H-o 157, £ fh ° o 203 339 (M+1) s x. i Ft. . .. yli W 158 244-248 416 (M+1) ° F i t : Example Melting Point Mass Spec. number (OC) (ESI) mlz 160 191 341 (M+l) s"C, WH'--vo .. 160 341 (M+I) a o'o ---N C =CFbH3. W.- Nu i i N, 160 I1 Ilo %, oH 191 341 (M+1) thin film 319 (M+1) t ° 9~ H N H3------"" HsC y I ?' H 162 326 (M+1) 0 0 °_ H' -,"' : r k, > _ H go 163 152 406 (M+1) : H 45 193 @ _ ~^'45e H, pv h Ns 164 k ° WOt-193 370 (M+1) s r g ¢ : ffi a I H C. I H . _ H3 164 e : o-= -193 370 (M+1) o =P O CH ltW H C'Ol CH3 Example Melting Point Mass Spec. number Structure (°C) (ESI) m/z ''. $- ;' °- N" FiaC Ih'F _ 165 249 365 (M+I) g | l 1 ! I g l E g ° c, r . S , g", H 166 193 331 (M+I) N 3 H'OH "s-<"l ! r H f) 167 I . 149 310 (M+1) I'-'' OH H C -. OH H 168 I ! < ! N I 173 310 (M+1) ; _ _...... _ ° _ : bH3__ 169 ° " 218 296 (M+1) ,,, .. °. H. v oH OH f, _ ! 170 H3C _,. , f O---- 170 w 195 322 (M+1) 4,-,.,,"=" #, v, _ CH3- 3f3 :-. 171 -, e o_ '\. cH3 223 323 (M+1) N i _ CH3 _ ; Example Melting Point Mass Spec. number Structure (°C) (ESI) m/z 172 ; M 3lUtAitl) , 173 205 348 (M+l) t,, H CX , 3-|-_-H R 4 .. ? if . a. 'r'OFI -M-o x% /.. N 173 . , ,-, , 205 348 (M+1) CHs i",,, a,. O 174 1 161 338 (M+1) cl C 175 212 334 (M+1) 0 cita 263 323 (M+I) nu 2 'if F F a,, 4, , ; . : :,, +, ., i, r _ 177 239 331 (M+I) F-. rj+ iH, 4a ; H = 177 I, +'i N ', ; N ° 239 331 M+1 Example Melting Point Mass Spec. number Structure (°C) (ESI) m/z l78 l67 34 . :- :-iN Hic"-, H v c-" .. a H C ; H3 ^ ~ ^"' . HCT : _. 3, 3..,, . t... '. i rf ' H3C __ 179'' p I 172 330 (M+1) ro'i i- HaC/.. H I I CH 154 336 (M+1) , ; XCH3 H3C) : H N CL 181-~ H3 281 337 (M+ 1) : H O 0 182 I ° I 154 347 (M+1) o Ni ,. .. 2 : : = _ _. :. _ HI, I, C ; lil, H3.. pv-<< ,.,..-, :.- :,-2, : e ; : ; u>., : -C ; H j,,, - 183 105 328 (M+l) ffi 0 <, 5 N H H3r.--3 f-IsCifl, l+ I t . - = \ I= ", ;, ; o- ÇH3 ~ H3C = f'-t+' Hm n 184 i 165 329 (M-1) Example Melting Point Mass Spec. number Structure (°C) (ESI) m/z '' i > | S E] t H + t 185.'| | | w n 332 ; ; n m.-,, X,, =" , H3 I H 68 331 (M+1) _.'-"., Example Structure Melting Mass Spec. number Point (°C) (ESI) m/z H 187 \~> (N) 2rN> 261 320 (M+1) N 1 : :. H \ H 188 277 321 (M+l) 0 194 '. S''H' 189-Ntl 194 319 (M+1) =rv o y ' _'1 ;-g' R, gY X5't, m ffi/H 190'r lí 101 319 (M+l) , Example Structure Melting Mass Spec. number Point (°C) (ESI) m/z N ,.. ; ! ? xt. ;. ou "'''"° .... kc' 203 sS 222 333 (M+l) ==. :, E 'vli. nv ; : ;. : : ;.'y : i' . _ ;, ;.' : ;. "'.,. M 201 178 352 (M+I) . ç-3 O _..... _. _. N 0 202 bo 196 395 (M+1) HaC tS' W Yo , 203 HN 222 333 (M+l) i N uti r i., i % ; Nti OÉt W-m H N b li, fd I/ _ iie# . \pEt 205 >% H 296-298 348 (M+1) 1 N N OH Example Melting Point Mass Spec. number Structure (°C) (ESI) m/z Bt H ru \ o. | g ! |. | ß ! | | g I 206 i S 1,-, I S | | W. a S 1 189 515 (M) H3C : r H. _ : 207 116-119 470 (M+1) +, H 8-G3S "'7 cu hic Hic ;, 208 . 162-163 302 (M+l) 0 209 3 S o _ o ; 162-163 302 (M+1) H3C CHCH3. t H-"--CH- H3CSq 208 <. mNgo q 186 352 (M+1) D 3g Ot H C' -o-, I , I 4 + tl'qN r q.. À,, 1 i a ; _.' 211, w 42-48 300 (M+1) Example Melting Point Mass Spec. number Structure (°C) (ESI) m/z HaC H ,, 212 229-230 300 (M+1) wu 'N I'-0 Y F' : . ;'iili, l, : ; , ,.', ; IE, ;, ;' : , : s3 ; , M'i ; : w ; : FT I 213 200 368 (M+l) h í-,-i O ' :" H N 0 -^ :. o-., = H 119 310 (M+l) 0 fui CL 216 XNt 69 352 (M+1) ;. F F w 217 amorphous glass 351 (M+1) fEM O4''' f".,-,", , O = 41 84 338 (M+l) 218'' : ;,--3 Example Melting Mass Spec. number Point ('C) (ESI) m/z 'SM""'" :.""'H :'f,''''.'' c "'H -H t 220 | t t O , ri "=-,"'~, e, H3C W ,. , , i i. n_ , ° . cH F C ; y a - :, //, N ; O 220 0 100 /,, I I u.. 0 nu H, C H N 0 i N w o 221 Fc 0 _ . N r<t CH3 C, /-. w r 1 , m | 223 X ; 78-80 444 (M+1) 1 f T , gW'WY A ^ w <NaMO s fz, y. wAvY,.,- ^-zi-Y-='-> 3 F 4r II f 3 F, r N 0 205-206 %""j rN 224 -o o r y 89-93 444 (M+1) c I o Example Melting Mass Spec. number Structure Point (°C) (ESI) m/z . H3 A CH, H6 I :.' K Fa. ir i I xl 1, HaC. Hic, _ 226 0 92-94 445 (M+I) N J o HaC, HaC. : I _. H 227 177-180 396 (M+1) '-NS H- 3l N v= I r <E Cj', HsC. . 228 138-141 428 (M+1) i g ht tCH = H| k aC ilfi. l I. e Gi rl r «'I : :, I b 2i M s la-% " I I y\ O 155 448 (M+1) ,"4 i Example Melting Mass Spec. number Point ('C) (ESI) mlz _ , -- " 231 t3 H 4a . I 4. 4 I"°m. F'il j, 4IiII : hlaC f,'y Id i 1 N s f :.. ...., rc' ? ^s, 3 u'Y. eG, llli tw, k : si a : x H 231//o N 121-124 426 (M+1) NU nez OMe oye H 232 I i N I ° 403 (M+1) nu 0 NU \ N 0 233 mH O 87 513 (M+1) o, o OCo N \ I in 1" 234 I N 415 (M+I) , o Example Structure Melting Mass Spec. number Point (°C) (ESI) m/z F F H 235 N O amorphous 427 (M+1) o i oJ N H 236 56 499 (M+I) , o , o UN \ H 237 I N 497 (M+1) o cN, Example Structure Melting Mass Spec. number Point (°C) (ESI) m/z r . Jl iul 238 207-208 395 (M+1) 0 'O CO CH 239 188-189 423 (M+1) o cozet 9, Et 240 < CONH2 198-199 380 (M+ 1) o CONH H i \CN Nl i 201-203 394 (M+1) ! : o coNr N w ; a 242 171-173 381 (M+1) _ § P J i = ~ //N . \. N 243 118-120 422 (M+1) 0 Example Melting Mass Spec. number Structure Point (°C) (ESI) m/z i i i : . a, I, 4, ; rcy 244 101-103 408 (M+l) u ß £ f N î j . : : _,. ' 126-128 408 (M+l) o y-_ :. F I/a/tj =jN 185-186 394 (M+l) ----t --. &/J COEt : co2e : I 248 >t < 194-196 381 (M+1) -h. F :-.-C- < $ ° i i,. L $ u 1 t- w 249 206-208 394 (M+ ) s- Example Melting Mass Spec. number Structure Point (°C) (ESI) m/z i i r" o 250 ° uN) 200-201 427 (M+1) H 251 N,, aO) 199-200 379 (M+l) 0 N oS\ H i i N o 252 o N) 236-237 441 (M+1) of3 I 0 H 169 356 (M+1) 0 254 H 'b 256-258 331 (M+1) H N 0 255 N O 264-266 394 (M+1) NI CONS, \ 256 t N\OD 102-103 365 (M+l) 0'CRIN Example Molting Mass Spec. number Structure Point (°C) (ESI) m/z H 257 +NCCOg 137-138 391 (M+I) IN F F F N N 0 198-200 391 (M+l) o i oH Su 259 I N 1 N ° 171-173 402 (M+1) 0 \OH H 260 % « NH) l58 160 409 (M+1) p I/OH \ 261 N N 168-170 365 (M+I) 0 OH 262 N,, aN 179-180 395 (M+ 1) L a H °H OH 263 117-119 411 (M+1) 0 OH Example Melting Mass Spec. number Structure Point (°C) (ESI) m/z Br 264 N, N 187-189 388 (M+I) oxo Bu H I 265 N N OH 154-157 402 (M+1) ozon 266 tOMe 160-161 395 (M+I) p I/OMe 267 N 152-153 422 (M+1) o F F F N s 186-188 364 (M+l) />-NH, 0'CON H Y 269 nan 134-135 409 (M+1) p /OOH F F F 270 R NgOMe 182-185 381 (M+l) O I/O/NHz Example Melting Mass Spec. number Structure Point (°C) (ESI) m/z 271 N 171-173 395 (M+1) p I/NMe2 \ 272 N_aOMe 101-105 369 (M+1) p I ONHx 273 Lo 176-178 411 (M+l) p ONH 0 H 274 N >¢ OMe 196-199 392 (M+l) p ONH2 \ 275 N'ao),,,, OMe 146-148 382 (M+1) 0 I/oOMe C. HH :. a H i _ 'I Ill, r 'I\ 276 231 363 (M+l) 277 1<, N oCO) sz 161-162 t t ; 7 t sI t t) 0 . JNH, ho i uilue.., u , . 277 N 0 161-162 367 (M+1) O I/ONHz Example Melting Mass Spec. number Structure Point (°C Y, oH OH 278 N N 108-110 425 (M+1) 0 oye \ 279 Not0N3Xz 186-187 409 (M+1) p I/OOMe \ 280 t, N>N) \ 160-162 381 1 (Mt l 0 OH H, C Hic 281 181 363 (M+I) o 282 ou amorphous 353 (M+I) 0) : x erz ou 283 \.-/ (oil) 366 (M) .., 6 ., _.. _.,. ,, y, I_s.. i 284 284 AF 348 (M+ 1) fi Example Melting Mass Spec. number Structure Point (°C) (ESI) m/z 285 H number \ \ 286"LHQ 330 (M+l) o 287 t N<F 382 (M+1) o L, 288 N 294 (M+1) zu 289 AN 314 (M+1) ° I ci 290 XIX1 ; XNNOX 294 (M+1) o H 291 N R 0 B t o Example Melting Mass Spec. number Structure Point (°C) (ESI) m/z 292 OLHc, 314 (M+l) N cri 293 H_6 294 (M+I) 0 0ici Han-1 H 294 N 367 (M+I) H, ORME OYE 295 ou 246-247 341 (M) o I 296 ) Nt 328 (M+1) ho 0 B 297 AN 233-235 341 (M) 0 N H \ 298 NCgOM 365/x °NCOMe Example Melting Mass Spec. number Structure Point (°C) (ESI) m/z () (ESI) m/z 299 AN>CN 9 GZ I M 0 H zu N 376 (M) 0Br F zu 0 N_ ( : : rO_o 372 (M+I) o omet 302 rNH4 186-187 391 (M+1) O fi H F 0, nu 224-226 414 (M+1) p I/OOH F F F H 304 nit 231-232 331 (M+1) ) : _N) H F 305 H H 219-220 349 (M+1) N N Melting Mass Spec. number Structure Point (°C) (ESI) m/z F F 306 F rN<S 231-232 383 (M+1) oh 0 NU F F 307 N H 203-204 365 (M+1) F ", 0 F 308 N 177-179 365 (M+1) 0 N H F ci N 0 226-227 384 (M+1) 0 ao) 310 3 CoD Amorphous 308 (M+l) 0 ao) H 311 s I N ° 150 360 (M) 0 F 312 N N 211 427 (M+1) O// 0 Example Melting Mass Spec. number e Point (°C) (ESI) m/z F F F ici \ H 313 N N S 78 433 (M+1) z N 0 N 314 N//N N O 286 350 (M+1) 0 F F II \ H 315 N N 0 Amorphous 434 (M+l) N 0 F F F 31ti N<, 226 415 (M+l) U o, F F F H \ 317 t ; v < 219 530 (M+l) "dz 0' 318 Amorphous 320 (M+1) N H F F 319 Amorphous 415 (M+1) N 0 N N Example Melting Mass Spec. number Structure point (°C) (ESI) m/z F F 320 vu 211 349 (M+l) N, CES F F F 321 N Amorphous 375 (M +1) "N"0 N H H 322 Amorphous 341 (M+l) p I N pOH F F 323 Amorphous 427 (M +1) N U B,, H 324 N"S 225 3 60 (M+ 1) o I N 325 H Amorphous 338 (M+I) O % N H H 326 N +N< 275 320t\4t) o I Example Melting Mass Spec. number Point ('C) (ESI) m/z F F 327 oC a >, Ns¢n 282 332 (M+l) F 0 F 328 N A f N >¢> 209 332 (M+ 1) 0 I H F F 329 F rNm Amorphous 430 (\1+ 1) CF, OH (nez NOR, F F 330 >),, NoW 197 443 (milz OH OU 331 N N N Amorphous 332 (M + l o F F 332 CF) t fNX Og Amorphous 448 (M) y O INCH, F F 333 N 202 353 (M+I) 0 OH Example Melting Mass Spec. number Point ('C) (ESI) m/z F F F . 1. T UO 431 (M+l) q OH H F F //N S 335 i II I ) 97 449 (M+l) OH H H3C 336 121 309 (M) o= ou F F F II \ H 337 Amorphous 444 (M+1) N O han H F F F II \ H 338 N ; Amorphous 462 (M+l) % N N H F F F II \ H 339 N 0 N'ao) Amorphous 463 (M+1) /\N O ZIP H F O n , 9. c j R 340 ",.'Hni o 163 366 (M+1) Example Melting Mass Spec. number Point ('C) (ESI) m/z H I 341 0 N 237-240 427 (M+l) -PRO N- N If o XO) 276-278 463 (M+l) 0" cl hui H 343 0N'ao) amorphous 423 (M+l) 0 ZON N H F 344 < S N¢>Og 202-204 47G (M) 0 , N Ol 345 0 i oJ 214-218 451 (M+l) zon po HCI 346 0'ao amorphous 447 (M+I) nez N 347 o I 201-205 423 (M+1) N zon N HCI L J j J Example Molting Mass Spec. number Structure point (°C) (ESI) m/z RIZ //N O 348 0 ao) 263-269 449 (M+1) PO hui H 349 0 273-275 451 (M+1) zoo H 350 0 N_ac 348 (M+I) ° I ci 351 N 295 (M+l) o F F 352 NoXNo amorphous 417 (M+1) N cor 0 H 353 X f Ns< 308 (M+1) o N-& ci 328 (M+I) o Example Melting Mass Spec. number Point ('C) (ESI) m/z F F 355 F ; amorphous 435 (M+l) % N cl CN 356 l N-) 319 (M+ 1) 0han 0 nu2 357 323 (M+I) 0HH H 0 358 N-e NH, 323 (M+1) zu o 359 t No¢9 334 (M+ 1) zu 360 N 320 (M+1) 360 t N J 324 (M+I) ou Example Melting Mass Spec. number Structure pont (°C) (ESI) m/z 362 H 294 (M+1) 0 ka H 363 N 298 (M+l) /NN \ //N CI 364 385 (M+1) H H 365 L. H 359 (M+l) 0 0 ISNH2 0 Me 366 I N iF 328 (M+1) H 367 Wf N 325 (M+1) ° NO2 368 1S ß j 1 5 t 0 Example Melting Mass Spec. number Point ('C) (ESI) m/z NN 374 (M+I) 0B, : a 370 371 H o 371 s5) (Nt 305 (Mf) o L's- N N 281 (M+I) o 373 358 (M+I) o -s- N' 0 Me 374 r f 310 (M+1) zu 375 +1) 0-0 Melting Mass Spec. number Structure Point (°C) (ESI) m/z N, N 282 (M+I) 377 H 377 ; NCs 315 (M+ 1) N 0 Cl 178 LH 360 (M+ l) /sur 379 N 344 (M+1) 0 NON more N, houes 449 (M+1) 381 I o N °1 amorphous 401 (M+1) 0 0 N 0 ici N-N H 382 H 382 N) : CN 350 (M+1) c Melting Mass Spec. number Structure Point (°C) (ESI) m/z H 383 oN 351 (M+1) ° N < 384 N 345 (M+ 1) W F F F98 H 344 (M+ 1) 0 N N-ao) 339 (M+I) "o, 0 Example Melting Mass Spec. number Structure Point (°C) (ESI) m/z 387 6 247-248 327 (M+1) "; ", o :- H3 : 0 \ ; i 0 3gg'HN b\ 179-180 312 (M+l) Example Structure Melting Mass Spec. number Point (°C) (ESI) m/z w 389 179-182 (M, M+2) 0 < o-,-,,, av ;, 182-183 282 (M+I) ,,, r, 0-, cri 390 3HN-I 0 182-183 282 (M+1) ci 391 HN 0 187-188 316 (M+1) zu 0 /-. zu 392 HN---195-196 300 (M+1) o F 393 Ft. ;/_ .. ' : 39 HN :. fi, o., 201-202 350 (M+1) .......... : 0 ; Example Melting Mass Spec. number Point ('C) (ESI) m/z H3' zut H c', t a v'III 4 a 4f } 7 y" 4, r, ~,,- 394 , ,',,, , u N, \_ao r 214-216 325 (M+1) Br £'" ;' o-° - » -, v, ClWog 395 HN =I °'01 150 360 (M+1) "0 ci ci I. ° 396 HNo 184-189 350 (M+l) I i oJ 0 F w.,'S 397 173-175 296 (M+1) ,, t _ , , b ;, : : 398 i$' 160-165 318 (M+1) ' F i ° _- . ç r X, v o - 1 399 F F ; HN ; ow 200 350 (M+1) Melting Mass Spec. number Structure Point (°C) (ESI) m/z = 400 203-207 332 (M+1) ,-mu a ; t", vs"Es ; ~, f-r n °,''-''i ,. : X bo, Wo ^- 401,- HNXÒ-155-158 326 (M+1) P-o F ;, F 0 i i O 402, F HNs¢>Ó32 181-182 318 tMtl) 0, r W 0 403 r ! 0> 196 408 (M+1) HN 0 Y. a, ; 404 185-186 332 (M+l) ; , y Example Structure Melting Mass Spec. number Point (°C) (ESI) m/z ,. . : r., rk. wS''"E m ,' 0 405 _ _ 1'°c (oil) 322 (M+1) > : _ _ : c : ; _vr =-L. o : u o 406,-."N 188 340 (M+1) I o f F 407 FX og D 176 350 (M+1) zou F o 408"N I w l (oil) 326 (M+1) i oJ F7 \ , l//O 202 396 (M+l) .,,, ^, o 409 c s-- N== ° 129 366 (M+1) _. : >..-H _. j F_, ..-.-..-., M,. ; <, t-.- ; _- 410 . 202 396 (milz r'-'' Example Structure Melting Mass Spec. number Point (°C) (ESI) m/z Fez F--O (,'t ^t'tH3atw åd",, 3C 411 N "' ; aN, w"'o 191 362 (M+1) 1 tfi H9C''' g 412 > e04 165 324 (M+1) , I : oJ.
Table. The following compounds were prepared according to General Schemes I, II or III: MS Example Melting Structure (ESI, pos. ion) number Point'C wiz 413 e N 303 (M+1) 157 N N C) CH3 333 (M+1) amorphous N N 0 347 (M+l) 156 N O 0 MS Example Structure (ESI, pos. ion) number Point °C m1z 416 N CH3 331 (M+1) 133 zizi H 417 <N ÇOCH3 393 (M+1) amorphous LOCH3 OCH3 LOCHS X XNm 342 (M+l) 106 ZIZI N N / N s 360 (M+1) 154 N ZON (i i 420 H 42t) 354 (M+l) 214 N N F3C S 372 (M+l) 203 N L Nu foc 422 xi 366 (M+l) 206 N MS Example Melting Structure (ESI, pos. ion) number Point C nez FOC H 423 N 0 373 (M+I) 114 N N Ber, ber (M, M+2) ZON O
Additional Examples Following the procedures described above, and applying the procedure in Example 109 to the cinnamides exemplified, or with slight modifications thereof, and following procedures familiar to one of ordinary skill in the art, the following examples may be prepared from commercially available reagents:
The following examples may also be made using the above generic schemes and synthetic examples :
Capsaicin-induced Ca2+ influx in primary dorsal root ganglion neurons Embryonic 19 day old (E19) dorsal root ganglia (DRG) were dissected from timed-pregnant, terminally anesthetized Sprague-Dawley rats (Charles River, Wilmington, MA) and collected in ice-cold L-15 media (Life Technologies, Grand Island, NY) containing 5% heat inactivated horse serum (Life Technologies). The DRG were then dissociated into single cell suspension using a papain dissociation system (Worthington Biochemical Corp. , Freehold, NJ). The dissociated cells were pelleted at 200 x g for 5 min and re-suspended in EBSS containing 1 mg/ml ovomucoid inhibitor, 1 mg/ml ovalbumin and 0.005% DNase.
Cell suspension was centrifuged through a gradient solution containing 10 mg/ml ovomucoid inhibitor, 10 mg/ml ovalbumin at 200 x g for 6 min to remove cell debris; and filtered through a 88-Am nylon mesh (Fisher Scientific, Pittsburgh, PA) to remove any clumps. Cell number was determined with a hemocytometer and cells were seeded into poly-ornithine 100 ug/ml (Sigma) and mouse laminin 1 Fg/ml (Life Technologies) -coated 96-well plates at 10 x 103 cells/well in complete medium. The complete medium consists of minimal essential medium (MEM) and Ham's F12,1 : 1, penicillin (100 U/ml), and streptomycin (100 yg/ml), and nerve growth factor (lOng/ml), 10% heat inactivated horse serum (Life Technologies). The cultures were kept at 37 °C, 5% C02 and 100% humidity.
For controlling the growth of non-neuronal cells, 5-fluoro-2'-deoxyuridine (75p. M) and uridine (180zM) were included in the medium. Activation of VR1 was achieved in these cellular assays using either a capsaicin stimulus (ranging from 0. 01-lOp. M) or by an acid stimulus (addition of 30mM Hepes/Mes buffered at pH 4.1). Compounds were also tested in an assay format to evaluate their agonist properties at VR1. The activation of VR1 is followed as a function of cellular uptake of radioactive calcium (45Ca2+ : Amersham CES3-2mCi).
Capsaicin Antagonist Assay: E-19 DRG cells at 3 days in culture are incubated with serial concentrations of VR1 antagonists, in HBSS (Hanks buffered saline solution supplemented with BSA O. lmg/ml and 1 mM Hepes at pH 7.4) for 15 min, room temperature. Cells are then challenged with a VR1 agonist, capsaicin (500 nM), in activation buffer containing O. lmg/ml BSA, 15 mM Hepes, pH 7.4, and 10 , Ci/ml 45Ca2+ (Amersham CES3-2mCi) in Ham's F12 for 2 min at room temperature.
Acid Antagonist Assay: Compounds are pre-incubated with E-19 DRG cells at room temperature for 2 minutes prior to addition of 45Ca2+ in 30mM Hepes/Mes buffer (Final Assay pH 5) and then left for an additional 2 minutes prior to compound washout. Final concentration of 45Ca2+ (Amersham CES3-2mCi) is 10 yCi/mL.
Agonist Assay: Compounds are incubated with E-19 DRG cells at room temperature for 2 minutes in the presence of 45Ca2+ prior to compound washout.
Final 45Ca2+ (Amersham CES3-2mCi) at 10, uCi/mL.
Compound Washout and Analysis: Assay plates are washed using an ELX405 plate washer (Bio-Tek Instruments Inc. ) immediately after functional assay. Wash 3 X with PBS, 0.1 mg/mL BSA. Aspirate between washes. Read plates using a MicroBeta Jet (Wallac Inc. ). Compound activity is then calculated using appropriate computational algorithms.
4sCalcium2+ Assay Protocol Compounds may be assayed using Chinese Hamster Ovary cell lines stably expressing either human VR1 or rat VR1 under a CMV promoter. Cells could be cultured in a Growth Medium, routinely passaged at 70% confluency using trypsin and plated in an assay plate 24 hours prior to compound evaluation.
Possible Growth Medium: DMEM, high glucose (Gibco 11965-084).
10% Dialyzed serum (Hyclone SH30079.03).
1X Non-Essential Amino Acids (Gibco 11140-050).
1X Glutamine-Pen-Strep (Gibco 10378-016).
Geneticin, 450yg/mL (Gibco 10131-035).
Compounds could be diluted in 100% DMSO and tested for activity over several log units of concentration [40RM-2pM]. Compounds may be further diluted in HBSS buffer (pH 7.4) 0.1 mg/mL BSA, prior to evaluation. Final DMSO concentration in assay would be 0.5-1%. Each assay plate could be controlled with a buffer only and a known antagonist compound (either capsazepine or one of the described VR1 antagonists).
Activation of VR1 could be achieved in these cellular assays using either a capsaicin stimulus (ranging from 0. l-l, uM) or by an acid stimulus (addition of 30mM Hepes/Mes buffered at pH 4.1). Compounds could also be tested in an assay format to evaluate their agonist properties at VR1.
Capsaicin Antagonist Assay: Compounds may be pre-incubated with cells (expressing either human or rat VR1) at room temperature for 2 minutes prior to addition of 45Ca2+ and Capsaicin and then left for an additional 2 minutes prior to compound washout. Capsaicin (200nM) can be added in HAM's F12,0. 1 mg/mL BSA, 15 mM Hepes at pH 7.4. Final 45Ca2+ (Amersham CES3-2mCi) added could be 10yCi/mL Acid Antagonist Assay: Compounds can be pre-incubated with cells (expressing either human or rat VR1) for 2 minutes prior to addition of 45Ca2+ in 30mM Hepes/Mes buffer (Final Assay pH 5) and then left for an additional 2 minutes prior to compound washout. Final 45Ca2+ (Amersham CES3-2mCi) added could be 10yCi/mL.
Agonist Assay: Compounds can be incubated with cells (expressing either human or rat VR1) for 2 minutes in the presence of 45Ca2+ prior to compound washout.
Final 45Ca2+ (Amersham CES3-2mCi) added could be 10, uCi/mL.
Compound Washout and Analysis: Assay plates would be washed using an ELX405 plate washer (Bio-Tek Instruments Inc. ) immediately after the functional assay. One could wash 3 X with PBS, 0.1 mg/mL BSA, aspirating between washes. Plates could then be read using a MicroBeta Jet (Wallac Inc. ) and compound activity calculated using appropriate computational algorithms.
Useful nucleic acid sequences and proteins may be found in U. S. Patent Nos. 6,335, 180,6, 406,908 and 6,239, 267, herein incorporated by reference in their entirety.
For the treatment of vanilloid-receptor-diseases, such as acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, the compounds of the present invention may be administered orally, parentally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used herein includes, subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques or intraperitoneally.
Treatment of diseases and disorders herein is intended to also include the prophylactic administration of a compound of the invention, a pharmaceutical salt thereof, or a pharmaceutical composition of either to a subject (i. e. , an animal, preferably a mammal, most preferably a human) believed to be in need of preventative treatment, such as, for example, pain, inflammation and the like.
The dosage regimen for treating vanilloid-receptor-mediated diseases, cancer, and/or hyperglycemia with the compounds of this invention and/or compositions of this invention is based on a variety of factors, including the type of disease, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular compound employed.
Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. Dosage levels of the order from about 0.01 mg to 30 mg per
kilogram of body weight per day, preferably from about 0.1 mg to 10 mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for all methods of use disclosed herein.
The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.
For oral administration, the pharmaceutical composition may be in the form of, for example, a capsule, a tablet, a suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a given amount of the active ingredient. For example, these may contain an amount of active ingredient from about 1 to 2000 mg, preferably from about 1 to 500 mg, more preferably from about 5 to 150 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods.
The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water. The daily parenteral dosage regimen will be from about 0.1 to about 30 mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg, and more preferably from about 0.25 mg to 1 mg/kg.
Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known are using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
A suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably one or two times daily. For topical administration, the active ingredient may comprise from 0.001% to 10% w/w, e. g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1% to 1% of the formulation.
Formulations suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin (e. g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose.
For administration, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, sodium alginate, polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration. Alternatively, the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
The pharmaceutical compositions may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e. g. , solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain
conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch.
Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e. g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e. g. , by formation of diastereoisomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of the invention can likewise be
obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
Likewise, the compounds of this invention may exist as isomers, that is compounds of the same molecular formula but in which the atoms, relative to one another, are arranged differently. In particular, the alkylene substituents of the compounds of this invention, are normally and preferably arranged and inserted into the molecules as indicated in the definitions for each of these groups, being read from left to right. However, in certain cases, one skilled in the art will appreciate that it is possible to prepare compounds of this invention in which these substituents are reversed in orientation relative to the other atoms in the molecule. That is, the substituent to be inserted may be the same as that noted above except that it is inserted into the molecule in the reverse orientation. One skilled in the art will appreciate that these isomeric forms of the compounds of this invention are to be construed as encompassed within the scope of the present invention.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. The salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate. Also, the basic nitrogen- containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids that may be employed to from pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid,
sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
Also encompassed in the scope of the present invention are pharmaceutically acceptable esters of a carboxylic acid or hydroxyl containing group, including a metabolically labile ester or a prodrug form of a compound of this invention. A metabolically labile ester is one which may produce, for example, an increase in blood levels and prolong the efficacy of the corresponding non-esterified form of the compound. A prodrug form is one that is not in an active form of the molecule as administered but which becomes therapeutically active after some in vivo activity or biotransformation, such as metabolism, for example, enzymatic or hydrolytic cleavage. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p- methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989) ). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).
Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use. Esters of a compound of this invention, may include, for example, the methyl, ethyl, propyl, and butyl esters, as well as other suitable esters formed between an acidic moiety and a hydroxyl containing moiety.
Metabolically labile esters, may include, for example, methoxymethyl, ethoxymethyl, iso-propoxymethyl, (x-methoxyethyl, groups such as oc- ((C-C4) alkyloxy) ethyl, for example, methoxyethyl, ethoxyethyl, propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1, 3-dioxolen-4-ylmethyl groups, such as 5-methyl-
2-oxo-1, 3, dioxolen-4-ylmethyl, etc.; Cl-C3 alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, etc.; acyloxymethyl groups, for example, pivaloyloxymethyl, a-acetoxymethyl, etc.; ethoxycarbonyl- 1-methyl ; or a-acyloxy-a-substituted methyl groups, for example a-acetoxyethyl.
Further, the compounds of the invention may exist as crystalline solids which can be crystallized from common solvents such as ethanol, N, N-dimethyl- formamide, water, or the like. Thus, crystalline forms of the compounds of the invention may exist as polymorphs, solvates and/or hydrates of the parent compounds or their pharmaceutically acceptable salts. All of such forms likewise are to be construed as falling within the scope of the invention.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes, which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.