TAYLOR JUSTIN (US)
CHAUDHRY SANA (US)
WO2018021977A1 | 2018-02-01 |
US20210041439A1 | 2021-02-11 | |||
US20160362396A1 | 2016-12-15 |
CLAIMS What is claimed is: 1. A compound having the formula: , or a pharmaceutically acceptable salt thereof, wherein A1 is aryl, cycloalkyl, heteroaryl, or heterocyclyl group A2 is an alkyl, cycloalkyl, heteroaryl or heterocyclyl group, or Q1-NR6aR6b, wherein Q1 is null or C1-4alkylene, R6a is hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl, R6b is hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; A3 is null or an aryl, cycloalkyl, heteroaryl, or heterocyclyl group A4 is null or an aryl, cycloalkyl, heteroaryl, or heterocyclyl group R1 is hydrogen, C1-8alkyl, or C3-8cycloalkyl; R2 is F, Cl, Br, I, NO2, CN, R2*, OR2*, N(R2*)2, SO3R2*, SO2R2*, SO2N(R2*)2, C(O)R2*; C(O)OR2*, OC(O)R2*; C(O)N(R2*)2, N(R2*)C(O)R2*, OC(O)N(R2*)2, N(R2*)C(O)N(R2*)2, wherein R2* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1- 8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R3 is F, Cl, Br, I, NO2, CN, R3*, OR3*, N(R3*)2, SO3R3*, SO2R3*, SO2N(R3*)2, C(O)R3*; C(O)OR3*, OC(O)R3*; C(O)N(R3*)2, N(R3*)C(O)R3*, OC(O)N(R3*)2, N(R3*)C(O)N(R3*)2, wherein R3* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1- 8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; Ra has the formula: -Z3-Zc-Z4-Zt, wherein Z3 is null, C1-6alkylene, C3-8cycloalkylene, arylene, C1-8hetercyclylene, or C1-8heteroarylene, Zc is -null, C(=O)-, SO2, -C(=O)O-, -C(=O)NH- Z4 is null, C1-6alkylene, C3-8cycloalkylene, arylene, C1-8hetercyclylene, or C1-8heteroarylene, Zt represents a bond to A4 or A3, or is F, Cl, Br, I, CN, NO2, Rza*, ORza*, SRza*, N(Rza*)2, C(=O)Rza*, C(=O)ORza*, C(=O)NHRza*, wherein Rza* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1- 8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; wherein any two of more A1, A2, A3, A4, R1, R2, R3, and Ra may together form a ring. 2. The compound according to claim 1, wherein R1 is hydrogen, methyl, ethyl, isopropyl, n- butyl, isobutyl, or cyclopropyl. 3. The compound according to claim 1, wherein R2 is F, Cl, Br, I, CN, R2*, OR2*, N(R2*)2, wherein R2* is in each case independently selected from hydrogen and C1-8alkyl. 4. The compound according to claim 2, wherein R2 is H, F, CH3, OCH3, or CF3. 5. The compound according to claim 1, wherein R3 is F, Cl, Br, I, R3*, OR3*, or N(R3*)2, wherein R3* is in each case independently selected from hydrogen and C1-8alkyl. 6. The compound according to claim 4, wherein R3 is H, F, CH3, OCH3, or CF3. 7. The compound according to claim 1, having the formula: , wherein X1a is selected from N and CR; X2a is selected from N and CR; X3a is selected from N and CR; X4a is selected from N and CR; wherein one R group is a single bond to the *-pyrimidine, and the remaining R groups are independently selected from F, Cl, Br, I, NO2, CN, R*, OR*, N(R*)2, SO3R*, SO2R*, SO2N(R*)2, C(O)R*; C(O)OR*, OC(O)R*; C(O)N(R*)2, N(R*)C(O)R*, OC(O)N(R*)2, N(R*)C(O)N(R*)2, wherein R* is in each case independently selected from hydrogen, C1- 8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl. wherein any two of more A1, A2, A3, A4, R1, R2, R3, R, and Ra may together form a ring. 8. The compound according to claim 7, having the formula: wherein R4 is is F, Cl, Br, I, NO2, CN, R4*, OR4*, N(R4*)2, SO3R4*, SO2R4*, SO2N(R4*)2, C(O)R4*; C(O)OR4*, OC(O)R4*; C(O)N(R4*)2, N(R4*)C(O)R4*, OC(O)N(R4*)2, N(R4*)C(O)N(R4*)2, wherein R4* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1- 8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R5 is F, Cl, Br, I, NO2, CN, R5*, OR5*, N(R5*)2, SO3R5*, SO2R5*, SO2N(R5*)2, C(O)R5*; C(O)OR5*, OC(O)R5*; C(O)N(R5*)2, N(R5*)C(O)R5*, OC(O)N(R5*)2, N(R5*)C(O)N(R5*)2, wherein R5* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1- 8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; wherein any two of more of A2, A3, A4, R1, R2, R3, R4, R5, and Ra may together form a ring. 9. The compound according to claim 8, wherein R4 is F, Cl, Br, I, CN, R4*, OR4*, N(R4*)2, wherein R4* is in each case independently selected from hydrogen and C1-8alkyl. 10. The compound according to claim 8, wherein R4 is H, F, CH3, OCH3, or CF3. 11. The compound according to claim 8, wherein R5 is F, Cl, Br, I, CN, R5*, OR5*, N(R5*)2, wherein R5* is in each case independently selected from hydrogen and C1-8alkyl. 12. The compound according to claim 8, wherein R5 is H, F, CH3, OCH3, or CF3. 13. The compound according to claim 8, having the formula: , 14. The compound according to claim 13, having the formula: wherein R2 is H or F. 15. The compound according to claim 13, wherein A2 has the formula: wherein Xa2 is selected from Z, Z-O, Z-S, Z-NRn1, wherein Z is null or a group having the formula: wherein Rn1 is selected from is hydrogen or C1-8alkyl; R1a is selected from F, Cl, Br, I, NO2, CN, R1a*, OR1a*, N(R1a*)2, SO3R1a*, SO2R1a*, SO2N(R1a*)2, C(O)R1a*; C(O)OR1a*, OC(O)R1a*; C(O)N(R1a*)2, N(R1a*)C(O)R1a*, OC(O)N(R1a*)2, N(R1a*)C(O)N(R1a*)2, wherein R1a* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R1a’ is selected from F, Cl, Br, I, NO2, CN, R1a’*, OR1a’*, N(R1a’*)2, SO3R1a’*, SO2R1a’*, SO2N(R1a’*)2, C(O)R1a’*; C(O)OR1a’*, OC(O)R1a’*; C(O)N(R1a’*)2, N(R1a’*)C(O)R1a’*, OC(O)N(R1a’*)2, N(R1a’*)C(O)N(R1a’*)2, wherein R1a’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; or wherein R1a and R1a’ together form an oxo, or thiooxo; R1b is selected from F, Cl, Br, I, NO2, CN, R1b*, OR1b*, N(R1b*)2, SO3R1b*, SO2R1b*, SO2N(R1b*)2, C(O)R1b*; C(O)OR1b*, OC(O)R1b*; C(O)N(R1b*)2, N(R1b*)C(O)R1b*, OC(O)N(R1b*)2, N(R1b*)C(O)N(R1b*)2, wherein R1b* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R1b’ is selected from F, Cl, Br, I, NO2, CN, R1b’*, OR1b’*, N(R1b’*)2, SO3R1b’*, SO2R1b’*, SO2N(R1b’*)2, C(O)R1b’*; C(O)OR1b’*, OC(O)R1b’*; C(O)N(R1b’*)2, N(R1b’*)C(O)R1b’*, OC(O)N(R1b’*)2, N(R1b’*)C(O)N(R1b’*)2, wherein R1b’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; or wherein R1b and R1b’ together form an oxo, or thiooxo R1c is selected from F, Cl, Br, I, NO2, CN, R1c*, OR1c*, N(R1c*)2, SO3R1c*, SO2R1c*, SO2N(R1c*)2, C(O)R1c*; C(O)OR1c*, OC(O)R1c*; C(O)N(R1c*)2, N(R1c*)C(O)R1c*, OC(O)N(R1c*)2, N(R1c*)C(O)N(R1c*)2, wherein R1c* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R1c’ is selected from F, Cl, Br, I, NO2, CN, R1c’*, OR1c’*, N(R1c’*)2, SO3R1c’*, SO2R1c’*, SO2N(R1c’*)2, C(O)R1c’*; C(O)OR1c’*, OC(O)R1c’*; C(O)N(R1c’*)2, N(R1c’*)C(O)R1c’*, OC(O)N(R1c’*)2, N(R1c’*)C(O)N(R1c’*)2, wherein R1c’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; or wherein R1c and R1c’ together form an oxo, or thiooxo R1d is selected from F, Cl, Br, I, NO2, CN, R1d*, OR1d*, N(R1d*)2, SO3R1d*, SO2R1d*, SO2N(R1d*)2, C(O)R1d*; C(O)OR1d*, OC(O)R1d*; C(O)N(R1d*)2, N(R1d*)C(O)R1d*, OC(O)N(R1d*)2, N(R1d*)C(O)N(R1d*)2, wherein R1d* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R1d’ is selected from F, Cl, Br, I, NO2, CN, R1d’*, OR1d’*, N(R1d’*)2, SO3R1d’*, SO2R1d’*, SO2N(R1d’*)2, C(O)R1d’*; C(O)OR1d’*, OC(O)R1d’*; C(O)N(R1d’*)2, N(R1d’*)C(O)R1d’*, OC(O)N(R1d’*)2, N(R1d’*)C(O)N(R1d’*)2, wherein R1d’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; or wherein R1d and R1d’ together form an oxo, or thiooxo R1e is selected from F, Cl, Br, I, NO2, CN, R1e*, OR1e*, N(R1e*)2, SO3R1e*, SO2R1e*, SO2N(R1e*)2, C(O)R1e*; C(O)OR1e*, OC(O)R1e*; C(O)N(R1e*)2, N(R1e*)C(O)R1e*, OC(O)N(R1e*)2, N(R1e*)C(O)N(R1e*)2, wherein R1e* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R1e’ is selected from F, Cl, Br, I, NO2, CN, R1e’*, OR1e’*, N(R1e’*)2, SO3R1e’*, SO2R1e’*, SO2N(R1e’*)2, C(O)R1e’*; C(O)OR1e’*, OC(O)R1e’*; C(O)N(R1e’*)2, N(R1e’*)C(O)R1e’*, OC(O)N(R1e’*)2, N(R1e’*)C(O)N(R1e’*)2, wherein R1e’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; or wherein R1e and R1e’ together form an oxo, or thiooxo R1f is selected from F, Cl, Br, I, NO2, CN, R1f*, OR1f*, N(R1f*)2, SO3R1f*, SO2R1f*, SO2N(R1f*)2, C(O)R1f*; C(O)OR1f*, OC(O)R1f*; C(O)N(R1f*)2, N(R1f*)C(O)R1f*, OC(O)N(R1f*)2, N(R1f*)C(O)N(R1f*)2, wherein R1f* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R1f’ is selected from F, Cl, Br, I, NO2, CN, R1f’*, OR1f’*, N(R1f’*)2, SO3R1f’*, SO2R1f’*, SO2N(R1f’*)2, C(O)R1f’*; C(O)OR1f’*, OC(O)R1f’*; C(O)N(R1f’*)2, N(R1f’*)C(O)R1f’*, OC(O)N(R1f’*)2, N(R1f’*)C(O)N(R1f’*)2, wherein R1f’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; or wherein R1f and R1f’ together form an oxo, or thiooxo; wherein any two adjacent R groups may together form a double bond; wherein any two or more of R1a, R1a’, R1b, R1b’, R1c, R1c’, R1d, R1d’, R1e, R1e’, R1f, R1f’, and Rn1 may together form a ring. 16. The compound according to claim 15, wherein R1a and R1a’ form an oxo, or wherein R1a is F, Cl, Br, I, CN, R1a*, OR1a*, N(R1a*)2, wherein R1a* is in each case independently selected from hydrogen and C1-8alkyl, and R1a’ together with another R group forms a ring, or is H. 17. The compound according to claim 15, wherein R1b and R1b’ form an oxo, or wherein R1b is F, Cl, Br, I, CN, R1b*, OR1b*, N(R1b*)2, wherein R1b* is in each case independently selected from hydrogen and C1-8alkyl, and R1b’ together with another R group forms a ring, or is H. 18. The compound according to claim 15, wherein R1c and R1c’ form an oxo, or wherein R1c is F, Cl, Br, I, CN, R1c*, OR1c*, N(R1c*)2, wherein R1c* is in each case independently selected from hydrogen and C1-8alkyl, and R1c’ together with another R group forms a ring, or is H. 19. The compound according to claim 15, wherein R1d and R1d’ form an oxo, or wherein R1d is F, Cl, Br, I, CN, R1d*, OR1d*, N(R1d*)2, wherein R1d* is in each case independently selected from hydrogen and C1-8alkyl, and R1d’ together with another R group forms a ring, or is H. 20. The compound according to claim 15, wherein R1e and R1e’ form an oxo, or wherein R1e is F, Cl, Br, I, CN, R1e*, OR1e*, N(R1e*)2, wherein R1e* is in each case independently selected from hydrogen and C1-8alkyl, and R1e’ together with another R group forms a ring, or is H. 21. The compound according to claim 15, wherein R1f and R1f’ form an oxo, or wherein R1f is F, Cl, Br, I, CN, R1f*, OR1f*, N(R1f*)2, wherein R1f* is in each case independently selected from hydrogen and C1-8alkyl, and R1f’ together with another R group forms a ring, or is H. 22. The compound according to claim 15, wherein A2 has the formula: wherein X2b is selected from Z1, Z1-O-Z1, Z1-S-Z1, Z1-NRn2-Z1, wherein Z1 is null or a group having the formula: wherein Rn2 is selected from H or C1-8alkyl, wherein R1g is selected from F, Cl, Br, I, NO2, CN, R1g*, OR1g*, N(R1g*)2, SO3R1g*, SO2R1g*, SO2N(R1g*)2, C(O)R1g*; C(O)OR1g*, OC(O)R1g*; C(O)N(R1g*)2, N(R1g*)C(O)R1g*, OC(O)N(R1g*)2, N(R1g*)C(O)N(R1g*)2, wherein R1g* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; wherein R1g’ is selected from F, Cl, Br, I, NO2, CN, R1g’*, OR1g’*, N(R1g’*)2, SO3R1g’*, SO2R1g’*, SO2N(R1g’*)2, C(O)R1g’*; C(O)OR1g’*, OC(O)R1g’*; C(O)N(R1g’*)2, N(R1g’*)C(O)R1g’*, OC(O)N(R1g’*)2, N(R1g’*)C(O)N(R1g’*)2, wherein R1g’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; or wherein R1g and R1g’ together form an oxo, or thiooxo wherein R1h is selected from F, Cl, Br, I, NO2, CN, R1h*, OR1h*, N(R1h*)2, SO3R1h*, SO2R1h*, SO2N(R1h*)2, C(O)R1h*; C(O)OR1h*, OC(O)R1h*; C(O)N(R1h*)2, N(R1h*)C(O)R1h*, OC(O)N(R1h*)2, N(R1h*)C(O)N(R1h*)2, wherein R1h* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; wherein R1h’ is selected from F, Cl, Br, I, NO2, CN, R1h’*, OR1h’*, N(R1h’*)2, SO3R1h’*, SO2R1h’*, SO2N(R1h’*)2, C(O)R1h’*; C(O)OR1h’*, OC(O)R1h’*; C(O)N(R1h’*)2, N(R1h’*)C(O)R1h’*, OC(O)N(R1h’*)2, N(R1h’*)C(O)N(R1h’*)2, wherein R1h’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; or wherein R1h and R1h’ together form an oxo, or thiooxo wherein R1i is selected from F, Cl, Br, I, NO2, CN, R1i*, OR1i*, N(R1i*)2, SO3R1i*, SO2R1i*, SO2N(R1i*)2, C(O)R1i*; C(O)OR1i*, OC(O)R1i*; C(O)N(R1i*)2, N(R1i*)C(O)R1i*, OC(O)N(R1i*)2, N(R1i*)C(O)N(R1i*)2, wherein R1i* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; wherein R1i’ is selected from F, Cl, Br, I, NO2, CN, R1i’*, OR1i’*, N(R1i’*)2, SO3R1i’*, SO2R1i’*, SO2N(R1i’*)2, C(O)R1i’*; C(O)OR1i’*, OC(O)R1i’*; C(O)N(R1i’*)2, N(R1i’*)C(O)R1i’*, OC(O)N(R1i’*)2, N(R1i’*)C(O)N(R1i’*)2, wherein R1i’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; or wherein R1i and R1i’ together form an oxo, or thiooxo wherein any two adjacent R groups may together form a double bond; wherein any two or more of R1a, R1a’, R1b, R1b’, R1c, R1c’, R1d, R1d’, R1e, R1e’, R1f, R1f’, R1g, R1g’, R1g, R1g’, R1i, and R1i may together form a ring; 23. The compound according to claim 14, wherein A2 has the formula: wherein X2a’ is CH2, O, or NH, and n is selected from 0, 1, or 2. 24. The compound according to claim 15, wherein X2b is selected from null, CH2, CH2CH2, CH2CH2CH2, OC(=O), SC(=O), NHC(=O), N(CH3)C(=O), CH2C(=O), OCH2, SCH2, NHCH2, N(CH3)CH2, CH2C(=O)CH2, CH2OCH2, CH2SCH2, CH2NHCH2, CH2N(CH3)CH2, CH2C(=O)CH2, CH2C(=O)O, CH2C(=O)S, CH2C(=O)NH, or CH2C(=O)N(CH3), 25. The compound according to claim 15, wherein R1g and R1g’ form an oxo, or wherein R1g is F, Cl, Br, I, CN, R1g*, OR1g*, N(R1g*)2, wherein R1g* is in each case independently selected from hydrogen and C1-8alkyl, and R1g’ is H. 26. The compound according to claim 15, wherein R1h and R1h’ form an oxo, or wherein R1h is F, Cl, Br, I, CN, R1h*, OR1h*, N(R1h*)2, wherein R1h* is in each case independently selected from hydrogen and C1-8alkyl, and R1h’ is H. 27. The compound according to claim 15, wherein R1i and R1i’ form an oxo, or wherein R1i is F, Cl, Br, I, CN, R1i*, OR1i*, N(R1i*)2, wherein R1i* is in each case independently selected from hydrogen and C1-8alkyl, and R1i’ is H. 28. The compound according to claim 14, wherein A2 has the formula: wherein X2b is: 29. The compound according to claim 28, wherein R1a, R2b, R1c, R1d, and R1e are each hydrogen. 30. The compound according to claim 28, wherein R1a’, R2b’, R1c’, R1d’, and R1e’ are each hydrogen. 31. The compound according to claim 28, wherein A2 has the formula: 32. The compound according to claim 31, wherein A2 has the formula: . 33. The compound according to claim 28, wherein R1a and R1a’ are both H. 34. The compound according to claim 28, wherein R1b is H and R1b’ is H or F. 35. The compound according to claim 28, wherein R1c is H and R1c’ is H or F. 36. The compound according to claim 28, wherein R1d and R1d’ are both H. 37. The compound according to claim 28, wherein R1e and R1e’ are both H. 38. The compound according to claim 1, wherein A2 is NH2, NHCH3, N(CH3)2, NHCH2CH2OH, N(CH2CH2OH)2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2NHCH2CH2OH, CH2N(CH2CH2OH)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, CH2CH2NHCH2CH2OH, or CH2CH2N(CH2CH2OH)2. 39. The compound according to claim 1 or claim 31, wherein A3 has the formula: wherein X3a is CR3a or N, X3b is CR3b or N, X3c is CR3c or N, X3d is CR3d or N, X3e is CR3e or N, X3f is CR3f or N, X4 is NRn3, S, O, Z2 is null, O, S, NRn4; R3a is F, Cl, Br, I, NO2, CN, R3a*, OR3a*, N(R3a*)2, SO3R3a*, SO2R3a*, SO2N(R3a*)2, C(O)R3a*; C(O)OR3a*, OC(O)R3a*; C(O)N(R3a*)2, N(R3a*)C(O)R3a*, OC(O)N(R3a*)2, N(R3a*)C(O)N(R3a*)2, wherein R3a* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R3b is F, Cl, Br, I, NO2, CN, R3b*, OR3b*, N(R3b*)2, SO3R3b*, SO2R3b*, SO2N(R3b*)2, C(O)R3b*; C(O)OR3b*, OC(O)R3b*; C(O)N(R3b*)2, N(R3b*)C(O)R3b*, OC(O)N(R3b*)2, N(R3b*)C(O)N(R3b*)2, wherein R3b* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R3c is F, Cl, Br, I, NO2, CN, R3c*, OR3c*, N(R3c*)2, SO3R3c*, SO2R3c*, SO2N(R3c*)2, C(O)R3c*; C(O)OR3c*, OC(O)R3c*; C(O)N(R3c*)2, N(R3c*)C(O)R3c*, OC(O)N(R3c*)2, N(R3c*)C(O)N(R3c*)2, wherein R3c* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R3d is F, Cl, Br, I, NO2, CN, R3d*, OR3d*, N(R3d*)2, SO3R3d*, SO2R3d*, SO2N(R3d*)2, C(O)R3d*; C(O)OR3d*, OC(O)R3d*; C(O)N(R3d*)2, N(R3d*)C(O)R3d*, OC(O)N(R3d*)2, N(R3d*)C(O)N(R3d*)2, wherein R3d* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R3e is F, Cl, Br, I, NO2, CN, R3e*, OR3e*, N(R3e*)2, SO3R3e*, SO2R3e*, SO2N(R3e*)2, C(O)R3e*; C(O)OR3e*, OC(O)R3e*; C(O)N(R3e*)2, N(R3e*)C(O)R3e*, OC(O)N(R3e*)2, N(R3e*)C(O)N(R3e*)2, wherein R3e* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R3f is F, Cl, Br, I, NO2, CN, R3f*, OR3f*, N(R3f*)2, SO3R3f*, SO2R3f*, SO2N(R3f*)2, C(O)R3f*; C(O)OR3f*, OC(O)R3f*; C(O)N(R3f*)2, N(R3f*)C(O)R3f*, OC(O)N(R3f*)2, N(R3f*)C(O)N(R3f*)2, wherein R3f* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; Rg is F, Cl, Br, I, NO2, CN, R3g*, OR3g*, N(R3g*)2, SO3R3g*, SO2R3g*, SO2N(R3g*)2, C(O)R3g*; C(O)OR3g*, OC(O)R3g*; C(O)N(R3g*)2, N(R3g*)C(O)R3g*, OC(O)N(R3g*)2, N(R3g*)C(O)N(R3g*)2, wherein R3g* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; Rn3 is hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; Rn4 is hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; wherein any one of R3a, R3b, R3c R3d, R3e, R3f, Rn3, or Rn4 may form a bond with Zt, R3a and R3b may together form a ring; R3c and R3d may together form a ring; any two of R3e, R3f, and Rn3 may together form a ring; wavy line 3 represents the point of attachment to NRn, and wavy line 4 represents the point of attachment to A4; wherein any two or more of R1a, R1a’, R1b, R1b’, R1c, R1c’, R1d, R1d’, R1e, R1e’, R1f, R1f’, Rn1, R1g, R1g’, R1g, R1g’, R1i, R1i, R3a, R3b, R3c, R3d, R3e, R3f, R3g, and Rn3 may together form a ring; 40. The compound according to claim 39, wherein A3 has the formula: 41. The compound according to claim 39, wherein A3 has the formula: 42. The compound according to claim 39, wherein R3e, R3f and R3g are each hydrogen. 43. The compound according to claim 39 wherein Rn3 is hydrogen or methyl. 44. The compound according to claim 39, wherein R3e is F, Cl, Br, CN, OC1-3alkyl, OC1- 3haloalkyl, or C1-3alkyl, and R3f and R3g are both hydrogen. 45. The compound according to claim 39, wherein R3f is F, Cl, Br, CN, OC1-3alkyl, OC1- 3haloalkyl, or C1-3alkyl, and R3e and R3g are both hydrogen. 46. The compound according to claim 39, wherein R3g is F, Cl, Br, CN, OC1-3alkyl, OC1- 3haloalkyl, or C1-3alkyl, and R3e and R3f are both hydrogen. 47. The compound according to claim 39, wherein A3 has the formula: 48. The compound according to claim 47, wherein R3a is F, Cl, Br, I, CN, R3a*, OR3a*, N(R3a*)2, C(O)R3a*; C(O)OR3a*, C(O)N(R3a*)2, N(R3a*)C(O)R3a*, wherein R3a* is in each case independently selected from hydrogen, C1- 4alkyl, aryl, C1-6heteroaryl, C3-8cycloalkyl, or C1-6heterocyclyl; R3b is F, Cl, Br, I, CN, R3b*, OR3b*, N(R3b*)2, C(O)R3b*; C(O)OR3b*, C(O)N(R3b*)2, N(R3b*)C(O)R3b*, wherein R3b* is in each case independently selected from hydrogen, C1- 4alkyl, aryl, C1-6heteroaryl, C3-8cycloalkyl, or C1-6heterocyclyl; R3c is F, Cl, Br, I, CN, R3c*, OR3c*, N(R3c*)2, C(O)R3c*; C(O)OR3c *; C(O)N(R3c*)2, N(R3c*)C(O)R3c*, wherein R3c* is in each case independently selected from hydrogen, C1- 4alkyl, aryl, C1-6heteroaryl, C3-8cycloalkyl, or C1-6heterocyclyl; R3d is F, Cl, Br, I, CN, R3d*, OR3d*, N(R3d*)2, C(O)R3d*; C(O)OR3d*, C(O)N(R3d*)2, N(R3d*)C(O)R3d*, OC(O)N(R3d*)2, wherein R3d* is in each case independently selected from hydrogen, C1-4alkyl, aryl, C1-6heteroaryl, C3-8cycloalkyl, or C1-6heterocyclyl. 49. The compound according to claim 39, wherein R3a is F, Cl, Br, I, CN, R3a*, OR3a*, or N(R3a*)2, wherein R3a* is in each case independently selected from hydrogen or C1-4alkyl; R3b is F, Cl, Br, I, CN, R3b*, OR3b*, or N(R3b*)2, wherein R3b* is in each case independently selected from hydrogen or C1-4alkyl; R3c is F, Cl, Br, I, CN, R3c*, OR3c*, or N(R3c*)2, wherein R3c* is in each case independently selected from hydrogen or C1-4alkyl; R3d is F, Cl, Br, I, CN, R3d*, OR3d*, or N(R3d*)2, wherein R3d* is in each case independently selected from hydrogen or C1-4alkyl. 50. The compound according to claim 39, wherein X3a is CR3a, X3b is CR3b, and each of R3a, R3b, R3c, and R3d are hydrogen. 51. The compound according to claim 39, wherein X3a is CR3a, X3b is CR3b, R3a is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, and each of R3b, R3c, and R3d are hydrogen. 52. The compound according to claim 39, wherein X3a is CR3a, X3b is CR3b, R3b is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, and each of R3a, R3c, and R3d are hydrogen. 53. The compound according to claim 39, wherein X3a is CR3a, X3b is CR3b, R3a is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, R3b is F, Cl, Br, CN, OC1-3alkyl, OC1- 3haloalkyl, or C1-3alkyl, and R3c and R3d are both hydrogen. 54. The compound according to claim 39, wherein X3a is CR3a, X3b is CR3b, R3a is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, R3d is F, Cl, Br, CN, OC1-3alkyl, OC1- 3haloalkyl, or C1-3alkyl, and R3b and R3c are both hydrogen. 55. The compound according to claim 39, wherein X3a is CR3a, X3b is CR3b, R3a is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, R3c is F, Cl, Br, CN, OC1-3alkyl, OC1- 3haloalkyl, and R3b and R3d are both hydrogen. 56. The compound according to claim 39, wherein X3a is CR3a, X3b is CR3b, R3b is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, R3c is F, Cl, Br, CN, OC1-3alkyl, OC1- 3haloalkyl, or C1-3alkyl, and R3a and R3d are both hydrogen. 57. The compound according to claim 39, wherein X3a is CR3a, X3b is CR3b, R3b is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, R3d is F, Cl, Br, CN, OC1-3alkyl, OC1- 3haloalkyl, or C1-3alkyl, and R3a and R3c are both hydrogen. 58. The compound according to claim 39, wherein X3a is N, X3b is CR3b, and each of R3b, R3c, and R3d are hydrogen. 59. The compound according to claim 39, wherein X3b is N, X3a is CR3a, and each of R3a, R3c, and R3d are hydrogen. 60. The compound according to claim 39, wherein X3a is N, X3b is CR3b, R3b is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, and R3c and R3d are both hydrogen. 61. The compound according to claim 39, wherein X3a is N, X3b is CR3b, R3c is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, and R3b and R3d are both hydrogen. 62. The compound according to claim 39, wherein X3a is N, X3b is CR3b, R3d is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, and R3b and R3c are both hydrogen. 63. The compound according to claim 39, wherein X3b is N, X3a is CR3a, R3a is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, and R3c and R3d are both hydrogen. 64. The compound according to claim 39, wherein X3b is N, X3a is CR3a, R3c is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, and R3a and R3d are both hydrogen. 65. The compound according to claim 39, wherein X3b is N, X3a is CR3a, R3d is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, and R3a and R3c are both hydrogen. 66. The compound according to claim 1, wherein the A4 has the formula: , wherein R4a is F, Cl, Br, I, NO2, CN, R4a*, OR4a*, N(R4a*)2, SO3R4a*, SO2R4a*, SO2N(R4a*)2, C(O)R4a*; C(O)OR4a*, OC(O)R4a*; C(O)N(R4a*)2, N(R4a*)C(O)R4a*, OC(O)N(R4a*)2, N(R4a*)C(O)N(R4a*)2, wherein R4a* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R4a’ is F, Cl, Br, I, NO2, CN, R4a’*, OR4a’*, N(R4a’*)2, SO3R4a’*, SO2R4a’*, SO2N(R4a’*)2, C(O)R4a’*; C(O)OR4a’*, OC(O)R4a’*; C(O)N(R4a’*)2, N(R4a’*)C(O)R4a’*, OC(O)N(R4a’*)2, N(R4a’*)C(O)N(R4a’*)2, wherein R4a’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; wherein R4a and R4a’ may together form an oxo or thiooxo; R4b is F, Cl, Br, I, NO2, CN, R4b*, OR4b*, N(R4b*)2, SO3R4b*, SO2R4b*, SO2N(R4b*)2, C(O)R4b*; C(O)OR4b*, OC(O)R4b*; C(O)N(R4b*)2, N(R4b*)C(O)R4b*, OC(O)N(R4b*)2, N(R4b*)C(O)N(R4b*)2, wherein R4b* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; R4b’ is F, Cl, Br, I, NO2, CN, R4b’*, OR4b’*, N(R4b’*)2, SO3R4b’*, SO2R4b’*, SO2N(R4b’*)2, C(O)R4b’*; C(O)OR4b’*, OC(O)R4b’*; C(O)N(R4b’*)2, N(R4b’*)C(O)R4b’*, OC(O)N(R4b’*)2, N(R4b’*)C(O)N(R4b’*)2, wherein R4b’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; wherein R4b and R4b’ may together form an oxo or thiooxo; X4a is N or CR4c X4b is N or CR4d R4c is F, Cl, Br, I, NO2, CN, R4c*, OR4c*, N(R4c*)2, SO3R4c*, SO2R4c*, SO2N(R4c*)2, C(O)R4c*; C(O)OR4c*, OC(O)R4c*; C(O)N(R4c*)2, N(R4c*)C(O)R4c*, OC(O)N(R4c*)2, N(R4c*)C(O)N(R4c*)2, wherein R4c* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R4d is F, Cl, Br, I, NO2, CN, R4d*, OR4d*, N(R4d*)2, SO3R4d*, SO2R4d*, SO2N(R4d*)2, C(O)R4d*; C(O)OR4d*, OC(O)R4d*; C(O)N(R4d*)2, N(R4d*)C(O)R4d*, OC(O)N(R4d*)2, N(R4d*)C(O)N(R4d*)2, wherein R4d* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; X5a is null or CR4eR4e’; X5b is null or CR4fR4f’, R4e is F, Cl, Br, I, NO2, CN, R4e*, OR4e*, N(R4e*)2, SO3R4e*, SO2R4e*, SO2N(R4e*)2, C(O)R4e*; C(O)OR4e*, OC(O)R4e*; C(O)N(R4e*)2, N(R4e*)C(O)R4e*, OC(O)N(R4e*)2, N(R4e*)C(O)N(R4e*)2, wherein R4e* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R4e’ is F, Cl, Br, I, NO2, CN, R4e’*, OR4e’*, N(R4e’*)2, SO3R4e’*, SO2R4e’*, SO2N(R4e’*)2, C(O)R4e’*; C(O)OR4e’*, OC(O)R4e’*; C(O)N(R4e’*)2, N(R4e’*)C(O)R4e’*, OC(O)N(R4e’*)2, N(R4e’*)C(O)N(R4e’*)2, wherein R4e’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; wherein R4e and R4e’ may together form an oxo or thiooxo; R4f is F, Cl, Br, I, NO2, CN, R4f*, OR4f*, N(R4f*)2, SO3R4f*, SO2R4f*, SO2N(R4f*)2, C(O)R4f*; C(O)OR4f*, OC(O)R4f*; C(O)N(R4f*)2, N(R4f*)C(O)R4f*, OC(O)N(R4f*)2, N(R4f*)C(O)N(R4f*)2, wherein R4f* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R4f’ is F, Cl, Br, I, NO2, CN, R4f’*, OR4f’*, N(R4f’*)2, SO3R4f’*, SO2R4f’*, SO2N(R4f’*)2, C(O)R4f’*; C(O)OR4f’*, OC(O)R4f’*; C(O)N(R4f’*)2, N(R4f’*)C(O)R4f’*, OC(O)N(R4f’*)2, N(R4f’*)C(O)N(R4f’*)2, wherein R4f’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; wherein R4f and R4f’ may together form an oxo or thiooxo; wherein any two or more of R4a, R4a’, R4b, R4b’, R4c, R4d, R4e, R4e’, R4f, and R4f’ may together form a ring; wherein wavy line 5 represents the point of attachment to A3 and wavy line 6 represents the point of attachment to Ra. 67. The compound according to claim 66, wherein R4a and R4a’ form an oxo, or wherein R4a is F, Cl, Br, I, CN, R4a*, OR4a*, N(R4a*)2, wherein R4a* is in each case independently selected from hydrogen and C1-8alkyl, and R4a’ together with another R group forms a ring, or is H. 68. The compound according to claim 66, wherein R4b and R4b’ form an oxo, or wherein R4b is F, Cl, Br, I, CN, R4b*, OR4b*, N(R4b*)2, wherein R4b* is in each case independently selected from hydrogen and C1-8alkyl, and R4b’ together with another R group forms a ring, or is H. 69. The compound according to claim 66, wherein R4c and R4c’ form an oxo, or wherein R4c is F, Cl, Br, I, CN, R4c*, OR4c*, N(R4c*)2, wherein R4c* is in each case independently selected from hydrogen and C1-8alkyl, and R4c’ together with another R group forms a ring, or is H. 70. The compound according to claim 66, wherein R4d and R4d’ form an oxo, or wherein R4d is F, Cl, Br, I, CN, R4d*, OR4d*, N(R4d*)2, wherein R4d* is in each case independently selected from hydrogen and C1-8alkyl, and R4d’ together with another R group forms a ring, or is H. 71. The compound according to claim 66, wherein R4e and R4e’ form an oxo, or wherein R4e is F, Cl, Br, I, CN, R4e*, OR4e*, N(R4e*)2, wherein R4e* is in each case independently selected from hydrogen and C1-8alkyl, and R4e’ together with another R group forms a ring, or is H. 72. The compound according to claim 66, wherein R4f and R4f’ form an oxo, or wherein R4f is F, Cl, Br, I, CN, R4f*, OR4f*, N(R4f*)2, wherein R4f* is in each case independently selected from hydrogen and C1-8alkyl, and R4f’ together with another R group forms a ring, or is H. 73. The compound according to claim 66, wherein A4 has the formula: 74. The compound according to claim 66, wherein A4 has the formula: wherein X6 is Z2, Z2-O, Z2-S, Z2-NRn4, Z2-O-Z2, Z2-S-Z2, Z2-NRn4-Z2, wherein Z2 is in each case null or a group having the formula: wherein R4g is selected from F, Cl, Br, I, NO2, CN, R4g*, OR4g*, N(R4g*)2, SO3R4g*, SO2R4g*, SO2N(R4g*)2, C(O)R4g*; C(O)OR4g*, OC(O)R4g*; C(O)N(R4g*)2, N(R4g*)C(O)R4g*, OC(O)N(R4g*)2, N(R4g*)C(O)N(R4g*)2, wherein R4g* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; wherein R4g’ is selected from F, Cl, Br, I, NO2, CN, R4g’*, OR4g’*, N(R4g’*)2, SO3R4g’*, SO2R4g’*, SO2N(R4g’*)2, C(O)R4g’*; C(O)OR4g’*, OC(O)R4g’*; C(O)N(R4g’*)2, N(R4g’*)C(O)R4g’*, OC(O)N(R4g’*)2, N(R4g’*)C(O)N(R4g’*)2, wherein R4g’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; or wherein R4g and R4g’ together form an oxo, or thiooxo wherein R4h is selected from F, Cl, Br, I, NO2, CN, R4h*, OR4h*, N(R4h*)2, SO3R4h*, SO2R4h*, SO2N(R4h*)2, C(O)R4h*; C(O)OR4h*, OC(O)R4h*; C(O)N(R4h*)2, N(R4h*)C(O)R4h*, OC(O)N(R4h*)2, N(R4h*)C(O)N(R4h*)2, wherein R4h* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; wherein R4h’ is selected from F, Cl, Br, I, NO2, CN, R4h’*, OR4h’*, N(R4h’*)2, SO3R4h’*, SO2R4h’*, SO2N(R4h’*)2, C(O)R4h’*; C(O)OR4h’*, OC(O)R4h’*; C(O)N(R4h’*)2, N(R4h’*)C(O)R4h’*, OC(O)N(R4h’*)2, N(R4h’*)C(O)N(R4h’*)2, wherein R4h’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; or wherein R4h and R4h’ together form an oxo, or thiooxo wherein R4i is selected from F, Cl, Br, I, NO2, CN, R4i*, OR4i*, N(R4i*)2, SO3R4i*, SO2R4i*, SO2N(R4i*)2, C(O)R4i*; C(O)OR4i*, OC(O)R4i*; C(O)N(R4i*)2, N(R4i*)C(O)R4i*, OC(O)N(R4i*)2, N(R4i*)C(O)N(R4i*)2, wherein R4i* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; wherein R4i’ is selected from F, Cl, Br, I, NO2, CN, R4i’*, OR4i’*, N(R4i’*)2, SO3R4i’*, SO2R4i’*, SO2N(R4i’*)2, C(O)R4i’*; C(O)OR4i’*, OC(O)R4i’*; C(O)N(R4i’*)2, N(R4i’*)C(O)R4i’*, OC(O)N(R4i’*)2, N(R4i’*)C(O)N(R4i’*)2, wherein R4i’* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; or wherein R4i and R4i’ together form an oxo, or thiooxo 75. The compound according to claim 74, wherein A4 is the formula: 76. The compound according to claim 75, wherein X6 is selected from null, CH2, CH2CH2, CH2CH2CH2, OC(=O), SC(=O), NHC(=O), N(CH3)C(=O), CH2C(=O), OCH2, SCH2, NHCH2, N(CH3)CH2, CH2C(=O)CH2, CH2OCH2, CH2SCH2, CH2NHCH2, CH2N(CH3)CH2, CH2C(=O)CH2, CH2C(=O)O, CH2C(=O)S, CH2C(=O)NH, or CH2C(=O)N(CH3), 77. The compound according to claim 76, wherein A4 has the formula: 78. The compound according claim 13 or claim 14, wherein A4 is null and Ra and A3 together form a ring having the formula: . 79. The compound according to claim 13 or claim 14, wherein A4 is null and Ra and A3 together form a ring having the formula: wherein Z2 is null. 80. The compound according to claim 13 or claim 14, wherein A4 is null and Ra and A3 together form a ring having the formula: wherein Z3 is null. 81. The compound according to claim 13 or claim 14, wherein A4 is null and Ra and A3 together form a ring having the formula: 82. The compound according to claim 81, wherein Z4 is C1-6alkylene, preferably CH2, CH2CH2, or CH2CH2CH2. 83. The compound according to claim 81, wherein X3a is N, X3b is CR3b, and R3b and Zt together form a bond. 84. The compound according to claim 81, wherein X3b is N, X3c is CR3c, and R3c and Zt together form a bond. 85. The compound according to claim 81, wherein X3a is CRa, X3b is CR3b, and R3b and Zt together form a bond. 86. The compound according to claim 81, wherein X3b is CRb, X3c is CR3c, and R3c and Zt together form a bond. 87. The compound according to claim 13 or claim 14, wherein Ra has the formula: -Z3-Zc-Z4-Zt, wherein Z3 is null Zc is null, -C(=O)-, -C(=O)O-, or -C(=O)NH- Z4 is C1-6alkylene, Zt is H, F, Cl, Br, I, CN, aryl, C1-8heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, ORza, N(Rza)2, C(=O)ORza, C(=O)NHRza*, wherein Rza* is in each case independently selected from hydrogen, C1-8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl. 88. The compound according to claim 87, wherein Zt is OH. 89. The compound according to claim 87, wherein Zt is H. 90. The compound according to claim 1, having the structure: 91. The compound according to claim 90, wherein X1 is N or CH. 92. The compound according to claim 66, having the structure: 93. The compound according to claim 92, wherein: R3a is H, F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl; R3b is H, F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl; R3c is H, F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl; R3d is H, F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl; 94. The compound according to claim 93, wherein R3a is F, Cl, Br, CN, OC1-3alkyl, OC1- 3haloalkyl, or C1-3alkyl, is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, and R3b, R3c, and R3d are each hydrogen. 95. The compound according to claim 93, wherein R3b is F, Cl, Br, CN, OC1-3alkyl, OC1- 3haloalkyl, or C1-3alkyl, is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, and R3a, R3c, and R3d are each hydrogen. 96. The compound according to claim 93, wherein R3c is F, Cl, Br, CN, OC1-3alkyl, OC1- 3haloalkyl, or C1-3alkyl, is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, and R3a, R3b, and R3d are each hydrogen. 97. The compound according to claim 93, wherein R3d is F, Cl, Br, CN, OC1-3alkyl, OC1- 3haloalkyl, or C1-3alkyl, is F, Cl, Br, CN, OC1-3alkyl, OC1-3haloalkyl, or C1-3alkyl, and R3a, R3b, and R3c are each hydrogen. 98. The compound according to claim 93, wherein X4a is CH or N. 99. The compound according to claim 98, wherein R4a is hydrogen. 100. The compound according to claim 98, wherein R4b is hydrogen. 101. The compound according to claim 98, wherein R4c is hydrogen. 102. The compound according to claim 98, wherein R4d is hydrogen. 103. The compound according to claim 98, wherein R4e and R4f together form a CH2, O, NH, NCH3, or CH2CH2. 104. The compound according claim 1, where Ra is Zc-H, Zc-(CH2)2OH, Zc-(CH2)3OH, Zc-(CH2)4OH, Zc-(CH2)5OH, Zc-(CH2)6OH, wherein Zc is null, C(=O), C(=O)NH, or C(=O)O. 105. The compound of claim 13 or claim 14, wherein A4, Ra and A3 together form a system having the formula: , wherein Rz4 is C1-3alkyl, preferably CH3, and Z4 is CH2, CH2CH2, or CH2CH2CH2. 106. The compound of claim 13 or claim 14, A4, Ra and A3 together form a system having the formula: wherein R1i is F, Cl, Br, I, NO2, CN, R1i*, OR1i*, N(R1i*)2, SO3R1i*, SO2R1i*, SO2N(R1i*)2, C(O)R1i*; C(O)OR1i*, OC(O)R1i*; C(O)N(R1i*)2, N(R1i*)C(O)R1i*, OC(O)N(R1i*)2, N(R1i*)C(O)N(R1i*)2, wherein R1i* is in each case independently selected from hydrogen, C1- 8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R2i is F, Cl, Br, I, NO2, CN, R2i*, OR2i*, N(R2i*)2, SO3R2i*, SO2R2i*, SO2N(R2i*)2, C(O)R2i*; C(O)OR2i*, OC(O)R2i*; C(O)N(R2i*)2, N(R2i*)C(O)R2i*, OC(O)N(R2i*)2, N(R2i*)C(O)N(R2i*)2, wherein R2i* is in each case independently selected from hydrogen, C1- 8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R3i is F, Cl, Br, I, NO2, CN, R3i*, OR3i*, N(R3i*)2, SO3R3i*, SO2R3i*, SO2N(R3i*)2, C(O)R3i*; C(O)OR3i*, OC(O)R3i*; C(O)N(R3i*)2, N(R3i*)C(O)R3i*, OC(O)N(R3i*)2, N(R3i*)C(O)N(R3i*)2, wherein R3i* is in each case independently selected from hydrogen, C1- 8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R4i is F, Cl, Br, I, NO2, CN, R4i*, OR4i*, N(R4i*)2, SO3R4i*, SO2R4i*, SO2N(R4i*)2, C(O)R4i*; C(O)OR4i*, OC(O)R4i*; C(O)N(R4i*)2, N(R4i*)C(O)R4i*, OC(O)N(R4i*)2, N(R4i*)C(O)N(R4i*)2, wherein R4i* is in each case independently selected from hydrogen, C1- 8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R5i is F, Cl, Br, I, NO2, CN, R5i*, OR5i*, N(R5i*)2, SO3R5i*, SO2R5i*, SO2N(R5i*)2, C(O)R5i*; C(O)OR5i*, OC(O)R5i*; C(O)N(R5i*)2, N(R5i*)C(O)R5i*, OC(O)N(R5i*)2, N(R5i*)C(O)N(R5i*)2, wherein R5i* is in each case independently selected from hydrogen, C1- 8alkyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; wherein any two or more of R1i, R2i, R3i, R4i, and R5i can together form a ring. 107. The compound of claim 106, wherein R1i, R2i, and R3i are each hydrogen. 108. The compound of claim 106, wherein R4i and R5i are independently selected from H, C1-6alkyl, C3-8cycloalkyl, or R4i and R5i together form a 5 atom, 6 atom, or 7 atom carbocyclic or heterocyclic ring. 109. The compound of claim 106, wherein R4i and R5i together form an aromatic ring. 110. The compound of claim 106, wherein R4i and R5i together form a heterocyclic ring. 111. The compound of claim 106, wherein R4i and R5i are each CH3, R4i is isopropyl and R5i is H, or R4i is H and R5i is isopropyl. 112. The compound of claim 106, wherein A3, A4, and Ra together form a system having the formula: , , 113. The compound according to claim 106, wherein A3, A4, and Ra together form a system having the formula: , wherein Rx1 and Rx2 are independently selected from H, F, Cl, Br, or CH3, and Rx3 and Rx4 are independently selected from H, F, Cl, Br, or CH3, or one of Rx3 and Rx4 is OH and the other is H or CH3. 114. The compound of claim 113, wherein: Rx1 and Rx2 are each H, and Rx3 and Rx4 are F; Rx1 is CH3, and each of Rx2, Rx3, and Rx4 are H; Rx2 is CH3, and each of Rx1, Rx3, and Rx4 are H; Rx3 is F, and each of Rx1, Rx2, and Rx4 are H; or Rx4 is F, and each of Rx1, Rx2, and Rx3 are H. 115. The compound of claim 13 or claim 14, wherein A3, A4, and Ra together form a system having the formula: , wherein Xq is CH2, O, or NRq3 Rq1 is H, F, Cl, Br, C1-3alkyl, OC1-3alkyl, Rq2 is H, F, Cl, Br, C1-3alkyl, OC1-3alkyl, Rq3 is H, (CH2)cOH or C(=O)OC1-3alkyl, a is 0, 1, or 2, b is 1, 2, or 3, and c is 1, 2, or 3. 116. The compound of claim 115 wherein one of Rq1 and Rq2 is F, and the other is H. 117. The compound of claim 115 wherein Rq2 is H and Rq1 is F. 118. The compound of claim 115 wherein X is NRq3, and Rq3 is H, (CH2)cOH or C(=O)OCH3. 119. The compound of claim 115 wherein, a is 1, b is 2, and c is 2 120. The compound of claim 115 wherein a is 0, b is 1, and c is 2. 121. The compound of claim 115, wherein Rq3 is H or CH2CH2OH. 122. A pharmaceutical composition comprising a compound according to any preceding claim and at least one pharmaceutical excipient. 123. A method of treating a proliferative disorder, comprising administering a subject in need thereof a compound according to any preceding claim. 124. The method according to any preceding claim, wherein the proliferative disorder comprises cancer. 125. The method according to any preceding claim, wherein the cancer is characterized by one or more solid tumors. 126. The method according to any preceding claim, wherein the proliferative disorder comprises a blood cancer. 127. The method according to any preceding claim, wherein the proliferative disorder comprises myelodysplastic syndrome. 128. The method according to any preceding claim, wherein the proliferative disorder comprises leukemia. 129. The method according to any preceding claim, wherein the proliferative disorder comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, mixed lineage leukemia, brain tumor, gliobastoma, or lymphoma. 130. The method according to any preceding claim, wherein the proliferative disorder comprises a bone cancer. 131. The method according to any preceding, wherein the proliferative disorder comprises osteosarcoma, Ewing sarcoma, chondrosarcoma, undifferentiated pleomorphic sarcoma, fibrosarcoma, chordoma, or malignant giant cell tumor. 132. The method according to any preceding claim, wherein the osteosarcoma comprises an osteoblastic cancer, chrondroblastic cancer, fibroblastic cancer, small cell cancer, or telangiectatic cancer. |
wherein R 4 is F, Cl, Br, I, NO 2 , CN, R 4* , OR 4* , N(R 4* ) 2 , SO 3 R 4* , SO 2 R 4* , SO 2 N(R 4* ) 2 , C(O)R 4* ; C(O)OR 4* , OC(O)R 4* ; C(O)N(R 4* ) 2 , N(R 4* )C(O)R 4* , OC(O)N(R 4* ) 2 , N(R 4* )C(O)N(R 4* ) 2 , wherein R 4* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 5 is F, Cl, Br, I, NO 2 , CN, R 5* , OR 5* , N(R 5* ) 2 , SO 3 R 5* , SO 2 R 5* , SO 2 N(R 5* ) 2 , C(O)R 5* ; C(O)OR 5* , OC(O)R 5* ; C(O)N(R 5* ) 2 , N(R 5* )C(O)R 5* , OC(O)N(R 5* ) 2 , N(R 5* )C(O)N(R 5* ) 2 , wherein R 5* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein any two of more of A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , R 5 , and R a may together form a ring. In some embodiments R 4 is F, Cl, Br, I, CN, R 4* , OR 4* , N(R 4* ) 2 , wherein R 4* is in each case independently selected from hydrogen and C 1-8 alkyl. In some embodiments R 4 is H, F, CH 3 , OCH 3 , or CF 3 . In some embodiments R 5 is F, Cl, Br, I, CN, R 5* , OR 5* , N(R 5* ) 2 , wherein R 5* is in each case independently selected from hydrogen and C 1-8 alkyl. In some embodiments R 5 is H, F, CH 3 , OCH 3 , or CF 3 . In some embodiments the compound has the formula:
,
In certain implementations, the compound has the structure: , wherein R 2 is H or F. In some embodiments A 2 has the formula: wherein X a2 is selected from Z, Z-O, Z-S, Z-NR n1 , wherein Z is null or a group having the formula: wherein R n1 is selected from is hydrogen or C 1-8 alkyl; R 1a is selected from F, Cl, Br, I, NO 2 , CN, R 1a* , OR 1a* , N(R 1a* ) 2 , SO 3 R 1a* , SO 2 R 1a* , SO 2 N(R 1a* ) 2 , C(O)R 1a* ; C(O)OR 1a* , OC(O)R 1a* ; C(O)N(R 1a* ) 2 , N(R 1a* )C(O)R 1a* , OC(O)N(R 1a* ) 2 , N(R 1a* )C(O)N(R 1a* ) 2 , wherein R 1a* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 1a’ is selected from F, Cl, Br, I, NO 2 , CN, R 1a’* , OR 1a’* , N(R 1a’* ) 2 , SO 3 R 1a’* , SO 2 R 1a’* , SO 2 N(R 1a’* ) 2 , C(O)R 1a’* ; C(O)OR 1a’* , OC(O)R 1a’* ; C(O)N(R 1a’* ) 2 , N(R 1a’* )C(O)R 1a’* , OC(O)N(R 1a’* ) 2 , N(R 1a’* )C(O)N(R 1a’* ) 2 , wherein R 1a’* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; or wherein R 1a and R 1a’ together form an oxo, or thiooxo; R 1b is selected from F, Cl, Br, I, NO 2 , CN, R 1b* , OR 1b* , N(R 1b* ) 2 , SO 3 R 1b* , SO 2 R 1b* , SO 2 N(R 1b* ) 2 , C(O)R 1b* ; C(O)OR 1b* , OC(O)R 1b* ; C(O)N(R 1b* ) 2 , N(R 1b* )C(O)R 1b* , OC(O)N(R 1b* ) 2 , N(R 1b* )C(O)N(R 1b* ) 2 , wherein R 1b* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 1b’ is selected from F, Cl, Br, I, NO 2 , CN, R 1b’* , OR 1b’* , N(R 1b’* ) 2 , SO 3 R 1b’* , SO 2 R 1b’* , SO 2 N(R 1b’* ) 2 , C(O)R 1b’* ; C(O)OR 1b’* , OC(O)R 1b’* ; C(O)N(R 1b’* ) 2 , N(R 1b’* )C(O)R 1b’* , OC(O)N(R 1b’* ) 2 , N(R 1b’* )C(O)N(R 1b’* ) 2 , wherein R 1b’* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; or wherein R 1b and R 1b’ together form an oxo, or thiooxo R 1c is selected from F, Cl, Br, I, NO 2 , CN, R 1c* , OR 1c* , N(R 1c* ) 2 , SO 3 R 1c* , SO 2 R 1c* , SO 2 N(R 1c* ) 2 , C(O)R 1c* ; C(O)OR 1c* , OC(O)R 1c* ; C(O)N(R 1c* ) 2 , N(R 1c* )C(O)R 1c* , OC(O)N(R 1c* ) 2 , N(R 1c* )C(O)N(R 1c* ) 2 , wherein R 1c* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 1c’ is selected from F, Cl, Br, I, NO 2 , CN, R 1c’* , OR 1c’* , N(R 1c’* ) 2 , SO 3 R 1c’* , SO 2 R 1c’* , SO 2 N(R 1c’* ) 2 , C(O)R 1c’* ; C(O)OR 1c’* , OC(O)R 1c’* ; C(O)N(R 1c’* ) 2 , N(R 1c’* )C(O)R 1c’* , OC(O)N(R 1c’* ) 2 , N(R 1c’* )C(O)N(R 1c’* ) 2 , wherein R 1c’* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; or wherein R 1c and R 1c’ together form an oxo, or thiooxo R 1d is selected from F, Cl, Br, I, NO 2 , CN, R 1d* , OR 1d* , N(R 1d* ) 2 , SO 3 R 1d* , SO 2 R 1d* , SO 2 N(R 1d* ) 2 , C(O)R 1d* ; C(O)OR 1d* , OC(O)R 1d* ; C(O)N(R 1d* ) 2 , N(R 1d* )C(O)R 1d* , OC(O)N(R 1d* ) 2 , N(R 1d* )C(O)N(R 1d* ) 2 , wherein R 1d* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 1d’ is selected from F, Cl, Br, I, NO 2 , CN, R 1d’* , OR 1d’* , N(R 1d’* ) 2 , SO 3 R 1d’* , SO 2 R 1d’* , SO 2 N(R 1d’* ) 2 , C(O)R 1d’* ; C(O)OR 1d’* , OC(O)R 1d’* ; C(O)N(R 1d’* ) 2 , N(R 1d’* )C(O)R 1d’* , OC(O)N(R 1d’* ) 2 , N(R 1d’* )C(O)N(R 1d’* ) 2 , wherein R 1d’* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; or wherein R 1d and R 1d’ together form an oxo, or thiooxo R 1e is selected from F, Cl, Br, I, NO 2 , CN, R 1e* , OR 1e* , N(R 1e* ) 2 , SO 3 R 1e* , SO 2 R 1e* , SO 2 N(R 1e* ) 2 , C(O)R 1e* ; C(O)OR 1e* , OC(O)R 1e* ; C(O)N(R 1e* ) 2 , N(R 1e* )C(O)R 1e* , OC(O)N(R 1e* ) 2 , N(R 1e* )C(O)N(R 1e* ) 2 , wherein R 1e* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 1e’ is selected from F, Cl, Br, I, NO 2 , CN, R 1e’* , OR 1e’* , N(R 1e’* ) 2 , SO 3 R 1e’* , SO 2 R 1e’* , SO 2 N(R 1e’* ) 2 , C(O)R 1e’* ; C(O)OR 1e’* , OC(O)R 1e’* ; C(O)N(R 1e’* ) 2 , N(R 1e’* )C(O)R 1e’* , OC(O)N(R 1e’* ) 2 , N(R 1e’* )C(O)N(R 1e’* ) 2 , wherein R 1e’* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; or wherein R 1e and R 1e’ together form an oxo, or thiooxo R 1f is selected from F, Cl, Br, I, NO 2 , CN, R 1f* , OR 1f* , N(R 1f* ) 2 , SO 3 R 1f* , SO 2 R 1f* , SO 2 N(R 1f* ) 2 , C(O)R 1f* ; C(O)OR 1f* , OC(O)R 1f* ; C(O)N(R 1f* ) 2 , N(R 1f* )C(O)R 1f* , OC(O)N(R 1f* ) 2 , N(R 1f* )C(O)N(R 1f* ) 2 , wherein R 1f* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 1f’ is selected from F, Cl, Br, I, NO 2 , CN, R 1f’* , OR 1f’* , N(R 1f’* ) 2 , SO 3 R 1f’* , SO 2 R 1f’* , SO 2 N(R 1f’* ) 2 , C(O)R 1f’* ; C(O)OR 1f’* , OC(O)R 1f’* ; C(O)N(R 1f’* ) 2 , N(R 1f’* )C(O)R 1f’* , OC(O)N(R 1f’* ) 2 , N(R 1f’* )C(O)N(R 1f’* ) 2 , wherein R 1f’* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; or wherein R 1f and R 1f’ together form an oxo, or thiooxo; wherein any two adjacent R groups may together form a double bond; wherein any two or more of R 1a , R 1a’ , R 1b , R 1b’ , R 1c , R 1c’ , R 1d , R 1d’ , R 1e , R 1e’ , R 1f , R 1f’ , and R n1 may together form a ring. In some embodiments R 1a and R 1a’ form an oxo, or wherein R 1a is F, Cl, Br, I, CN, R 1a* , OR 1a* , N(R 1a* ) 2 , wherein R 1a* is in each case independently selected from hydrogen and C 1- 8 alkyl, and R 1a’ together with another R group forms a ring, or is H. In some embodiments R 1b and R 1b’ form an oxo, or wherein R 1b is F, Cl, Br, I, CN, R 1b* , OR 1b* , N(R 1b* ) 2 , wherein R 1b* is in each case independently selected from hydrogen and C 1- 8 alkyl, and R 1b’ together with another R group forms a ring, or is H. In some embodiments R 1c and R 1c’ form an oxo, or wherein R 1c is F, Cl, Br, I, CN, R 1c* , OR 1c* , N(R 1c* ) 2 , wherein R 1c* is in each case independently selected from hydrogen and C 1- 8 alkyl, and R 1c’ together with another R group forms a ring, or is H. In some embodiments R 1d and R 1d’ form an oxo, or wherein R 1d is F, Cl, Br, I, CN, R 1d* , OR 1d* , N(R 1d* ) 2 , wherein R 1d* is in each case independently selected from hydrogen and C 1- 8 alkyl, and R 1d’ together with another R group forms a ring, or is H. In some embodiments R 1e and R 1e’ form an oxo, or wherein R 1e is F, Cl, Br, I, CN, R 1e* , OR 1e* , N(R 1e* ) 2 , wherein R 1e* is in each case independently selected from hydrogen and C 1- 8 alkyl, and R 1e’ together with another R group forms a ring, or is H. In some embodiments R 1f and R 1f’ form an oxo, or wherein R 1f is F, Cl, Br, I, CN, R 1f* , OR 1f* , N(R 1f* ) 2 , wherein R 1f* is in each case independently selected from hydrogen and C 1-8 alkyl, and R 1f’ together with another R group forms a ring, or is H. In certain implementations A 2 has the formula: wherein X 2a’ is CH 2 , O, or NR n1 , and n is selected from 0, 1, or 2. In some embodiments A 2 has the formula: wherein X 2b is selected from Z 1 , Z 1 -O-Z 1 , Z 1 -S-Z 1 , Z 1 -NR n2 -Z 1 , wherein Z 1 is null or a group having the formula: wherein R n2 is selected from H or C 1-8 alkyl, wherein R 1g is selected from F, Cl, Br, I, NO 2 , CN, R 1g* , OR 1g* , N(R 1g* ) 2 , SO 3 R 1g* , SO 2 R 1g* , SO 2 N(R 1g* ) 2 , C(O)R 1g* ; C(O)OR 1g* , OC(O)R 1g* ; C(O)N(R 1g* ) 2 , N(R 1g* )C(O)R 1g* , OC(O)N(R 1g* ) 2 , N(R 1g* )C(O)N(R 1g* ) 2 , wherein R 1g* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein R 1g’ is selected from F, Cl, Br, I, NO 2 , CN, R 1g’* , OR 1g’* , N(R 1g’* ) 2 , SO 3 R 1g’* , SO 2 R 1g’* , SO 2 N(R 1g’* ) 2 , C(O)R 1g’* ; C(O)OR 1g’* , OC(O)R 1g’* ; C(O)N(R 1g’* ) 2 , N(R 1g’* )C(O)R 1g’* , OC(O)N(R 1g’* ) 2 , N(R 1g’* )C(O)N(R 1g’* ) 2 , wherein R 1g’* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; or wherein R 1g and R 1g’ together form an oxo, or thiooxo wherein R 1h is selected from F, Cl, Br, I, NO 2 , CN, R 1h* , OR 1h* , N(R 1h* ) 2 , SO 3 R 1h* , SO 2 R 1h* , SO 2 N(R 1h* ) 2 , C(O)R 1h* ; C(O)OR 1h* , OC(O)R 1h* ; C(O)N(R 1h* ) 2 , N(R 1h* )C(O)R 1h* , OC(O)N(R 1h* ) 2 , N(R 1h* )C(O)N(R 1h* ) 2 , wherein R 1h* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein R 1h’ is selected from F, Cl, Br, I, NO 2 , CN, R 1h’* , OR 1h’* , N(R 1h’* ) 2 , SO 3 R 1h’* , SO 2 R 1h’* , SO 2 N(R 1h’* ) 2 , C(O)R 1h’* ; C(O)OR 1h’* , OC(O)R 1h’* ; C(O)N(R 1h’* ) 2 , N(R 1h’* )C(O)R 1h’* , OC(O)N(R 1h’* ) 2 , N(R 1h’* )C(O)N(R 1h’* ) 2 , wherein R 1h’* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; or wherein R 1h and R 1h’ together form an oxo, or thiooxo wherein R 1i is selected from F, Cl, Br, I, NO 2 , CN, R 1i* , OR 1i* , N(R 1i* ) 2 , SO 3 R 1i* , SO 2 R 1i* , SO 2 N(R 1i* ) 2 , C(O)R 1i* ; C(O)OR 1i* , OC(O)R 1i* ; C(O)N(R 1i* ) 2 , N(R 1i* )C(O)R 1i* , OC(O)N(R 1i* ) 2 , N(R 1i* )C(O)N(R 1i* ) 2 , wherein R 1i* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein R 1i’ is selected from F, Cl, Br, I, NO 2 , CN, R 1i’* , OR 1i’* , N(R 1i’* ) 2 , SO 3 R 1i’* , SO 2 R 1i’* , SO 2 N(R 1i’* ) 2 , C(O)R 1i’* ; C(O)OR 1i’* , OC(O)R 1i’* ; C(O)N(R 1i’* ) 2 , N(R 1i’* )C(O)R 1i’* , OC(O)N(R 1i’* ) 2 , N(R 1i’* )C(O)N(R 1i’* ) 2 , wherein R 1i’* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; or wherein R 1i and R 1i’ together form an oxo, or thiooxo wherein any two adjacent R groups may together form a double bond; wherein any two or more of R 1a , R 1a’ , R 1b , R 1b’ , R 1c , R 1c’ , R 1d , R 1d’ , R 1e , R 1e’ , R 1f , R 1f’ , R 1g , R 1g’ , R 1g , R 1g’ , R 1i , and R 1i may together form a ring; In some embodiments X 2b is selected from null, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , OC(=O), SC(=O), NHC(=O), N(CH 3 )C(=O), CH 2 C(=O), OCH 2 , SCH 2 , NHCH 2 , N(CH 3 )CH 2 , CH 2 C(=O)CH 2 , CH 2 OCH 2 , CH 2 SCH 2 , CH 2 NHCH 2 , CH 2 N(CH 3 )CH 2 , CH 2 C(=O)CH 2 , CH 2 C(=O)O, CH 2 C(=O)S, CH 2 C(=O)NH, or CH 2 C(=O)N(CH 3 ), In some embodiments R 1g and R 1g’ form an oxo, or wherein R 1g is F, Cl, Br, I, CN, R 1g* , OR 1g* , N(R 1g* ) 2 , wherein R 1g* is in each case independently selected from hydrogen and C 1- 8 alkyl, and R 1g’ is H. In some embodiments R 1h and R 1h’ form an oxo, or wherein R 1h is F, Cl, Br, I, CN, R 1h* , OR 1h* , N(R 1h* ) 2 , wherein R 1h* is in each case independently selected from hydrogen and C 1- 8 alkyl, and R 1h’ is H. In some embodiments R 1i and R 1i’ form an oxo, or wherein R 1i is F, Cl, Br, I, CN, R 1i* , OR 1i* , N(R 1i* ) 2 , wherein R 1i* is in each case independently selected from hydrogen and C 1-8 alkyl, and R 1i’ is H. In some embodiments A 2 has the formula: , wherein X 2b is: In some embodiments R 1a , R 2b , R 1c , R 1d , and R 1e are each hydrogen. In some embodiments R 1a’ , R 2b’ , R 1c’ , R 1d’ , and R 1e’ are each hydrogen. In some embodiments A 2 has the formula:
In some embodiments A 2 has the formula: . In some embodiments R 1a and R 1a’ are both H. In some embodiments R 1b is H and R 1b’ is H or F. In some embodiments R 1c is H and R 1c’ is H or F. In some embodiments R 1d and R 1d’ are both H. In some embodiments R 1e and R 1e’ are both H. In some embodiments A 2 is NH 2 , NHCH 3 , N(CH 3 ) 2 , NHCH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 NHCH 2 CH 2 OH, CH 2 N(CH 2 CH 2 OH) 2 , CH 2 CH 2 NH 2 , CH 2 CH 2 NHCH 3 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 NHCH 2 CH 2 OH, or CH 2 CH 2 N(CH 2 CH 2 OH) 2 . In some embodiments A 3 has the formula: wherein X 3a is CR 3a or N, X 3b is CR 3b or N, X 3c is CR 3c or N, X 3d is CR 3d or N, X 3e is CR 3e or N, X 3f is CR 3f or N, X 4 is NR n3 , S, O, Z 2 is null, O, S, NR n4 ; R 3a is F, Cl, Br, I, NO 2 , CN, R 3a* , OR 3a* , N(R 3a* ) 2 , SO 3 R 3a* , SO 2 R 3a* , SO 2 N(R 3a* ) 2 , C(O)R 3a* ; C(O)OR 3a* , OC(O)R 3a* ; C(O)N(R 3a* ) 2 , N(R 3a* )C(O)R 3a* , OC(O)N(R 3a* ) 2 , N(R 3a* )C(O)N(R 3a* ) 2 , wherein R 3a* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 3b is F, Cl, Br, I, NO 2 , CN, R 3b* , OR 3b* , N(R 3b* ) 2 , SO 3 R 3b* , SO 2 R 3b* , SO 2 N(R 3b* ) 2 , C(O)R 3b* ; C(O)OR 3b* , OC(O)R 3b* ; C(O)N(R 3b* ) 2 , N(R 3b* )C(O)R 3b* , OC(O)N(R 3b* ) 2 , N(R 3b* )C(O)N(R 3b* ) 2 , wherein R 3b* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 3c is F, Cl, Br, I, NO 2 , CN, R 3c* , OR 3c* , N(R 3c* ) 2 , SO 3 R 3c* , SO 2 R 3c* , SO 2 N(R 3c* ) 2 , C(O)R 3c* ; C(O)OR 3c* , OC(O)R 3c* ; C(O)N(R 3c* ) 2 , N(R 3c* )C(O)R 3c* , OC(O)N(R 3c* ) 2 , N(R 3c* )C(O)N(R 3c* ) 2 , wherein R 3c* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 3d is F, Cl, Br, I, NO 2 , CN, R 3d* , OR 3d* , N(R 3d* ) 2 , SO 3 R 3d* , SO 2 R 3d* , SO 2 N(R 3d* ) 2 , C(O)R 3d* ; C(O)OR 3d* , OC(O)R 3d* ; C(O)N(R 3d* ) 2 , N(R 3d* )C(O)R 3d* , OC(O)N(R 3d* ) 2 , N(R 3d* )C(O)N(R 3d* ) 2 , wherein R 3d* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 3e is F, Cl, Br, I, NO 2 , CN, R 3e* , OR 3e* , N(R 3e* ) 2 , SO 3 R 3e* , SO 2 R 3e* , SO 2 N(R 3e* ) 2 , C(O)R 3e* ; C(O)OR 3e* , OC(O)R 3e* ; C(O)N(R 3e* ) 2 , N(R 3e* )C(O)R 3e* , OC(O)N(R 3e* ) 2 , N(R 3e* )C(O)N(R 3e* ) 2 , wherein R 3e* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 3f is F, Cl, Br, I, NO 2 , CN, R 3f* , OR 3f* , N(R 3f* ) 2 , SO 3 R 3f* , SO 2 R 3f* , SO 2 N(R 3f* ) 2 , C(O)R 3f* ; C(O)OR 3f* , OC(O)R 3f* ; C(O)N(R 3f* ) 2 , N(R 3f* )C(O)R 3f* , OC(O)N(R 3f* ) 2 , N(R 3f* )C(O)N(R 3f* ) 2 , wherein R 3f* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R g is F, Cl, Br, I, NO 2 , CN, R 3g* , OR 3g* , N(R 3g* ) 2 , SO 3 R 3g* , SO 2 R 3g* , SO 2 N(R 3g* ) 2 , C(O)R 3g* ; C(O)OR 3g* , OC(O)R 3g* ; C(O)N(R 3g* ) 2 , N(R 3g* )C(O)R 3g* , OC(O)N(R 3g* ) 2 , N(R 3g* )C(O)N(R 3g* ) 2 , wherein R 3g* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R n3 is hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R n4 is hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein any one of R 3a , R 3b , R 3c R 3d , R 3e , R 3f , R n3 , or R n4 may form a bond with Z t , R 3a and R 3b may together form a ring; R 3c and R 3d may together form a ring; any two of R 3e , R 3f , and R n3 may together form a ring; wavy line 3 represents the point of attachment to the aminopyrimidine group, and wavy line 4 represents the point of attachment to A 4 ; wherein any two or more of R 1a , R 1a’ , R 1b , R 1b’ , R 1c , R 1c’ , R 1d , R 1d’ , R 1e , R 1e’ , R 1f , R 1f’ , R n1 , R 1g , R 1g’ , R 1g , R 1g’ , R 1i , R 1i , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R n2 , and R n3 , and A 4 may together form a ring; In some embodiments A 3 has the formula: In some embodiments A 3 has the formula:
In some embodiments R 3e , R 3f and R 3g are each hydrogen. In some embodiments R n3 is hydrogen or methyl. In some embodiments R 3e is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, and R 3f and R 3g are both hydrogen. In some embodiments R 3f is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, and R 3e and R 3g are both hydrogen. In some embodiments R 3g is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, and R 3e and R 3f are both hydrogen. In some embodiments A 3 has the formula: In some embodiments R 3a is F, Cl, Br, I, CN, R 3a* , OR 3a* , N(R 3a* ) 2 , C(O)R 3a* ; C(O)OR 3a* , C(O)N(R 3a* ) 2 , N(R 3a* )C(O)R 3a* , wherein R 3a* is in each case independently selected from hydrogen, C 1-4 alkyl, aryl, C 1-6 heteroaryl, C 3-8 cycloalkyl, or C 1-6 heterocyclyl; R 3b is F, Cl, Br, I, CN, R 3b* , OR 3b* , N(R 3b* ) 2 , C(O)R 3b* ; C(O)OR 3b* , C(O)N(R 3b* ) 2 , N(R 3b* )C(O)R 3b* , wherein R 3b* is in each case independently selected from hydrogen, C 1-4 alkyl, aryl, C 1-6 heteroaryl, C 3-8 cycloalkyl, or C 1-6 heterocyclyl; R 3c is F, Cl, Br, I, CN, R 3c* , OR 3c* , N(R 3c* ) 2 , C(O)R 3c* ; C(O)OR 3c * ; C(O)N(R 3c* ) 2 , N(R 3c* )C(O)R 3c* , wherein R 3c* is in each case independently selected from hydrogen, C 1-4 alkyl, aryl, C 1-6 heteroaryl, C 3-8 cycloalkyl, or C 1-6 heterocyclyl; R 3d is F, Cl, Br, I, CN, R 3d* , OR 3d* , N(R 3d* ) 2 , C(O)R 3d* ; C(O)OR 3d* , C(O)N(R 3d* ) 2 , N(R 3d* )C(O)R 3d* , OC(O)N(R 3d* ) 2 , wherein R 3d* is in each case independently selected from hydrogen, C 1-4 alkyl, aryl, C 1-6 heteroaryl, C 3-8 cycloalkyl, or C 1-6 heterocyclyl. In some embodiments R 3a is F, Cl, Br, I, CN, R 3a* , OR 3a* , or N(R 3a* ) 2 , wherein R 3a* is in each case independently selected from hydrogen or C 1-4 alkyl; R 3b is F, Cl, Br, I, CN, R 3b* , OR 3b* , or N(R 3b* ) 2 , wherein R 3b* is in each case independently selected from hydrogen or C 1-4 alkyl; R 3c is F, Cl, Br, I, CN, R 3c* , OR 3c* , or N(R 3c* ) 2 , wherein R 3c* is in each case independently selected from hydrogen or C 1-4 alkyl; R 3d is F, Cl, Br, I, CN, R 3d* , OR 3d* , or N(R 3d* ) 2 , wherein R 3d* is in each case independently selected from hydrogen or C 1-4 alkyl. In some embodiments X 3a is CR 3a , X 3b is CR 3b , and each of R 3a , R 3b , R 3c , and R 3d are hydrogen. In some embodiments X 3a is CR 3a , X 3b is CR 3b , R 3a is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, and each of R 3b , R 3c , and R 3d are hydrogen. In some embodiments X 3a is CR 3a , X 3b is CR 3b , R 3b is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, and each of R 3a , R 3c , and R 3d are hydrogen. In some embodiments X 3a is CR 3a , X 3b is CR 3b , R 3a is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, R 3b is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, and R 3c and R 3d are both hydrogen. In some embodiments X 3a is CR 3a , X 3b is CR 3b , R 3a is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, R 3d is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, and R 3b and R 3c are both hydrogen. In some embodiments X 3a is CR 3a , X 3b is CR 3b , R 3a is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, R 3c is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, and R 3b and R 3d are both hydrogen. In some embodiments X 3a is CR 3a , X 3b is CR 3b , R 3b is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, R 3c is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, and R 3a and R 3d are both hydrogen. In some embodiments X 3a is CR 3a , X 3b is CR 3b , R 3b is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, R 3d is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, and R 3a and R 3c are both hydrogen. In some embodiments X 3a is N, X 3b is CR 3b , and each of R 3b , R 3c , and R 3d are hydrogen. In some embodiments X 3b is N, X 3a is CR 3a , and each of R 3a , R 3c , and R 3d are hydrogen. In some embodiments X 3a is N, X 3b is CR 3b , R 3b is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, and R 3c and R 3d are both hydrogen. In some embodiments X 3a is N, X 3b is CR 3b , R 3c is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, and R 3b and R 3d are both hydrogen. In some embodiments X 3a is N, X 3b is CR 3b , R 3d is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, and R 3b and R 3c are both hydrogen. In some embodiments X 3b is N, X 3a is CR 3a , R 3a is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, and R 3c and R 3d are both hydrogen. In some embodiments X 3b is N, X 3a is CR 3a , R 3c is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, and R 3a and R 3d are both hydrogen. In some embodiments X 3b is N, X 3a is CR 3a , R 3d is F, Cl, Br, CN, OC 1-3 alkyl, OC 1- 3 haloalkyl, or C 1-3 alkyl, and R 3a and R 3c are both hydrogen. In some embodiments the A 4 has the formula: , wherein R 4a is F, Cl, Br, I, NO 2 , CN, R 4a* , OR 4a* , N(R 4a* ) 2 , SO 3 R 4a* , SO 2 R 4a* , SO 2 N(R 4a* ) 2 , C(O)R 4a* ; C(O)OR 4a* , OC(O)R 4a* ; C(O)N(R 4a* ) 2 , N(R 4a* )C(O)R 4a* , OC(O)N(R 4a* ) 2 , N(R 4a* )C(O)N(R 4a* ) 2 , wherein R 4a* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 4a’ is F, Cl, Br, I, NO 2 , CN, R 4a’* , OR 4a’* , N(R 4a’* ) 2 , SO 3 R 4a’* , SO 2 R 4a’* , SO 2 N(R 4a’* ) 2 , C(O)R 4a’* ; C(O)OR 4a’* , OC(O)R 4a’* ; C(O)N(R 4a’* ) 2 , N(R 4a’* )C(O)R 4a’* , OC(O)N(R 4a’* ) 2 , N(R 4a’* )C(O)N(R 4a’* ) 2 , wherein R 4a’* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein R 4a and R 4a’ may together form an oxo or thiooxo; R 4b is F, Cl, Br, I, NO 2 , CN, R 4b* , OR 4b* , N(R 4b* ) 2 , SO 3 R 4b* , SO 2 R 4b* , SO 2 N(R 4b* ) 2 , C(O)R 4b* ; C(O)OR 4b* , OC(O)R 4b* ; C(O)N(R 4b* ) 2 , N(R 4b* )C(O)R 4b* , OC(O)N(R 4b* ) 2 , N(R 4b* )C(O)N(R 4b* ) 2 , wherein R 4b* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 4b’ is F, Cl, Br, I, NO 2 , CN, R 4b’* , OR 4b’* , N(R 4b’* ) 2 , SO 3 R 4b’* , SO 2 R 4b’* , SO 2 N(R 4b’* ) 2 , C(O)R 4b’* ; C(O)OR 4b’* , OC(O)R 4b’* ; C(O)N(R 4b’* ) 2 , N(R 4b’* )C(O)R 4b’* , OC(O)N(R 4b’* ) 2 , N(R 4b’* )C(O)N(R 4b’* ) 2 , wherein R 4b’* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein R 4b and R 4b’ may together form an oxo or thiooxo; X 4a is N or CR 4c X 4b is N or CR 4d R 4c is F, Cl, Br, I, NO 2 , CN, R 4c* , OR 4c* , N(R 4c* ) 2 , SO 3 R 4c* , SO 2 R 4c* , SO 2 N(R 4c* ) 2 , C(O)R 4c* ; C(O)OR 4c* , OC(O)R 4c* ; C(O)N(R 4c* ) 2 , N(R 4c* )C(O)R 4c* , OC(O)N(R 4c* ) 2 , N(R 4c* )C(O)N(R 4c* ) 2 , wherein R 4c* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 4d is F, Cl, Br, I, NO 2 , CN, R 4d* , OR 4d* , N(R 4d* ) 2 , SO 3 R 4d* , SO 2 R 4d* , SO 2 N(R 4d* ) 2 , C(O)R 4d* ; C(O)OR 4d* , OC(O)R 4d* ; C(O)N(R 4d* ) 2 , N(R 4d* )C(O)R 4d* , OC(O)N(R 4d* ) 2 , N(R 4d* )C(O)N(R 4d* ) 2 , wherein R 4d* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; X 5a is null or CR 4e R 4e’ ; X 5b is null or CR 4f R 4f’ , R 4e is F, Cl, Br, I, NO 2 , CN, R 4e* , OR 4e* , N(R 4e* ) 2 , SO 3 R 4e* , SO 2 R 4e* , SO 2 N(R 4e* ) 2 , C(O)R 4e* ; C(O)OR 4e* , OC(O)R 4e* ; C(O)N(R 4e* ) 2 , N(R 4e* )C(O)R 4e* , OC(O)N(R 4e* ) 2 , N(R 4e* )C(O)N(R 4e* ) 2 , wherein R 4e* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 4e’ is F, Cl, Br, I, NO 2 , CN, R 4e’* , OR 4e’* , N(R 4e’* ) 2 , SO 3 R 4e’* , SO 2 R 4e’* , SO 2 N(R 4e’* ) 2 , C(O)R 4e’* ; C(O)OR 4e’* , OC(O)R 4e’* ; C(O)N(R 4e’* ) 2 , N(R 4e’* )C(O)R 4e’* , OC(O)N(R 4e’* ) 2 , N(R 4e’* )C(O)N(R 4e’* ) 2 , wherein R 4e’* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein R 4e and R 4e’ may together form an oxo or thiooxo; R 4f is F, Cl, Br, I, NO 2 , CN, R 4f* , OR 4f* , N(R 4f* ) 2 , SO 3 R 4f* , SO 2 R 4f* , SO 2 N(R 4f* ) 2 , C(O)R 4f* ; C(O)OR 4f* , OC(O)R 4f* ; C(O)N(R 4f* ) 2 , N(R 4f* )C(O)R 4f* , OC(O)N(R 4f* ) 2 , N(R 4f* )C(O)N(R 4f* ) 2 , wherein R 4f* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 4f’ is F, Cl, Br, I, NO 2 , CN, R 4f’* , OR 4f’* , N(R 4f’* ) 2 , SO 3 R 4f’* , SO 2 R 4f’* , SO 2 N(R 4f’* ) 2 , C(O)R 4f’* ; C(O)OR 4f’* , OC(O)R 4f’* ; C(O)N(R 4f’* ) 2 , N(R 4f’* )C(O)R 4f’* , OC(O)N(R 4f’* ) 2 , N(R 4f’* )C(O)N(R 4f’* ) 2 , wherein R 4f’* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein R 4f and R 4f’ may together form an oxo or thiooxo; wherein any two or more of R 4a , R 4a’ , R 4b , R 4b’ , R 4c , R 4d , R 4e , R 4e’ , R 4f , and R 4f’ may together form a ring; wherein wavy line 5 represents the point of attachment to A 3 and wavy line 6 represents the point of attachment to R a . In some embodiments R 4a and R 4a’ form an oxo, or wherein R 4a is F, Cl, Br, I, CN, R 4a* , OR 4a* , N(R 4a* ) 2 , wherein R 4a* is in each case independently selected from hydrogen and C 1- 8 alkyl, and R 4a’ together with another R group forms a ring, or is H. In some embodiments R 4b and R 4b’ form an oxo, or wherein R 4b is F, Cl, Br, I, CN, R 4b* , OR 4b* , N(R 4b* ) 2 , wherein R 4b* is in each case independently selected from hydrogen and C 1- 8 alkyl, and R 4b’ together with another R group forms a ring, or is H. In some embodiments R 4c and R 4c’ form an oxo, or wherein R 4c is F, Cl, Br, I, CN, R 4c* , OR 4c* , N(R 4c* ) 2 , wherein R 4c* is in each case independently selected from hydrogen and C 1- 8 alkyl, and R 4c’ together with another R group forms a ring, or is H. In some embodiments R 4d and R 4d’ form an oxo, or wherein R 4d is F, Cl, Br, I, CN, R 4d* , OR 4d* , N(R 4d* ) 2 , wherein R 4d* is in each case independently selected from hydrogen and C 1- 8 alkyl, and R 4d’ together with another R group forms a ring, or is H. In some embodiments R 4e and R 4e’ form an oxo, or wherein R 4e is F, Cl, Br, I, CN, R 4e* , OR 4e* , N(R 4e* ) 2 , wherein R 4e* is in each case independently selected from hydrogen and C 1- 8 alkyl, and R 4e’ together with another R group forms a ring, or is H. In some embodiments R 4f and R 4f’ form an oxo, or wherein R 4f is F, Cl, Br, I, CN, R 4f* , OR 4f* , N(R 4f* ) 2 , wherein R 4f* is in each case independently selected from hydrogen and C 1-8 alkyl, and R 4f’ together with another R group forms a ring, or is H. In some embodiments A 4 has the formula: In some embodiments A 4 has the formula: wherein X 6 is Z 2 , Z 2 -O, Z 2 -S, Z 2 -NR n4 , Z 2 -O-Z 2 , Z 2 -S-Z 2 , Z 2 -NR n4 -Z 2 , wherein Z 2 is in each case null or a group having the formula: wherein R 4g is selected from F, Cl, Br, I, NO 2 , CN, R 4g* , OR 4g* , N(R 4g* ) 2 , SO 3 R 4g* , SO 2 R 4g* , SO 2 N(R 4g* ) 2 , C(O)R 4g* ; C(O)OR 4g* , OC(O)R 4g* ; C(O)N(R 4g* ) 2 , N(R 4g* )C(O)R 4g* , OC(O)N(R 4g* ) 2 , N(R 4g* )C(O)N(R 4g* ) 2 , wherein R 4g* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein R 4g’ is selected from F, Cl, Br, I, NO 2 , CN, R 4g’* , OR 4g’* , N(R 4g’* ) 2 , SO 3 R 4g’* , SO 2 R 4g’* , SO 2 N(R 4g’* ) 2 , C(O)R 4g’* ; C(O)OR 4g’* , OC(O)R 4g’* ; C(O)N(R 4g’* ) 2 , N(R 4g’* )C(O)R 4g’* , OC(O)N(R 4g’* ) 2 , N(R 4g’* )C(O)N(R 4g’* ) 2 , wherein R 4g’* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; or wherein R 4g and R 4g’ together form an oxo, or thiooxo wherein R 4h is selected from F, Cl, Br, I, NO 2 , CN, R 4h* , OR 4h* , N(R 4h* ) 2 , SO 3 R 4h* , SO 2 R 4h* , SO 2 N(R 4h* ) 2 , C(O)R 4h* ; C(O)OR 4h* , OC(O)R 4h* ; C(O)N(R 4h* ) 2 , N(R 4h* )C(O)R 4h* , OC(O)N(R 4h* ) 2 , N(R 4h* )C(O)N(R 4h* ) 2 , wherein R 4h* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein R 4h’ is selected from F, Cl, Br, I, NO 2 , CN, R 4h’* , OR 4h’* , N(R 4h’* ) 2 , SO 3 R 4h’* , SO 2 R 4h’* , SO 2 N(R 4h’* ) 2 , C(O)R 4h’* ; C(O)OR 4h’* , OC(O)R 4h’* ; C(O)N(R 4h’* ) 2 , N(R 4h’* )C(O)R 4h’* , OC(O)N(R 4h’* ) 2 , N(R 4h’* )C(O)N(R 4h’* ) 2 , wherein R 4h’* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; or wherein R 4h and R 4h’ together form an oxo, or thiooxo wherein R 4i is selected from F, Cl, Br, I, NO 2 , CN, R 4i* , OR 4i* , N(R 4i* ) 2 , SO 3 R 4i* , SO 2 R 4i* , SO 2 N(R 4i* ) 2 , C(O)R 4i* ; C(O)OR 4i* , OC(O)R 4i* ; C(O)N(R 4i* ) 2 , N(R 4i* )C(O)R 4i* , OC(O)N(R 4i* ) 2 , N(R 4i* )C(O)N(R 4i* ) 2 , wherein R 4i* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein R 4i’ is selected from F, Cl, Br, I, NO 2 , CN, R 4i’* , OR 4i’* , N(R 4i’* ) 2 , SO 3 R 4i’* , SO 2 R 4i’* , SO 2 N(R 4i’* ) 2 , C(O)R 4i’* ; C(O)OR 4i’* , OC(O)R 4i’* ; C(O)N(R 4i’* ) 2 , N(R 4i’* )C(O)R 4i’* , OC(O)N(R 4i’* ) 2 , N(R 4i’* )C(O)N(R 4i’* ) 2 , wherein R 4i’* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; or wherein R 4i and R 4i’ together form an oxo, or thiooxo In some embodiments A 4 is the formula:
In some embodiments X 6 is selected from null, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , OC(=O), SC(=O), NHC(=O), N(CH 3 )C(=O), CH 2 C(=O), OCH 2 , SCH 2 , NHCH 2 , N(CH 3 )CH 2 , CH 2 C(=O)CH 2 , CH 2 OCH 2 , CH 2 SCH 2 , CH 2 NHCH 2 , CH 2 N(CH 3 )CH 2 , CH 2 C(=O)CH 2 , CH 2 C(=O)O, CH 2 C(=O)S, CH 2 C(=O)NH, or CH 2 C(=O)N(CH 3 ), In some embodiments A 4 has the formula: In further implementations, In certain implementations, A 4 , R a and A 3 together form a system having the formula: . In certain implementations, A 4 , R a and A 3 together form a system having the formula: wherein Z 2 is null. In certain implementations, A 4 , R a and A 3 together form a system having the formula: wherein Z 3 is null. In some embodiments A 4 , R a and A 3 together form a system having the formula: , , , . In some embodiments Z 4 is C 1-6 alkylene, preferably CH 2 , CH 2 CH 2 , or CH 2 CH 2 CH 2 . In some embodiments X 3a is N, X 3b is CR 3b , and R 3b and Z t together form a bond. In some embodiments X 3b is N, X 3c is CR 3c , and R 3c and Z t together form a bond. In some embodiments X 3a is CR a , X 3b is CR 3b , and R 3b and Z t together form a bond. In some embodiments X 3b is CR b , X 3c is CR 3c , and R 3c and Z t together form a bond. In further implementations, A 4 , R a and A 3 together form a system having the formula: , wherein R z4 is C 1-3 alkyl, preferably CH 3 , and Z 4 is CH 2 , CH 2 CH 2 , or CH 2 CH 2 CH 2 . In some embodiments R a has the formula: -Z 3 -Z c -Z 4 -Z t , wherein Z 3 is null Z c is null, -C(=O)-, -C(=O)O-, or -C(=O)NH- Z 4 is C 1-6 alkylene, Z t is H, F, Cl, Br, I, CN, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, C 1-8 heterocyclyl, OR za , N(R za ) 2 , C(=O)OR za , C(=O)NHR za* , wherein R za* is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl. In some embodiments Z t is OH. In some embodiments Z t is H. In some implementations, A 3 , A 4 , and R a together form a system having the formula: wherein R 1i is F, Cl, Br, I, NO 2 , CN, R 1i* , OR 1i* , N(R 1i* ) 2 , SO 3 R 1i* , SO 2 R 1i* , SO 2 N(R 1i* ) 2 , C(O)R 1i* ; C(O)OR 1i* , OC(O)R 1i* ; C(O)N(R 1i* ) 2 , N(R 1i* )C(O)R 1i* , OC(O)N(R 1i* ) 2 , N(R 1i* )C(O)N(R 1i* ) 2 , wherein R 1i* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 2i is F, Cl, Br, I, NO 2 , CN, R 2i* , OR 2i* , N(R 2i* ) 2 , SO 3 R 2i* , SO 2 R 2i* , SO 2 N(R 2i* ) 2 , C(O)R 2i* ; C(O)OR 2i* , OC(O)R 2i* ; C(O)N(R 2i* ) 2 , N(R 2i* )C(O)R 2i* , OC(O)N(R 2i* ) 2 , N(R 2i* )C(O)N(R 2i* ) 2 , wherein R 2i* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 3i is F, Cl, Br, I, NO 2 , CN, R 3i* , OR 3i* , N(R 3i* ) 2 , SO 3 R 3i* , SO 2 R 3i* , SO 2 N(R 3i* ) 2 , C(O)R 3i* ; C(O)OR 3i* , OC(O)R 3i* ; C(O)N(R 3i* ) 2 , N(R 3i* )C(O)R 3i* , OC(O)N(R 3i* ) 2 , N(R 3i* )C(O)N(R 3i* ) 2 , wherein R 3i* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 4i is F, Cl, Br, I, NO 2 , CN, R 4i* , OR 4i* , N(R 4i* ) 2 , SO 3 R 4i* , SO 2 R 4i* , SO 2 N(R 4i* ) 2 , C(O)R 4i* ; C(O)OR 4i* , OC(O)R 4i* ; C(O)N(R 4i* ) 2 , N(R 4i* )C(O)R 4i* , OC(O)N(R 4i* ) 2 , N(R 4i* )C(O)N(R 4i* ) 2 , wherein R 4i* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; R 5i is F, Cl, Br, I, NO 2 , CN, R 5i* , OR 5i* , N(R 5i* ) 2 , SO 3 R 5i* , SO 2 R 5i* , SO 2 N(R 5i* ) 2 , C(O)R 5i* ; C(O)OR 5i* , OC(O)R 5i* ; C(O)N(R 5i* ) 2 , N(R 5i* )C(O)R 5i* , OC(O)N(R 5i* ) 2 , N(R 5i* )C(O)N(R 5i* ) 2 , wherein R 5i* is in each case independently selected from hydrogen, C 1- 8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein any two or more of R 1i , R 2i , R 3i , R 4i , and R 5i can together form a ring. In certain implementations, R 1i , R 2i , and R 3i are each hydrogen. In certain implementations, R 4i and R 5i are independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl or R 4i and R 5i together form a 5 atom, 6 atom, or 7 atom carbocyclic or heterocyclic ring. In certain implementations, R 4i and R 5i together form a carbocyclic ring, in certain implementations, R 4i and R 5i together an aromatic ring. In further implementation R 4i and R 5i together form a heterocyclic ring. In some implementations R 4i and R 5i are each CH 3 . In some implementations R 4i is C 1-3 alkyl and R 5i is H. In some implementations R 4i is H and R 5i is C 1-3 alkyl. In some implementations R 4i is isopropyl and R 5i is H. In some implementations R 4i is H and R 5i is isopropyl. In some implementations, A 3 , A 4 , and R a together form a system having the formula:
In some implementations, A 3 , A 4 , and R a together form a system having the formula: , wherein R x1 and R x2 are independently selected from H, F, Cl, Br, or CH 3 , and R x3 and R x4 are independently selected from H, F, Cl, Br, or CH 3 , or one of R x3 and R x4 is OH and the other is H or CH 3 . In some implementations, R x1 and R x2 are each H, and R x3 and R x4 are F. In some implementations, R x1 is CH 3 , and each of R x2 , R x3 , and R x4 are H. In some implementations, R x2 is CH 3 , and each of R x1 , R x3 , and R x4 are H. In some implementations, R x3 is F, and each of R x1 , R x2 , and R x4 are H. In some implementations, R x4 is F, and each of R x1 , R x2 , and R x3 are H. In some embodiments the compound has the structure:
In some embodiments X 1 is N or CH. In some embodiments the compound has the structure:
In certain embodiments, R a is C3-6carbocyclyl, C 1-6 heterocyclyl, or C(=O)NHC 1-6 alkyl. Z c -H, Z c -(CH 2 ) 2 OH, Z c -(CH 2 ) 3 OH, Z c -(CH 2 )4OH, Z c -(CH 2 ) 5 OH, Z c -(CH 2 ) 6 OH, wherein Z c is null, C(=O), C(=O)NH, or C(=O)O. In some implementations, R a is C 3-6 carbocyclyl or C 1- 6 heterocyclyl optionally substituted with OH, -CH 2 OH, -(CH 2 ) 2 OH -(CH 2 ) 3 OH. R 3a is H, F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl; R 3b is H, F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl; R 3c is H, F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl; R 3d is H, F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl; In some embodiments R 3a is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, and R 3b , R 3c , and R 3d are each hydrogen. In some embodiments R 3b is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, and R 3a , R 3c , and R 3d are each hydrogen. In some embodiments R 3c is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, and R 3a , R 3b , and R 3d are each hydrogen. In some embodiments R 3d is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, is F, Cl, Br, CN, OC 1-3 alkyl, OC 1-3 haloalkyl, or C 1-3 alkyl, and R 3a , R 3b , and R 3c are each hydrogen. In some embodiments X 4a is CH or N. In some embodiments R 4a is hydrogen. In some embodiments R 4b is hydrogen. In some embodiments R 4c is hydrogen. In some embodiments R 4d is hydrogen. In some embodiments R 4e and R 4f together form a CH 2 , O, NH, NCH 3 , or CH 2 CH 2 . In some implementations, A 3 , A 4 , and R a together form a system having the formula: , wherein X q is CH 2 , O, or NR q3 R q1 is H, F, Cl, Br, C 1-3 alkyl, OC 1-3 alkyl, R q2 is H, F, Cl, Br, C 1-3 alkyl, OC 1-3 alkyl, R q3 is H, (CH 2 )cOH or C(=O)OC 1-3 alkyl, a is 0, 1, or 2, b is 1, 2, or 3, and c is 1, 2, or 3. In certain implementations, one of R q1 and R q2 is F, and the other is H. In some implementations, R q2 is H and R q1 is F. In certain implementations, X is NR q3 , and R q3 is H, (CH 2 )cOH or C(=O)OCH 3 . In certain implementations, a is 1, b is 2, and c is 2; in other implementations, a is 0, b is 1, and c is 2. In certain implementations, R q3 is H or CH 2 CH 2 OH. The following compounds are within the scope of the invention and have STK17A inhibitory activity include the following: (in all cases n is 1, 2, 3, 4, or 5; m = 0, 1, or 2; R = H, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 heterocyclyl; R1 = H, F, Cl, Br, I, CN, C 1-8 alkyl, OC 1-8 alkyl:
. wherein R is C 3-6 carbocyclyl, C 1-6 heterocyclyl, or C(=O)NHC 1-6 alkyl, Z c -H, Z c -(CH 2 ) 2 OH, Z c - (CH 2 ) 3 OH, Z c -(CH 2 ) 4 OH, Z c -(CH 2 ) 5 OH, Z c -(CH 2 ) 6 OH, wherein Z c is null, C(=O), C(=O)NH, or C(=O)O. In some implementations, R a is C3-6carbocyclyl or C 1-6 heterocyclyl optionally substituted with OH, -CH 2 OH, -(CH 2 ) 2 OH -(CH 2 ) 3 OH. The compounds disclosed herein may be formulated in pharmaceutical compositions for administration to a subject. Exemplary compositions will include at least one pharmaceutically acceptable excipient A pharmaceutical composition comprising a compound according to any preceding claim and at least one pharmaceutical excipient. Such compositions include, but are not limited to, unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution, transdermal patches and sprinkles, however, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like. Liquid or semisolid dosage form (liquids, suspensions, solutions, dispersions, ointments, creams, emulsions, microemulsions, sprays, patches, spot-on), injection preparations, parenteral, topical, inhalations, buccal, nasal etc. may also be envisaged under the ambit of the invention. Suitable excipients may be used for formulating the dosage forms according to the present invention such as, but not limited to, surface stabilizers or surfactants, viscosity modifying agents, polymers including extended release polymers, stabilizers, disintegrants or super disintegrants, diluents, plasticizers, binders, glidants, lubricants, sweeteners, flavoring agents, anti-caking agents, opacifiers, anti-microbial agents, antifoaming agents, emulsifiers, buffering agents, coloring agents, carriers, fillers, anti-adherents, solvents, taste-masking agents, preservatives, antioxidants, texture enhancers, channeling agents, coating agents or combinations thereof. The compounds disclosed herein may be administered by a number of different routes. For instance, the compounds may be administered orally, topically, transdermally, intravenously, subcutaneously, by inhalation, or by intracerebroventricular delivery. In some embodiments, the compounds disclosed herein may be formulated as nanoparticles. The nanoparticles may have an average particle size from 1-1,000 nm, preferably 10-500 nm, and even more preferably from 10-200 nm. The compounds may be administered to a patient systemically, e.g., by oral or intravenous administration, topically, i.e., by application of a cream, lotion or the like, or locally, e.g., by direct perfusion of a composition containing the compound to a target tissue. The disclosed compounds have STK17A inhibitory activity and as such may be effectively used for the treatment of proliferative disorders, including cancer and similar diseases. The compounds may be used to treat cancers characterized by one or more solid tumors. In other embodiments, the proliferative disorder is a blood cancer. In some embodiments, the proliferative disorder is myelodysplastic syndrome. In some embodiments, the proliferative disorder is leukemia. In some instances the compounds may be used to treat proliferative disorder such as acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, mixed lineage leukemia, brain tumor, glioblastoma, or lymphoma. In certain embodiments, the compounds may be used to treat bone cancer. In certain embodiments, the compounds may be used to treat glioblastoma. In certain embodiments, the compounds may be used to treat osteosarcoma, Ewing sarcoma, chondrosarcoma, undifferentiated pleomorphic sarcoma, fibrosarcoma, chordoma, or malignant giant cell tumor. In certain embodiments, the compounds may be used to treat an osteosarcoma such as an osteoblastic cancer, chrondroblastic cancer, fibroblastic cancer, small cell cancer, telangiectatic cancer. In other embodiments, the compounds may be used to treat other cancers. Exemplary cancers include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancer in adrenocortical carcinoma, adrenal cortex cancer, AIDS-related cancers, Kaposi sarcoma, AIDS- related lymphoma, primary CNS lymphoma, anal cancer, appendix cancer, carcinoid tumors, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, skin cancer (nonmelanoma), bile duct cancer, extrahepatic bladder cancer, bladder cancer, bone cancer (includes Ewing sarcoma and osteosarcoma and malignant fibrous histiocytoma), brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma (non-Hodgkin), carcinoid tumor, cardiac (heart) tumors, atypical teratoid/rhabdoid tumor, embryonal tumors, germ cell tumors, lymphoma, primary - cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, central nervous system, endometrial cancer, ependymoma, esophageal, esthesioneuroblastoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, intraocular melanoma, retinoblastoma, fallopian tube cancer, fibrous histiocytoma of bone, malignant, and osteosarcoma, gallbladder cancer, gastric (stomach) cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), gastrointestinal stromal tumors (GIST), germ cell tumors, central nervous system, extracranial, extragonadal, ovarian testicular, gestational trophoblastic disease, gliomas, hairy cell leukemia, head and neck cancer, heart tumors, hepatocellular (liver) cancer, histiocytosis, Langerhans Cell, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney - langerhans cell histiocytosis, laryngeal cancer, laryngeal cancer and papillomatosis, leukemia, lip and oral cavity cancer, liver cancer (primary), lung cancer, lung cancer, lymphoma - macroglobulinemia, Waldenström –Non-Hodgkin lymphoma, male breast cancer, malignant fibrous histiocytoma of bone and osteosarcoma, melanoma, intraocular (eye), Merkel cell carcinoma, mesothelioma, malignant, mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasms, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms and chronic myeloproliferative neoplasms, myelogenous leukemia, chronic (CML), myeloid leukemia, acute (AML), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nasopharyngeal cancer, neuroblastoma, non- hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer and oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer and pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pheochromocytoma, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, salivary gland tumors, Ewing sarcoma, Kaposi sarcoma, osteosarcoma, rhabdomyosarcoma, uterine sarcoma, vascular tumors, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer with occult primary, metastatic, stomach (gastric) cancer, stomach (gastric) cancer, T-cell lymphoma, cutaneous, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, ureter and renal pelvis, transitional cell cancer, urethral cancer, uterine cancer, endometrial and uterine sarcoma, vaginal cancer, vaginal cancer, vascular tumors, vulvar cancer, Waldenström Macroglobulinemia, Wilms Tumor. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of such conjoint treatment in addition to compositions of the present invention may be, for example, surgery, radiotherapy, chemotherapy, signal transduction inhibitors and/or monoclonal antibodies. As such, the compounds disclosed herein may be administered as part of a combination treatment regime, for instance prior to or following surgery or prior to or following radiation treatment. In some embodiments, the compounds disclosed herein may be administered in combination with one or more anticancer agents for example mitotic inhibitors, alkylating agents, anti-metabolites, antisense DNA or RNA, intercalating antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, cytostatic agents anti-androgens, targeted antibodies, HMG-CoA reductase inhibitors, and prenyl-protein transferase inhibitors. Exemplary anti-cancer agents include nucleoside analogues, antifolates, antimetabolites, topoisomerase I inhibitor, anthracyclines, podophyllotoxins, taxanes, vinca alkaloids, alkylating agents, platinum compounds, proteasome inhibitors, nitrogen mustards & oestrogen analogue, monoclonal antibodies, tyrosine kinase inhibitors, mTOR inhibitors, retinoids, immunomodulatory agents, histone deacetylase inhibitors, and combinations thereof. In certain embodiments, the anti-cancer agent is selected from one or more of abiraterone acetate, methotrexate, paclitaxel albumin-stabilized nanoparticle, brentuximab vedotin, ado- trastuzumab emtansine, doxorubicin hydrochloride, afatinib dimaleate, everolimus, netupitant, palonosetron hydrochloride, imiquimod, aldesleukin, alectinib, alemtuzumab, melphalan hydrochloride, melphalan, pemetrexed disodium, chlorambucil, aminolevulinic acid, anastrozole, aprepitant, pamidronate disodium, exemestane, nelarabine, arsenic trioxide, ofatumumab, asparaginase erwinia chrysanthemi, atezolizumab, bevacizumab, axitinib, azacitidine, carmustine, belinostat, bendamustine hydrochloride, bevacizumab, bexarotene, tositumomab, bicalutamide, bleomycin, blinatumomab, blinatumomab, bortezomib, bosutinib, busulfan, cabazitaxel, cabozantinib, alemtuzumab, irinotecan hydrochloride, capecitabine, fluorouracil, carboplatin, carfilzomib, bicalutamide, lomustine, ceritinib, daunorubicin hydrochloride, cetuximab, chlorambucil, cyclophosphamide, clofarabine, cobimetinib, dactinomycin, cobimetinib, crizotinib, ifosfamide, ramucirumab, cytarabine, dabrafenib, dacarbazine, decitabine, daratumumab, dasatinib, daunorubicin hydrochloride, decitabine, efibrotide sodium, defibrotide sodium, degarelix, denileukin diftitox, denosumab, dexamethasone, dexrazoxane hydrochloride, dinutuximab, docetaxel, doxorubicin hydrochloride, dacarbazine, rasburicase, epirubicin hydrochloride, elotuzumab, oxaliplatin, eltrombopag olamine, aprepitant, elotuzumab, enzalutamide, epirubicin hydrochloride, cetuximab, eribulin mesylate, vismodegib, erlotinib hydrochloride, etoposide, raloxifene hydrochloride, melphalan hydrochloride, toremifene, panobinostat, fulvestrant, letrozole, filgrastim, fludarabine phosphate, flutamide, methotrexate, pralatrexate, recombinant hpv quadrivalent vaccine, recombinant hpv nonavalent vaccine, obinutuzumab, gefitinib, gemcitabine hydrochloride, gemtuzumab ozogamicin, afatinib dimaleate, imatinib mesylate, glucarpidase, goserelin acetate, eribulin mesylate, trastuzumab, topotecan hydrochloride, palbociclib, ibritumomab tiuxetan, ibrutinib, ponatinib hydrochloride, idarubicin hydrochloride, idelalisib, imiquimod, axitinib, recombinant interferon alfa-2b, tositumomab, ipilimumab, gefitinib, romidepsin, ixabepilone, ixazomib citrate, ruxolitinib phosphate, cabazitaxel, ado-trastuzumab emtansine, palifermin, pembrolizumab, lanreotide acetate, lapatinib ditosylate, lenalidomide lenvatinib mesylate, leuprolide acetate, olaparib, vincristine sulfate, procarbazine hydrochloride, mechlorethamine hydrochloride, megestrol acetate, trametinib, mercaptopurine, temozolomide, mitoxantrone hydrochloride, plerixafor, busulfan, azacitidine, gemtuzumab ozogamicin, vinorelbine tartrate, necitumumab, nelarabine, sorafenib tosylate, nilotinib, ixazomib citrate, nivolumab, romiplostim, obinutuzumab, ofatumumab, olaparib, omacetaxine mepesuccinate, pegaspargase, ondansetron hydrochloride, osimertinib, panitumumab, panobinostat, peginterferon alfa-2b, pembrolizumab, pertuzumab, plerixafor, pomalidomide, ponatinib hydrochloride, necitumumab, pralatrexate, procarbazine hydrochloride, aldesleukin, denosumab, ramucirumab, rasburicase, regorafenib, lenalidomide, rituximab, rolapitant hydrochloride, romidepsin, ruxolitinib phosphate, siltuximab, dasatinib, sunitinib malate, thalidomide, dabrafenib, osimertinib, talimogene, atezolizumab, temsirolimus, thalidomide, dexrazoxane hydrochloride, trabectedin, trametinib, trastuzumab, lapatinib ditosylate, dinutuximab, vandetanib, rolapitant hydrochloride, bortezomib, venetoclax, crizotinib, enzalutamide, ipilimumab, trabectedin, ziv-aflibercept, idelalisib, ceritinib, and pharmaceutically acceptable salts thereof. EXAMPLES The following examples are for the purpose of illustration of the invention only and are not intended to limit the scope of the present invention in any manner whatsoever. Example 1. N-(4-(piperazin-1-yl)phenyl)-4-(2-(pyrrolidin-1-yl)quinazoli n-6-yl)pyrimidin-2- amine. Analytical LC showed a single peak by UV absorption at 254 nM with a purity of >95%. Chemical Formula: C 26 H 28 N 8 , Mass Spectroscopy, [M + H] + , calculated: 453, observed: 453. The following compounds were prepared under analogous conditions. Each of the compounds was characterized through a combination of NHR, LC/MS, and other techniques.
Example 88: IC 50 determinations of enzymatic activities of kinase inhibitors. All enzymatic assays and panel profiling studies are activity assays, which were carried out by Reaction Biology Corporation according to the company’s protocols. IC 50 data against some kinases for a few selected compounds are shown in Table 1 below: ***: IC 50 < 50 nM; ** 50 nM < IC 50 < 100 nM; *: IC 50 > 100 nM Example 89. IC 50 values for Example 7 in hematological malignancies.
Example 90: IC 50 values for Example 27 in hematological malignancies.
The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less, however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments of the invention and are also disclosed. Other than in the examples, or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches.
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