Background of the invention Glucagon is a key hormonal agent that, in cooperation with insulin, mediates homeostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain ceils (mostly liver cells) to release glucose when blood glucose levels fall. The action of gluca- gon is opposed by insulin which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones.

Glucagon is produced in the alpha islet cells and insulin in the beta islet cells of the pancreas.

Diabetes meilitus, the common disorder of glucose metabolism, is characterized by hypergly- cemia, and can present as type 1, insulin-dependent, or type 11, a form that is non-insulin- dependent in character. Subjects with type I diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin. However, in some patients with type I or 11 diabetes, absolute or relative eievated glucagon levels have been shown to contribute to the hyperglycemic state. Both in healthy animals as well as in animal models of type I and 11, removal of circulating glucagon with selective and specific anti- bodies has resulted in reduction of the glycemic level (Brand et al. Diabetologia 37, 985 (1994 Diabetes 43, [suppl 1], 172A (1994); Am J Physiol 269, E469-E477 (1995); Diabetes 44 [suppl 1], 134A t1995); Diabetes 45, 1076 (1996)). These studies suggest that glucagon suppression or an action antagonistic to glucagon could be a useful adjunct to conventional antihypergly- cemia treatment of diabetes. The action of glucagon can be suppressed by providing an an- tagonist or an inverse agonist, substances that inhibit or prevent glucagon induced response.

The antagonist can be peptide or non-peptide in nature. Native glucagon is a 29 amino acid- containing peptide having the sequence:

His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp- Ser-Arg-Arg-Ala-Gln-Asp- Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-NH2.

Glucagon exerts its action by binding to and activating its receptor, which is part of the Glu- cagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family (Jelinek et al. Science 259, 1614, (1993)). The receptor functions by activation of the adenylyl cyclase second messenger system and the result is an increase in cAMP levels.

Several publications disclose peptide antagonists. Probably, the most thoroughly character- ized antagonist is DesHis1[Glu9]-glucagon amide (Unson et al., Peptides 10, 1171 (1989); Post et al., Proc. Natl. Acad. Sci. USA 90, 1662 (1993)). Other antagonists are eg DesHis',Phe5[Giu9]-glucagon amide (Azizh et al., Bioorganic & Medicinal Chem. Lett. 16, 1849 (1995)) or NLeu9,A1a1116-glucagon amide (Unson et al., J. Biol. Chem. 269(17), 12548 (1994)).

Peptide antagonists of peptide hormones are often quite potent; however, they are defective as drugs because of degradation by physioiogical enzymes, and poor biodistribution. Therefore, non-peptide antagonists of the peptide hormones are preferred. Among the non-peptide glu- cagon antagonists, a quinoxaline derivative, (2-styryl-3-[3-(dimethylamino)propylmethyl- amino]-6,7-dichloroquinoxaline was found to displace glucagon from the rat liver receptor (Collins, J.L. et al. (1992) Bioorganic and Medicinal Chemistry Letters 2(9):915-918). West, R.R;-et al. (1994), WO 94/14426 discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as glucagon antagonists.

Anderson, P.L., U.S. Patent No. 4,359,474 discloses the glucagon antagonistic properties of 1- phenyl pyrazole derivatives. Barcza, S., U.S. Patent No. 4,374,130, discloses substituted disi- lacyclohexanes as glucagon antagonists. WO 98/04528 (Bayer Corporation) discloses substi- tuted pyridines and biphenyls as glucagon antagonists. Furthermore, WO 97/16442 (Merck & Co., Inc.) discloses substituted pyridyl pyrroles as glucagon antagonists and WO 98/21957 (Merck & Co., Inc.) discloses 2,4-diaryl-5-pyridylimidazoles as glucagon antagonists. These glucagon antagonists differ structurally from the present compounds.

Description of the invention Definitions The following is a detailed definition of the terms used to describe the compounds of the inven- tion: "Halogen" designates an atom selected from the group consisting of F, Cl, Br or The term "alkyl" in the present context designates a hydrocarbon chain or a ring that is either saturated or unsaturated (containing one or more double or triple bonds where feasible) of from 1 to 10 carbon atoms in either a linear or branched or cyclic configuration. Thus, alkyl includes for example n-octyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, allyl, propargyl, 2- hexynyl, cyclopropyl, cyciopropylmethyl, cyclopentyl, cyclohexyl, cyclooctyl, 4-cyclohexylbutyl, and the like.

Further non-limiting examples are sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n- hexyl, isohexyl, n-heptyl, n-nonyl, n-decyl, vinyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1- hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 2,4-heptadienyl, 1-octenyl, 2,4- octadienyl, ethynyl, I -propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-hepynyl, 1-octynyl, 2-decynyl, cyclobutyl, cyclopentyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cyclopropylethyl, cyclobutylmethyl, 2- cyclobutylethyl, cyclohexenylmethyl, 4-cyclohexyl-2-butenyl, 4-(1 -cyclohexenyl)-vinyl and the like.

The term "lower alkyl" designates a hydrocarbon moiety specified above, of from 1 to 6 carbon atoms.

"Aryl" means an aromatic ring moiety, for example: phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,

1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, isothiazolyi, tetrazolyl, 1 -H-tetrazol-5-yl, indolyl, quinolyl, quinazolinyl, benzofuryl, benzothiophenyl (thianaphthenyl) and the like.

Further non-limiting examples are biphenyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, 1,2, 3,4-tetrahydronaphthyl, 2,3-dihydrobenzofuryl, triazolyi, pyranyl, thiadiazinyl, isoindolyl, in- dazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, benzothienyl, benzimidazolyl, benzthiazolyl, ben- zisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyi, quinolizinyl, isoquinolyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyi, pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl, piperidinyl and the like.

The aryl moieties are optionally substituted by one or more substituents, for example selected from the group consisting of F, Cl, I, and Br; lower alkyl; lower alkanoyl such as formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like; -OH; -NO2; -CN; -CO2H; -O-lower alkyl; aryl; aryl-lower alkyl; -CO2CH3; -CON H2; -OCH2CONH2; -N H2; -N(CH3)2; -SO2NH2; -OCHF2; -CF3; -OCF3 and the like. A further non-limiting example is -NH-(C=S)-NH2.

Such aryl moieties may also be substituted by two substituents forming a bridge, for example -OCH2O-.

"Aryi-lower alkyl" means a lower alkyl as defined above, substituted by an aryl, for example: The aryl group is optionally substituted as described above.

Description of the invention The present invention is based on the unexpected observation that compounds having a se- lected nitrogen-bearing central motif and the general structural features disclosed below an- tagonize the action of glucagon.

Accordingly, the invention is concemed with compounds of the general formula I: wherein: R' and R2 independently are hydrogen or lower alkyl or together form a valence bond; R3 and R4 independently are hydrogen or lower alkyl; nisO, 1,2or3; m is 0 or 1; X is >C=O, >C=S, >C=NR5 or >SO2 wherein R5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR6; wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; A is wherein:

R7 is hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR", -NR11R12, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SO2NR11R12, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -OCH2CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13 or -OSO2CF3; R8 and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, lower alkyl, aryl, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13 or -OSO2CF3, or R8 and R9 together form a bridge -OCH2O- or -OCH2CH2O-; wherein R11 and R12 independently are hydrogen, -COR13, -SO2R13, lower alkyl or aryl; wherein R'3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and R10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; B is or a valence bond;

wherein: R'4 and R15 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CH2)iCF3, -NO2, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -SC F3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2)iCONR16R17, -O(CH2)iCONR16R17, -(CH2)iCOR16, -(CH2)iCOR16, -(CH2)iOR16, -O(CH2)iOR16, -(CH2)iNR16R17, -O(CH2)iNR16R17, -OCOR16, -CO2R18, -O(CH2)iCO2R18, -O(CH2)1CN, -O(CH2)iCl, or R14and R'5 together form a bridge -O(CH2),O- or -(CH2),-; wherein I is 1,2,3 or 4; R16 and R17 independently are hydrogen, -COR18, -SO2R18, lower alkyl, aryl, or R16 and R'7 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms; wherein R16 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; W is -N= or -CR19=; Y is -N= or -CR20=; Z is -N= or -CR21=; V is -N= or -CR22=; and Q is -NR23-, -0- or -S-; wherein: R'9, R20, R21 and R22 independently are hydrogen, halogen, -CN, -C F3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR24, -CHF2, -OCHF2, -OCF2CH F2, -OSO2CF3, -CON R24R25, -CH2CONR24R25, -OCH2CON R24R25, -CH2OR24, -CH2NR24R25, -OCOR24 or -CO2R24, or R19and R20, R20 and R21, or R21 and R22 together form a bridge -OCH2O-;

wherein R24 and R25 independently are hydrogen, -COR26, -SO2R26, lower alkyl, aryl or aryl- lower alkyl; wherein R26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and R23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; K is wherein: R3a, R3b, R4a and R4b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24aR25a, lower alkyl, aryl, aryl-lower alkyl, -SC F3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24aR25a, -CH2CONR24aR25a, -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24aR25a, -OCOR24a or -CO2R24a; wherein R24a and R25a independently are hydrogen, COR26a, -SO2R26a, lower alkyl, aryl or aryl-lower alkyl; wherein R26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl; or R3a and R3b, R4a and R4b, or R3a and R4b together form a bridge -(CH2)i-; wherein i is 1,2,3 or 4; a, b, c and d independently are 0, 1, 2, 3 or 4;

e, f and p independently are 0 or 1; q is 0, 1 or 2; and L and M independently are -O-, -S-, -CH=CH-, -C-C-, -NRSa-, -CH2NR5a-, -CO-, -OCO-, -COO-, -CON R5a-, -CONR5b-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2NR5a-, -NR5aSO2-, -NR5aCONR5b-, -CONR5aNR5b-, -NR5aCSNR5b-, -OCONR5b, -CH2CONR5b-, -OCH2CONR5b-, -P(O)(OR5a)O-, -NR5aC(O)O- or wherein R5a and R5b independently are hydrogen, lower alkyl, -OH, -(CH2)k-OR6a, -COR6a, -(CH2)k-CH(OR6a)2, -(CH2)k-CN, -(CH2)k-NR6aR6b, aryl, aryl-lower alkyl, -(CH2)g-COOR43 or - (CH2)9-CF3; wherein k is 1,2,3 or 4; R6a and R6b independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; g is 0, 1, 2, 3 or 4; R43 is hydrogen or lower alkyl; G" is -OCH2CO-, -CH2CO-, -CO- or a valence bond; and E" is -CH2-, -CH2CH2-, -CH=CH-, -CH2NH- or -CH2CH2NH-; D is hydrogen,

wherein: r is 0 or 1;

s is 0, 1, 2 or 3; E, E', F, G and G' independently are -CHR38-, >C=O, >NR39, -0- or -S-; F' is >CR38- or >N-; Y' is -N= or -CR32=; Z' is -N= or -CR33=; V' is -N= or -CR34=; W' is -N= or -CR35=; and Q' is -NR36-, -0- or -S-; wherein: R27, R28, R32, R33, R34 and R35 independently are hydrogen, halogen, -CN, -CF3, -O(CH2)yCF3, -(CH2)yNHCOCF3 -NO2, lower alkyl, aryl, aryl-lower alkyl, -SC F3, -SR29, -CHF2, -OCHF2, -OCF2CHF2, -OSO2R29, -OSO2CF3, -(CH2)yCONR29R30, -O(CH2)yCONR29R30, -(CH2)yOR29, -(CH2)yNR29R30, -OCOR29, -COR29 or -CO2R29; or R27and R26, R32 and R33, R33 and R34, or R34 and R35 together form a bridge -O(CH2)yO-; wherein y is 0,1, 2, 3 or 4; and R29 and R30 independently are hydrogen, -COR31, -CO2R3', -SO2R31, lower alkyl, aryl or aryl-lower alkyl;

wherein R31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and and R39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; and R38 is hydrogen, -OR40, -NR40R41, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)xCONR40R41, -O(CH2)xCONR40R41, -(CH2)xOR40, -(CH2)xNR40R41, -OCOR40 or -CO2R40; wherein xis 1,2,3 or 4; R40 and R4' independently are hydrogen, -COR42, -SO2R42, lower alkyl, aryl or aryl-lower al- kyl; wherein R42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.

Where the formulae for B make it possible, R19, R20, R21, RP and Rn may alternatively be re- placed by R14 or R15, respectively. In such case eg W may be selected from -N=, -CR19- and -CR14-.

Similarly, where the formulae for D make it possible, R32, R33, R34, R35, R36, Ra and R39 may al- tematively be replaced by R27 or R28, respectively. In such case eg E may be selected from -CHR38-, >C=O, >NR39, -0--S-, -CHR27- and >NR27.

In a preferred embodiment the invention relates to compounds of the following general formula II: wherein A, B, K, D, R3, R4, n and m are as defined for formula I.

In another preferred embodiment the invention relates to compounds of the following general formula Ill: wherein A, B, K, D, R3, R4, n and m are as defined for formula I.

In still another preferred embodiment the invention relates to compounds of the following formula IV: wherein A, B, K, D, R3, R4, n and m are as defined for formula In the compounds of the above formulae I to IV the following substituents are preferred: R3 is preferably hydrogen.

R4 is preferably hydrogen.

A is preferably selected from the group consisting of:

wherein R7, R8, R9 and R'O are as defined for formula I.

A is more preferably wherein R7, R8 and R9 are as defined for formula In the above embodiments of A, R7 is preferably halogen, lower alkyl, -OH, -NO2, -CN, -CO2H, -O-lower alkyl, aryl, aryl-lower alkyl, -CO2CH3, -CON H2, -OCH2CONH2, -N H2, -N(CH3)2, -SO2NH2, -OCHF2, -CF3 or -OCF3.

Preferably, R6and R9 are independently hydrogen, halogen, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCH2CF3, -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, and R10 is hydrogen, lower alkyl or phenyl.

More preferably, R6 and R9 are independently selected from hydrogen, halogen such as -F and -Cl, -O-lower alkyl such as methoxy and ethoxy, -N H2, -CN or -NO2, and R10 is hydrogen.

In a particularly preferred embodiment A is wherein R8 and R9 independently are hydrogen, halogen, -OH, -NO2, -N H2, -CN, -OCF3, -SCF3, -CF3, -OCH2CF3, -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, preferably hydrogen, halogen such as -F and -Cl, -O-lower alkyl such as methoxy and ethoxy, -N H2, -CN or -NO2.

In a further particularly preferred embodiment A is

wherein R8 is hydrogen, halogen such as -F or -CI, -O-lower alkyl such as -OCH3 or-OC2Hs, -N H2, -CN or -NO2; and R9 is hydrogen or halogen such as -F or -CI.

In a preferred embodiment R8 is halogen and R9 is hydrogen.

In still a preferred embodiment the invention relates to compounds of the following formula V: wherein R4, B, K, D and m are as defined for formula I and R8 and R9 are as defined for formula I and preferably as defined for the preferred embodiments of A above.

B is preferably: wherein V, W, Z, Y and Q are as defined for formula I; and R14 and R15 independently are hydrogen, halogen, -CF3, -OCF3, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16 or -CO2R18; or R'4 and R'5 together form a bridge -OCH2O- or -(CH2),-; wherein I, R'6, R17 and R18 are as defined for formula I.

Q is preferably -0- or -NH-.

Particularly preferred compounds are those in which B is wherein V, W, Z, Y and Q are as defined for formula I; and R14 and R'5 independently are hydrogen, halogen, -CF3, -OCF3, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -OSO2CF3, -C0NR16R17, -CH2OR16, -CH2NR16R17, -OCOR16or -C02R18; or R14 and R15 together form a bridge -OCH2O- or -(CH2)l-; wherein I, R'6, R17 and R18 are as defined for formula I.

Still more preferred are compounds of the following formula VI:

as well as compounds of the following formula VII: as well as compounds of the general formulae VIIIa or Vlilb: wherein R14and R15 independently are hydrogen, halogen, -CF3, -OCF3, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16 or -CO2R18; or R14 and R15 together form a bridge -OCH2O- or -(CH2)l-; wherein I, R'6, R17 and R18 are as defined for formula

K, D and m are as defined for formula I; and R8 and R9 are as defined for formula I and preferably as defined for the preferred embodiments of A above.

In the above formulae VI, VII and VIII, R14and R'5 are preferably independently hydrogen, halogen, lower alkyl, aryl such as phenyl, or -O-lower alkyl such as methoxy.

In the above formulae VI and Vll, K is preferably bound in para-position and in the above for- mulae Vllla and Vlllb, K is preferably bound at the nitrogen atom of the indole group.

K is preferably selected from the group consisting of: -(CH2)b-O-(CH2)d- , -(CH2)b-S-(CH2)d- , -(CH2)b-CH=CH-(CH2)d-, -O-(CH2)b-O-(CH2)d- , -O-(CH2)b-CHR3a- , wherein R3a, R3b, R4a, R4b, R5a, R5b, a, b, c, d, p and q are as defined for formula I.

More preferably, K is selected from the group consisting of:

wherein R3a, R3b, R4a, R4b, R5a, R5b, a, b, c, d, p and q are as defined for formula I.

In a further preferred embodiment K is selected from the group consisting of: a valence bond

wherein R3a, R3b, R4a, R4b, R5a, R5b, b, c, d, p and q are as defined for formula I.

In the above embodiments of K, R5a and R5b are preferably independently hydrogen, lower alkyl, -OH, -(CH2)kOR6a, aryl, aryl-lower alkyl, -CH2CF3, -(CH2)9-COOR43, -COOR43, -(CH2)k CN or -(CH2)k-NR6aR6b wherein g, k, R43, R6a and R6b are as defined for formula I.

Preferably, g and k are independently 1, 2 or 3, and R6a and R6b are independently hydrogen, lower alkyl such as methyl or ethyl, or aryl such as phenyl, In the above embodiments of K, R3" and R3b are preferably independently hydrogen, halo- gen, -OH, -O-lower alkyl, -COO-lower alkyl, lower alkyl or aryl-lower alkyl.

In the above embodiments of K, R4" and R4b are preferably independently hydrogen, -CN, -CON H2, -(CH2)-N(CH3)2, -O-lower alkyl, -CH2OH, -CH2O-aryl, -N(CH3)2, -OH, -CO2-lower alkyl or lower alkyl.

D is preferably hydrogen, wherein s, r, R27, R28, V', Y', Q', Z', W', E, E', F, F', G and G' are as defined for formula I.

In still a further preferred embodiment D is hydrogen,

wherein s, r, R27, R28, V', Y', Z', Q', Z', W', E, E', F, F', G and G' are as defined for formula I.

D is more preferably hydrogen,

wherein E and E' independently are >CHR38, >NR39 or -O-; F, G and G' independently are >CHR38, >C=O or >NR39 F' is >CR38- or >N-; and s, r, R27, R28, R38, R39, V', Y', Z', Q' and W' are as defined for formula I.

R27 and R28 are preferably independently hydrogen; halogen such as -Cl-Br or -F; -CF3; -OCF3; -OCHF2; -OCH2CF3; -(CH2)yNHCOCF3; -NHCOCF3; -CN; -NO2; -COR29, -COOR29, -(CH2)yOR29 or -OR29 wherein R29 is hydrogen, aryl or lower alkyl and y is 1, 2, 3 or 4; lower alkyl such as methyl, ethyl, 2-propenyl, isopropyl, tert-butyl or cyclohexyl; lower alkylthio; -SC F3; aryl such as phenyl; (CH2)yNR29R30 or -NR29R30 wherein R29 and R30 independently are hydrogen, -COO-lower alkyl or lower alkyl and y is 1, 2, 3 or 4; or -CON H2; or R27and R28 together form a bridge -OCH2O-; R38 is hydrogen; -OCHF2; -OR40 wherein R40 is hydrogen or lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; lower aikylthio; -SC F3; -CH2OH; -COO-lower alkyl or -CONH2; and R39 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.

In a further embodiment the invention relates to the compounds of the formula I wherein: R' and R2 independently are hydrogen or lower alkyl or together form a valence bond; R3 and R4 independently are hydrogen or lower alkyl; X is >C=O, >C=S, >C=NRs or >SO2 nisO, 1,2Or3; m is O or 1; R5 is hydrogen, lower alkyl, aryl-lower alkyl, or -OR6; wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; A is wherein

R7 is hydrogen, halogen, -CN, -C F3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, lower al- kyl, aryl, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13, -OSO2CF3; R6 and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR", -NR11R12, lower alkyl, aryl, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR", -CH2NR11R12, -OCOR11, -CO2R13, -OS02CF3, or R6 and R9 together form a bridge -OCH2O-; R" and R12 independently are hydrogen, -COR13, -SO2R13, lower alkyl or aryl; R'3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; R10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; B is or a valence bond; preferably

R14and R15 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CH2),CF3, -NO2, -OR16, -NR16R17, lower alkyl, aryl, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2)iCONR16R17, -O(CH2)iCONR16R17, -(CH2)iCOR16, -O(CH2)iCOR16, -(CH2)10R16, -O(CH2)1OR16, -(CH2)1NR16R17, -O(CH2)1NR16R17, -OCOR16, -C02R16, -O(CH2),CN, -O(CH2),CI, or R'4 and R's together form a bridge -O-CH2-O-; R'4 and R15 preferably independently representing hydrogen, halogen, -CF3, -OCF3, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR'6R'7, -OCOR16 or -CO2R18; or together forming a bridge -OCH2O-; I is 1, 2,3or4; R16 and R'7 independently are hydrogen, -COR18, -SO2R18, lower alkyl, aryl, or R16 and R'7 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms; R18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; W is -N= or -CR19=; Y is -N= or -CR20=;

Z is -N= or -CR21=; V is -N= or -CR22=; Q is -NR23-, -O- or -S-; wherein: R'9, R20, R21 and R22 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SR24, -CHF2, -OCHF2, OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24,- CH2NR24R25, -OCOR24 or -C02R24, or R19and R20, R20 and R21or R21 and R22 together form a bridge -OCH2O-; R24 and R25 independently are hydrogen, -COR26, -SO2R26, lower alkyl, aryl or aryl-lower alkyl; R26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; R23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; K is wherein: R3a, R3b, R4a and R4b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24aR25a, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24aR25a, -CH2CONR24aR25a, -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24aR25a, -OCOR24a or -CO2R24a;

wherein R24a and R25a independently are hydrogen, -COR26a, -SO2R26a, lower alkyl, aryl or aryl-lower alkyl; R26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl; or R3a and R3b, R4a and R4b or R3a and R4b together form a bridge -(CH2)i-, wherein i is 1, 2, 3, or 4; a, b, c and d independently are 0, 1, 2, 3 or 4; e, f, p and q independently are 0 or 1; L and M independently are -O-, -S-, -CH=CH-, -C#C-, -NR5a-, -COO-, -CONR5a-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2-NR5a-, -NR5aSO2-, -NR5aCONR5b-, -NR5aCSNR5b-, -OCONR5b- or -NR5aC(O)O wherein R5aand R5b independently are hydrogen, lower alkyl, -(CH2)k-OH, -(CH2)k- NR6aR6b, aryl or aryl-lower alkyl; wherein k is 2, 3 or 4; R6" and R6b independently are hydrogen, lower alkyl or aryl-lower alkyl; K preferably representing -CH2)b-O-(CH2)d- , -(CH2)b-CH-CH-(CH2)d- , D is hydrogen or preferably hydrogen,

wherein: r and s independently are 1 or 2; E, F and G independently are -CHR38-, >C=O, >NR39, -0- or -S-; Y' is -N= or -CR32=;

Z' is -N= or -CR33=; V' is -N= or -CR34=; W' is -N= or -CR35=; Q' is -NR36-, -O- or -S-; wherein R27, R28, R32, R33, R34and R35 are independently hydrogen, halogen, -CN, -CF3, -OCF3, O(CH2)yCF3, -NO2, -OR29, -NR29R30, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR29, -CHF2, -OCHF2, -OCF2CHF2, -OSO2R29, -OSO2CF3, -CONR29R30, -(CH2)yCONR29R30, -O(CH2)yCONR29R30, -(CH2)yOR29, -(CH2)yNR29R30, -OCOR29, -CO2R29; or R27 and R28, R32 and R33, R33 and R34 or R34 and R35 together form a bridge -OCH2O-; R27and R28 preferably independently representing hydrogen, halogen,-CF3, -OCF3, -OCH2CF3, -OR29, lower alkyl, aryl or aryl-lower alkyl, or together forming a bridge -OCH20-; y is 1,2, 3 or 4; R29 and R30 independently are hydrogen, -COR3', -So2R3', lower alkyl, aryl or aryl-lower alkyl; R3'is hydrogen, lower alkyl, aryl or aryl-lower alkyl; R36 and R39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; R38is hydrogen, -OR40, -NR40R41, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR40, -CHF2, - OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)xCONR40R41, -O(CH2)xCONR40R41, -(CH2)xOR40, -(CH2)xNR40R41, -OCOR40 or -CO2R40;

xis 1,2,3 or4; R40 and R41 independently are hydrogen, -COR42, -SO2R42, lower alkyl, aryl or aryl-lower alkyl; and R42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.

In a further embodiment the invention relates to the compounds of the formula I wherein: R' and R2 independently are hydrogen or lower alkyl or together form a valence bond; R3 and R4 independently are hydrogen or lower alkyl; <BR> <BR> <BR> <BR> <BR> nisO, 1,2Or3; <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> m is O or 1; X is >C=O, >C=S, >C=NRs or >SO,; wherein R5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR6; wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; A is wherein:

R7 is hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, lower al- kyl, aryl, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13 or -OSO2CF3; R8 and R9 independently are hydrogen, halogen, -ON, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, lower alkyl, aryl, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH20R11, -CH2NR11R12, -OCOR11, -CO2R13or -OSO2CF3, or R8 and R9 together form a bridge -OCH2O- or - OCH2CH2O-; wherein R" and R12 independently are hydrogen, -COR13, -SO2R'3, lower alkyl or aryl; wherein R'3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and R10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; B is or a valence bond; preferably

wherein: R'4 and R'5 independently are hydrogen, halogen, -ON, -CF3, -OCF3, -O(CH2),CF3, -NO2, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2)iCONR16R17, -O(CH2)iCONR16R17, -(CH2)iCOR16, -(CH2)iCOR16, -(CH2)iOR16, -O(CH2)iOR16, -(CH2)iNR16R17, -O(CH2)iNR16R17, -OCOR16, -CO2R18, -O(CH2)iCO2R18, -O(CH2)iCN, -O(CH2)iCl, or R14 and R15 together form a bridge -OCH2O-; R'4 andR15 preferably independently representing hydrogen, halogen, -CF3, -OCF3, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -OSO2CF3, -CONR'6R'7, -CH2OR'6, -CH2NR16R17, -OC0R16or-CO2R16; or together forming a bridge -OCH2O-; wherein I is 1, 2, 3 or 4; R16 and R'7 independently are hydrogen, -COR18, -SO2R16, lower alkyl, aryl, or R16 and R17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms; wherein R18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; W is -N= or -CR19=; Y is -N= or -CR20=;

Z is -N= or -CR21=; V is -N= or -CR22=; and Q is -NR23-, -O- or -S-; wherein: R'9, R20, R21 and R22 independently are hydrogen, halogen, -ON, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SR24, -OH F2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24, -CH2NR24R25, -OCOR24 or -CO2R24, or R19and R20, R20 and R21or R2' and R22 together form a bridge -OCH2O-; wherein R24 and R25 independently are hydrogen, -COR26, -S02R26, lower alkyl, aryl or aryl-lower alkyl; wherein R26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and R23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; K is wherein: R3a, R3b, R4a and R4b independently are hydrogen, halogen, -ON, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24a25a, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24aR25a, -CH2CONR24aR25a, -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24aR25a, -OCOR24a or - CO2R24a;

wherein R24a and R25a independently are hydrogen, -COR26a, -SO2R26a, lower alkyl, aryl or aryl-lower alkyl; wherein R26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl; or R3a and R3b, R4a and R4b or R3a and R4b together form a bridge -(CH2)i-; wherein i is 1,2,3 or 4; a, b, c and d independently are 0, 1, 2, 3 or 4; e, f and p independently are 0 or 1; q is 0,1 or 2; and L and M independently are -O-, -S-, -CH=CH-, -C#C-, -NR5a-, -CO-, -OCO-, -COO-, -CONR5a-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2-NR5a-, -NR5aSO2-, -NR5aCONR5b-, -NR5aCSNR5b-, -OCONR5b- or -NR5aC(O)O-; wherein R5a and R5b independently are hydrogen, lower alkyl, -(CH2)k-OH, -(CH2)k- NR6aR6b, aryl or aryl-lower alkyl; wherein k is 2, 3 or 4; and R6a and R6b independently are hydrogen, lower alkyl or aryl-lower alkyl; K preferably representing a valence bond D is hydrogen, preferably hydrogen,

wherein: r and s independently are 0, 1 or 2; E, F and G independently are -CHR38-, >C=O, >NR39, -0- or -S-; F' is >CR38- or >N-; Y' is -N= or -CR32=; Z' is -N= or -CR33=; V' is -N= or -CR34=;

W' is -N= or -CR35=; and Q' is -NR36-, -0- or -S-; wherein: R27, R28,R32, R33, R34and R35 are independently hydrogen, halogen, -ON, -C F3, -OCF3, -O(CH2)yCF3, -NO2, -OR29, -NR29R30, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR29, -CHF2, -OCHF2, -OCF2CHF2, -OSO2R29, -OS02CF3, -CONR29R30, -(CH2)yCONR29R30, -O(CH2)yCONR29R30, -(CH2)yOR29, -(CH2)yNR29R30, -OCOR29 or -C02R29; or R27and R28, R32 and R33, R33 and Razor R34 and R35 together form a bridge -OCH2O-; R27 and R28 preferably independently representing hydrogen; halogen such as -Cl or -F; -CF3; -OCF3; -OCHF2; -OCH2CF3; -OR29 wherein R29 is hydrogen or lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; lower alkylthio; -SC F3; -CH2OH; -COO-lower alkyl; aryl or -CON H2; or together forming a bridge -OCH2O-; wherein y is 1, 2, 3 or 4; and R29 and R30 independently are hydrogen, -COR31, -S02R31, lower alkyl, aryl or aryl-lower alkyl; wherein R31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; R36 and R39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; and R38 is hydrogen, -OR40, -NR40R41, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)xCONR40R41, -O(CH2)xCONR40R41, -(CH2)xOR40, -(CH2)xNR40R41, -OCOR40 or -CO2R40; wherein x is 1, 2, 3 or 4; R40 and R41 independently are hydrogen, -COR42, -SO2R42, lower alkyl, aryl or aryl-lower alkyl; and wherein R42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.

Examples of specific compounds represented by the above general formula V are the follow- ing: 3-Chloro-4-hydroxybenzoic acid [5-chloro-2- methoxy-4-(4-isopropylbenzyloxy)- benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid [2,3-dimethoxy-4-(4-isopropylbenzyloxy)- benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid [2,3-dimethyl-4-(4-isopropylbenzyloxy)- benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5-dichloro- 4-(4-isopropylbenzyloxy)benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid [2,3-dichloro- 4-(4-isopropylbenzyloxy)benzylidene]hydrazide 3-Chloro-4-hyd roxybenzoic acid [3-isopropyl-4- (4-isopropylbenzyloxy)-5- methoxybenzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3-isopropyl- 4-(4-isopropylbenzyloxy)-5- methylbenzylidene]hydrazide 3-ChloroA-hydroxybenzoic acid [3-(2-diethylaminoethoxy)-4-(4-isopropyl- benzyloxy)-5-methoxybenzylidene] hyd razide 3-Chloro-4-hydroxybenzoic acid [3-diethylaminomethyl-4-(4-isopropylbenzyl- oxy)-5-methoxybenzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid <BR> <BR> <BR> <BR> (3-[2-(1 -pyrrolidino)ethoxy)]-4-(4- isopropylbenzyloxy)-5- <BR> <BR> <BR> methoxybenzylidene)hydrazide 3-Chloro-4-hyd roxybenzoic acid [3-(2-diethylaminoethyl)-4-(4- isopropylbenzyloxy)-5- methoxybenzylidene]hydrazide 5-[(3-Chloro-4-hydroxybenzoyl)hydrazono- methyl]-3-methoxy-2-(4-isopropylbenzyloxy)- phenoxyacetic acid 3-Chloro-4-hydroxybenzoic acid [3-(2-hydroxyethoxy)-4-(4-isopropyl- benzyloxy)-5-methoxybenzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid <BR> <BR> [2,3, 5-trimethoxy-4-(4-isopropylbenzyloxy)- <BR> <BR> <BR> benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-ethoxybenzyloxy)- benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5-bis-(2-hydroxyethoxy)-4-(4- isopropylbenzyloxy)benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-n-propylbenzyloxy)- benzylidene]hydrazide 3-Fluoro-4-hydroxybenzoic acid <BR> <BR> <BR> [3,5-dimethoxy-4-(4-isopropylbenzyloxy)- benzylidene]hydrazide 3-Nitro-4-hydroxybenzoic acid [3 ,5-dimethoxy-4-(4-isopropylbenzyloxy)- benzylidene]hydrazide 3-Carbamoyl-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-isopropylbenzyloxy)- benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid (3, 5-d imethoxy-4-[4-(2,2,2-trifluoroethoxy)- <BR> <BR> <BR> benzyloxy]-benzylidene)hyd razide 3-Carboxy-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-isopropylbenzyloxy)- ben- zylidene]hydrazide 3-Cyano-4-hydroxybenzoic acid <BR> <BR> <BR> [3, 5-di methoxy-4-(4-isopropylbenzyloxy)- benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5-dimethoxy-4-(3-chloro-4- trifluoromethoxybenzyloxy)benzylid- ene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5- dimethoxy-4-(4-chlorophenoxy) benzylid- ene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5- dimethoxy-4-(4-trifluoromethyl-2- pyridylmethoxy)- benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5- dimethoxy-4-(5-hexenyloxy) benzylid- ene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5- dimethoxy-4-(4-isopropylphenoxy) benzylid- ene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5- d imethoxy-4-(6-methylheptyloxy) benzylid- ene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5- dimethoxy-4-(5,5-dimethyl-3-hexynyloxy) benzylidene]hydrazide 3-Chloro-4-hyd roxybenzoic acid [4-(4- trifluoromethoxyphenoxy)-1 - naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid (3,5- dimethoxy-4-[2-(4-E-trifluoromethylphenyl)- ethenyl]benzylidene)hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5- dimethoxy-4- <BR> <BR> (cyclohexylethynyl)benzylidenehydrazide 3-Chloro-4-hydroxybenzoic acid [4-(4- isopropylphenoxy)-1 - naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid (3,5-di- methoxy-4-[(4-isopropylphenyl)- ethynyl] benzylidene)hydrazide 3-Chloro-4-hydroxybenzoic acid [3-(2- methoxy-4-methylphenyl)ethynyl-5- methoxybenzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1- naphthylmethylene)hydrazide 3-chloro-4-hyd roxybenzoic acid [4-(2- chloroethoxy)-1 -naphthylmethylene]hydrazide 4-Hydroxy-3-methoxybenzoic acid (4- methoxy-1 -naphthylmethylene)hydrazide 4-Hydroxy-3-methoxybenzoic acid (4- isopropylbenzylidene)hydrazide 3-chloro-4-hydroxybenzoic acid [4-(3,5-bis- trifluoromethylbenzyloxy)-1 - naphthylmethylene]hydrazide 4-Hydroxy-3-methoxybenzoic acid (2- naphthylmethylene)hydrazide 4-Hydroxy-3-methoxybenzoic acid (4-tert- butylbenzyiidene)hydrazide 4-Hydroxy-3-methoxybenzoic acid (4- <BR> <BR> trifluoromethoxybenzylidene)hydrazide 4-Hyd roxy-3-methoxybenzoic acid (1 H-indol-3- ylmethylene)hydrazide 4-Hydroxy-3-methoxybenzoic acid (4- phenylbenzylidene)hydrazide 4-Hydroxybenzoic acid (4-methoxy-1 - naphthylmethylene)hydrazide 4-Hyd roxy-3-methoxybenzoic acid (1- naphthylmethylene)hydrazide 4-Hydroxy-3-methoxybenzoic acid (4- dimethylamino-1 - naphthylmethylene)hydrazide 4-Hydroxybenzoic acid (1- naphthylmethylene)hydrazide 3,4-Dihydroxybenzoic acid (1- naphthylmethylene)hydrazide 4-Hydroxy-3-methoxybenzoic acid [3-(3-tri- fluoromethylphenoxy)benzylidene] hydrazide 4-Hydroxy-3-methoxybenzoic acid (4- quinolinylmethylene)hydrazide 4-Hydroxybenzoic acid [3-(4-tert-butylphenyl)- E-but-2-enylidene]hydrazide 4-Hydroxybenzoic acid (benzylidene)hydrazide 3-Amino-4-hydroxybenzoic acid (1- naphthyl- methylene)hydrazide 4-Hydroxybenzoic acid [3-(1,1,2,2- tetrafluoroethoxy)benzylidene]hydrazide 4-Hydroxy-3-methoxybenzoic acid (4- hydroxy-1 -naphthylmethylene)hydrazide 4-Hydroxybenzoic acid (1- <BR> <BR> naphthylmethyiene)hydrazide 3-Amino-4-hydroxybenzoic acid (4-hydroxy- 1- naphthylmethylene)hydrazide 4-Hyd roxybenzoic acid [3-(3-trifluoro- methylbenzyloxy)benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid (4-hydroxy- 1 - naphthylmethylene)hydrazide 4-Hydroxybenzoic acid [4-(3- trifluoromethylphenoxy)benzylidene]hydrazide 2,4-Dihydroxybenzoic acid (4-hydroxy-1 - naphthylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid (1- naphthylmethylene)hydrazide 4-Hydroxybenzoic acid (4-hydroxy-1 - naphthylmethylene)hyd razide 4-Hydroxybenzoic acid (5-phenyl-3- pyrazolylmethylene)hydrazide 4-Hydroxy-3-n itrobenzoic acid (1- naphthylmethylene)hydrazide 4-Hydroxy-3-nitrobenzoic acid (4-hydroxy-1 - naphthylmethylene)hydrazide 4-Hydroxybenzoic acid (6-methoxy-2- naphthylmethylene)hydrazide 4-Hyd roxy-3-methoxybenzoic acid (9-ethyl-9H- 3-carbazolylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid (3-phenyl-E- allylidene)hydrazide 3,4-Dihydroxybenzoic acid (4-hydroxy-1 - naphthylmethylene)hydrazide 3,5-Dichloro-4-hydroxybenzoic acid (4- hydroxy-1 -naphthylmethylene)hydrazide 4-Hydroxy-3-methoxybenzoic acid [5-(3- chlorophenyl)-2-furanylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid (4-allyloxy-1 - naphtylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid (4- ethynylmethoxy-1- naphthylmethylene)hydrazide 2-(4-[(3-Chloro-4-hydroxyben zoyl)hydra- zo- nomethyl]-1 -naphthyloxy)acetamide 3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1 - naphthylmethylene)hydrazide N-(2-[(3-Chloro-4- <BR> <BR> <BR> hydroxybenzoyl)hyd razono]ethyl)-2,2- diphenylacetamide 3-Chloro-4-hydroxybenzoic acid (4- benzyloxy-1-naphthylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid (4-methyl-I - naphthylmethylene)hydrazide 3-Chloro-4-hyd roxybenzoic acid (4-methoxy- 1 -naphthylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid (1-hydroxy- 2-naphthylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid (2,2- diphenylethylidene)hydrazide 3-Chloro-4-hydroxybenzoic acid [3-(4-tert- butylphenoxy)benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid (3-bromo-4- hydroxy-1 -naphthylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid (4- cyanomethoxy-I - naphthylmethylene)hydrazide 3-Chioro-4-hydroxybenzoic acid (4- benzyloxy-3,5- dimethoxybenzylidene)hydrazide 3-Chloro-4-hydroxybenzoic acid (4-methyl-I - naphthylmethylene)hydrazide Acetic acid 4-[(3-Chloro-4- hydroxybenzoyl)hydrazonomethyl]-1-naphthyl ester 3-Chloro-4-hydroxybenzoic acid (2-hydroxy- 1 -naphthylmethyiene)hydrazide 3-ChloroA-hydroxybenzoic acid (2,3- <BR> <BR> <BR> methylenedioxybenzyiidene)hydrazide 3-Chloro-4-hydroxybenzoic acid (9- <BR> <BR> <BR> phenanthrenylmethylene)hydrazide 3-Bromo-4-hydroxybenzoic acid (4-hydroxy-1- naphthylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid [4-(1,3-dioxo- 1 ,3-dihydroisoindol-2-ylmethoxy)-1 -naphthyl- methylene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3-(4- methoxyphenoxy)benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid [4-(2- hydroxyethoxy)-1- naphthylmethylene]hydrazide Nicotinic acid 4-[(3-chloro-4- hydroxybenzoyl)hydrazonomethyi]-1 -naphthyl ester 3-Chloro-4-hydroxybenzoic acid [4- (cyclohexylmethoxy)-1 - naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid [4- (tetrahyd ro-2-pyranylmethoxy)-1 -naphthyl- methylene]hydrazide 4-[(3-Ch loro-4- hyd roxybe nzoyl)hyd razon omethyl]-l - naphthyloxy)acetic acid ethyl ester 3-Chloro-4-hydroxybenzoic acid (2,4- dichlorobenzylidene)hydrazide 3-Chloro-4-hydroxybenzoic acid [4-(3- pyridylmethoxy)-1- naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid (3- nitrobenzylidene)hydrazide 3-Chloro-4-hydroxybenzoic acid (4-fiuoro-I - naphthylmethylene)hydrazide 3-Fluoro-4-hyd roxybenzoic acid (4-hydroxy-1- naphthylmethylene)hydrazide 3-Fluoro-4-hydroxybenzoic acid (1- naphthylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid [4-(4- fluorobenzyloxy)-I - naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid [4-(2,4- difluorobenzyloxy)-1- naphthyimethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid [4-(3- methoxybenzyloxy)-1- naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid [4-(2- tetrahydrofuranylmethoxy)-1 - naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid (3-bromo-4- methoxy-1 -naphthylmethylene)hydrazide 4-(4-[3-Chloro-4- hydroxybenzoyl)hyd razonomethyl]-1 - naphthyloxymethyl)benzoic acid methyl ester 3-ChloroA-hyd roxybenzoic acid [4-(4- trifluoromethoxybenzyloxy)-1 - naphthylmethylene] hydrazide 3-Chloro-4-hydroxybenzoic acid [4-(3- tetrahydrofuranylmethoxy)-1 - naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid [3,5- dimethoxy-4-(4-trifluoromethoxybenzyloxy)- benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid [4-(2- methoxybenzyloxy)-l - naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid [4-(2- fluorobenzyloxy)-1 - naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid [4-(2,6- difluorobenzyloxy)-1- naphthylmethylene]hydrazide

The most preferred specific compounds represented by the above general formula Ill are the following:

The most preferred specific compounds represented by the above general formula IV are the following: Preferred specific compounds represented by the formulae VI and VII are the following: The most preferred specific compounds of formula I wherein A is a heterocyclic and/or bicyclic moiety are the following: Indole-5-carboxylic acid [4-(4- trifluoromethylbenzyloxy)-1- naphthylmethylene]hydrazide Pyrazole-3-carboxylic acid [4-(4- trifluoromethylbenzyloxy)-1- naphthylmethylenejhydrazide Indazole-5-carboxylic acid [4-(4- trifluoromethylbenzyloxy)-l - naphthylmethylene]hydrazide 3-Hydroxyisoxazole-5-carboxylic acid[4-(4- trifiuoromethylbenzyloxy)-I - naphthylmethylene]hydrazide Especially preferred according to the present invention are the following compounds which show a particularly high affinity to the human giucagon receptor:

The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included in the scope of the invention.

Furthermore, one or more carbon-carbon or carbon-nitrogen double bonds may be present in the compounds which brings about geometric isomers. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included in the scope of the invention.

Furthermore, the compounds of the present invention may exist in different tautomeric forms, eg the following tautomeric forms: It is intended that any tautomeric forms which the compounds are able to form are included in the scope of the present invention.

Owing to their efficacy in antagonizing the glucagon receptor the present compounds may be suitable for the treatment and/or prevention of any glucagon-mediated conditions and dis- eases.

Accordingly, the present compounds may be applicable for the treatment of hyperglycemia as- sociated with diabetes of any cause or associated with other diseases and conditions, eg im- paired glucose tolerance, insulin resistance syndromes, syndrome X, type I diabetes, type II diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, glucagonomas, acute pancreatitis, cardiovascular diseases, cardiac hypertrophy, gastrointestinal disorders, diabetes as a conse- quence of obesity etc. Furthermore, they may be applicable as diagnostic agents for identifying patients having a defect in the glucagon receptor, as a therapy to increase gastric acid secre- tions, to reverse intestinal hypomobility due to glucagon administration, to reverse catabolism and nitrogen loss in states of negative nitrogen balance and protein wasting including all causes of type I and type II diabetes, fasting, AIDS, cancer, anorexia, aging and other condi- tions, for the treatment of any of the above conditions or diseases post-operative or during surgery and for decreasing saitety and increasing energy intake. Thus, in a further aspect the present invention relates to a pharmaceutical composition comprising, as an active ingredi- ent, at least one compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients.

The present invention furthermore relates to methods of treating type I or type II diabetes or hyperglycemia which methods comprise administering to a subject in need thereof an effec- tive amount of a compound according to the invention.

Moreover, the present invention relates to a method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to the invention.

The present invention is also concerned with the use of a compound according to the inven- tion for the manufacture of a medicament for treating type I or type II diabetes or hypergly- cemia, or for lowering blood glucose in a mammal.

Pharmaceutical formulations and administration methods The compounds according to the invention, which may also be referred to as an active ingredi- ent, may be administered for therapy by any suitable route including oral, rectal, nasal, pul- monal, topical (including buccal and sublingual), transdermal, vaginai and parenteral (including subcutaneous, intramuscular, intravenous and intradermal), the oral route being preferred. It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the condition to be treated, and the chosen active ingredient.

The compounds of the invention are effective over a wide dosage range. A typical dosage is in the range of from 0.05 to about 1000 mg, preferably of from about 0.1 to about 500 mg, such as of from about 0.5 mg to about 250 mg for administration one or more times per day such as 1 to 3 times per day. It should be understood that the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated as well as other factors evident to those skilled in the art.

The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.

For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administra- tion, typically doses are on the order of about 1/2 the dose employed for oral administration.

The compounds of this invention are generally utilized as the free substance or as a pharma- ceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of formula I contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of for- mula I with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bis- methylene salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, sali- cylic, citric, pyruvic, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluensulfonic, hydro- chloric, hydrobromic, sulfuric, phosphoric or nitric acids. Physiologically acceptable salts of a

compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.

The compounds of the invention may be administered alone or in combination with pharma- ceutically acceptable carriers, in either single or multiple doses.

For parenteral administration, solutions of the novel compounds of formula I in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily avaiiable by standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or filters, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cy- ciodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, poiyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of ad- ministration. The formulations may convenientiy be presented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administration may be presented as dis- crete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.

The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.

If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

A typical tablet which may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt 100 mg thereof) Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcryst. (Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium stearate Coating: HPMC approx. 9 mg *Mywacett 940 T approx. 0.9 mg *Acylated monoglyceride used as plasticizer for film coating.

For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.

Optionally, the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more other pharmacologically active compounds, e.g. an an- tidiabetic or other pharmacologically active material, including compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pato- physiological mechanism. Suitable antidiabetics comprise insulin, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S) which is incorporated herein by refer- ence as well as orally active hypoglycaemic agents such as sulphonylureas, e.g. glibencla-

mide and giipizide; biguanides, e.g. mefformin; benzoic acid derivatives, e.g. repaglinide; and thiazolidinediones, e.g. troglitazone and ciglitazone, as well as PPAR and RXR agonists.

EXPERIMENTAL Glucagon binding: In the following section binding assays as well as functional assays useful for evaluating the efficacy of the compounds of the invention are described.

Glucagon Binding Assay (I) Binding of compounds to the glucagon receptor was determined in a competition binding as- say using the cloned human glucagon receptor.

In the screening setup, antagonism was determined as the abiiity of the compounds to inhibit the amount of cAMP formed in the presence of 5 nM glucagon.

For full characterization, antagonism was determined in a functional assay, measured as the ability of the compounds to right-shift the glucagon dose-response curve. Using at least 3 different antagonist concentrations, the K was calculated from a Schild plot.

Receptor binding was assayed using cloned human receptor (Lok et al, Gene 140, 203-209 (1994)). The receptor inserted in the pLJ6' expression vector using EcoRI/SStl restriction sites (Lok et al) was expressed in a baby hamster kidney cell line (A3 BHK 570-25). Clones were selected in the presence of 0.5 mg/ml GAl 8 and were shown to be stable for more than 40 passages. The Kcj was shown to be 0.1 nM.

Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI), pH 7.4 containing 30 mM NaCI, 1 mM dithiothreitol, 5 mg/l leupeptin (Sigma), 5 mg/l pepstatin (Sigma), 100 mg/l baci- tracin (Sigma) and 15 mg/l recombinant aprotinin (Novo Nordisk)), homogenization by two 10-s bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation upon a layer of 41 w/v% sucrose at 95.000 * g for 75 min. The white band located between the two layers was

diluted in buffer and centrifuged at 40.000 * g for 45 min. The precipitate containing the plasma membranes was suspended in buffer and stored at -80°C until required.

Glucagon was iodinated according to the chloramine T method (Hunter and Greenwood, Na- ture 194, 495 (1962)) and purified using anion exchange chromatography (Jrgensen et al, Hormone and Metab. Res. 4, 223-224 (1972). The specific activity was 460 pLCi/>g on day of iodination. Tracer was stored at -18"C in aliquots and were used immediately after thawing.

Binding assays were carried out in triplicate in filter microtiter plates (MADV N65, Millipore).

The buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1% human serum albu- min (Sigma, grade V). Glucagon was dissolved in 0.05 M HCI, added equal amounts(w/w) of HSA and freeze-dried. On the day of use, it was dissolved in water and diluted in buffer to the desired concentrations.

175 µl of sample (glucagon or test compounds) was added to each well. Tracer (50.000 cpm) was diluted in buffer and 15 pI was added to each well. 0.5 CLg freshly thawed plasma mem- brane protein diluted in buffer was then added in 15 ,ul to each well. Plates were incubated at 25°C for 2 hours. Non specific binding was determined with 104 M glucagon. Bound and un- bound tracer were then separated by vacuum filtration (Millipore vacuum manifold). The plates were washed once with 150 lli buffer/ well. The plates were air dried for a couple of hours, whereafter filters were separated from the plates using a Millipore Puncher. The filters were counted in a y counter.

Functional Assay (I) The functional assay was carried out in 96 well microtiter plates (tissue culture plates, Nunc).

The resulting buffer concentrations in the assay were 50 mM tris/HCI, 1 mM EGTA, 1.5 mM MgSO4, 1.7 mM ATP, 20 ,uM GTP, 2 mM IBMX, 0.02% tween-20 and 0.1% HSA. pH was 7.4 Glucagon and proposed antagonist were added in 35 ,ul diluted in 50 mM tris/HCI, 1 mM EGTA, 1.85 mM MgSO4, 0.0222 % tween-20 and 0.111 % HSA, pH 7.4. 20 l of 50 mM tris/HCI, 1 mM EGTA, 1.5 mM MgSO4, 11.8 mM ATP, 0.14 mM GTP, 14 mM iso-buthyl-methyl- xanthine (IBMX) and 0.1% HSA, pH 7.4 was added. GTP was dissolved immediately before the assay.

50 111 containing 5 p9 plasma membrane protein was added in a tris/HCI, EGTA, MgSO4, HSA buffer (the actual concentrations were dependent upon the concentration of protein in the stored plasma membranes).

The total assay volume was 140 lli. The assay was incubated for 2 hours at 37"C with continu- ous shaking. Reaction was terminated by addition of 25 pl 0.5 N HCI. cAMP was measured by the use of a scintillation proximity kit (Amersham).

Glucagon Binding Assay (II) Receptor binding was assayed using the cloned human receptor (Lok et al, Gene 140, 203- 209 (1994)). The receptor inserted in the pLJ6' expression vector using EcoRI/SStl restriction sites (Lok et al) was expressed in a baby hamster kidney cell line (A3 BHK 570-25). Clones were selected in the presence of 0.5 mg/ml G418 and were shown to be stable for more than 40 passages. The Kd was shown to be 0.1 nM.

Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI), pH 7.4 containing 30 mM NaCI, 1 mM dithiothreitol, 5 mg/l leupeptin Sigma), 5 mg/l pepstatin (Sigma), 100 mg/l baci- tracin (Sigma) and 15 mg/l recombinant aprotinin (Novo Nordisk)), homogenization by two 10-s bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation. The ho- mogenate was resuspended and centrifuged again. The final precipitate containing the plasma membranes was suspended in buffer and stored at -80°C until required.

Binding assays were carried out in duplicate in polypropylene tubes or microtiter plates. The buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1 % bovine serum albumin (Sigma, fraction V). Sample (glucagon (Bachem CA) or test compounds) was added to each tube or well. Tracer (- 25000 cpm) was diluted in buffer and was added to each tube or well.

0.5 Cig freshly thawed plasma membrane protein diluted in buffer was then added in aliquots to each tube or well. Tubes or plates were incubated at 37"C for 1 hour. Non specific binding was determined with 10-7 M glucagon. Bound and unbound tracer were then separated by vacuum filtration (Brandel). The tubes or wells were washed twice with buffer. The filters or plates were counted in a gamma counter.

Functional Assay (Il) The functional assay determined the ability of the compounds to antagonize glucagon- stimulated formation of cAMP in a whole-cell assay. The assay was carried out in borosiiicate giass 12 x 75 tubes. The buffer concentrations in the assay were 10 mM HEPES, 1 mM EGTA, 1.4 mM MgCl2, 0.1 mM IBMX, 30 mM NaCI, 4.7 mM KCI, 2.5 mM NaH2PO4, 3mM glucose and 0.2% BSA. The pH was 7.4. Loose whole cells (0.5 ml, 106/ml) were pretreated with various concentrations of compounds for 10 min at 370C, then challenged with glucagon for 20 min.

Some aliquots (500 pL) of cells were treated with test compounds (55 uL) alone to test for agonist activity. The reactions were terminated by centrifugation, followed by cell lysis with the addition of 500 pl 0.1% HCI. Cellular debris was pelleted and the supernatant containing cAMP evaporated to dryness. cAMP was measured by the use of an RIA kit (NEN, NEK-033). Some assays were carried out utilizing the adenylate cyclase FlashPlate system from NEN.

Synthesis methods The following synthesis protocols refer to intermediate compounds and final products identi- fied in the specification and in the synthetic schemes. The preparation of the compounds of the present invention is described in detail using the following examples, but the chemical reactions described are disclosed in terms of their general applicability to the preparation of the glucagon antagonists of the invention. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifica- tions known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions.

Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative meth- ods, all starting materials are known or readily preparable from known starting materials. All temperatures are set forth in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight when referring to yields and all parts are by volume when refer- ring to solvents and eluents.

General procedures for the preparation of alkylidene hydrazides: The compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula II, as indicated in Scheme I, that is, by converting an ester of a carboxylic acid, for example, an aromatic acid to a hydrazide derivative and further reacting that product compound with a substituted aldehyde or ketone to yield a substituted alkylidene hydrazide.

SCHEME I o - Ra NHNH2 / solvent An + NH2NH2 o AK 0 reflux o o 4(CH2)nB(K)rnD R ~~~~~~~~~~~~~~~~~ 4-(CH2)n B--(K), D solvent, reflux 0 wherein A, B, K, D, m, n and R4 are as defined for formula I and Ra is lower alkyl.

General procedure for the synthesis of precursor hydrazides A-(C=O)-NHNH,: The reaction is known (Org. Syn., Coll. Vol. II, A.H.Blatt, ed., John Wiley & Sons, New York, 1943, p. 85; Org. Syn., Coll. Vol. IV, N. Rabjohn, ed., John Wiley & Sons, New York, 1963, p.

819) and is generally performed by stirring the corresponding ester (either methyl, ethyl or other lower alkyl ester) with 2-10 molar excess of hydrazine in the presence of a solvent such as ethyl alcohol, methyl alcohol, isopropyl or tert-butyl alcohol or tetrahydrofuran, dioxane, DMSO, ethylene glycol, ethylene glycol dimethyl ester, benzene, toluene or a mixture of the above solvents or, in the absence of a solvent where excess of hydrazine acts as a solvent.

The reactions are performed between 0°C to 1 30°C, preferably between 20"C to 100"C, most preferably at or about the reflux temperature of the solvent. The reactions are preferably con- ducted under an inert atmosphere such as N2 or Ar. When the reaction is complete as judged by disappearance of the starting ester by TLC or HPLC, the solvent may be removed by con- centration at atmospheric or reduced pressure.

The product can be further purified by either recrystallization from a solvent such as ethyl alco- hol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Altematively, the product can be purified by column chromatography using dicnloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent. The corresponding fractions are concentrated either at atmos- pheric pressure or in vacuo to provide the pure aroyl hydrazide.

Preparation of aromatic acid hydrazides: The methyl or ethyl ester of the corresponding aromatic acid, such as for example a substi- tuted benzoic acid ester, is dissolved in ethanol and hydrazine (5 eq) is added. The reaction is refluxed overnight under nitrogen. Upon cooling the substituted hydrazide derivative usually precipitates. After filtration the product is usually recrystallized from hot methanol, ethanol or isopropyl alcohol. In cases where the hydrazide does not precipitate, the reaction is concen- trated under vacuo and chromatographed over silica gel using dichloromethane/methanol as the eluent. Specific examples illustrating the preparation of aromatic hydrazides are provided below.

Preparation of 5-hydroxyindole-2-carboxylic acid hydrazide: To a sample of ethyl 5-hydroxyindole-2-carboxylate (5g, 24 mmol), dissolved in ethanol (250 mL) was added hydrazine (4 mL, 121 mmol). The reaction was refluxed overnight under ni- trogen. Upon cooling the reaction vessel, the desired product crystallized. The white solid was isolated by filtration. Recrystallization from hot ethanol gave the 5-hydroxyindole-3- carboxylic acid hydrazide in 85% yield.

1H NMR (DMSO-d6): 64.38 (s, 2H); 6.62 (dd, 1H); 6.76 (dd, 2H); 7.13 (d, 1H); 8.70 (s, 1H); 9.57 (s, 1H); 11.21 (s, 1H); MS (FAB): m/z 192 (M+H)+.

Preparation of 3-chloro-4-hydroxybenzoic acid hydrazide: To a sample of methyl 3-chloro-4-hydroxybenzoate (2 g) dissolved in ethanol (50 mL) was added hydrazine (1.8 mL). The reaction was refluxed overnight under nitrogen. Upon cooling the reaction vessel, the desired product crystallized out of solution. The white solid was iso- lated by filtration. Recrystallization from hot ethanol gave the 3-chloro-4-hydroxybenzoic acid hydrazide in 60% yield.

1H NMR (DMSO-d6): 8 4.49 (broad s, 2H), 7.05 (dd, 1H), 7.71 (dd, 1H), 7.89 (d, 1H), 9.669 (s, 1H), 10.72 (broad s, 1H).

By use of the above methodology, other hydrazides useful as intermediates in preparing the compounds of the invention are prepared, for example: 3-Bromo-4-hydroxybenzoic acid hydrazide 1H NMR (DMSO-d6): 8 9.95 (s, 1H), 9.65 (d, 1 H), 9.61 (broad s, 1H), 6.95 (d, 1H), 4.40 (broad s, 2H); MS m/z 233.1.

3-Nitro4-hydroxybenzoic acid hydrazide 1H NMR (DMSO-d6): # 9.28 (broad s,lH), 8.28 (s, 1 H), 7.52 (d, 1H), 6.41 (d, 1H). MS m/z 198.

3-FluoroA-hydroxybenzoic acid hydrazide 1H NMR (DMSO-d6): 5 9.45 (broad s, 1 H), 7.5 (d, 1 H), 7.43 (d, 1H), 6.85 (t, 1H), 5.55 (broad s, 3H).

Preparation of 2-chloro-4-hydroxybenzoic acid hydrazide, 2,3-dichloro"4- hydroxybenzoic acid hydrazide and 2,5-dichloro4-hydroxybenzoic acid hydrazide.

Preparation of 2-chloro-4-hydroxybenzoic acid hydrazide: Step A: 4-amino-2-chlorobenzoic acid (10 g, 58 mmol) was dissolved in H2SO4 (12 N, 120 mL) with heating. After cooling the solution in an ice-bath aqueous NaNO2 (2.5 M, 25 mL) was added dropwise such that the internal temperature remained at 5 °C. Urea was added to the mixtu- re for after stirring for 15 minutes to destroy excess NaNO2 (monitored by starch iodine test).

CuSO4 (100-200 mg) was added and the mixture was heated to 90 OC until evolution of gas stopped. After cooling, the mixture was extracted with ethyl ether (3x). The combined orga- nic fractions were extracted with 3N NaOH (3x). The combined aqueous layer was acidified with conc. HCI and the product was extracted with ethyl ether (3x). The organic fractions were washed with water, brine, and dried over MgSO4. The crude product was introduced into a silica gel column and eluted with ethyl acetate/hexane (1/1) to afford 2-chloro-4- hydroxybenzoic acid.

1H NMR (DMSO-D6): 86,97 (dd, 1H), 7.05 (d, 1H), 7.95 (d, 1H), 10.90 (brd s, 1H).

Step B: To a solution 2-chloro-4-hydroxybenzoic acid in anhydrous methanol was added thionyl chlo- ride (1.5 eq). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgSO4 and concentrated in vacuo to give methyl 2-chloro-4-hydroxybenzoate.

Step C: To a solution of methyl 2-chloro-4-hydroxybenzoate (13.6 g, 73.1 mmol) in acetic acid (300 mL) was added N-chlorosuccinimide (9.8 g, 73.7 mmol). The solution was refluxed for 24 h and the solvent was evaporated under vacuo. The residue was taken up in chloroform, washed with water, brine, dried over magnesium sulfate, filtered and concentrated. Methyl 2,3-dichloro-4-hydroxybenzoate precipitated out of ethyl acetate. Chromatography of the re- sidue using ethyl acetate/hexane (1/9 to 3/7) afforded methyl 2,5-dichloro-4- hydroxybenzoate (1.4 g, 60%) as well as an additional batch of methyl 2,3-dichloro-4- hydroxybenzoate isomer (total of 8.4 g, 10%).

Methyl 2,3-dichloro-4-hydroxybenzoate: 'H NMR (DMSO-D6) 8 3.81 (s, 3H), 7.02 (d, 1H), 7.70 (d 1H), 11.52 (s, 1H); MS (APCI): 221, 223.

Methyl 2,5-dichloro-4-hydroxybenzoate:

'H NMR (CDCl3): 83.90 (s, 3H), 6.00 (s, 1H), 7.14 (s, 1H), 7.27 (s, 1H), 7.96 (s, 1H); MS (APCI): 221.9.

Step D: The title compound was prepared according to the general procedure for the synthesis of precursor hydrazides A-(C=O)-NHNH2.

1H NMR (DMSO-D6): 86.82 (dd, 1H), 6.90 (d, 1H), 7.79 (d, 1 H, 10.68 (brd s, 1H).

Preparation of 2.3-Dichloro4-hydroxybenzoic acid hydrazide and 2.5-dichloro"4- hydroxybenzoic acid hydrazide (step D): The 2,3-dichloro-4-hydroxybenzoic acid hydrazide was prepared from the methyl 2,3- dichloro-4-hydroxybenzoate above according to the general procedure for the synthesis of precursor hydrazides A-(C=O)-NHNH2 with the exception that pentanol was the solvent of choice. The product was purified via silica gel column chromatography using CH2Cl2/MeOH (95/5 to 80/20), yield = 50%.

2,5-dichloro-4-hydroxybenzoic acid hydrazide was prepared in a similar way starting from 2,5-dichloro-4-hydroxybenzoate.

2,3-Dichloro-4-hydroxybenzoic acid hydrazide: 1H NMR (DMSO-D6) 8 4.41 (brd s, 2H), 6.99 (1, 1 H), 7.37 (s, 1H), 9.46 (s, 1H), 11.04 (s, 1H).

2,5-Dichloro-4-hydroxybenzoic acid hydrazide; 1H NMR (DMSO-D6) # 4.48 (brd s, 3H), 6.92 (d, 2H), 7.18 (d, 2H), 9.45 (brd s, 1H).

Preparation of 2,3-difluoro-4-hydroxybenzoic acid hydrazide:

Step A: A mixture of 2,3-difluoro-4-cyanophenol (1 g, 6.45 mmol) in water (8 mL), H2SO4 (8 mL), and acetic acid (8 mL) was refluxed for 48 hours. The solvents were removed by rotary evapo- ration to give a slurry which was poured onto ice. The product precipitated out of solution and filtered. The solid was washed with water and dried to give 2,3-difluoro-4- hydroxybenzoic acid (800 mg, 71%).

'H NMR (DMSO-D6): 36.87 (t, 1H), 7.60 (t, 1H), 11.28 (s, 1H), 12.53 (brd s, 1H).

Step B: To the 2,3-difluoro-4-hydroxybenzoic acid (800 mg, 5.1 mmol) dissolved in anhydrous methanol (50 mL) was added thionyl chloride (0.55 mL, 7.3 mmol). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgSO4 to give methyl 2,3-difluoro-4-hydroxybenzoate (540 mg, 62%).

'H NMR (CDCl3): 53.92 (s, 3H), 6.34 (brd s, 1H), 6.82 (dt, 1H), 7.68 (dt, 1H).

Step C: The 2,3-difluoro-4-hydroxybenzoic acid hydrazide was prepared from the methyl 2,3-difluoro- 4-hydroxybenzoate above according to the general procedure for the synthesis of precursor hydrazides A-(C=O)-NHNH2. The product was purified via silica gel column chromatography using CH2Cl2/MeOH ( 95/5 to 80/20) to afford the title compound.

1H NMR (DMSO-D6): 84.48 (s, 2H), 6.80 (m, 1H), 7.22 (m, 1H), 9.36 (s, 1H), 10.89 (s, 1H); MS (APCI): 189.

Preparation of 3-cyano 4-hydroxybenzoic acid hydrazide. trifluoroacetate: Step A: Methyl-4-hydroxybenzoate (35.5 g, 0.233 mol) was dissolved in 200 mL of warm (65 "C) acetic acid. A solution of iodine monochloride (37.8 g, 0.233 mol) in 50 mL of acetic acid was added slowly (40 minutes) to the methyl-4-hydroxybenzoate solution, while maintaining a temperature of 65 OC and vigorous stirring. The product crystallizes from solution upon cooling to room temperature and standing overnight. The crystals were collected on a filter, washed with water, then dried under vacuum. Methyl-4-hydroxy-3-iodobenzoate was obtai- ned as white crystals (28.6 g, 44%).

1H NMR (DMSO-D6): 6 3.79 (s, 3H), 6.95 (d, J = 8.3, 1H), 7.81 (dd, J = 8.3, 2.2, 1H), 8.22 (d, J = 2.2, 1H); 13C NMR (DMSO- D6) 652.8,85.2, 115.5, 123.0, 132.0, 141.0, 161.9, 165.6.; MS (APCI, neg): 277.

Step B: Methyl-4-hydroxy-3-iodobenzoate (2.00 g, 7.2 mmol) was dissolved into 5 mL of dry DMF.

Copper(l) cyanide (0.72 g, 8.0 mmol) and a small crystal of sodium cyanide was added. The mixture was flushed with nitrogen, placed in an oil heating bath (100-110 "C), and stirred overnight. TLC indicated nearly complete reaction. The mixture was cooled and the solids removed by filtration. The solids were extracted with DMF (3 mL). The filtrate and washings were taken up in 100 mL of ethyl acetate, then washed with 3 portions of saturated sodium chloride solution. The solids and aqueous washings were combined, and shaken with a

mixture of 50 mL of ethyl acetate and a ferric chloride solution (4 g of hydrated ferric chloride in 7 mL of conc. hydrochloric acid). The ethyl acetate layers were combined, washed with brine containing sodium metabisulfite, dried over sodium sulfate, filtered, and the solvent removed in vacuo. The resulting solids were purified by flash chromatography on silica gel (20% ethyl acetate/ hexane) to afford methyl-3-cyano-4-hydroxybenzoate, 0.939 (73%). <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>1H NMR (DMSO- D,): 6 3.79 (s, 3H), 7.07 (d, J = 8.7, 1H), 8.02 (dd, J = 8.7, 1.9, 1H), 8.10 <BR> <BR> <BR> <BR> <BR> <BR> <BR> (d,J= 1.9, 1H).

Step C: Methyl-3-cyano-4-hydroxybenzoate (2.719, 15.3 mmol) was dissolved in 50 mL of THF. The solution was chilled in an ice bath, and 2.0M potassium hydroxide (17 mL, 34 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. TLC in- dicated complete reaction. The THF was removed by rotary evaporation. The aqueous re- sidue was acidified with aqueous trifluoroacetic acid and purified by reverse-phase HPLC (C- 18, 0.1% TFA in water and acetonitrile). 3-Cyano-4-hydroxybenzoic acid was obtained as a white powder (2.it, 84%) after lyophilization. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>1H NMR (DMSO- D6): 67.09 (d, J = 9.0, 1H), 8.00 (dd, J = 9.0, 2.3, 1H), 8.07 (d, J = 2.3, 1H) 12.50 (br s, 2H); MS (APCI, neg): 162. IR: 2252 cm1, CN.

Step D: 3-Cyano-4-hydroxybenzoic acid (I .88g, 11.5 mmol) was dissolved in 20 mL of methylene chloride/DMF (1/1) and chilled in an ice-bath. Diisopropylethylamine (12 mL, 69 mmol), t- butyl carbazate (1.76g, 13.3 mmol), and PyBroP (bromo-tris-pyrrolidino-phosphonium he- xafluorophosphate, 6g, 12.9 mmol) were added, and the mixture was stirred to form a clear solution. The solution stood in the refrigerator overnight. TLC indicated that the reaction was not complete, so additional diisopropylethylamine (22 mL, 127 mmol), t-butyl carbazate (0.859, 6.4 mmol) and PyBroP (3.09, 6.4 mmol) were added. After 8 more hours at 0 "C, the reaction was worked up as follows. The solution was reduced by rotary evaporation. The remaining DMF solution was diluted with 100 mL of ethyl acetate, and washed with several portions of 0.1 M HCI (until the wash remained acidic to litmus paper). The ethyl acetate layer was further washed with 3 portions of brine, dried over magnesium sulfate, filtered, and

reduced to an oil in vacuo. The oil was purified by chromatography on silica gel (6:4 hexa- ne:ethyl acetate) to afford tert-butyloxycarbonyl (3-cyano-4-hydroxy)benzoic acid hydrazide as a white solid (1.8g, 56%).

'H NMR (DMSO- D6): 81.42 (s, 9H), 7.09 (d, J = 8.7, 1H), 7.98 (m, 1H), 8.11 (br s, IH), 8.92 (s, 1H), 10.15 (s, 1H), 11.73 (brs, 1H); MS (APCI, neg): 276; IR: 2232 cm-1, CN.

Step E: The Boc-hydrazide (1.89, 6.5 mmol) was suspended in 50 mL of chloroform and cooled in an ice-bath. Trifluoroacetic acid was added with stirring, and the resulting solution stood for 4 hours at 0 °C. TLC indicated complete reaction. Solvent and excess TFA were removed by rotary evaporation. The remaining oil was purified by reverse-phase liquid chromatography (Aquasil C-18 column, water/acetonitrile/0.1% TFA). The title compound was obtained as a white solid (0.24 g, 13%).

1H NMR (DMSO- D6): 87.16 (d, J = 9.0, 1H), 8.00 (dd, J = 1.5, 9.0, 1H), 8.14 (d, J = 1.5, 1H), 10.47 (brs, 5H); MS (APCI, neg): 176.

Preparation of 4-hydroxynaphthoic acid hydrazide: Step A: Silver nitrate (17 g, 0.1 mol) was dissolved in water (10 mL) and treated with 1 N NaOH (300 mL, 0.3 mol). The brown precipitate which was formed was stirred for 30 minutes and the supernatant was decanted. The brown silver oxide was washed with additional volumes of water (3x).

To the silver oxide above was added 1N NaOH (150 mL) and 4-hydroxynaphthaldehyde (1 g, 6 mmol)). The mixture was heated to 70 °C for 10 minutes after which additional amounts of 4-hydroxynaphthaldehyde (5.5 g, 32 mmol) was added in portions. The mixture was kept at 80 °C for 16 hours. TLC analysis indicated incomplete conversion. An additional portion of silver oxide was prepared as above and added to the reaction mixture. After heating the mixture for an additional 6 hours, the mixture was cooled and acidified with 1N HCI. The aqueous layer was extracted with ethyl acetate (3x) and upon concentration 4- hydroxynaphthoic acid precipitated (3.7 g, 60%) out of solution.

'H NMR (DMSO-D6): 86.69 (d, 1H), 7.28 (t, 1H), 7.39 (t, 1H), 7.93 (d, 1H), 8.03 (d, 1H), 8.82 (d, 1H), 10.82 (s, 1H), 12.29 (s, 1H).

Step B: To a solution 4-hydroxynaphthoic acid in anhydrous methanol at 0 °C was added thionyl chloride (1.5 eq). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgSO4 to give methyl 4- hydroxynaphthoate. tH NMR (DMSO-D6): 83.87 (s, 3H), 6.92 (d, 1H), 7.53 (t, 1H), 7.65 (t, 1H), 8.13 (d, 1H), 8.26(d, 1H), 8.93(d, 1H), 11.16(s, 1H).

Step C: The title compound was prepared from methyl 4-hydroxynaphthoate according to the proce- dure for the synthesis of precursor hydrazides A-(C=O)-NHNH2.

1H NMR (DMSO-D6): 8 6.60 (d, 1H), 7.28 (m, 3H), 7.95 (d, 1H), 8.07 (d, 1H), 9.25 (brd s, 1H).

Moreover, by use of the above methodology, the following hydrazides useful as intermediates in preparing the compounds of the invention may be prepared:

General procedure for the synthesis of ether-substituted aryl-aidehydes: The ether-linked aldehydes may be prepared by 0-alkylation of the corresponding phenolic compounds using various electrophilic alkylating agents that introduce the -(K)m-D moiety as defined above in a reaction generally known as Williamson ether synthesis (H. Feuer, J. Hooz in The Chemistry of the Ether Linkage, S. Patai Ed., Wiley, New York 1967, p. 446460).

SCHEME II R3aR3bR4aR4b R1i){O Lx (CH2)b(CH2)a-(M)f (CH2)c>(CH2)d D R'4 5," Lx (CH, \- 2e R OH Base, solvent H RR1{½HO CH2)a-(M)f(Ct 0 (CH2)p(CH2)a(M)(CH2)cq(CH2) D wherein Lx is a leaving group such as -Cl, -Br, -I, -OSO2CH3, -OSO2p-tolyl or-OSO2CF3; and R3a, R3b, R4a, R4b, a, b, c, d, f, p, q, D, M, R'4 and R15 are as defined for formula According to Scheme II an ether-substituted aryl-aldehyde can be prepared by stirring hy- droxybenzaldehydes or hydroxynaphthaldehydes in an organic solvent such as acetone, meth- ylethyl ketone, dimethylformamide, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or more of the above sol- vents with an equimolar amount of an alkyl halide or an aryl-lower alkyl halide and in the pres- ence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydride, sodium or potassium methoxide, ethoxide or tert-butoxide, sodium, potas- sium or cesium carbonate, potassium or cesium fluoride, sodium or potassium hydroxide or organic bases such as diisopropylethylamine, 2,4,6-collidine or benzyldimethyl- ammonium methoxide or hydroxide. The reaction can be performed at O"C to 150"C, preferably at 200C to 100°C and preferably in an inert atmosphere of N2 or Ar. When the reaction is complete the mixture is filtered, concentrated in vacuo and the resulting product optionally purified by column chromatography on silica gel using ethyl acetate/hexane as eluent. The compound can also (when appropriate) be purified by recrystallization from a suitable solvent such as ethyl alcohol,

ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture. Specific examples illustrating the preparation of ether-substituted aryl-aldehydes are provided below.

Preparation of 4-(2-tetrahydropyranylmethoxy)-1-naphthaldehyde.

A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 2-bromomethyl tetrahydropyran (1 g, 5.8 mmol) and powdered K2CO3 (1.2 g, 8.7 mmol) in dimethyl formamide was stirred at 60°C overnight. The mixture was taken up in water and ethyl acetate. The organic layer was sepa- rated and washed with water, brine, dried over MgSO4, filtered, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate/hexane.

1H NMR (DMSO-d6): 8 1.48 (m, 4H), 1.74 (d, 1H), 1.84 (m, 1H), 3.44 (m, 1H), 3.78 (m, 1H), 3.92 (d, 1H), 4.23 (m, 2H), 7.17 (d, 1H), 7.64 (t, 1H), 7.74 (t, 1H), 8.11 (d, 1H), 8.27 (d, 1H), 9.22 (d, 1H), 10.17 (s,1H).

Preparation of 4-[(3,5-bis-trifluoromethyl)benzyloxy]-1-naphthaldehyde: A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 3,5-bis-trifluoromethylbenzylbromide (1.8 g, 5.8 mmol), and powdered K2CO3 (1.2 g, 8.7 mmoi) was stirred in acetone (40 mL) over- night. The mixture was poured onto 200 mL of ice-chips and stirred until the ice melted. The yellow precipitate, 4-((3,5-bis-trifluoromethyl)benzyloxy)-l -naphthaldehyde, was collected and dried.

'H NMR (DMSO-d6): 85.58 (s, 2H), 7.07 (d, 1H), 7.22 (d, 1H), 7.63 (t, 1H), 7.69 (t, 1H), 7.79 (d, 1H), 7.86(d, 1H), 7.99(s, 1H), 8.14(s, 1H), 8.30(s, 3H), 8.94(s, 1H) 8.97(d, 1H), 11.0 (broad s, 1H), 11.69 (s,lH); MS (ESI) m/z 675.2 (M+H)+.

Preparation of 4-(2-chloroethoxy)-1-naphthaldehyde, To a solution of 4-hydroxy-1-naphthaldehyde (8.6 g, 50 mmoles) and potassium carbonate (13.8 g, 100 mmoles) in N,N-dimethylformamide (DMF)(40 mL) was added 1-bromo-2- chloroethane (7.4 g, 50 mmoles). The mixture was heated at 600C overnight. The solution was diluted with ethyl acetate (500 mL), extracted with water and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated to obtain 12.1 g product (52 % yield).

MS (Cl): 403, 405, 407. 1H NMR (CDCl3): 8 10.2 (s, 1H), 9.3 (d, 1H) 8.35 (d, 1H), 7.85 (d, 1H), 7.65(m, 1H), 7.5(m, 1H), 7.1(d, 1H), 4.35(t, 2H), 4.15(t, 2H).

The products were used as such in further transformations.

By application of the above methodology the following substituted aldehyde intermediates were synthesized: 4-carbomethoxymethoxy-1-naphthaldehyde m.p.: 115-1160C 4-(4-chlorobenzyloxy)-1 -naphthaldehyde 4-(4-trifluoromethoxybenzyloxy)-l- naphthaldehyde 4-(4-trifluoromethylbenzyloxy)-l - naphthaldehyde 4-benzyloxy-1 -naphthaldehyde 4-allyloxy-1-naphthaldehyde 4-propargyloxy-1-naphthaldehyde 2-[(4-carboxaldehydo)-1 - naphthyloxy]acetamide m.p. 174-1750C 4-(3-trifluoromethylbenzyioxy)-l - naphthaldehyde 4-(4-trifluoromethoxybenzyloxy)-3,5- dimethoxybenzaldehyde 4-(4-isopropylbenzyloxy)-3,5- dimethoxybenzaldehyde (oil) 4-(4-isopropylbenzyloxy)-1-naphthaldehyde 4-(2-(4-trifluoromethoxyphenyl)-2-oxo- ethoxy)-1-naphthaldehyde m.p. 112-1140C Nicotinic acid 4-formyl-1-naphthyl ester m.p. 142-143°C 4-(1 ,3-dioxo-1 ,3-dihydroisoindol-2- ylmethoxy)-l -naphthaldehyde m.p. 191-192°C 4-(tetrahydro-2-pyranylmethoxy)-1- naphthaldehyde

4-(3,5-difluorobenzyloxy)-l -naphthaldehyde m.p. 100-1010C Preparation of 3-Allyl-4-hydroxy-5-methoxy-benzaldehyde: To a solution of vanillin (1.0 g, 6.57 mmol) in acetone (30 mL) was added potassium carbon- ate (4.50 g, 32.8 mmol) and allyl bromide (0.62 mL, 7.3 mmol). The mixture was heated un- der reflux for 6 h. TLC showed appearance of a new spot. Potassium salts were removed by filtration and the filtrate was concentrated to a syrup. A small sample was purified using prep TLC using hexane/ethyl acetate 7:3 as developing solvent. 1H NMR (CDCI3) 8 = 3.94 (s, 3H), 4.67 - 4.83 (m, 2H), 5.30 - 5.55 (m, 2H), 6.01 - 6.21 (m, 1H), 6.98 (d, J = 9 Hz, 1H), 7.40 - 7.56 (m, 2H), 9.85 (s, 1 H); MS (APCI): 193.6 The crude syrup was heated neat in an oil bath at 200 °C for 6 h. The crude material was dissolved in chloroform and filtered through a pack of silica gel. The crude product (yield 72%) was used as is in the next step for O-alkylation. A small portion was purified using prep-TLC to give a pure sample of 3-allyl-4-hydroxy-5-methoxy-benzaldehyde. 1H NMR (CDC13) 8 = 3.46 (d, J = 6 Hz, 2 H), 3.96 (s, 3H), 5.02 - 5.22 (m, 2H), 5.94 - 6.11 (m, 1H), 6.30 (s, 1H), 7.45 (s, 2H), 9.80 (s, 1 H); MS (APCI): 193.3.

Preparation of 3-Allyl-4-(4-isopropylbenzyloxy)-5-methoxybenzaldehyde: The crude 3-allyl-4-hydroxy-5-methoxy-benzaldehyde was taken up in acetone and treated with 4-isopropylbenzyl chloride in the presence of potassium carbonate to give the desired product.

1H NMR (CDCl3) 8 = 1.26 (d, J = 7 Hz, 6 H), 2.92 (m, 1H), 3.38 (d, J = 7 Hz, 2H), 3.95 (s, 3H), 4.98 - 5.12 (m, 4H), 5.93 - 5.75 (m, 1H), 7.20 - 7.43 (m, 6H), 9.87 (s, 1H).

General procedure for the synthesis of compounds of formulae IXa and IXb: ci NHN ocB 0NH2 + ci m*tepA step 0 0 step B 0 H T ./NH, 0 0BN S H q/ ;g R8XH </ 0 D H 0 HO H 0 step D R Formula Ixa step c \ K2CO3 STEPS 0 RH NB ,eD HO O K,/NB,N/D step D HO R9 H step D R9 Formula IXb In the above formulae B, D, R5 and R9 have the same meanings as defined for formula I.

Step A: To a solution of aniline (or an aniline derivative) (1 eq.) in THF was added dropwise chloroacetyl chloride (1.2 eq.). After stirring at room temperature overnight, 100 mL water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed twice with dilute hydrochloric acid, twice with water, dried over MgSO4 and then con- centrated to give pure product.

Step B: To a solution of chloroacetanilide (or a derivative thereof) (1.2 eq.) and 2-methoxy-4- hydroxy benzaldehyde (or another aromatic aldehyde substituted with a hydroxy group) (1 eq.) in DMSO was added potassium carbonate (1.5 eq.). After stirring overnight at room temperature, 100 ml water was added. The mixture was extracted with ethyl acetate, the or- ganic extracts were washed twice with a satd. sodium bicarbonate solution, twice with water, and dried over MgSO4. After concentration in vacuo, the product was obtained.

The following two aldehydes were prepared as examples of compounds that can be pre- pared using this methodology: N-(4-Chlorophenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide: 1H NMR (CDCI3 ): 84.28 (s, 3H), 5.01 (s, 2H), 6.90 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 8.6, 2.1 Hz, 1H), 7.67( d, J = 8.9Hz , 2H), 7.89 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.6Hz, 1H), 8.51 (s, 1H), 10.66(s, 1H); MS (APCI ): 319.9 .

N-(4-isopropylphenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide : 1H NMR (DMSO-D6); # 2.07(d, J=6.9 Hz, 6H), 2.70(m, J=6.9 Hz, 1H), 3.77(s, 3H), 4.68 (s, 2H), 6.56(dd, J=8.7, 2.1 Hz, 1H), 6.66(d, J=2.1Hz, 1H), 7.06(d, J=8.5Hz, 2H), 7.39 (d, J=8.50 Hz, 2H), 7.55(d, J=8.7 Hz, 1H), 9.93(s, 1H), 10.05(s, 1H); MS(APCl): 328.

This type of aldehydes can be coupled to hydrazides using the methodology as described in step D to give a compound of formula IXa. Alternatively these compounds can undergo re- arrangement by treatment with base as described below (step C), followed by coupling to a hydrazide (step D) to give a compound of formula IXb.

Step C: The mixture of aldehyde (1 eq.) and potassium carbonate (1.5 eq.) in acetonitrile was re- fluxed. The reaction was monitored by TLC (hexane: ethyl acetate = 2:1). When TLC showed almost complete conversion (about 48 h), 100 mi water was added. The mixture was extracted with ethyl acetate, the organic extracts were dried over MgSO4, and concen- trated to give the desired product which can be further purified by column chromatography, or used directly for the next step.

The following two aldehydes were prepared as examples of compounds that can be pre- pared using this methodology: 4-(4-Chlorophenylamino)-2-methoxybenzaldehyde Prepared from N-(4-chlorophenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide using the pro- cedure described in step C above.

1H NMR (CDCl3): 83.84 (s, 3 H), 6.14 (s, 1H), 6.45 (d, J = 2.0 Hz, 1H), 6.54 (dd, J = 8.4, 1.8Hz, IH), 7.14 (d, J = 8.7Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.5Hz, 1H), 10.22 (s, 1H); MS (APCI ): 261.9.

4-(4-lsopropylphenylamino)-2-methoxybenzaldehyde: Prepared from N-(4-isopropylphenyi)-2-(4-formyl-3-methoxyphenoxy)acetamide using the procedure described in step C above.

1H NMR (CDCI3) 8 1.26 (d, J = 6.9Hz, 6H), 2.88 (m, J = 6.9Hz, 1H), 3.84 (s, 3H), 6.50 (d, J = 1.9Hz, 1H), 6.55 (dd, J = 8.6, 1.8Hz, 1H), 6.96 (s, 1H), 7.15 (d, 2H, J = 8.5Hz, 2H), 7.22 (d, J = 8.5Hz, 2H), 7.69 (d, J = 8.5Hz, 1H), 10.18 (s, 1H); MS (APCI ): 269.

Step D: The resulting carbonyl compounds are treated with the corresponding acylhydrazide in a sol- vent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloro- form, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylorthoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystallized if necessary from a solvent such as the above described reaction sol-

vents. The product can also be isolated by concentration of the reaction mixture in vacuo, fol- lowed by column chromatography on silica gel using a solvent system such as chloro- form/methanol or dichloromethane/methanol or chloroform/ethyl acetate to give a compound of formula IXb.

The following compounds of formulae IXa or IXb according to the invention were prepared as examples of compounds that can be prepared using this methodology: EXAMPLE 1: 3-ChloroA-hydroxybenzoic acid [4-(4-chlorophenylamino)-2-methoxybenzylidene]hydra-zide 1H NMR ( DMSO-D6 ): 83.81 (s, 3H), 6.72-6.67 (m, 2H), 7.04 (d, J = 8.5Hz, 1H), 7.17 (d, J = 8.7Hz, 2H) 7.31 (d, J = 8.7Hz, 2H), 7.77- 7.70 (m, 2H), 7.96 (d, J = 1.6Hz, 1H), 8.65 (s, 1H), 8.70 (s, 1H), 10.87 (s, 1H), 11.51 (s, 1H); MS (APCI ): 430.

EXAMPLE 2: 3-Chloro-4-hydroxybenzoic acid [4-(4-isopropylphenylamino)-2-methoxybenzylidene]hy- d razide 1H NMR (DMSO-D6): # 1.18(2s, 6H), 2.86 (m, 1H), 3.79 (s, 3H), 6.65 (m, 2H), 7.03 (d, 1H), 7.11 (d, 2H), 7.19 (d, 2H), 7.70 (d, 1H), 7.75 (dd, 1H), 7.97 (s, 1H), 8.49 (s, 1H), 8.64 (s, 1H), 10.88 (s, 1H), 11.48 (s, 1H); MS (FAB): 438.16.

EXAMPLE 3: 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyp henoxy}-N-(4- chlorophenyl)acetamide 1H NMR (DMSO-D6): 83.66 (s, 3H), 4.57 (s, 2H), 6.48 (d, 1H), 6.55 (s, 1H), 6.83 (d, 1H), 7.20 (d, 2H), 7.48 (d, 2H), 7.56 (dd, 1H), 7.58 (d, 1H), 7.77 (d, 1H), 8.48 (s, 1H), 10.05 (s, 1H), 10.72 (brd s, 1H). 11.40 (s, 1H); MS (APCI): 487.8.

EXAMPLE 4: 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyp henoxy}-N-(4- isopropylphenyl)acetamide 1H NMR (DMSO-D6): # 1.17(2 s, 6H), 2.85 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 6.70 (d, 1H), 6.76(d, 1H), 7.05(d, 1H), 7.20(d, 2H), 7.55(d, 2H), 7.77(dd, 1H), 7.80(d, 1H), 7.98(s, IH), 8.70 (s, 1H), 10.03 (s, 1H), 10.92 (s, 1H), 11.62 (s, 1H); MS (FAB): 496.16.

EXAMPLE 5: 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyp henoxy}-N-(3,5- dichlorophenyl?acetamide 1H NMR (DMSO-D6): 84.06 (s, 3H), 4.94 (s, 2H), 6.8 (d, 1H), 6.88 (s, 1H), 7.20 (d, 1H), 7.45 (s, 1H), 7.90 (m, 3H), 8.10 (s, 1H), 8.82 (s, 1H), 10.62 (s, 1H), 11.07 (brd s, 1H), 11.75 (s, 1H); MS (APCI): 524.8.

General procedure for the synthesis of alkylidene hydrazides of formula 11 according to the invention: The acylhydrazides are treated with the corresponding carbonyl compounds, such as aldehy- des or ketones, in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, teit-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between 0°C to 140"C, preferably between 100C to 80"C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystal- lized if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/-methanol or di- chloromethane/methanol or chloroform/ethyl acetate. The product is isolated by concentration in vacuo of the appropriate fractions. Specific examples illustrating the preparation of com- pounds according to the invention are provided below.

EXAMPLE 6: 3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 ml) was added 4-hydroxynaphthaldehyde and a catalytic amount of glacial acetic acid (5 drops).

The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate, water, brine, and dried over MgSO4. The or- ganic volume was concentrated in vacuo to give the crude product. The product was purified by silica gel column chromatography using CH2Cl2/MeOH as the mobile phase.

1H NMR (DMSO-d6): 86.89 (d, 2H), 7.02 (d, 1H), 7.47 (t, 1H), 7.58 (t, 1H), 7.66 (d, 1H), 7.73 (d, 1H), 7.93 (s, 1H), 8.17 (d, 1H), 8.84 (s, 1H), 8.88 (d, 1H), 10.73 (s, 1H), 10.88 (s, 1H), 11.54 (s, 1 H); MS (ESI): m/z 341.04 (M+H)+.

EXAMPLE 7: 3-chloro-4-hydroxybenzoic acid [4-(3,5-bis-trifluoromethylbenzyloxy)-1-naphthylmethylene]- hydrazide To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 mL) was added 4-(3,5-bis-trifluoromethylbenzyloxy)-l -naphthaldehyde (440 mg, 1.1 mmol) and a catalytic amount of glacial acetic acid (5 drops). The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicar- bonate, water, brine, and dried over MgSO4. The organic volume was concentrated under

vacuo to give the crude product. The product was purified by silica gel column chromatogra- phy using CH2Cl2/MeOH as the mobile phase.

1H NMR (DMSO-d6): 8 3.77 (s, 6H), 4.91 (s, 2H), 6.95 (s, 2H), 6.99 (d, 1H), 7.30 (d, 2H), 7.52 (d, 2H), 7.68 (m, 1H), 7.89 (s, 1H), 8.29 (s, 1H), 10.90 (broad s, 1H), 11.69 (s, 1H); MS (ESI): m/z 525.37 (M+H)+.

EXAMPLE 8: 3-chloro-4-hydroxybenzoic acid [4-(2-chloroethoxy)-1-naphthylmethylene]hydrazide A solution of 1-(4-chloroethoxy)naphthaldehyde (2.35 g, 10 mmoles), 3-chloro-4-hydroxy benzoic acid hydrazide (1.87g, 10 mmoles), glacial acetic acid (0.2 mL) and dimethylsulfox- ide (DMSO)(15 mL) was stirred at room temperature overnight. Ethyl acetate (100 mL) was added. The solution was extracted with water and brine which induced precipitation. The product (3.1 g, 77% yield) was obtained by suction filtration. The product was purified by recrystallization from ethyl acetate.

MS (Cl): 235. 1H NMR (DMSO-d6): 811.5 (s, 1H), 10.7 (s, 1H), 8.7 (bs, 2H), 8.1 (m, 1H), 7.8 (s, 1 H), 7.6-7.3 (m, 2H), 7.0 (m, 2H), 4.3 (t, 2H), 3.7 (t, 2H).

By application of the above methodology the following compounds of the invention are synthe- sized employing the following general procedure: To a solution of 1 mmol of an arylcarboxylic acid hydrazide in 2 ml of anhydrous DMSO was added 1 mmol of the carbonyl compound (an aldehyde or ketone), followed by a catalytic amount of glacial acetic acid. The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water, brine, and dried over MgSO4. Upon partial concentration of the solvent in vacuo, the alkylene

hydrazides usually precipitated. The alkylene hydrazides were further purified by recrystalliza- tion from hot ethanol or ethyl acetate, or chromatographed using CH2Cl2/MeOH as an eluent.

EXAMPLE 9: 4-Hydroxy-3-methoxybenzoic acid (2-naphthylmethylene)hydrazide 1H NMR (DMSO-d6) # 3.66 (s, 3 H), 6.67 (d, J = 8.2 Hz, 1 H), 7.32 - 7.47 (m, 5 H), 7.74 (d, J = 7.2 Hz, 1H), 7.79(d, J= 8.2 Hz, 2H), 8.60(d, J= 8.2 Hz, 1H), 9.11(s, 1H), 11.80(s, 1 H).

APCI m/z: 321 EXAMPLE 10: 4-Hydroxy-3-methoxybenzoic acid (4-methoxy-1-naphthylmethylene)hydrazide 1H NMR (CDCl3): 84.80 (s, 3 H), 3.86 (s, 3 H), 6.00 (s, 1 H), 6.59 (d, 1 H), 6.83 (d, 1 H), <BR> <BR> <BR> 7.39 (m, 3 H), 7.52 (s, 1 H), 7.73 (s, 1 H), 8.18 (d, 1 H), 8.58 (d, 1 H), 8.88 (s, 1 H), 9.95 (s,1 H). MS (APCI): 351.

EXAMPLE 11: 4-Hydroxy-3-methoxybenzoic acid (4-tert-butylbenzylidene)hydrazide 1H NMR (CDC13): 6 1.30 (s, 9 H), 3.91 (s, 3 H), 6.16 (s, 1 H), 6.88 (d, 1 H), 7.23 - 7.78 (m, 6 H), 8.28 (s, 1 H), 9.58 (s, 1 H). MS (APCI): 327.

EXAMPLE 12: 4-Hydroxy-3-methoxybenzoid acid (4-isopropylbenzylidene)hydrazide 1H NMR (CDC13)61.29 (d, 6 H), 2.94 (q, 1 H), 3.98 (s, 3 H), 6.13 (s, 1 H), 6.97 (d, 1 H), 7.20 - 7.80 (m, 6 H), 8.29 (s, 1 H), 9.38 (s, 1 H). MS (APCI): 313 EXAMPLE 13: 4-Hydroxy-3-methoxybenzoic acid (4-trifluoromethoxybenzylidene)hydrazide 1H NMR (DMSO-d6): 84.01 (s, 3 H), 7.04 (d, J = 8.1 Hz, 1 H), 7.60 - 7.65 (m, 4 H), 8.01 (d, J = 8.4 Hz, 2 H), 8.63 (s, 1 H), 9.92 (s, 1 H), 11.89 (s, 1 H). MS (APCI): 355, 313, 222, 205.

EXAMPLE 14: 4-Hydroxy-3-methoxybenzoic acid (1 H-indol-3-ylmethylene)hydrazide 1H NMR (DMSO-d6) 83.79 (s, 3 H), 6.80 (d, J = 8.2Hz, 1 H), 7.11 (m, 2 H), 7.38 (m, 3 H), 7.73 (d, J = 2.0 Hz, 1 H), 8.53 (d, J = 7.5 Hz, 1 H), 8.53 (s, 1 H), 9.58 (s, 1 H), 11.23 (s, 1 H), 11.49 (s, 1 H). MS (APCI): 310.

EXAMPLE 15: 4-Hydroxy-3-methoxybenzoic acid (4-dimethylamino-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 6 3.05 (s, 6 H), 4.03 (s, 3 H), 7.06 (d, J = 8.1 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1H), 7.63 - 7.80 (m, 4H), 7.97 (d, J= 8.0 Hz, 1H), 8.38(d, J=7.9 Hz, 1H), 9.10(d, J = 8.4 Hz, 1 H), 9.15 (s, 1 H), 9.90 (s, 1 H), 11.73 (s, 1 H). MS (APCI): 364.

EXAMPLE 16: 4-Hydroxy-3-methoxybenzoic acid (4-phenylbenzylidene!hydrazide 1H NMR (DMSO-d6): 8 4.02 (s, 3 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.63 - 7.68 (m, 5 H), 7.88 - 7.96 (m, 6 H), 8.64 (s, 1 H), 9.91 (s, 1 H), 11.83 (s, 1 H). MS (APCI): 347.

EXAMPLE 17: 4-Hydroxybenzoic acid (1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 8 6.82 (d, J = 8.2 Hz, 2 H), 7.48 - 7.68 (m, 3 H), 7.72 - 7.88 (m, 3 H), 7.95(d, J=8.2 Hz, 2H), 8.80(d, 1H), 9.04(s, 1H), 10.14(s, 1H), MS(APCI): 291.

EXAMPLE 18: 4-Hydroxybenzoic acid (4-methoxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 6 3.97 (s, 3 H), 6.82 (d, J = 8.6 Hz, 2 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.52 (dd,J=7.3, 7.7 Hz, 1H), 7.62(dd, J=6.8, 7.7 Hz, 1H), 7.77(d, J=8.5 Hz, 3H), 8.19(d, J = 8.2 Hz, 1 H), 8.89 (m, 2 H), 10.06 (s, 1 H). MS (APCI): 321.

EXAMPLE 19: 3,4-Dihydroxybenzoic acid (1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): # 6.64(d, J=8.6 Hz, 1H), 7.13(d, J=8.2 Hz, 1H), 7.19(d, J=2.0 Hz, 1 H), 7.36 - 7.42 (m, 3 H), 7.68 (d, J = 8.2 Hz, 1 H), 7.80 (d, J = 8.2 Hz, 2 H), 8.65 (d, J = 8.2 Hz, 1 H), 8.88 (s, 1 H), 9.07 (s, 1 H), 9.46 (s, 1H), 11.45 (s, 1 H). MS (APCI): 307.

EXAMPLE 20: 4-Hydroxy-3-methoxybenzoic acid (1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6) # 3.94 (s, 3H), 6.74 (d, 1H), 7.37-7.52 (m, 6H), 7.77 (d, 1H), 7.89 (d, 2H), 8.67 (d, 1H), 9.93 (s, 1H), 10.90 (s, 1H), MS (APCI): 321.

EXAMPLE 21: 4-Hydroxy-3-methoxybenzoic acid [3-(3-trifluoromethylphenoxy)benzylidene]hydrazide 1H NMR (DMSO-d6) # 3.83 (s, 3H), 6.85 (d, 1H), 7.16 (dd, 1H), 7.36 (m, 5H), 7.44 (m, 3H), 7.61 (t, 1H), 8.43 (s, 1H), 1.75 (s, 1H), 11.69 (s, 1H). MS (APCI): 431.

EXAMPLE 22: 4-Hydroxy-3-methoxybenzoic acid (4-quinolinylmethylene)hydrazide 1H NMR (DMSO-d6): 6 3.58 (s, 3 H), 6.52 (d, J = 8.0 Hz, 1 H), 7.28 (d, J = 7.8 Hz, 2 H), 7.47 (dd, J = J' = 8.1 Hz, 1 H), 7.59(m, 2H), 7.86(d, J=8.4 Hz, 1 H), 8.50(d, J=8.4 Hz, 1 H), 8.73 (d, J = 4.5 Hz, 1 H), 8.94 (s, 1 H). MS (APCI): 322.

EXAMPLE 23: 4-Hydroxybenzoic acid [3-(1,1,2,2-tetrafluoroethoxy)benzylidene]hydrazide 1H NMR (DMSO-d6) 86.49-6.78 (m, 3H), 7.10 (d, 1H), 7.32 (t, 1H), 7.41 (m, 2H), 7.57 (d, 2H), 8.23 (s, 1H), 10.01 (s, 1H), 11.59 (s, 1H). MS (APCI): 357.

EXAMPLE 24: 4-Hydroxybenzoic acid [3-(4-tert-butylphenyl)but-2-enylidene]hydrazide 1H NMR (DMSO-d6) 8 1.15 (s, 9H), 1.99 (s, 3H), 6.64 (s, 1H), 6.17 (d, 2H), 7.29 (s, 4H), 7.64 (d, 2H), 8.06 (s, 1 H), 9.98 (s, 1 H), 11.36 (s, 1H). MS (APCI): 337.

EXAMPLE 25: 4-Hydroxy-3-methoxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 8 3.90 (s, 3 H), 6.89 (d, 1 H), 6.99 (d, 1 H), 7.19 (d, 1 H), 7.45 - 7.80 (m, 5 H), 8.22 (d, 1 H), 8.90 (s, 2 H), 9.62 (s, 1 H), 10.68 (s, 1 H). MS (APCI): 337.

EXAMPLE 26: 4-Hydroxybenzoic acid (benzylidene)hydrazide 1H NMR (DMSO-d6): # 6.86 (d, 2 H), 7.41 - 7.52 (m, 3 H), 7.72 (m, 2 H), 7.82 (d, 2 H), 8.41 (s, 1 H), 10.14 (s, 1 H). MS (APCI): 241.

EXAMPLE 27: 3-Amino-4-hydroxybenzoic acid (1 -naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 84.71 (bs, 2 H), 6.68 (d, J = 8.1 Hz, 1 H), 7.01 (dd, J = 2.0, 8.2 Hz, 1 H), 7.17 (d, J = 2.0 Hz, 1 H), 7.51 - 7.62 (m, 3 H), 7.84 (d, J = 7.2 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 2 H), 8.75 (d, J = 7.6 Hz, 1 H), 9.01 (s, 1 H), 9.70 (s, 1 H), 11.54 (s, 1 H). MS (APCI): 306.

EXAMPLE 28: 3-Amino-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 8 4.68 (bs, 2 H), 6.67 (d, J = 8.2 Hz, 1 H), 6.91 (d, J = 7.3 Hz, 1 H), 7.03 (d, J = 8.2 Hz, 1 H), 7.15 (s, 1 H), 7.43 - 7.65 (m, 3 H), 8.16 (d, J = 8.2 Hz, 1 H), 8.83 (m, 2 H), 10.71 (s, 1 H), 11.34 (s, 1 H). MS (APCI): 322.

EXAMPLE 29: 4-Hydroxybenzoic acid [3-(3-trifluoromethylbenzyloxy)benzylidene]hydrazide 1H NMR (DMSO-d6): 8 5.28 (s, 2 H), 6.88 (d, 2 H), 7.12 (m, 1 H), 7.24 - 7.50 (m, 3 H), 7.55 - 7.92 (m, 6 H), 8.41 (s, 1 H), 10.16 (s, 1 H), 10.86 (s, 1 H). MS (APCI): 415.

EXAMPLE 30: 3-Chloro-4-hydroxybenzoic acid (1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): # 7.03 (d, J = 8.2 Hz, 1 H), 7.52 - 7.62 (m, 3 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.86 (d, J =7.0 Hz, 1 H), 7.96 (m, 3 H), 8.79 (d, J = 8.2 Hz, 1 H), 9.01 (s, 1 H), 10.94 (s, 1 H), 11.76 (s, 1 H). MS (APCI): 325.

EXAMPLE 31: 3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 8 6.90 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.50 (dd, J = J' = 7.8 Hz, 1 H), 7.58 (dd, J = 7.1, 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.93 (s, 1 H), 8.17 (d, J = 8.2 Hz, 1 H), 8.83 (s, 1 H), 8.88 (d, J =8.5 Hz, 1 H), 10.73 (s, 1 H), 10.88(s, 1 H), 11.54 (s, 1 H). MS (APCI): 343,341.

EXAMPLE 32: 4-Hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): # 6.88 (d, 2 H), 6.98 (d, 1 H), 7.55 (dd, 1 H), 7.64 (dd, 1 H), 7.71 (d, 1 H), 7.82 (d, 2 H), 8.22 (d, 1 H), 8.94 (m, 2 H), 10.11 (s, 1 H), 10.77 (s, 1 H). MS (APCI): 307.

EXAMPLE 33: 4-Hydroxybenzoic acid [4-(3-trifluoromethylphenoxy)benzylidene]hydrazide 1H NMR (DMSO-d6): 8 6.81(d, 2 H), 6.98 (d, 1 H), 7.13 (dd, 1 H), 7.30 - 7.48 (m, 3 H), 7.48 - 7.60 (m, 3 H), 7.68 (dd, 1 H), 7.81 (d, 2 H), 8.41 (s, 1 H). MS (APCI): 401.

EXAMPLE 34: 4-Hydroxybenzoic acid (5-phenyl-3-pyrazolyimethylene)hydrazlde 1 H NMR (DMSO-d6): 8 6.81 (d, 2 H), 7.40 - 7.62 (m, 5 H), 7.78 (d, 2 H), 8.09 (s, 1 H), 8.50 (s, 1 H). MS (APCI): 307.

EXAMPLE 35: 2,4-Dihydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 6.35 (s, 1 H), 6.39 (d, 1 H), 6.99 (d, 1 H), 7.51 (dd, 1 H), 7.65 (dd, 1H), 7.73 (d, 1H), 7.82(d, 1 H), 8.26 (d, 1 H), 8.88 (s, 1 H), 8.98 (d, 1 H), 10.0-11.0(m, 4 H). MS (APCI): 323.

EXAMPLE 36: 4-Hydroxy-3-nitrobenzoic acid (1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 86.15 (d, J = 9.3 Hz, 1 H), 7.37 - 7.48 (m, 4 H), 6.70 (d, J = 7.1 Hz, 1 H), 7.78 - 7.82 (m, 2 H), 8.29 (s, 1 H), 8.43 (d, J = 8.5 Hz, 1 H), 8.85 (s, 1 H).

EXAMPLE 37: 4-Hydroxy-3-nitrobenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 6 6.24 (d, J = 9.3 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 7.37-7.52(m, 3 H), 7.57 (d, J = 8.0 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 8.34 (s, 1 H), 8.76 (s, 1 H), 8.79 (s, 1 H), 10.57 (s, 1 H), 11.17 (m, 1 H).

EXAMPLE 38: 3,4-Dihydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 8 6.86 (d, 1 H), 6.98 (d, 1 H), 7.32 (d, 1 H), 7.42 (s, 1H), 7.56 (dd, 1 H), 7.63 (dd, 1 H), 7.71 (d, 1 H), 8.24 (d, 1 H), 8.88 (s, 1 H), 8.92 (m, 2 H), 9.26 (s, 1 H), 9.54 (s, 1 H), 10.75 (s, 1 H). MS (APCI): 323.

EXAMPLE 39: 4-Hydroxybenzoic acid (6-methoxy-2-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 8 3.89 (s, 3 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.22 (dd, J = 2.3, 8.9 Hz, 1 H), 7.37 (d, J = 2.3 Hz, 1 H), 7.80 - 7.93 (m, 6 H), 8.04 (s, 1 H), 8.53 (s, 1 H), 11.67 (s, 1 H).

MS(APCI): 321.

EXAMPLE 40: 3,5-Dichloro-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 8 6.98 (d, 1 H), 7.58 (dd, 1 H), 7.68 (dd, 1 H), 7.78 (d, 1 H), 8.02 (s, 2 H), 8.27 (d, 1 H), 8.90 (s, 1 H), 8.96 (d, 1 H), 10.81 (s, 1 H), 10.98 (s, 1 H), 11.67 (s, 1 H).

MS (APCI): 375, 377.

EXAMPLE 41: 6-Hydroxy-2-naphthoic acid (4-hydroxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 86.04 (d, 2 H), 6.33 (m, 1 H), 6.62 (dd, 2 H), 6.79 (dd, 2 H), 7.06 (d, 2 H), 7.44 (d, 2 H), 8.27 (d, 2 H), 8.39 (s, 2 H).

EXAMPLE 42: 4-Hydroxy-3-methoxybenzoic acid (9-ethyl-9H-3-carbazolylmethylene)hydrazide

1H NMR (DMSO-d5) 8 1.34 (t, J = 7.0 Hz, 3 H), 3.88 (s, 3 H), 4.47 (q, J = 7.0 Hz, 2 H), 6.90 (d, J=8.0 Hz, 1 H), 7.25 (t, J = 7.5 Hz, 1 H), 7.47 - 7.54 (m, 3 H), 7.64 (d, J = 8.2 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 8.24 (d, J = 7.7 Hz, 1 H), 8.45 (s, 1 H), 8.62 (s, 1 H) 9.62 (s, 1 H), 11.51 (s, 1H). MS (APCI): 388.

EXAMPLE 43: 4-Hydroxy-3-methoxybenzoic acid [5-(3-chlorophenyl)-2-furanylmethylene]hydrazide 1H NMR (DMSO-d6): # 3.93(s, 3H), 6.97(d, J=8.2 Hz, 1H), 7.14(d, J=3.5 Hz, 1H), 7.37(d, J=3.5 Hz, 1H), 7.48-7.63(m, 4 H), 7.84(d, J=8.0 Hz, 1H), 7.93(s, 1H), 8.47 (s, 1H), 9.85(s, 1H), 11.5(s, 1H), MS(APCI): 371.

EXAMPLE 44: 3-Chloro-4-hydroxybenzoic acid (3-phenylallylidene)hydrazide 1H NMR (DMSO-d6): 87.00 (m, 3 H), 7.22 - 7.40 (m, 3 H), 7.57 (d, 2 H), 7.69 (d, 1 H), 7.89 (s, 1 H), 8.12 (d, 1 H), 11.0 (s, 1 H), 12.0 (s, 1 H). MS (APCI): 301.

EXAMPLE 45: 3-Chloro-4-hydroxybenzoic acid (4-allyloxy-1-naphtylmethylene)hydrazide

1H NMR (DMSO-d6): 84.68 (m, 2 H), 5.21 (d, 1 H), 5.38 (d, 1 H), 5.90 -6.10 (m, 1 H), 6.86 (dd, 2 H), 7.42 (dd, 1 H), 7.53 (dd, 1 H), 7.67 (dd, 2 H), 7.86 (s, 1 H), 8.18 (d, 1 H), 8.78 (s, 1 H), 8.82 (d, 1 H), 10.9 (s, 1 H), 12.0 (s, 1 H). MS (APCI): 381.

EXAMPLE 46: 3-Chloro-4-hydroxybenzoic acid (4-ethynylmethoxy-l -naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 83.60 (s, 1 H), 5.06 (s, 2 H), 6.99 (d, 1 H), 7.12 (d, 1 H), 7.55 (t, 1 H), 7.66(t, 1 H),7.73(t, 1 H),7.93(s, 1 H),8.02(d, 1 H),8.16(t, 1 H),8.86(d, 1 H),9.27(d, 1 H), 10.90 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 378.

EXAMPLE 47: 3-Chloro-4-hydroxybenzoic acid (4-benzyloxy-1 -naphthylmethylene)hydrazide

1H NMR (DMSO-d6): 8 5.40 (s, 2 H), 7.08 (d, 1 H), 7.08 (s, 1 H), 7.39 (d, 1 1 H), 7.43 (m, 3 H), 7.70 (m, 5 H), 8.00 (s, 1 H), 8.01 (d, 1 H), 8.33 (t, 1 H), 8.94 (d, 1 H), 9.35 (d, 1 H), 10.98 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 431, 433.

EXAMPLE 48: 2-(4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-1-naphthyl oxy)acetamide 1H NMR (DMSO-d6): 84.68 (d, 2 H), 6.94 (d, 1 H), 6.98 (dd, 1H), 7.40 - 7.86 (m, 5 H), 8.00 (m, 1 H), 8.48 (dd, 1 H), 8.93 (m, 1 H), 9.38 (m, 1 1 H). MS (APCI): 398.

EXAMPLE 49: 3-Chloro-4-hydroxybenzoic acid (4-methyl-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 82.70 (s, 3 H), 7.10 (d, 1 H), 7.49 (d, 1 H), 7.67 (m, 2 H), 7.81 (m, 2 H), 8.00 (s, 1 H), 8.11 (d, 1 H), 8.88 (d, 1 H), 9.07 (s, 1H), 11.0 (s, 1 H). MS (APCI): 339, 341.

EXAMPLE 50: 3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1-naphthylmethylene)hydrazide

1H NMR (DMSO-d6): 8 6.98 (d, 1 H), 7.98 (d, 1 H), 7.29 (dd, 1 H), 7.48 (dd, 1 H), 7.69 (d, 1 H), 7.78 (dd, 2 H), 7.90 (s, I H), 8.06 (d, 1 H), 9.32 (s, 1 H), 11.00(s, 1 H). MS (APCI): 341.

EXAMPLE 51: 3-Chloro-4-hydroxybenzoic acid (4-methoxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): # 4.05 (s, 3 H), 7.06 (m, 2 H), 7.59 (dd, 1 H), 7.70 (dd, 1 H), 7.81 (d, 1 H), 7.86(d, 1H), 8.00(s, 1H), 8.27(d, 1H), 8.93(s, 1H), 8.99(d, 1H), 11.00(s, 1H). MS (APCI): 341, 339.

EXAMPLE 52: N-(2-[(3-Chloro-4-hydroxybenzoyl)hydrazonolethyl)-2,2-diphen ylacetamide

1H NMR (DMSO-d6) 83.85 (t, 2 H), 4.93 (s, 2 H), 7.16 - 7.25 (m, 10 H), 7.26 (m, 1 H), 7.62 (d, 1H), 7.82(s, 1 H), 8.69 (t, 1 H), 10.85 (s, 1 H), 11.39 (s, 1 H). MS (APCI): 422 EXAMPLE 53: 3-Chloro-4-hydroxybenzoic acid (1 -hydroxy-2-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 8 6.99 (d, 1 H), 7.22 (d, 1 H), 7.37 -7.56 (m, 4 H), 7.68 (dd, 1 H), 7.77 (d, 1 H), 7.90 (s, 1 H), 8.19(d, 1 1 H), 8.58 (s, 1 H), 11.00 (s, 1 H). MS (APCI): 341.

EXAMPLE 54: 3-ChloroA-hydroxybenzoic acid (2 .2-diphenylethylidene)hydrazide 1H NMR (DMSO-d6): 8 4.94 (d, 1 H), 6.98 (d, 1 H), 7.11 - 7.22 (m, 5 H), 7.22 -7.34 (m, 4 H), 7.68 (d, 1 H), 7.82 (s, 1 H), 8.19 (d, 1 H), 11.00 (s, 1 H). MS (APCI): 365, 367.

EXAMPLE 55: 3-Chloro-4-hydroxybenzoic acid (4-benzyloxy-3.5-dimethoxybenzylidene)hydrazide

1H NMR (DMSO-d6): # 3.86(s, 6H), 4.98(s, 2H), 7.03(s, 2H), 7.09(d, 1H), 7.25-7.33 (m, 3 H), 7.48 (m, 2 H), 7.89 (dd, 1 H), 7.99 (s, 1 H), 8.32 (s, 1 H), 11.00 (s, 1 H). MS (APCI): 441.

EXAMPLE 56: 3-Chloro-4-hydroxybenzioc acid [3-(4-tert-butylphenoxy)benzylidene]hydrazide 1H NMR (DMSO-d6): 8 1.05 (s, 9 H), 6.90 (m, 3 H), 7.09 (d, 1 H), 7.30 (t, 1 H), 7.40 (m, 3 H), 7.69 (m, 2 H), 7.88 (s, 1 H), 8.44 (s, 1 H), 10.60 (s, 1 H), 11.55 (s, 1 H). MS (APCI): 423.

EXAMPLE 57: 3-Chloro-4-hydroxybenzoic acid (4-methyl-1-naphthylmethylene)hydrazide

1H NMR (DMSO-d6): 82.64 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.41 (d, J = 7.4 Hz, 1 H), 7.58 (m, 2 H), 7.78 (m, 2 H), 7.95 (d, J = 2.0 Hz, 1 H), 8.06 (dd, J = 2.0, 8.0 Hz, 1 H), 8.82 (d, J = 8.0 Hz, 1 H), 9.07 (s, 1 H), 10.93 (s, 1 H), 11.71 (s, 1 H). MS (APCI): 337. 339.

EXAMPLE 58: 3-Chloro-4-hydroxybenzoic acid (3-bromo-4-hydroxy-1-naphthylmethylene)hydrazide 1H NMR (CDCI3): 87.02 (d, J = 8.5 Hz, 1 H), 7.51 - 7.62 (m, 4 H), 7.80 (dd, J = 2.0, 8.5 Hz, 1H), 8.00(d, J=2.0 Hz, 1H), 8.21(s, 1H), 8.59(d, J=8.5 Hz, 1H), 8.91(s, 1H), MS (APCI): 421, 423.

EXAMPLE 59: Acetic acid 4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-1-naphthyl ester 1H NMR (DMSO-d6): 6 2.63 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.60(dd, J=7.0, 7.5 Hz, 1H), 7.68(dd, J=7.0, 8.0 Hz, 1H), 7.75(dd, J=1.4, 8.0 Hz, 1H), 7.89(d, J=8.0 Hz, 1H), 7.97(d, J=8.0 Hz, 2H), 8.85(d, J=8.5 Hz, 1H), 9.08 (s, 1H), 11.0 (s, 1 H), 11.78 (s, 1 H). MS (APCI): 383.

EXAMPLE 60: 3-Chloro-4-hydroxybenzoic acid 4-cyanomethoxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 8 5.40 (s, 2 H), 7.00 (d, 1 H), 7.21 (d, 1 H), 7.58 - 7.80 (m, 3 H), 7.82 (d, 1 H), 7.96 (s, 1 H), 8.18 (d, 1 H), 8.90 (s, 2 H), 9.28 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 380, 382.

EXAMPLE 61: 3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 87.18 (d, 1 H), 7.30 (d, 1 H), 7.50 (dd, 1H), 7.68 (dd, 1 H), 7.88 (d, 1 H), 7.95 (m, 2 H), 8.08 (s, 1 H), 8.29 (d, 1 H), 9.51 (s, 1 H), 11.12 (s, 1 H), 12.12 (s, 1 H).

MS (APCI): 341, 343.

EXAMPLE 62: 3-Chloro-4-hydroxybenzoic acid (2,3-methylenedioxybenzylidene)hydrazide

1H NMR (DMSO-d6): 86.06 (s, 2 H), 6.86 (dd, 1 H), 6.90 (dd, 1 H), 7.01 (d, 1 H), 7.25 (d, 1 H), 7.71 (dd, 1 H), 7.92 (s, 1 H), 8.49 (s, 1 H), 10.93 (s, 1 H), 11.70 (s, 1 H). MS (APCI): 319, 321.

EXAMPLE 63: 3-Chloro-4-hydroxybenzoic acid [3-(4-methoxyphenoxy)benzylidene]hydrazide 1H NMR (DMSO-d6): # 3.98 (s, 3 H), 7.38 (m, 6 H), 7.48 (s, 1 H), 7.72 (m, 2 H), 7.97 (d, 1 H), 8.19 (s, 1 H), 8.64 (s, 1 H), 11.93(s, 1 H). MS (APCI): 397, 399.

EXAMPLE 64: 3-ChloroA-hydroxybenzoic acid (9-phenanthrenylmethylene)hydrazide 1H NMR (DMSO-d6): # 7.02 (d, 1 H), 7.52 - 7.83 (m, 5 H), 7.99 (d, 1 H), 8.08 (d, 1 H), 8.21 (s, 1 H), 8.82 (d, 1 H), 8.89 (dd, 1 H), 8.96(dd, 1 H), 9.06(s, 1 H), 10.96 (s, 1 H),11.82 (s, 1 H). MS (APCI): 375, 377.

EXAMPLE 65: 3-Chloro-4-hydroxybenzoic acid [4-(2-hydroxyethoxy)-1-naphthylmethylene]hydrazide

1H NMR (DMSO-d6): 83.81 (t, J = 4.8 Hz, 2 H), 4.16 (t, J = 4.8 Hz, 2 H), 6.46 (d, J = 8.5 Hz, 1 H), 7.01 (d, J = 8.5 Hz, 1 H), 7.51 - 7.61 (m, 3 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.82 (d, J = 2.1 Hz, 1 H), 8.30 (d, J = 8.2 Hz, 1 H), 8.85 (s, 1 H), 8.87 (d, J = 8.5 Hz, 1 H), 11.38 (s, 1 H).

MS (APCI): 385, 387.

EXAMPLE 66: 3-Bromo-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 8 6.90 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = J' = 8.0 Hz, 1 H), 7.58(dd, J=J"=8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.77 (dd, J = 2.0, 8.0 Hz, 1H), 8.08(d, J=2.0 Hz, 1H), 8.17(d, J=8.0 Hz, 1H), 8.83(s, 1H), 8.88(d, J=8.0 Hz, 1 H), 10.73 (s, 1 H), 11.53 (s, 1 H). MS (APCI): 385, 387.

EXAMPLE 67: Nicotinic acid 4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-1-naphthyl ester

1H NMR (DMSO-d6): 8 7.04 (d, J = 8.5 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.64 - 7.69 (m, 4 H), 7.74 - 8.02 (m, 3 H), 8.56 (dd, J = 2.0, 8.0 Hz, 1 H), 8.91 (m, 2 H), 9.05 (s, 1 H), 8.35 (d, J = 1.8 Hz, 1 H), 10.96 (s, 1 H), 11.84 (s, 1 H). MS (APCI): 446, 448.

EXAMPLE 68: 3-Chloro-4-hydroxybenzoic acid [4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethoxy)-1-naphthyl- methylene]hydrazide 1H NMR (DMSO-d6): 8 5.78 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.48 (m, 1 H), 7.61 (m, 1 H), 7.73 - 7.81 (m, 8 H), 8.90 (m, 2 H), 10.91 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 500, 502.

EXAMPLE 69: 3-Chloro-4-hydroxybenzoic acid [4-(cyclohexylmethoxy)-1-naphthylmethylene]hydrazide 1H NMR (DMSO-d6): 81.08 - 1.19 (m, 4 H), 1.66 - 1.72 (m, 3 H), 1.83 - 1.92 (m, 3 H), 3.21 (m, I H), 3.95 (m, 2 H), 6.99 (d, J = 8.1 Hz, 1 H), 7.03(d, J = 8.5 Hz, 1 H), 7.53 (dd, J =

= 7.4 Hz, 1 H), 7.62 (dd, J = J '= 7.5 Hz, 1 H), 7.72-7.93 (m, 2 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.2? (d, J = 8.0Hz, 1 H), 8.87 (s, 1 H), 8.90 (d, J = 8.5Hz, 1 H), 10.94 (s, 1 H), 11.60 (s, 1 H). MS (APCI): 437, 439.

EXAMPLE 70: 3-Chloro-4-hydroxybenzoic acid [4-(tetrahydro-2-pyranylmethoxy)-1-naphthylmethylene]- hyd razide 1H NMR (DMSO-d6): 8 1.35 (m, 3 H), 1.60 - 1.71 (m, 2 H), 3.15 - 3.38 (m, 2 H), 3.64 (m, 1 H), 3.78(m, 1H), 4.02(m, 2H), 6.94(d, J=8.5 Hz, 2H), 7.46(dd, J=J'=7.4 Hz, 1H), 7.54 (dd, J = J '=8.2Hz, 1 H), 7.66 (m, 2 H), 7.86 (d, J = 2.1 Hz, 1 H), 8.13 (d, J = 8.0Hz, 1 H), 8.78 (s, 1 H), 8.83 (d, J = 8.5Hz, 1 H), 10.83 (s, 1 H), 11.52 (s, 1 H). MS (APCI): 439, 441.

EXAMPLE 71: 3-Chloro-4-hydroxybenzoic acid [4-(3-pyridylmethoxy)-l -naphthylmethylene]hydrazide 1H NMR (DMSO-d6): 85.28 (m, 2 H), 6.94 (d, J = 8.5 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1 H), 7.34 (dd, J = 4.8, 7.8 Hz, 1 H), 7.45 (dd, J = J' = 7.6 Hz, 1 H), 7.54 (dd, J = J '= 7.5 Hz, 1 H), 7.66(d, J=8.5 Hz, 1H), 7.70(d, J=8.2 Hz, 1H), 7.86(m, 2H), 8.15(d, J=8.0 Hz, 1H),

8.45 (dd, J =1.5,4.8Hz, 1 H), 8.65 (s, 1 H), 8.81 (m, 2 H), 10.90 (s, 1 H), 11.56 (s, 1 H). MS (APCI): 432, 434.

EXAMPLE 72: 4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-1-naphthyloxy )acetic acid ethyl ester 1H NMR (DMSO-d6): 8 1.25 (t, J = 7.0Hz, 3 H), 4.25 (q, J = 7.0Hz, 2 H), 5.11 (s, 2 H), 7.06 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.64-7.70(m, 2H), 7.76(d, J=8.2 Hz, 2H) 8.04(d, J=2.1 Hz, 1H), 8.36(d, J=8.2 Hz, 1H), 8.97(s, 1H), 9.02(d, J=8.5 Hz, 1H), 11.01 (s, 1 H), 11.74 (s, 1 H). MS (APCI): 427, 429.

EXAMPLE 73: 3-Chloro-4-hydroxybenzoic acid (3-nitrobenzylidene)hydrazide 1H NMR (DMSO-d6): 87.13 (d, J = 8.5 Hz, 1 H), 7.79 -7.86 (m, 2 H), 8.03 (d, J = 2.1 Hz, 1 H), 8.18(d, J=7.5 Hz, 1 H), 8.30(d, J=8.0 Hz, 1 H), 8.58 (s, 2 H), 11.08 (s, 1 H), 12.05 (s, 1 H). MS (APCI): 320, 322.

EXAMPLE 74: 3-Chloro-4-hydroxybenzoic acid (2.4-dichlorobenzylidene)hydrazide

1H NMR (DMSO-d6): # 7.02(d, J=8.5 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.66 (s, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.95 (m, 2 H), 8.71 (s, 1 H), 11.97 (s, 1 H), 11.94 (s, 1 H). MS (APCI): 345.

EXAMPLE 75: 3-Chloro-4-hydroxybenzoic acid (4-fluoro-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 87.00 (d, J = 8.5 Hz, 1 H), 7.33 (dd, J = 8.2, 10.3 Hz, 1 H), 7.62 - 7.72 (m, 3H), 7.82(m, 1H), 7.91(d, J=1.9 Hz, 1H), 8.04(d, J=8.1 Hz, 1H), 8.09(m, 1H), 8.91 (s, 1 H), 10.81 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 343.

EXAMPLE 76: 3-Fluoro-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide

1H NMR (DMSO-d6): # 6.90 (d, J = 8.0 Hz, 1 H), 7.00 (t, J = 8.6 Hz, 1 H), 7.44 - 7.72 (m, 6 H), 8.17 (d, J = 8.6 Hz, 1 H), 8.84 (s, 1 H), 8.89 (d, J = 8.5 Hz, 1 H), 10.60 (s, 1 H), 11.50 (s, 1 H). MS (APCI): 325.

EXAMPLE 77: 3-Chloro-4-hydroxybenzoic acid [4-(2,4-difluorobenzyloxy)-1-naphthylmethylene]hydrazide 1H NMR (DMSO-d6): 8 5.33 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.12 (m, 1 H), 7.21 (d, J = 8.2 Hz, 1 H), 7.31 (m, 1 H), 7.52 (m, 1 H), 7.54 (m, 1H), 7.69 - 7.80 (m, 3 H), 7.94 (s, 1 H), 8.16 (d, J = 8.2 Hz, 1 H), 8.90 (m, 2 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 467, 469.

EXAMPLE 78: 3-Fluoro-4-hydroxybenzoic acid (1-naphthylmethylene)hydrazide MS (APCI): 309, EXAMPLE 79: 3-Chloro-4-hydroxybenzoic acid [4-(3-methoxybenzyloxy)-1-naphthylmethylene]hydrazide

1H NMR (DMSO-d6): 8 3.71 (s, 3 H), 5.29 (s, 2 H), 6.87 (d, J = 8.5 Hz, 1 H), 7.00 - 7.14 (m, 4 H), 7.29 (t, J = 8.0 Hz, 1H), 7.55 (m, 1H), 7.68 (m, 1H), 7.75 (m, 2H), 7.94 (d, J = 2.0 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 11.00 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 461.

EXAMPLE 80: 3-Chloro-4-hydroxybenzoic acid [4-(4-fluorobenzyloxy)-1-naphthylmethylene]hydrazide 1H NMR (DMSO-d6): 85.30 (s, 2 H), 7.02 (d, J = 8.5Hz, 1 H), 7.13 - 7.25 (m, 3 H), 7.53 - 7.60 (m, 4 H), 7.79 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.93 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 449, 451.

EXAMPLE 81: 3-Chloro-4-hydroxybenzoic acid [4-(2-tetrahydrofuranylmethoxy)-1-naphthylmethylene]- hydrazide

1H NMR (DMSO-d6): 8 1.77 - 2.04 (m, 4 H), 3.68 (m, 1 H), 3.78 (m, 1 H), 4.12 - 4.16 (m, 2 H),- 4.26 (m, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.53 (m, 1 H), 7.62 (m, 1 H), 7.74 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 8.87 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.93 (s, 1 H), 11.61 (s, 1 H). MS (APCI): 425, 427.

EXAMPLE 82: 3-Chloro-4-hydroxybenzoic acid (3-bromo-4-methoxy-1-naphthylmethylene)hydrazide 1H NMR (DMSO-d6): 83.91 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.65 - 7.76 (m, 3 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.02 (s, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.71 (d, J = 8.0 Hz, 1 H), 8.95 (s, 1 H), 10.96 (s, 1H), 11.85 (s, 1H). MS (APCI): 433, 435.

EXAMPLE 83: 3-Chloro-4-hydroxybenzoic acid [4-(3-tetrahydrofuranylmethoxy)-l -naphthylmethylene]- hydrazide 1H NMR (DMSO-d6): 8 1.92 (m, 1 H), 2.10 (m, 1 H), 2.77 (m, 1 H), 3.28 - 3.88 (m, 4 H), 4.12 (m, 2H), 7.03 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 7.55 (m, 1H), 7.62 (m, 1H), 7.74 (d, J = 8.5 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 8.88 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 425, 427.

EXAMPLE 84: 4-(4-[3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-1-naphthylo xymethyl)benzoic acid methyl ester 1H NMR (DMSO-d6): 83.80 (s, 3 H), 5.43 (s, 2 H), 7.03 (d, J = 8.5Hz, 1 H), 7.12 (d, J = 8.2 Hz, 1 H), 7.54 (m, 1 H), 7.57 (d, J = 8.0 Hz, 4 H), 7.93 - 7.99 (m, 3 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.93 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 489, 491.

EXAMPLE 85: 3-Chloro-4-hyd roxybenzoic acid [3.5-dimethoxy-4-(4-trifluoromethoxybenzyloxy!benzyli- dene]hydrazide 1H NMR (DMSO-d6): 8 3.76 (s, 6 H), 4.91 (s, 2 H), 6.95 - 7.00 (m, 3 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 2.0, 8.5 Hz, 1 H), 7.88 (s, 1 H), 8.29 (s, 1 H), 10.91 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 525,527.

EXAMPLE 86: 3-Chloro-4-hydroxybenzoic acid [4-(4-trifluoromethoxybenzyloxy)-I -naphthylmethylene]- hydrazide

1H NMR (DMSO-d6): # 5.36 (s, 2H), 7.02 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2 H), 7.56 (m, 1 H), 7.62 (m, 3 H), 7.76 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.26 (d, J = 8.3 Hz, 1 H), 8.88 (s, 1 H), 8.93 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 515, 517.

EXAMPLE 87: 3-Chloro-4-hydroxybenzoic acid [4-(2-methoxybenzyloxy)-1-naphthylmethylene]hydrazide 1H NMR (DMSO-d6): 8 3.79 (s, 3 H), 5.27 (s, 2 H), 6.95 (m, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 7.31 (m, 1H), 7.46 - 7.53 (m, 2H), 7.61 (m, 1H), 7.76 (m, 2H), 7.94 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.88 (s, 1H), 8.92 (d, J = 8.5 Hz, 1 H), 10.90 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 461,463.

EXAMPLE 88: 3-Chloro-4-hydroxybenzoic acid [4-(2-fluorobenzyloxy)-1-naphthylmethylene]hydrazide

1H NMR (DMSO-d6): 8 5.36 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.19 - 7.28 (m, 3 H), 7.39 (m, 1H), 7.53 (m, 1 H), 7.63 (m, 2 H), 7.72 - 7.80 (m, 2 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.19 (d, J = 8.3Hz, 1 H), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.90 (s, 1 H), 11.64 (s, 1 H). MS (APCI): 449, 451.

EXAMPLE 89: 3-Chloro-4-hydroxybenzoic acid [4-(2,6-difluorobenzyloxy)-1-naphthylmethylene]hydrazi- de 1H NMR (DMSO-d6): # 5.34 (s, 2H), 7.03 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.51 (m, 2 H), 7.72 (m, 1 H), 7.74 (d, J= 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 8.89 (s, 1 H), 8.91 (d, J = 8.5 Hz, 1 H), 10.97 (s, 1 H), 11.65 (s, 1 H). MS (APCI): 467, 469.

EXAMPLE 90: 4-Hydroxy-3-methoxybenzoic acid [3,5-dimethoxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro- naphth-1-ylmethoxy)benzylidene]hydrazide 1H NMR (DMSO-d6): 81.2 (s, 12H), 1.63 (s, 4H), 3.82 (s, 6H), 3.85 (s, 3H), 4.90 (s, 2H), 6.88 (d, 1H), 7.01 (s, 2H), 7.18 (d, 1H), 7.29 (d, 1H), 7.38 (s, 1H), 7.44 (d, 1H), 7.48 (s, 1H), 8.40 (brd s, 1H), 11.62 (s 1H); MS (APCI): 547.1.

EXAMPLE 91: 3-Fluoro-4-hydroxybenzoic acid [4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzylidene]hy- drazide 1H NMR (DMSO-d6): 8 1.05 (d, 6H), 2.67 (m, 1H), 3.61 (s, 6H), 4.69 (s, 2H), 6.79 (s, 2H), 6.86 (t, 1H), 7.01 (d, 2H), 7.24 (d, 1H), 7.44 (dd, 1H), 7.51 (d, 1H), 8.10 (brd s, 1H), 10.32 (s, 1H), 11.41 (s, 1H); MS (APCI): 467.19.

EXAMPLE 92: 3-Chloro-4-hydroxybenzoic acid [4-(4-tert-butylbenzyloxy)-3,5-dimethylbenzyldene]hy- drazide 1H NMR (DMSO-d6): 81.06 (s, 9H), 1.99 (s, 6H), 4.55 (s, 2H), 6.83 (d, 1H), 7.19 (s, 6H), 7.52 (d, 1 H), 7.73 (s, 1H), 8.09 (s, 1H), 10.74 (brd s, H), 11.44 (s, 1H); MS (FAB): 465.6.

EXAMPLE 93: 3-Chloro-4-hydroxybenzoic acid [3-bromo-5-methoxy-4-(4-trifluoromethoxybenzyl- oxy)benzylidene]hydrazide

1H NMR (DMSO-d6): 83.92 (s, 3H), 5.07 (s, 2H), 7.07 (d, 1H), 7.40 (m, 3H), 7.52 (s, 1H), 7.63 (d, 2H), 7.77 (dd, 1H), 7.97 (d, 1H), 8.35 (s, 1H), 11.00 (brd s, 1H), 11.86 (s, 1H); MS (FAB): 575.0 EXAMPLE 94: 4-Hydroxybenzoic acid [4-(4-isopropylbenzyloxy)-3,5-dimethoxybenzylidene]hydrazide 1H NMR (DMSO-d6): # 1.05 (d, 6H), 2.71 (m, 1H), 3.67 (s, 6H), 4.75 (s, 2H), 6.70 (d, 2H), 6.85 (s, 2H), 7.14 (d, 2H), 7.21 (d, 2H), 7.64 (d, 2H), 8.21 (brd s, 1H), 9.97 (brd s, 1H), 11.47 (s, IH); MS (APCI): 448.9.

EXAMPLE 95: 2-Chloro-4-hydroxybenzoic acid [4-(4-isopropylbenzyloxy)-3,5-dimethoxybenzylidene]hy- drazide:

'H NMR (DMSO-D6): d 1.18 (d, 6H), 2.87 (septet, 1H), [3.68 (s, 1H)+ 3.81 (s, 5H), 6H], [4.83 (s, 0.5H) + 4.90 (s, 1.5H), 2H], [6.76 (s, 0.5H)+ 7.01 (s, 1.5 H), 2H], [6.80 (dd, 1H) + 6.88 (d, 1H), 2H], 7.23 (d, 2H), 7.35 (d, 2H), 7.38 (m, 1H), [7.91 (s, 0.3H) + 8.18 (s, 0.7H), 2H], 10.17 (s, 0.7H) + 11.73 (s, 0.3H), 1H]; MS (APCI): 483.0.

EXAMPLE 96: 3-Chloro-4-hydroxybenzoic acid [3-(4-isopropylbenzyloxy!-4.5-dimethoxybenzylidene]hy- drazide 1H NMR (DMSO-d6): # 1.05 (d, 6H), 2.70 (m, 1H), 3.54 (s, 3H), 3.66 (s, 3H), 4.94 (s, 2H), 6.87 (m, 3H), 7.08 (d, 2H), 7.20 (d, 2H), 7.56 (dd, 1H), 7.77 (s, 1H), 8.15 (s, 1H), 10.76 (s, 1 H), 11.52 (s, 1H); MS (APCI): 483.7.

EXAMPLE 97: 3-Chloro-4-hydroxybenzoic acid [3-(4-isopropylbenzyloxy)-2,4-dimethoxybenzylide- ne]hydrazide 1H NMR (DMSO-d6): # 1.20 (d, 6H), 2.89 (m, 1H), 3.85 (s, 6H), 4.95 (s, 2H), 6.95 (d, 1H), 7.07 (d, 1H), 7.22 (d, 2H), 7.40 (d, 2H), 7.64 (d, 1H), 7.78 (dd, 1 H), 7.97 (d, 1H), 8.62 (s, 1H), 11.68 (s, 1H); MS (APCI): 483.8.

EXAMPLE 98:

3-Chloro-4-hydroxybenzoic acid [4-(3-trifluoromethoxybenzyloxy)naphth-1- ylmethylenejhydrazide 1H NMR (DMSO-d6): 8 5.46 (s, 2H), 7.10 (d, 1H), 7.20 (d, 1H), 7.37 (d, 1H), 7.65 (m, 5H), 7.82 (m, 2H), 8.01 (s, 1H), 8.32 (d, 1H), 8.97 (m, 2H), 11.70 (s, 1 H); MS (APCI): 514.8 EXAMPLE 99: 3-Chloro-4-hydroxy-benzoic acid [4-(4-isopropylbenzyloxy)-8-methoxynaphthalen-1- ylmethylene]-hydrazide 4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (2 g, 9.9 mmol) was dissolved in DMF (25 mL). To this mixture potassium carbonate (6.8 g, 50 mmol) and 4-isopropylbenzylchloride (1.8 g, 10.4 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the resulting mixture was extracted with diethyl ether (3 x 100 mL). The combined organic extracts were washed with saturated sodium chlo- ride (100 mL), dried (MgSO4) and evaporated in vacuo to afford 3.0 g crude product. This was purified using column chromatography on silica gel (300 mL) eluting with a mixture of ethyl acetate and heptane (1:4). This afforded 2.57 g (81%) of 4-isopropylbenzyloxy-8- methoxynaphthalene-1-carbaldehyde.

Calculated for C22H22O3: C, 79.02%; H, 6.63%. Found:

C, 79.10%, H, 6.69%, C, 79.17%, H, 6.69%.

3-Chloro-4-hydroxybenzoic acid hydrazide (205 mg, 1.1 mmol) was dissolved in DMSO (2 mL) and the above 4-isopropylbenzyloxy-8-methoxynaphthalene-1-carbaldehyde (365 mg, 1.1 mmol) and glacial acetic acid (5 drops) were added and the resulting mixture was stirred at room temperature for 20 minutes. More DMSO (2 mL) was added and the mixture was stirred at room temperature for 16 hours. The solid was collected by filtration and washed successively with DMSO and ethyl acetate to afford 330 mg (66%) of the title compound.

M.p.: > 250 °C.

EXAMPLE 100: 'H NMR ( DMSO-d5 ) # 1.13 (d, 6H), 2.82 (sept, 1H), 3.77 (s, 6H), 4.8 (s, 2H), 7.15 (s, 1H), 7.18 (s, 2H), 7.30 (d, 2H), 8.00 (dd, 1H), 8.30 (s, 1H), 8.44 (s, 1H), 11.84 (s, 1H);. MS (APCI): 494.0 EXAMPLE 101: 1H NMR ( DMSO-d5) # 5.38 (s, 2H), 6.95 (d, 1H), 7.06 (d, 1H), 7.49 (t, 1H), 7.56 (t, 1H), 7.65-7.71 (m, 6H), 7.87 (d, 1H), 8.22 (d, 1H), 8.80 (s, 1H), 8.86 (d, 1H), 10.82 (s, 1H), 11.55 (s, 1H); MS (FAB): 499

EXAMPLE 102: 1H NMR ( DMSO-d6 )# 5.85 (s, 2H), 7.05 (t, 2H), 7.52-7.63 (m, 4H), 7.73 (m, 2H), 7.95 (s, 1H), 8.16 (d, 2H), 8.33 (d, 1H), 8.90 (s, 1H), 893 (s, 1H), 10.90 (brd s, 1H), 11.63 (s, 1H); MS (FAB): 543 EXAMPLE 103: 3-Chloro-4-hydroxybenzoic acid {4-[2-(4-bromophenoxy)ethoxy]-3,5-dimethoxybenzylide- ne}hydrazide 1H NMR (DMSO-d6): 83.78 (s, 6H), 4.21 (m, 4H), 6.87 (d, 2H), 7.00 (s, 2H), 7.05 (d, 1H), 7.44 (d, 2H), 7.75 (dd, 1H), 7.96 (s, 1H), 8.36 (s, 1H), 10.95 (brd s, 1H), 11.66 (s, 1H); MS(APCI): 548.8.

EXAMPLE 104: 3-Chloro-4-hydroxybenzoic acid [4-(3-methoxy-3-(4-methylphenyl)-propyloxy!naphth-1 - ylmethylene]hydrazide

MS (APCI): 502.9 EXAMPLE 105: (2-Ethylphenyl)carbamic acid 2-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-naphth-1- yloxy}ethyl ester 1H NMR (CDCl3): # 1.12 (t, 3H), 2.50 (qt, 2H), 3.69 (t, 2H), 4.39 (t, 2H), 5.20 (t, 1H), 6.57 (t, 1 H), 6.74 (d, 1H), 6.97 (d, 1 H), 7.08 (m, 3H), 7.57 (t, 1 H), 7.67 (t, 1 H), 7.81 (t, 2H), 8.01 (s, 1H), 8.35 (d, 1 H), 8.95 (m, 2H), 11.67 (s, 1 H).

EXAMPLE 106: 3-Chloro-4-hydroxybenzoic acid [3-allyl-4-(4-isopropylbenzyloxy)-5- methoxybenzylidene]hydrazide 1H NMR (DMSO-d6): : # 1.13 (d, 6H), 2.80 (m, 1H), 3.20 (m, 2H), 3.85 (s, 3H), 4.82 (s, 2H), 5.00 (d, 2H), 5.70 (m, 1H), 6.96 (s, 1H), 7.05 (s, 1H), 7.20 (d, 2H), 7.30 (d, 2H), 7.70 (d, 1H), 7.89 (s, 1H), 8.28 (s, 1H), 10.80 (brd s, 1H), 11.61 (s, 1H); MS (APCI): 493.1.

Similarly, the following compounds were made: EXAMPLE 107: 'H NMR (DMSO-D5): # 0.99 (d, 6H), 2.68 (septet, 1H), 4.89 (s, 2H), 6.84 (d, 2H), 7.06 (m, 2H), 7.16 (m, 3H), 7.55 (d, 1H), 7.75 (s, 1H), 8.18 (s, 1H), 10.75 (s, 1H), 11.52 (s, 1H); MS (APCI): 423.7, 425.6.

EXAMPLE 108: 'H NMR (DMSO-D6): # 1.18 (d, 1H), 2.88 (septet, 1H), 5.20 (s, 2H), 7.04 (d, 1H), 7.28 (t, 2H), 7.30 (s, 1H), 7.38 (d, 2H), 7.62 (d, 1H), 7.73 (dd, 1 H), 7.79 (s, 1H), 7.94 (d, 1H), 8.32 (s, 1H), 11.94 (s, 1H), 11.72 (s, 1H); MS (APCI): 457.4, 459.1.

EXAMPLE 109: 'H NMR (DMSO-D6): 8 1.1 (d, 6H), 2.2 (s, 6H), 2.8 (septet, 1H), 4.7 (s, 2H), 7.0 (d, 1H), 7.2 (d, 2H), 7.4 (d, 4H), 7.7 (d, 1H), 7.9 (s, 1H), 8.2 (s, 1H), 10.9 (s, 1H), 11.6 (s, 1H); MS (APCI): 451.6, 453.3.

EXAMPLE 110: 'H NMR (DMSO-D5): 8 1.1 (d, 6H), 2.8 (septet, 1H), 3.3 (d, 1H), 5.0 (d, 1H), 5.1 (d, 1H), 5.2 (s, 2H), 5.9 (m, 1H) 7.0 d, 1H), 7.1 (d, 1H), 7.2 (d, 2H), 7.3 (d, 2H), 7.4 (d, 1H), 7.5 (s, 1H), 7.7 (dd, 1H), 7.9 (d, 1H), 8.3 (s, 1H), 10.9 (brd s, 1H), 11.5 (s, 1H); MS (APCI): 463.5, 465.1.

EXAMPLE 111: 'H NMR (DMSO-D6): 84.47 (t, 2H), 4.54 (t, 2H), 7.01 (d, 2H), 7.07 (d, 1H), 7.14 (d, 1H), 7.45 (d, 2H), 7.53 (t, 1H), 7.27 (d, 1H), 7.79 (m, 2H), 7.96 (d, 1H), 8.17 (d, 1H), 8.91 (s, 1H), 8.94 (d, 1H), 10.92 (s, 1H), 11.64 (s, 1H), MS (APCI): 539.3, 541.1, 543.1.

EXAMPLE 112: 1H NMR (DMSO-D6): 8 1.18 (d, 6H), 2.87 (septet, 1H), [3.67 (s, 1.5H) + 3.81 (s, 4.5H), 6H], [4.83 (s, 0.5H) + 4.90 (s, 1.5H), 2H], 6.73 (s, 0.5H) + [7.02 (m, 2.5H), + 7.27 (m, 2.5H) + 7.37 (m, 2.5H), 8H], [7.92 (s, 0.3H) + 8.17 (s, 0.7H), 1H], [10.96 (s, 0.3H) + 11.12 (s, 0.7H), 1H], [11.82 (s, 0.7H) + 11.95 (s, 0.3H), 1H]; MS (APCI): 517.6, 519.2.

EXAMPLE 113: 'H NMR (DMSO-D5): 8 1.19 (d, 6H), 2.89 (septet, 1H), [3.68 (s, 1.5H) + 3.82 (s, 4.5H), 6H], [4.84 (s, 0.5H) + 4.89 (s, 1.5H), 2H], [6.76 (s, 0.5H) + 7.02 (m, 2.5H), 3H], 7.20 (m, 2H), 7.34 (m, 2H), [7.50 (s, 0.3H) + 7.62 (s, 0.7H), 1H], 7.92 (s, 0.3H) + 8.18 (s, 0.7H), 1H], 11.17 (brd s, 1H), 11.81 (s, 0.7H) + 11.96 (s, 0.3H), 1H]; MS (APCI): 517.7, 519.2.

EXAMPLE 114: 'H NMR (DMSO-D6): # 1.20 (d, 6H), 2.87 (septet, 1H), 3.82 (s, 6H), 4.89 (s, 2H), 6.69 (d, 1H), 6.98 (m, 3H), 7.21 (m, 3H), 7.36 (d, 2H), 8.32 (s, 1H), 9.8 (brd s, 1H), 11.50 (s, 1H); MS (APCI): 464.7.

EXAMPLE 115: 'H NMR (DMSO-D6): 8 1.19 (d, 6H), 2.30 (septet, $1H), [3.71 (s) + 3.82 (s), 6H], 4.90 (s, 2H), [6.81 (m, 1.5H) + 6.88 (s, 1.5H), 3H], [7.24 (s, 0.2H) + 8.24 (s, 0.8H), 1H], 11.05 (brd, 1H), 11.69 (s, 0.75H) + 11.94 (s, 0.25H), 1 H]; MS (APCI): 485.5, 486.3.

EXAMPLE 116: 'H NMR (DMSO-D5): # 1.19 (d, 6H), 2.88 (septet, 1H), 3.83 (s, 6H), 4.90 (s, 2H), 6.87 (d, 1H), 7.03 (s, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.53 (m, 3h), 8.26 (m, 3H), 10.73 (s, 1H), 11.82 (s, 1H); MS (APCI): 499.8.

EXAMPLE 117: 'H NMR (DMSO-D5): 8 1.20 (d, J = 6.9, 6H), 2.89 (sept, J = 6.9, 1H), 3.84 (s, 6H), 4.91 (s, 2H), 7.03 (br s, 2H), 7.12 (d, J = 8.8, 1H), 7.23 (d, J = 8.0, 2H), 7.37 (d, J = 8.0 2H), 8.04 (dd, J = 2.2, 8.8, 1 H), 8.21 (br s, 1H), 8.35 (br s, 1H), 11.78 (s, 1H), 11.89 (br s, H); MS (APCI, neg): 472.

Preparation of acyl-hydrazones of 4-(2-hydroxyethyl)-1-naphthaldehyde: General procedure for synthesis of compounds of the general formula X formula X

wherein b is 1, 2, 3 or 4 Preparation of 4-(2-hydroxyethyl)-I -naphthaldehyde: 1-Bromo-4-(2-hydroxyethyl)naphthalene: To a solution of methyl 4-bromo naphthalene acetate (2.0 g, 7.16 mmol) in anhydrous THF (15 mL) was added drop wise at 0°C 1 M lithium aluminum hydride in THF (4 mL). The mix- ture was stirred at room temperature for 16 h, diluted with water (5 ml), acidified with conc. hydrochloric acid, and extracted with ethyl acetate (3 x 20 mL). The combined organic ex- tracts were dried (MgSO4), and concentrated to provide a 1.71 g (95%) colorless oil (1.71 g, 95%). A similar synthetic reference is described in A. A. Kiprianov, A. A. Shulezhko. Zh.

Org. Khim. 2 (1966), 1852, English translation: J. Org. Chem. (USSR) 2 (1966) 1820].

H NMR (CDCl3) 8 = 2.36 (s, 1H), 3.33 (t, J = 6.7 Hz, 2H), 3.99 (t, J = 6.7 Hz, 2H), 7.24 (d, J =7.3 Hz, 1H), 7.58 - 7.63 (m, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.61 (m, 1H), 8.31 (dd, J = 1.1, 8.0 Hz, 1H). GCMS (pos.) 250, 252.

1 -Bromo4-(2-tetrahydropyranyloxyethyl)naphthalene.

To a solution of l-bromo-4-(2-hydroxyethyi)naphthalene (1.71 g, 6.8 mmol) in dichloro- methane (20 mL) was added 3,4-dihydro-2H-pyrane (1 mL, 0.92 g, 11.0 mmol) and p- toluene sulfonic acid (80 mg). The mixture was stirred at room temperature for 90 min, dilu- ted with dichloromethane (20 mL), washed with satd. NaHCO3 sol. (20 mL), dried (Mg SO4), and concentrated. Flash chromatography using hexane/ethyl acetate 9:1 as eluent provided 1.69 g (75%) of a colorless oil.

1H NMR (CDCl3) 8 = 1.51 -1.60 m (6H), 3.37 (t, J = 7.2 Hz, 2H), 3.39 - 3.47 (m, 1H), 3.74 (t, J = 7.2 Hz, 2H), 4.08 (dd, J = 2.4, 7.5 Hz, 1H), 4.60 (m, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.56 -

7.61 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 8.09 - 8.12 (m, 1H), 8.29 (dd, J = 2.5, 7.1 Hz, 1H).

GCMS (pos), 334, 336.

1 -Formyl-4-(2-tetrahydropyranyioxyethyl)naphthalene.

A solution of 1-bromo-4-(2-tetrahydropyranyloxyethyl)naphthalene in anhydrous THF (15 mL) under nitrogen was cooled to -78°C. n-Butyl lithium (1.4 mL of a 2.5 M solution in hexa- ne) was added via syringe, and the mixture was stirred at the same temperature for 30 min.

DMF (1.1 mL) was added, and the mixture was allowed to reach room temperature. It was diluted with satd. NH4Cl solution (10 mL), extracted with ether (3 x 10 ml), dried (MgSO4) and concentrated. Flash chromatography using hexane/ethyl acetate 5:1 as eluent provided 408 mg (54%) of a colorless oil.

H NMR (CDCl3) 8 = 1.48 -1.69 m (6H), 3.45 - 3.50 (m, 3H), 3.69 - 3.85 (m, 2H), 4.07-4.17 (m, 1 H), 4.61 (m, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.62 -7.73 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H), 8.20 (d, J = 1.0, 8.1 Hz, 1H), 10.36 (s, 1H). GCMS: 284 I -Formyl4-(2-hydroxyethyl)naphthalene: 1-Formyl-4-(2-tetrahydropyranyloxyethyl)naphthalene (400 mg, 1.40 mmol) was dissolved in methanol (15 mL), and p-toluene sulfonic acid (45 mg) was added. The mixture was stirred at room temperature for 16 h, and concentrated. The residue was dissolved in ethyl acetate (3 x 10 mL), washed with satd. NaHCO3 (20 mL), dried (MgSO4) and concentrated. Purifica- tion by flash chromatography using hexane/ethyl acetate 3:1 as eluent provided 182 mg (65%) of a colorless oil. <BR> <BR> <BR> <BR> <BR> <P> H NMR (CDCl3) 8 = 2.09 (s, 1H), 3.40 (t, J = 6.6 Hz, 2H), 4.02 (t, J = 6.6 Hz, 2H), 7.54 (d, J <BR> <BR> <BR> <BR> = 7.3 Hz, 1H), 7.61- 7.71 (m, 2H), 7.88 (d, J =7.3 Hz, 1H), 8.13 (dd, J = 1.3, 8.0 Hz, 1H), 9.29 (dd, J = 1.3, 8.0 Hz, 1H), 10.28 (s, 1H). GCMS: 200 The following compounds were prepared according to the general procedure for the synthe- <BR> <BR> <BR> sis of alkylidene hydrazones from the condensation of 1 1-formyl-4-(2-hydroxyethyl) naphtha- lene (from step D) with 4-hydroxy benzoic acid hydrazides.

EXAMPLE 118: 1H NMR (DMSO-D5) 8 = 3.25 (t, J = 6.5 Hz, 2H), 3.73 (dt, J =J'=6.5 Hz, 2H), 4.84 (t, J = 6.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.60 - 7.68 (m, 2H), 7.80 (dd, J = 1.8, 7.4 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 9.19 (d, J = 6.7 Hz, 1H), 8.85 (d, J = 7.7 Hz, 1H), 9.05 (s, 1H), 10.98 (s, 1H), 11.76 (s, 1H); MS (APCI, pos.): 369.4, 371.2.

EXAMPLE 119: 1H NMR (DMSO-D6) # = 3.18 (t, J = 7.0 Hz, 1H), 3.25 (t, J = 7.0 Hz, 1H), 3.65 (dd, J = 7.0 Hz, 1H), 3.74 (dd, J = 5.3, 7.0 Hz, 1H), 4.74 (t, J = 5.3 Hz, 0.5H), 4.79 (t, J = 5.3 Hz, 0.5H), <BR> <BR> <BR> 7.04 (d, J = 8.3 Hz, 0.5H), 7.05 (d, J = 8.3 Hz, 0.5H), 7.25 (d, J = 8.3 Hz, 0.5H), 7.28 (d, J = 8.3 Hz, 0.5H), 7.38 (d, J = 7.4 Hz, 0.5H), 7.43 (d, J = 8.4 Hz, 0.5H), 7.47 - 7.57 (m, 1.5H), <BR> <BR> <BR> 7.61-7.72 (m, 1H), 7.82 (d, J = 7.2 Hz, 0.5H), 8.10 (d, J = 8.6 Hz, 0.5H), 8.19 (dd, J = 2.2, 7.2 Hz, 0.5H), 8.45 (d, J = 8.6 Hz, 0.5H), 8.48 (s, 0.5H), 8.85 (s, 0.5H), 8.87 (dd, J = 2.2, 6.5 Hz, 0.5H), 11.00 (s, 0.5H), 11.15 (s, 0.5H), 11.86 (s, 0.5H), 11.92 (s, 0.5H); MS (APCI, pos.): 403.4, 405.2, 406.1.

Preparation of acylhydrazones of 4-hydroxymethylnaphthaldehyde: Step A: The 1,4-Naphthalenedicarboxylic acid (25 g, 116 mmol) was dripped into a mixture of Lithi- um Aluminum Hydride (15 g, 395 mmol) in 600 mL of anhydrous THF and refluxed for two days. The mixture was cooled in an ice bath and excess LAH was decomposed by the slow addition of methanol followed by ice chips. THF was removed under vacuum and the residue was acidified with 1N HCI. The product was extracted with ethyl acetate (3x), washed with aqueous sodium bicarbonate (3x), water, brine, and dried over magnesium sulfate. 1,4- Bishydroxymethyinaphthalene (70%) was obtained as a solid after evaporation of the solvent and can be used in the subsequent oxidation step without further purification. A portion of the material was purified by column chromatography using hexane/ethyl acetate (80/20 to 75/25) for characterization purposes.

'H NMR (DMSO-D6): 8 5.19 (s, 4H), 7.77 (m, 4H), 8.32 (m, 2H).

Step B: To a solution of 1,4-bishydroxymethyinaphthalene (12 g, 65 mmol) in ethyl acetate (300 ml) was added manganese dioxide ( 28 g, 325 mmol). After stirring for 45 minutes most of the starting material had disappeared and two new spots (mono aldehyde and dialdehyde) were seen on TLC. The upper spot corresponds to the dialdehyde. The mixture was passed through a bed of Celite and eluted with additional volumes of ethyl acetate. The solvent was evaporated and 4-hydroxymethylnaphthaldehyde was purified by column chromatography using hexane/ethyl acetate (80/20 to 75/25) in 50% yield.

H NMR (DMSO-D6): 85.19 (s, 2H), 5.71 (brd s, 1H), 7.73 (t, 1H), 7.78 (t, 1H), 7.95 (d, 1H), 8.26 (m, 2H), 9.34 (d, 1 H), 10.46 (s, 1H).

Examples of products employing the above aldehyde: EXAMPLE 120: The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-cyano-4- hydroxybenzoic acid hydrazide.

1H NMR (DMSO-D5): 8 5.02 (s, 2H), 5.44 (s, 1H), 7.14 (d, 1H), 7.69 (m, 3H), 7.91 (d, 1H), 8.10 (d, 1H), 8.14 (d, 1H), 8.27 (s, 1H), 8.87 (d, 1H), 9.06 (s, 1H), 11.84 (brd s, 2H); MS (ACPI): 346.3, 347.2.

EXAMPLE 121: The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-chloro-4- hydroxybenzoic acid hydrazide.

'H NMR (DMSO-D5): # 5.02 (s, 2H), 5.43 (t, 1H), 7.10 (d, 1H), 7.66 (m, 3H), 7.80 (d, 1H), 7.90 (d, 1H), 8.02 (s, 1H), 8.15 (d, 1H),8.87 (d, 1H), 9.08 (s, 1H), 10.98 (s, 1H), 11.79 (s, 1H); MS (APCI): 355.5

EXAMPLE 122: The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-fluoro-4- hydroxybenzoic acid hydrazide.

1H NMR (DMSO-D6): d4.84 (s, 2H), 6.91 (t, 1H), 7.43-7.53 (m, 4H), 7.62 (d, 1H), 7.72 (d, 1H), 7.96 (d, 1H), 8.68 (d, 1H), 8.98 (s, 1H), 11.71 (brd s, 1H); MS (APCI): 339.4, 340.3.

The compounds of formula II can also be prepared by parallel synthesis using the protocol mentioned above in a combinatorial approach. Thousands of compounds of formula II can thus be prepared by this combinatorial approach which can be semi- or fully automated. The auto- mation of this protocol can be performed using solution phase combinatorial chemistry in e.g. a 96 well setup using an automated synthesizer device. In the first step of the synthesis the al- dehydes or ketones may be prepared according to Scheme II by a combination of a selected number of aldehydes or ketones with a selected number of alkylating reagents. In the second step the formed aldehydes/ketones can be combined with a selected number of the hydrazides (which may be synthesized according to Scheme I) thereby generating a predetermined very large number of compounds as single entities.

The synthesized compounds mentioned above are examples of such compounds that can be prepared using this combinatorial methodology.

By application of the above methodology, the following compounds may also be synthesized:

EXAMPLE 123: EXAMPLE 124: EXAMPLE 125: EXAMPLE 126:

EXAMPLE 127: EXAMPLE 128: EXAMPLE 129: EXAMPLE 130: EXAMPLE 131:

EXAMPLE 132: EXAMPLE 133: EXAMPLE 134: EXAMPLE 135: EXAMPLE 136:

EXAMPLE 137: EXAMPLE 138: EXAMPLE 139: EXAMPLE 140: EXAMPLE 141.

EXAMPLE 142: General procedure for the synthesis of further derivatized hydrazides of formula II: The compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula II, as indicated in Scheme Ill, that is, by converting an alkylidene hydrazide (prepared according to the general method shown in Scheme I, and more specifically as in example 8) into a further derivatized alkylidene hydraz- ide. Thus, by reacting an amine with an alkylidene hydrazide that contains a leaving group X, (Scheme Ill) a new alkylidene hydrazide containing an amine in the group K of formula II can be formed.

SCHEME lil 0 R5a H AHT72n2b 3a (H2)aX N (H2)D R solvent, base 0 R5a N-l (CH,), B-- O--(CH,),,- CH (H2)a (CH,),-- R wherein A, B, D, n, R4, R3a a, b and d are as defined for formula I and R5" is lower alkyl.

Specific examples illustrating the preparation of further derivatized hydrazides of formula II are provided below: EXAMPLE 143:

3-Chloro-4-hydroxybenzoic acid (4-[2-[N '-(2-N . N-diethylaminoethyl)-N '-(4-trifluoromethoxy- benzylamino)]]ethoxy -1 -naphthylmethylene)hydrazide N, N-diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine: A solution of (4-trifluoromethoxy)benzaldehyde (1.9 g, 10 mmoles), N,N-diethylethylene- diamine (1.16 g, 10 mmoles), zinc chloride (1.36 g, 10 mmoles) and sodium cyanoborohy- dride (1.26 g, 20 mmoles) in methanol (10 mL) in a dry 100 mL round- bottom flask was stirred at room temperature for 8 hours. Water (20 mL) was then added and most of the methanol was removed in vacuo. The residue was distributed between ethyl acetate and 1 N HCI. The acidic aqueous phase was basified with excess of sodium hydroxide. Crude N,N- diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine was obtained. The crude product was used in the following reaction without further purification.

MS (Cl): 291. 1H NMR (CDCl3): 67.4 (m, 2H), 7.2 (m, 2H), 3.9 (bs, 2H), 3.1-2.6 (m, 9H), 1.4- 1.1 (t, 6H).

To a flask containing N,N-diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine (0.29 g, 1 mmole) in DMF (5 mL) was added [1-(4-chloroethoxy)naphthyi](3-chloro-4-hydroxy)benzOic acid hydrazide (0.41g, 1 mmole) and triethylamine (0.1 g, Immole). The resulting solution was heated at 800C overnight. Removal of most of the solvent in vacuo followed by flash chromatography (10:1 CHCI3/MeOH) on silica gel provided the title compound as a brown solid.

1HNMR (DMSO-d6): # 11.7 (1H), 9.0 bs, 2H), 8.4-7.0 (m, 12 H), 4.75 (bs, 1H), 4.65 (bs, 1H), 4.55 (t, 1H), 4.35 (t, 1H), 4.15 (t, 1H), 3.9 (bs, 1H), 3.5 (q, 4H), 3.05 (t, 1H), 1.3 (t, 3H), 0.95 (t, 3H). M.p.: 134-136°C. MS (Cl): 657, 659.

EXAMPLE 144: 3-Chloro-4-hydroxybenzoic acid {4-[2-(4-trifluoromethoxy)benzylaminoethoxy]-1-naphthyl- methylene}hydrazide To a flask containing 4-trifluoromethoxybenzylamine (0.29 g, 1 mmole) in DMF (5 mL) was added 3-ch loro4-hyd roxybenzoic acid [4-(2-chloroethoxy)-1 -naphthylmethylene]hydrazide (0.403g, 1 mmole) and triethyiamine (0.1 g, 1mmole). The resulting solution was heated at 80°C for 16 hours. Removal of most of the solvent in vacuo, followed by flash chromatogra- phy (10:1 CHCl3/MeOH) oh silica gel provided the title compound as a brown solid.

1HNMR (DMSO-d6): 811.6 (s, 1H), 9.0 (m 2H), 8.3 (m 1H), 8.0 (m, 1H), 7.8 (s, 2H), 7.7 (m,1H), 7.6 (m, 1H), 7.5 (m, 3H), 7.3 (m, 2H), 7.1 (m, 2H), 4.3 (t, 2H), 3.9 (s, 2H), 3.0 (t, 2H).

MS (C I): 557, 559.

By application of the above methodology the following compounds of the invention were syn- thesized: EXAMPLE 145:

3-Chloro-4-hydroxybenzoic acid {3,5-dimethoxy-4-[2-(4-trifluoromethoxybenzylamino)- ethoxy]benzylidene}hydrazide 1H NMR (CD3OD): 6 2.90 (brd t, 2H), 3.75 (s, 6H), 3.89 (s, 2H), 4.08 (brd t, 2H), 6.87 (d, 1H), 7.10 (s, 2H), 7.20 (d, 2H), 7.43 (d, 2H), 7.65 (m, 1H), 7.82 (m, 1H), 8.11 (brd s, 1H); MS (APCI): 567.9.

EXAMPLE 146: 3-Chloro-4-hydroxybenzoic acid {4-[2-(2-piperidin-1-yl-ethylamino)ethoxy]naphth-1- ylmethylene}hydrazide 1H NMR (DMSO-d6): 8 1.53 (m, 2H), 1.74 (m, 4H), 3.12 (m, 2H), 3.40 (m, 2H), 3.54 (m, 2H), 3.63 (m, 4H), 4.52 (s, 2H), 7.10 (d, 1H), 7.14 (d, 1H), 7.60 (t, 1H), 7.71 (m,1H), 7.80 (dd, 1H), 7.83 (d, 1H), 8.00 (d, 1H), 8.51 (d, 1H), 8.95 (d, 1H), 8.98 (s, 1H), 11.69 (s, 1H); MS (APCI): 495.0 EXAMPLE 147: 3-Chloro-4-hydroxybenzoic acid {4-[2-(3-diethylaminopropylamino)ethoxy]naphth-1- ylmethylene}hydrazide

1H NMR (DMSO-d6): 81.21 (t, 6H), 2.10 (m, 2H), 3.14 (m, 10H), 4.52 (t, 2H), 7.10 (d, 1H), 7.14 (d, 1H), 7.63 (t, 1H), 7.73 (m, 1H), 7.80 (dd, 1H), 7.84 (d, 1H), 8.00 (d, 1H), 8.46 (d, 1H), 8.93 (s, 1H), 8.98 (m, 1H), 9.20 (m, 2H), 9.69 (m, 1H), 11.00 (s, 1H), 11.69 (s, 1H); MS (APCl): 497.0.

EXAMPLE 148: 1-(2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphth-1 -yloxy}ethyl)-4- phenylaminopiperidine-4-carboxylic acid amide 1H NMR (DMSO-d6): 81.16 (m, 2 H), 1.88 (m, 2H), 2.03 (m, 2H), 2.80 (m, 2H), 2.92 (m, 2H), 4.37 (m, 2 H), 4.40 (brd s, 2H), 4.44 (s, 1 H), 6.55 - 6.62 (m, 3 H), 6.96 (s,1 H), 7.03- 7.16 (m, 5H), 7.61(dd, 1H), 7.68 (dd,1 H), 8.00 (d, 1H), 8.27 (d, 1H), 8.94 (s,1 H), 8.97 (s, 1H), 11.63 (s, 1H); MS (APCI): 586.4 EXAMPLE 149: 4-(2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphth-1 -yloxy}ethylamino)piperidine- I -carboxylic acid ethyl ester

1H NMR (DMSO-d5): 81,10 (t, 3H), 1.15 - 1.23 (m, 2H), 1.86 (m, 2H), 2.79 (m, 3H), 3.30 (m, 2H), 3.87 (m, 2H), 3.94 (q, 2H), 4.28 (m, 2H), 7.03 (d,lH), 7.05 (m, 1H), 7.51 - 7.63 (m, 3H), 7.13 (d, 1H), 7.75 (m,1 H), 7.93 (d, 1H), 8.29 (d,l H), 8.87 (m,2 H), 11.55 (s, 1H); MS (APCI): 539.1, 541.0.

EXAMPLE 150: 3-Chloro-4-hydroxybenzoic acid {4-[2-(1,2,3,4-tetrahydronaphth-1-ylamino)ethoxy]-naphth-1- yimethylene}hydrazide 1H NMR (DMSO-d5): # 1.76 (m, 1H), 2.04 (m, 1H), 2.17 (m, 2H), 2.75 - 2.94 (m, 2H), 3.61 (m, 2H), 4.55 (m,2H), 4.71(s, 1H), 7.11 (d, 1H), 7.13 (d, 1 H), 7.23 - 7.35 (m, 3H), 7.61 (d, 1H), 7.67 (d, 1H), 7.71 (dd, 1H), 7.81 (dd, 1H), 7.86 (d, 1H), 8.01 (d, 1H), 8.48 (d, 1H), 8.94 (m, 1H), 8.99 (m, 1H), 9.22 (m, 2H), 11.00 (s,1 H), 11.64 (s,lH); MS (APCI): 514.0, 516.0 EXAMPLE 151: 1-(2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphth-1 -yloxy}ethyl)piperidine-4- carboxylic acid amide

MS (APCI): 495.0 EXAMPLE 152: 3-Chloro-4-hydroxybenzoic acid {4-[2-(2-trifluoromethoxybenzylamino)-ethoxy]-1-naphthyl- methylene)hydrazide EXAMPLE 153: 3-Chloro-4-hydroxybenzoic acid {4-[2-(4-morpholinylethylamino)ethoxy]-1-naphthylmethylene}- hyd razide By application of the above methodology the following compounds may also be synthezised: EXAMPLE 154:

EXAMPLE 155: EXAMPLE 156: EXAMPLE 157: EXAMPLE 158:

EXAMPLE 159: EXAMPLE 160: General procedures for the preparation of alkylidene arylsulfonyl hydrazides according to the invention The compounds of general formula I are prepared according to one embodiment of the inven- tion, the alkylidene arylsulfonyl hydrazides of general formula Ill, that is, by converting an aryl- sulfonyl halide, for example chloride or bromide to the corresponding hydrazide derivative and further reacting the product arylsulfonyl hydrazide compound with a substituted aldehydes or ketones to yield alkylidene aryisulfonyl hydrazide derivatives as illustrated in Scheme IV.

SCHEME IV

,0 NHNH A-S-Cl + NH2NH2 A-S-0 O 0 »(CH2)n B(K)m D HN- N(CH)-B-K-D R4 I =72nm A--S=O R4 solvent, reflux 0 wherein A, B, K, D, m, n and R4 are as defined for formula I.

The synthesis of the arylsulfonylhydrazide precursors is performed by application of general methodology, for example as described by Friedman, L.; Litle, R.L; Reichle, W. R. in Org.

Synth. Coll. Vol. V, 1973, 1055-1057, by slowly adding the arylsulfonyl chloride either neat, or in a solution in an inert solvent such as tetrahydrofuran, dimethyl ether, dioxane or diethyl ether to an excess of hydrazine, either neat or in solution in the one of the above solvents or a mix- ture of these at -20°C to 100"C, preferably between 0CC to 60"C. When the reaction is judged to be completed, the excess of solvent and volatile reagents is removed by distillation either at atmospheric pressure or in vacuo. The residual product can be further purified by recrystalli- zation from a solvent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, water, toluene, acetic acid, dioxane, tetrahydrofuran or a mixture of two or more of the above solvents when compatible.

Alternatively, the product can be purified by column chromatography using dichloromethane/- methanol or chloroform/methanol or isopropyl alcohol as eluent. The corresponding fractions are concentrated either at atmospheric pressure or in vacuo to provide the pure arylsulfonyl hydrazide.

By use of the above methodology the following compounds can be prepared: EXAMPLE 161: 3-Chloro-4-hydroxybenzenesulfonic acid (benzylidene?hydrazide

3-Chloro-4-hydroxybenzenesulfonyl hydrazide: A solution of 4.82 g (21.2 mmol) 3-chloro-4-hydroxy-benzenesulfonyl chloride, (prepared ac- cording to the procedure described by Popoff, I. C.; Frank, J. R.; Whitaker R. L.; Miller H. J., Demaree K. D. J. Agr. Food Chem. 1969,17, 810.) in 15 ml THF was added dropwise with stirring to 3.4 ml 50% hydrazine hydrate (54.4 mmol, 2.5 eq.) at such a rate that the tem- perature is maintained below 10"C. A precipitate formed after the addition was completed.

The mixture was stirred for an additional 30 min, and cooled to 0 "C. The solid was collected in a Buchner funnel, washed several times with distilled water, and air dried. Recrystalliza- tion from methanol provided 1.20 g 3-chloro-4-hydroxybenzenesulfonyl hydrazide as a white solid.

H NMR (DMSO-d6): 8 4.78 (bs, 4 H), 6.72 (d, J = 8.6 Hz, 1 H), 7.35 (dd, J = 2.3, 8.6 Hz, 1 H), 5.55 (J = 2.2 Hz, 1 H); MS(CI): m/z 223, 221.

To a solution of 105 mg (0.48 mmol) of the above 3-chloro-4-hydroxybenzenesulfonyl hy- drazide in 5 ml methanol was added 0.05 ml (52 mg, 0.49 mmol) benzaldehyde and one drop of acetic acid. After 30 min the mixture was concentrated. Flash chromatography (silica gel, 2:1 hexane/ethylacetate) provided 67 mg (45%) of the title compound as a solid.

1 H (DMSO-d6): 8 7.10 (d, J = 8.6 Hz, I H), 7.38 (m, 3 H), 7.55 (dd, J = 2.3, 6.0 Hz, 2 H), 7.66 (d, J = 2.2, 8.6 Hz, 1 H), 7.76 (d, J = 2.2 Hz, 1 H), 7.90 (s, 1 H), 11.3 (m, 2 H). MS(CI): m/z 311.

EXAMPLE 162:

3-ChloroA-hydroxy-benzenesulfonic acid [4-(4-trifluoromethoxybenzyloxy)-l - naphthylmethyleneahydrazide To a solution of 3-chloro-4-hydroxy-benzene sulfonyl hydrazide (105 mg, 0.48 mmol) in 5 ml methanol was added 4-trifluoromethoxybenzyloxy-1-naphthaldehyde (163 mg, 0.49 mmol) and a catalytical amount of glacial acetic acid (5 drops). The reaction mixture was stirred overnight, and filtered. The filtrate was concentrated under vacuo to give the crude product. Flash chro- matography (silica gel, 1:1 hexane/ethylacetate) provided 145 mg (56%) of the title compound as a solid.

1H NMR (DMSO-d6) 8 5.27 (s, 2 H), 6.06 (s, 1 H), 6.83 (d, J = 8.1 Hz, 1 H), 7.10 (d, J = 8.1 Hz, 1 H), 7.26 (d, J = 7.3 Hz, 2 H), 7.50 - 7.60 (m, 5 H), 7.80 (s, 1 H), 7.85 (dd, J = 3.0, 8.2 Hz, 1 H), 8.08 (d, J = 2.1 Hz, 1 H), 8.26 (s, 1H), 8.36 (d, J = 7.76 Hz, 1H), 8.67 (d, J = 8.5 Hz, 1H).

CIMS m/z: 551, 553.

By using the above methodology, the following compounds may be prepared: EXAMPLE 163: EXAMPLE 164: EXAMPLE 165: EXAMPLE 166: Synthesis of alkylhydrazides according to the invention: The alkylidene hydrazide derivatives given above can be reduced to the dihydroderivatives by the method given in Scheme V: SCHEME V where A, R4, B, K, D, m and n are as defined for formula I.

The alkylhydrazide derivatives can be prepared by reduction (i.e. Lane, C.F.(1975), Synthesis, p.135) of the corresponding alkylidene hydrazides using a metal hydride, such as sodium bo- rohydride or sodium cyanoborohydride. The alkylidene hydrazide derivative is treated with between 1-10 equivalents, preferentially 1-3 equivalents, of sodium cyanoborohydride in a sol- vent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran, dioxane, water or

a compatible mixture of two or more solvents. Optionally a small amount of an acid is used as a catalyst such as hydrochloric acid, trifluoroacetic acid, acetic acid, or sulfuric acid. The reac- tions are performed at 0°C to 60"C, preferably at 100C to 30"C. When the reaction is complete as judged by HPLC or TLC (silica gel, 1% methanol in dichloromethane as eluent) the sol- vent(s) are removed and the residue is chromatographed on a silica gel column using 1% methanol in dichloromethane or chloroform as an eluent. The corresponding fractions are con- centrated to give the desired product. Specific examples illustrating the preparation of alkylhy- drazides according to the invention are provided below.

EXAMPLE 167: 4-hydroxybenzoic acid (1-naphthylmethyl)hydrazide 4-Hydroxybenzoic acid (1-naphthylmethyiene)hydrazide (100 mg, 0.34 mmol) was dissolved in methanol (10 mL) and treated with sodium cyanoborohydride (236 mg, 4.1 mmol) followed by two drops of trifluoroacetic acid. After stirring the reaction solution for three hours at room temperature, the solvent was evaporated in vacuo. The residue was introduced into a silica gel column and eluted with dichloromethane/methanol (99/1). Evaporation of the corresponding fractions in vacuo gave the title compound in 30% yield. MS (ESI) m/z 293 (M+H)+.

Using the same methodology as described above the following compound was prepared: EXAMPLE 168: 3-Chloro-4-hydroxybenzoic acid N-[4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzyl]hydra-zide 1H NMR (DMSO-d6): 61.18 (d, 6H), 2.87 (m, 1H), 3.75 (s, 6H), 3.90 (m, 2H), 4.80 (s, 2H), 5.43 (brd s, 1H), 6.68 (s, 2H), 6.98 (d, 1H), 7.20 (d, 2H), 7.34 (d, 2H), 7.64 (dd, 1H), 7.87 (d, 1H), 9.89 (brd s, 1H), 10.80 (s, 1H); MS (APCI): 485.2.

Furthermore, the following compounds may also be prepared: EXAMPLE 169: EXAMPLE 170: EXAMPLE 171:

EXAMPLE 172: EXAMPLE 173: General procedure for synthesis of compounds of the general formula Xl: formula XI A and B are as defined for formula I and -NR5CR5d is where R5a, R4, R4b, c, q, d and D are as defined for for- mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.

Step A: The reaction is known and is generally performed by stirring hydroxy benzaldehyde, hydroxy naphthaldehyde or the like together with a bromo acetic acid ester (either methyl, ethyl or other lower alkyl ester) in the presence of a base such as lithium, sodium, potassium or ce- sium carbonate in a solvent such as acetone, 2-methyl-3-pentanone, tetrahydrofuran, dioxane, DMSO, DMF, ethylene glycol, benzene, toluene or a mixture of the above solvents. The reac- tions are performed between 0°C to 1300C, preferably between 20"C to 100"C, most prefera- bly at or about the reflux temperature of the solvent. The reactions are preferably conducted under an inert atmosphere such as N2 or Ar. When the reaction is complete as judged by dis- appearance of the starting ester by TLC or HPLC, the solvent may be removed by concentra- tion at atmospheric or reduced pressure. The product can be further purified by either recrys- tallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xy- lene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloro- methane/methanol or chloroform/methanol or isopropyl alcohol as eluent.

Step B: The resulting derivative of acetic ester is then saponified using methods well-known to those skilled in the art such as dissolving the compound in an appropriate solvent such as a lower alcohol (e.g methanol, ethanol or isopropanol), DMF, dioxane or DMSO and adding an aqueous base like lithium, sodium or potassium hydroxide. The reactions are performed be- tween 0°C to 1 30°C, preferably between 20"C to 100"C. When the reaction is complete as judged by disappearance of the staring ester by TLC or HPLC, the solvent may be removed by concentration at atmospheric or reduced pressure. The product can then be isolated by pour- ing the residue into water or cooled water and acidifying the mixture using an inorganic acid such as hydrochloric acid or sulfuric acid. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure.

The product can be further purified by either recrystallization from a solvent such as ethyl alco- hol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent.

Step C: The resulting carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, di- chloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethy- lorthoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between 0°C to 140"C, preferably between 10°C to 80"C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further re- crystallized if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture in vacuo, followed by col- umn chromatography on silica gel using a solvent system such as chloroform/methanol or di- chloromethane/methanol or chloroform/ethyl acetate.

Step D: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an an- hydride or an acid halide that can then react with the amine to give a compound of formula Xl.

Step D can also be done combinatorially with a selected number of amines. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, tolu- ene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hex- ane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloro- methane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula Xl.

Specific examples illustrating the preparation of compounds of the general formula Xl ac- cording to the invention are provided below.

EXAMPLE 174: 2-{4-[(3-Chloro-4-hydroxy-benzoyl)hydrazonomethyl]naphthyl-1 -yloxy}-N-(4-chloro- phenyl)acetamide Step A: Hydroxynaphthaldehyde (10 g, 58 mmol), potassium carbonate (16 g, 110 mmol), and methyl bromoacetate (16 g, 100 mmol) were refluxed in acetone (120 mL) overnight.

The reaction mixture was poured into an Erlenmeyer flask containing approximately 500 mL of ice chips. The mixture was stirred until all of the ice was melted. (4-Formylnaphth-l-yloxy) acetic acid methyl ester (13 g, 50 mmol) was filtered and dried in vacuo overnight. <BR> <BR> <BR> <BR> <BR> <P>1H NMR (CDC13): 83.86 (s, 3H), 4.93 (s, 2H), 6.80 (d, IH), 7.61 (t, IH), 7.72 (t, IH), 7.90 (d, 1H), 8.42 (d, lH), 9.29 (d, IH), 10.22 (s, IH).

Step B: The above ester (13 g, 50 mmol) was dissolved in methanol (100 mL) and 2 M NaOH (40 mL) was added. The reaction solution was stirred overnight and concentrated to approximately 100 mL under vacuo. The residue was poured into approximately 500 mL of ice chips and the mixture was acidified (by pH paper) with the addition of 3N HCI. The mix- ture was stirred until all of the ice was melted. (4-Formyinaphth-1-yloxy) acetic acid was filtered and washed with water.

Step C: To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (2g, 10.7 mmol) in DMSO (20 mL) was added the above (4-formylnaphth-1-yloxy) acetic acid (3g, 13 mmol) and a catalytic amount of acetic acid (10 drops). The solution was stirred overnight and diluted with ethyl acetate. The solution was washed with water (3x), brine, and dried over MgSO4.

The volume was reduced to approximately 100 mL and placed in an ice-bath. The resulting solid was filtered and washed with cold ethyl acetate to afford (4-[(3-chloro-4-hydroxy- benzoyl)hyd razonomethyl]naphth- l-yloxy) acetic acid.

1H NMR (DMSO-d6): 8 4.91 (s, 2H), 6.95 (d, 1H), 7.02 (d, 1H), 7.55 (t, 1H), 7.64 (t, 1H), 7.74 (d, 1H), 7.92 (d, 1H), 8.27 (d, 1H), 8.90 (m, 2H), 10.92 (brd s, 1H), 11.63 (s, 1H), 13.14 (brd s, 1H).

Step D: To a solution of the hydrazone-carboxylic acid (50 mmol) in anhydrous DMSO was added a solution of carbonyldiimidazole (55 mmol) in anhydrous DMSO. After the evolution of gases ceased (approximately 3-4 minutes), the amine was added and the reaction mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate and washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent afforded the crude material, which was purified by reverse phase HPLC chromatography to give the title com- pound.

1H NMR (DMSO-d6): 84.99 (s, 2H), 7.04 (m, 2H), 7.36 (d, 2H), 7.65 (m, 4H), 7.79 (t, 2H), 7.99 (s, 1H), 8.40 (d, 1H), 8.72 (s, 1H), 8.92 (d, 1H), 10.42 (s, 1H), 10.96 (s, 1H), 11.69 (s, 1H); MS (APCI): 507.9.

By using the same methodology, the following compounds were prepared: EXAMPLE 175: N-(1-Benzylpyrrolidin-3-yl)-2-{4-{(3-chloro-4-hydroxy-benzoy l)hydrazonomethyl]naphth-1- yloxy}acetamlde

1H NMR (DMSO-d6): # 1.96 (m, 2H), 2.32 (m, 5H), 4.58 (s, 2H), 6.78 (d, 1H), 6.92 (d, lH), 7.15 (m, 5H), 7.47 (t, 1H), 7.52 (t, 1H), 7.62 (d, 2H), 7.82 (d, 1H), 8.18 (m, 2H), 8.78 (d, 2H), 10.75 (brd s, 1H), 11.52 (s, 1H); MS (APCI): 556.9.

EXAMPLE 176: 2-{4-{(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphth-1-yl oxy}-N-indan-1-yl-acetamide 1H NMR (DMSO-d5): # 1.94 (m, 1 H), 2.40 (m, 1H), 2.80-3.07 (m, 3H), 4.87 (s, 2H), 7.04 (d, 1H), 7.10 (d, 1H), 7.21 (m, 4H), 7.61 (t, 1H), 7.69 (t, 1H), 7.80 (t, 2H), 8.10 (s, 1H), 8.42 (d, 1H), 8.64 (d, 1H), 8.98 (m, 2H), 11.00 (brd s, 1H), 11.68 (s, 1H); MS (APCI): 514, 516.

EXAMPLE 177: 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphth-1-yl oxy}-N-(1,2,3,4-tetrahydro- naphthalen-1 -yl)acetamide 1H NMR (DMSO-d6): # 1.75 (m, 2H), 1.92 (m, 2H), 2.74 (m, 2H), 4.87 (m, 2H), 5.12 (m, 1H), 7.12 (m, 6H), 7.61 (t, 1H), 7.74 (t, 1H), 7.84 (m, 2H), 8.01 (s, 1H), 8.40 (d, 1H), 8.62 (d, 1H), 8.97 (m, 2H), 11.72 (s, 1 H); MS (APCI): 528, 530.

EXAMPLE 178: 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphth-1-yl oxy}-N-[2-(4-chloro- phenyl)ethyl]acetamide 1H NMR (DMSO-d6): 82.40 (t, 2H), 2.79 (t, 2H), 4.74 (s, 2H), 6.96 (d, 1H), 7.10 (d, 1H), 7.63 (t, 1H), 7.69 (t, 1H), 7.72 (m, 2H), 7.81 (s, 1H), 8.01 (m, 2H), 8.23 (t, 1H), 8.40 (d, 1H), 8.95 (s, 1H), 9.01 (d, 1H), 10.98 (brd s, 1H), 11.70 (s, 1H); MS (APCI) 538.8, 537.8.

EXAMPLE 179: 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphth-1-yl oxy}-N-[3-(4-methylpiperazin- 1-yl)propyl}acetamide 1H NMR (DMSO-d5): # 1.50 (m, 2H), 2.26 (m, 2H), 2.48 (m, 5H), 3.01 (m, 8H), 4.53 (s, 2H), 6.78 (d, 1 H), 6.89 (d, 1 H), 7.38 (t, 1 H), 7.47 (t, 1H), 7.5 (t, 2H), 7.76 (d, 1H), 8.01 (t, 1 H), 8.22 (d, 1H), 8.68 (d, 1H), 8.74 (s, 1H), 10.74 (brd s, 1H), 11.45 (s, 1H); MS (APCI): 538.0.

EXAMPLE 180: 3-Chloro-4-hydroxybenzoic acid {4-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-oxoethoxy]- naphth-1-ylmethylene}hydrazide 1H NMR (DMSO-d6): 82.90 (d, 2H), 2.75 (m, 2H), 4.70 (d, 2H), 5.24 (s, 2H), 6.90 (t, 2H), 7.10 (m, 4H), 7.66 (m, 4H), 8.01 (s, 1H), 8.34 (t, 1H), 8.95 (m, 2H), 10.97 (brd s, 1H), 11.68 (brd s, 1H); MS (APCI): 514.2.

EXAMPLE 181: 2-{4-[(3-Chloro-4-hydroxy-benzoyl)hydrazonomethyl]naphth-1-y lxy}-N-(3- trifluoromethoxybenzyltacetamide 1H NMR (DMSO-d6): 84.49 (d, 2H), 4.90 (s, 2H), 7.13 (m, 2H), 7.42 (m, 4H), 7.59 (dd, 1H), 7.68 (dd, 1H), 7.78 (m, 2H), 8.03 (s, 1H), 8.51 (d, 1H), 8.79 (t, 1H), 9.0 (m, 2H), 10.85 (brd s, 1H), 11.72 (s, 1H); MS (APCI): 572.1.

EXAMPLE 182: 3-Chloro-4-hydroxybenzoic acid (4-{2-[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]-2- oxoethoxy}naphth-1-ylmethylene)hydrazide

MS (APCI): 636, 638.

EXAMPLE 183: 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphth-1-yl oxy}-N-(4- trifluoromethylsulfanylbenzyl)acetamide 1H NMR (DMSO-d6): 84.48 (d, 2H), 4.88 (s, 2H), 7.08 (m, 2H), 7.45 (d, 2H), 7.68 (m, 4H), 7.82 (m, 2H), 8.01 (d, 1H), 8.52 (d, 1H), 8.87 (t, 1H), 8.96 (s, 1H), 9.01 (d, 1H), 10.98 (brd s, IH), 11.72 (s, 1H); MS (APCI): 588.2

EXAMPLE 184: 2-{4-[(3-Chloro-4-hydroxy-benzoyl)hydrazonomethyl]naphth-1-y loxy}-N-(3,4- dichloropbenzyl)acetamide 1H NMR (DMSO-d6): 84.42 (d, 2H), 4.91 (s, 2H), 7.08 (d, 1H), 7.11 (d, 1H), 7.22 (d, 1H), 7.48 - 7.76 (m, 4H), 7.82 (d, 2H), 8.04 (d, 1 H), 8.51 (dd, 1H), 8.83 (m, 1 1 H), 8.91 (s, 1 H), 10.02 (d, 1H), 11.00 (brd s, 1H), 11.73 (s, 1H); MS (APCI): 556.0 EXAMPLE 185: 'H NMR (DMSO-D6): 8 0.97 (d, 6H), 2.42 (m, 2H), 2.50 (m, 2H), 2.68 (septet, 1H), 3.49 (m, 4H), 5.12 (s, 2H), 7.03 (d, lH), 7.08 (d, 1H), 7.60 (t, 1H), 7.68 (t, 1H), 7.80 (d, 2H), 8.01 (d, 1H), 8.33 (d, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.68 (s, 1H); MS (APCI, neg.): 507.1, 509.1.

EXAMPLE 186: 'H NMR (DMSO-D6): 8 1.75 (m, 2H), 2.25 (m, 2H), 2.24 (d, 3H), 2.39 (quintet, 1H), 3.26 (m, 2H), [2.84 (s, 1.5H) + 3.04 (s, 1.5H), 3H], 5.16 (d, 2H), 6.72 (t, 1H), 7.07 (d, 1H), 7.62 (t, 1H),

7.68 (t, 1 H), 7.78 (dd, 2H), 8.00 (d, 1 H), 8.34 (m, 1 H), 8.94 (s, 1 H), 9.00 (d, 1 H), 11.65 (brd s, lH); MS (APCI): 495.2, 497.2.

EXAMPLE 187: 'H NMR (DMSO-D5): # 0.86 (s, 3H), 1.48 (m, 4H), 2.38 (t, 1H), 2.72 (m, 1H), 3.09 (t, 1H), 3.84 (t, 1H), 4.18 (t, 1H), 5.09 (m, 2H), 7.03 (d, 1H), 7.11 (d, 1H), 7.59 (t, 1H), 7.64 (t, 1H), 7.82 (d, 2H), 8.01 (s, 1H), 8.33 (d, 1H), 8.94 (s, 1 H), 9.00 (d, 1H), 11.0 (brd, 1H), 11.69 (brd s, 1H); MS (APCI): 480.1, 482.1.

EXAMPLE 188: 'H NMR (DMSO-D6): # 2.88 (s, 1.5H) + (s, 1.5H), 3H], 2.95 (t, IH), 3.01 (s, 1.5H), 3.10 (s, 1.5H), 3.10 (t, 1H), 3.69 (t, IH), 3.81 (t, IH), 5.05 (d, 2H), [6.66 + 6.95 (d), 1H], 7.10 (d, 1H0, [7.20 + 7.38(d), IH], 7.29 (d, IH), 7.67 (m, 5H), 8.01 (s, 1H), 8.30 (t, 1H), 8.53 (dd, 1H), 8.97 (m, 2H), 11.67 (brd s, 1H); MS (APCI): 517.3, 519.2.

EXAMPLE 189:

'H NMR (DMSO-D6): # 3.88 (s, 6H), 4.75 (s, 2H), 6.93 (d, 1H), 7.08 (m, 3H), 7.34 (dd, 1H), 7.74 (dd, 1H), 7.79 (d, 1H), 7.95 (s, 1H), 8.37 (s, 1H), 9.74 (s, 1H), 10.03 (m, 1H), 10.96 (brd s, 1H), 11.76 (brd s, 1H); MS (APCI): 534.4, 536.2.

EXAMPLE 190: 1H NMR (DMSO-D6): 8 1.18 (d, 6H), 2.85 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 6.71 (d, 1H), 6.78 (d, 1H), 7.06 (d, 1H), 7.20 (d, 2H), 7.58 (d, 2H), 7.78 (dd, 1H), 7.82 (d, 1H), 7.99 (d, 1H), 8.70 (s, 1H). 10.04 (s, 1H), 10.92 (brd s, 1H), 11.62 (brd s, 1H); MS (APCI): 496.5, 498.2.

EXAMPLE 191: 'H NMR (DMSO-D6): 8 4.88 (s, 2H), 6.93 (t, 2H), 7.23 (d, 2H), 7.47 - 7.70 (m, 6H), 7.86 (d, 1H), 8.30 (d, 1H), 8.80 (s, 1H), 8.87 (d, 1H), 10.34 (s, 1H), 10.82 (brd s, 1H), 11.55 (brd s, 1H); MS (APCI): 558.5, 560.0.

EXAMPLE 192: 'H NMR (DMSO-D6): # 4.06 (s, 3H), 4.94 (s, 2H), 6.81 (d, 1H), 6.89 (s, 1H), 7.19 (d, 1H), 7.45 (s, 1H), 7.90 (m, 3H), 8.10 (s, 1H), 8.82 (s, 1H), 10.62 (s, lH), 11.07 (brd s, 1H), 11.75 (s, 1H); MS (APCI): 523.3, 524.8, 526.6.

EXAMPLE 193: 1H NMR (DMSO-D6): 81.68 (m, 2H), 2.01 (m, 2H), 3.05 (m, 2H), 3.35 (m, 2H), 3.86 (m, 1H), 4.26 (s, 2h), 4.81 (s, 2H), 6.95 (d, 1 H), 7.09 (d, 1H), 7.46 (s, 5H), 7.59 (m, 1 H), 7.66 (t, 1 H), 7.77 (d, 1H), 7.98 (d, 1H), 8.34 (d, 1H), 8.41 (d, 1H), 8.92 (m, 2H), 9.65 (brd s, 1H), 11.02 (brd s, 1 H), 11.80 (brd s, @ H); MS (APCI): 571.3, 572.3, 573.3.

EXAMPLE 194: 1H NMR (DMSO-D6): # 2.79 (t, 2H), 3.43 (qt, 2H), 4.71 (s, 2H), 6.95 (d, 1H), 7.08 (d, 1H), 7.17 (m, 1H), 7.26 - 7.30 (m, 3H), 7.61 (t, 1H), 7.67 (t, 1H), 7.76 (m, 2H), 7.99 (d, 1H), 8.24 (t, 1H), 8.38 (d, 1H), 8.91 (s, 1H), 8.98 (d, 1 H), 10.94 (s, 1 H), 11.67 (s, 1 H); MS (APCI): 536.3, 538.2, 539.1.

EXAMPLE 195: 'H NMR (DMSO-D6): # 4.42 (d, 2H), 4.87 (s, 2H), 7.06 (m, 2H), 7.38 (d, 2H), 7.60 (t, 1 H), 7.63 (m, 1H), 7.80 (t, 1H), 7.99 (d, 1H), 8.49 (d, 1H), 8.79 (t, 1HJ), 8.93 (s, 1H), 8.98 (d, 1H), 10.95 (s. 1H), 11.68 (s, 1H); MS (APCI): 558.2, 560.1.

EXAMPLE 196: 4-(4-bromophenyl-3,4-dihydropiperadinylacetamideoxy)naphth-1 -yl methylene-3-chloro-4- hydroxybenzoic acid hydrazone Reaction scheme:

4-(4-bromophenyl)-4-piperidinol chloroacetamide (step A): To a solution of 4-(4-bromophenyl)-4-piperidinol (5 g, 19.5 mmol) and diisopropylethylamine (2.8 g, 21.5 mmol) in DMF (30 mL) was added dropwise chloroacetylchloride (2.2 g, 21.5 mmol). After stirring the mixture for one hour, the mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate (2x), 1 N HCI (3x), water, brine, and dried over MgSO4. The solution was concentrated and chromatographed over silica gel with ethyl ace- tate to give the product as a brown solid (4 g, 62 %).

'H NMR (DMSO-D5): 8 1.21 (d, 2H), 1.71 (t. 1H), 1.96 (t, 1H), 2.71 (t, 1H), 3.37 (t, 1H), 3.70 (d, 1H), 4.27 (d, 1 H), 4.54 (s, 2H), 5.26 (s, 1 H), 7.42 (d, 2H), 7.51 (d, 2H).

4-(4-bromophenyl)-3.4-dihydropiperidine chloroacetamide (step B): To a solution of 4-(4-bromophenyl)-4-piperidinol chloroacetamide (4 g, 12 mmol) and diiso- propylethylamine (4.6 mL, 26 mmol) in THF (40 mL) cooled in an ice-bath was added methanesulfonyl chloride (2 mL, 26 mmol) and the mixture was refluxed for 16 hours under a nitrogen blanket. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCI (2x), aqueous NaHCO3 (2x), brine (2x), and dried over MgSO4. The solvent was evapo- rated and the product was chromotographed over silica gel with ethyl acetate/hexane (4/6).

The product was obtained as a yellow solid (1.5 g, 32%).

'H NMR (DMSO-D6): 82.44 (t, 2H), 3.62 (m, 2H), 4.14 (dd, 2H), 4.42 (d, 2H), 6.21 (s, 1H), 7.36 (m, 2H), 7.51 (d, 2H).

4(-4-bromohenyl-3,4-dihydropiperadinylacetamideoxy)naphth aldehyde (step C): A mixture of 4-(4-bromophenyl)-3,4-dihydropiperidine chloroacetamide (1.5 g, 4.8 mmol). 4- hydroxynapthaldehyde (1.2 g ,7 mmol), and powdered potassium carbonate (1 g, 7.2 mmol) in acetonitrile (50 mL) was refluxed for 16 hours. The mixture was diluted with ethyl acetate and washed with brine (3x), dried over MgSO4, and concentrated. Silica gel chromatography with ethyl acetate/hexane (1/1) provided the product (1.4 g, 65%).

'H NMR (DMSO-D6): # 2.27-2.32 (m, 2H), 3.49-3.55 (m, 2H), 3.94 (brd s, 1H), 4.06 (brd s, 1H), 5.08 (s, 1H), 5.13 (s, 1H), 6.05 (s, 1H), 6.97 (t, 1H), 7.20 (t, 1H), 7.34 (d, 2H), 7.42-7.47 (m, 1H), 7.52-7.57 (m, 1H), 7.92 (d, 1H), 8.16 (d, lH), 9.01 (d, 1H), 9.97 (s, 1H), 4(-4-bromophenyl-3,4-dihydropiperadinylacetamideoxy)naphth-1 -yl methylene-3-chloro-4- hydroxybenzoic acid hydrazone (step D): The title compound was prepared according to the general procedure for the synthesis of alkylidene hydrazides from the condensation of 3-chloro-4-hydroxybenzoic acid hydrazide and 4-(4-bromophenyl-3,4-dihydropiperadinylacetamideoxy)naphthal dehyde: 1H NMR (DMSO-D6): # 2.47-2.58 (m, 2H), 3.72 (br s, 2H), 4.13 (s, 1H), 4.26 (s, 1H), 5.14 (s, 1H), 5.18 (s, 1H), 6.23 (s, 1H), 6.50-6.53 (m, 1H), 7.03-7.06 (m, 1H), 7.35-7.38 (m, 2H), 7.52 (d, 2H), 7.58 (d, 2H), 7.59-7.67 (m, 1H), 7.75 (d, 1H), 7.84 (s, 1H), 8.32 (d, 1H), 8.89 (s, 1H), 8.92 (s, 1H), 11.41 (s, 1H); MS (APCI): 618.1, 620.1, 621.1, 622.1

EXAMPLE 197: EXAMPLE 198: EXAMPLE 199: EXAMPLE 200: EXAMPLE 201:

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General procedure for synthesis of compounds of the general formula XII: formula XII A and B are as defined for formula I and -NR5CR5d is where R5", R4, R4b, c, q, d and D are as defined for for- mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.

Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloro- methane, DMSO, acetic acid, water or a compatible mixture of two or more of the above sol- vents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylort- hoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between 0°C to 140"C, preferably between 10°C to 80"C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystalli- zed if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture invacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloro- methane/methanol or chloroform/ethyl acetate.

Step B: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an an- hydride or an acid halide that can then react with the amine to give a compound of formula XII.

Step B was also done combinatorially with a preactivated acid and a selection of amines. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethyiether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XII.

Specific examples illustrating the preparation of compounds of the general formula XII accor- ding to the invention are provided below.

Preparation of 4-formyl-l-naphthylacetic acid: This compound was prepared from the reduction of 4-cyano-1-naphthylacetic acid in the presence of 85% formic acid and Raney alloy as described in the literature. References: 1 ) A.A. Shulezhko and A.l. Kiprianov, J. org. Chem., (USSR) English translation, 4, 1968, p.1052. 2) Zh. Org. Khim., 4, 1968, p. 1089.

Preparation of 4-[3-Chloro-4-hydroxybenzoyl)-hydrazonomethyl]-l -naphthylacetic acid (step A): This compound was prepared according to the general procedure for the synthesis of alkyli- dene hydrazides from the condensation of 4-formyl-l -naphthylacetic acid above and 3- chloro4-hydroxybenzoic acid hydrazide.

'H NMR (DMSO-D5): 6 4.1 (s, 2H), 7.1 (d, 1H), 7.5 (d, 1H), 7.7 (qt, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 8.0 (s, 1H), 8.1 (d, 1H), 8.8 (d, 1H), 9.1 (s, 1H), 11.0 (brd s, 1H), 11.8 (s, 1H), 12.2 (brd s, 1 H); MS (APCI): 383.4, 385.2.

Preparation of (3-formylindolyl)acetic acid: Ethyl (3-formylindolyl)acetate: 3-Formylindole (10.0 g, 69 mmoles) was dissolved in DMF (100 ml). Under N2 was a 60% suspension of NaH in mineral oil (3.0 g) added in portions with cooling (temp < 15 °C). At < 15 °C was a solution of ethyl bromoacetate (8.4 ml) in DMF (15 ml) added drop wise over 30 minutes. The resulting mixture was stirred at room temperature for 16 hours and evaporated invacuo. The residue was added water (300 ml) and extracted with ethyl acetate (2 x 150 ml), the combined organic extracts were washed with satd. NH4CI, dried (MgSO4) and con- centrated to afford 15.9 g ethyl (3-formylindolyl)acetate.

1H NMR ( CDCl3 ) 8 1.26 (t, 3H), 4.22 (q, 2H), 4.90 (s, 2H), 7.21 - 7.35 (m, 3H), 7.72 (s, 1H), 8.30 (d, 1H), 10.0 (s, 1H).

(3-formylindolyl)acetic acid: Ethyl (3-formylindolyl)acetate (15.9 g) was dissolved in 1,4-dioxane (100 ml) and added 36% aq. NaOH (10 ml). The resulting mixture was stirred at room temperature for 4 days. Water (500 ml) was added and the mixture was washed with diethyl ether (150 ml). The aqueous phase was made acidic with 5N HCI and extracted with ethyl acetate (250 + 150 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to afford 10.3 g (73 % over two steps) of (3-formylindolyl)acetic acid.

1H NMR ( DMSO-d6 ) # 4.94 (s, 2H), 7.27 - 7.36 (m, 3H), 7.98 (s, 1H), 8.25 (d, 1H), 10.0 (s, 1H), 12.5 (bs, 1H).

Preparation of (4-Formylindolyl)acetic acid: 4-Formylindole:

This compound was synthesized according to F. Yamada, M. Somei, Heterocycles 26 (1987)1173.

'H NMR ( CDCI 3 ) 6 7.28 - 7.36 (m, 2H), 7.41 (t, J = 3.0 Hz, 1 H), 7.60 - 7.70 (m, 2H), 8.62 (brd s, 1H), 10.20 (s, 1H). GC-MS (pos.): 146 Ethyl (4-formylindolyl)acetate: This compound was synthesized according to the general procedure for N-alkylation of in- doles. <BR> <BR> <BR> <BR> <BR> <BR> <P>1H NMR (CDCl3) 8 1.13 (t, J = 6.9Hz, 3H), 4.15 (q, J = 7.2 Hz, 2H), 4.86 (s, 2H), 7.22 - 7.35 (m, 3H), 7.49 (d, J = 8.6 Hz, IH), 7.60 (d, J = 7.3 Hz, IH), 10.20 (s, 1H).

(4-Formylindolyl)acetic acid: This compound was synthesized according to the general procedure for saponification of esters. <BR> <BR> <BR> <BR> <BR> <BR> <P>1H NMR ( DMSO-d, )6 5.15 (s, 2H), 7.12 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 3.1 Hz, IH), 7.71 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 10.20 (s, 1H), 12.94 (brd s, H).

Preparation of (5-formylindolyl)acetic acid: 5-Cyano-N-tosylindole: In a 100 mL round-bottom flask was placed NaH (0.4 g, 60% dipersion in mineral oil, 10 mmol) and anhydrous THF (10 mL) was added. To the suspension was added a solution of 5-cyanoindole (1.0 g, 7 mmol) in anhydrous THF (10 mL) by syringe at 0°C. The mixture was stirred for 10 min, and tosyl chloride (1.6 g, 8.4 mmol) was added. After stirring at room temperature for 2 h, water (100 mL) was added. The mixture was extracted with ethyl ace- tate (3x50 mL), dried (MgSO4), and concentrated. The residue was purified by column chro- matography using hexane: ethyl acetate = 2:1 as eluent to yield 1.86 g (92%) of the desired product.

1H NMR (CDCl3)# 2.32 (s, 3H), 6.65 (d, J = 3.6 Hz, 1H), 7.19 (d, J = 7.9 Hz, 2H), 7.41 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 3.6 Hz, 1H), 7.63 (s, 1H),7.75 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H).

5-Formyl-N-tosylindole: To a solution of 5-cyano-N-tosylindole (0.66 g, 2.2 mmol) in anhydrous THF (20 mL), was added 1M DIBAL in hexane (4 mL, 4 mmol) via syringe at 0°C. The mixture was stirred at room temperature for 16 h, poured into ice-cooled 1N hydrochloric acid (50 mL), extracted with ethyl acetate (3 x 80 mL). The combined organic extracts were dried (MgSO4), and concentrated to give an oil. After a short column chromatography using hexane/ethyl acetate 2: 1 as eluent 0.62 g (95%) pure 5-formyl-N-tosylindole was obtained.

1H NMR (CDCl3) 2.29 (s, 3H), 6.74 (d, J = 3.7 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.65 (d, J <BR> <BR> <BR> = 3.7 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.82 (dd, J = 1.4, 8.6 Hz, 1H), 8.02 (d, J = 1.1 Hz, <BR> <BR> <BR> <BR> <BR> 1H), 8.09 (d, J = 8.6 Hz, 1H), 9.99 (s, 1H).

5-Formylindole: 5-formyl-N-tosylindole (0.5 g, 1.7 mmol) was dissolved in a mixture of methanol (10 mL) containing 5% aqueous KOH solution (5 mL). The mixture was refluxed for 3 h, neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate (3x50 mL). The combined organic extracts were dried (MgSO4), and concentrated. The residue was purified by short column chromatography to provide 240 mg (97%) of the desired product.

1H NMR (CDCl3) # 6.70 (t, J = 2.1 Hz, 1H), 7.32 (t, J = 2.3 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 1.5, 8.6 Hz, 1H), 8.19 (s, 1H), 9.45 (b, 1H), 10.15 (s, 1H). GC-MS (pos.): 146.

Ethyl (5-formylindolyl)acetate: This compound was synthesized according to the general procedure for N-alkylation of in- doles.

1H NMR (CDCl3) 8 1.27 (t, J = 6.8 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H), 4.87 (s, 2H), 6.70 (d, J = 3.4 Hz, 1H), 7.18 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 8.14 (s, 1H), 10.01 (s, 1H).

(5-Formylindolyl)acetic acid: this compound was synthesized according to the general procedure for saponification of esters.

1H NMR (DMSO-d6) 5.10 (s, 2H), 6.66 (d, J = 3.0 Hz, 1H). 7.48 (d, J = 3.0 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H0, 8.17 (s, 1H), 9.97 (s, 1H), 12.9 (brd s, 1H).

General procedure for preparation of [(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acids: These compounds were prepared according to the general procedure for the synthesis of alkylidene hydrazones by condensation of the various formylindolylacetic acids with 3-chloro- 4-hydroxy benzoic acid hydrazide.

3-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acid: 'H NMR (DMSO-D6): 82.81 (t, J = 6.5, 2H), 4.43 (t, J = 6.5, 2H), 7.06 (d, J = 8.5, 1H), 7.15- <BR> <BR> <BR> 7.28 (m, 2H), 7.56 (d, J = 8.1, 1H), 7.75 (d, J = 8.5, 1H), 7.83 (s, 1H), 7.95 (s, 1H), 8.27 (d, J = 7.65, 1 H), 8.54 (s, 1H), 10.88 (br s, H), 11.41 (s, 1H), LRMS calcd for C19 H,6 Cl1 N3 O4 (M - H) 384, found 384.0.

4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acid: <BR> <BR> <BR> <BR> <BR> <BR> 1H NMR ( DMSO-d5) 85.09 (s, 2H), 7.09 (d, J = 8.6 Hz, 1H), 7.16 - 7.25 (m, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.45 - 7.55 (m, 2H), 7.81 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 8.68 (s, 1 H), 10.96 (s, 1H), 11.71 (s, 1H), 12.90 (b, 1H). MS (APCI, neg.): 370.

5-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acid:

1H NMR (DMSO-d6) # 5.09 (s, 2H), 6.35 (d, J = 2.9 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 7.39 (d J = 3.1 Hz, 1H), 7.47 (d, J = 8.6Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.83 (s, 1H), 7.97 (s, 1H), 8.48 (s, 1H), 10.93 (s, 1H), 11.58 (s, 1H), 12.90 (brd s, 1H). MS (APCI, neg. ): 370.

4-[3-Chloro-4-hydroxybenzoyl)-hydrazonomethyl]-l -naphthylacetamides and the various indolacetamides (step B): General library production procedures: To solutions of 4-[(3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]naphthylaceti c acid and the various indolylacetic acids in DMSO was added carbonyldiimidazole (1.2 eq). The solution was agitated for 5 minutes and diluted with DMSO to a concentration of 50 mM. The soluti- on was then dispensed into 88 deep well plates containing solutions of amines in DMSO (50 mM). The plates were covered and agitated for 16 hours. The products were purified by HPLC.

Examples of compounds of the formula XII: EXAMPLE 343: 'H NMR (DMSO-D6): 8 1.06 (t, 3H), 1.17 (t, 3H), 3.31 (qt, 2H), 3.50 (qt, 2H), 4.19 (s, 2H), 7.10 (d, 1H), 7.45 (d, 1H), 7.64 (quintet, 2H), 7.83 (d, 1H), 7.88 (d, 1H), 7.98 (m, 2H), 8.87 (d, 1H), 9.09 (s, 1H), 10.99 (brd s. 1H), 11.80 (brd s, 1H); ms (APCI); 438.1, 440.1.

EXAMPLE 344: 1H NMR (DMSO-D6): 80.98 (d, 4H), 2.76 (t, 2H), 3.02 (quintet, 1H), 3.59 (t, 2H), 4.40 (s, 2H), 7.10 (d, 1H),7.48 (d, 1H), 7.48 (d, 1H), 7.59 (qt, 1H), 7.67 (t, 1H), 7.81 (d, 1H), 7.89 (d, 1H), 7.97 (d, 1H), 8.02 (s, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 10.99 (brd s, 1H) 11.80 (brd s, 1H); MS (APCI, neg.): 473.1, 475.1.

EXAMPLE 345: 'H NMR (DMSO-D6): # 2.50 (2H), 2.68 (t, 2H), 4.00 (s, 2H), 7.10 (d, 1H), 7.53 (d, 1H), 7.65 (tt, 2H), 7.80 (dd, 1H), 7.90 (d, 1H), 8.02 (d, 1H), 8.14 (d, 1H), 8.62 (t, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 11.0 (brd s, 1H) 11.80 (s, 1H); MS (APCI): 433.1, 435.1 EXAMPLE 346: 1H NMR (DMSO-D6): # 1.08 (m, 4H), 1.54 (m, 6H), 2.70 (t, 2H), 3.45 (t, 2H), 3.76 (m, 1H), 4.30 (s, 2H), 7.06 (d, 1H), 7.49 (d, 1H), 7.64 (m, 2H), 7.80 (d, 1H), 7.88 (d, 1H), 8.01 (s, 1H), 8.07 (d, 1H), 8.83 (d, 1H), 9.09 (s, 1H), 10.5 (brd d, 1H), 11.78 (brd s, 1H); MS (APCI, neg.): 515.2.

EXAMPLE 347: 'H NMR (DMSO-D5): 8 1.26 (m, 2H), 1.37 (m, 4H), 1.67 (m, 2H), 2.43 (m, 4H), 2.62 (m, 3H), 3.10 (t, 2H), 3.90 (d, 1H), 4.32 (s, 2H), 4.48 (d, 1H), 7.10 (d, 1H), 7.31 (d, 1H), 7.48 (m, 2H), 7.81 (d, 1H), 7.88 (d, 1H), 8.03 (m, 2H), 8.85 (d, 1H), 9.08 (brd s, 1H), 11.76 (brd s, 1H): MS (APCI): 533.2.

EXAMPLE 348: 1H NMR (DMSO-D6): 8 3.03 (m, 4H), 3.68 (t, 2H), 3.79 (t, 2H), 4.30 (s, 2H), 7.14 (m, 5H), 7.47 (d, 1H), 7.66 (quintet, 2H), 7.82 (d, 1H), 7.88 (d, 1 H), 8.02 (d, 1H), 8.07 (d, 1H), 8.87 (d, 1H), 9.10 (s, 1H), 10.99 (s, 1H), 11.80 (s, 1H); MS (ACPI): 545.6.

EXAMPLE 349:

'H NMR (DMSO-D5): # 3.10 (d, 4H), 3.67 (d, 4H), 4.30 (s, 2H), 7.00 (m, 2H), 7.09 (m, 3H), 7.47 (d, 1H, 7.62 (quintet, 2H), 7.82 (d, 1 H), 7.88 (d, 1 H), 8.03 (s, 1H), 8.06 (d, 1 H), 8.85 (d, 1H), 9.10 (s, 1H), 10.99 (s, 1H), 11.80 (s, 1H); MS (APCI) 544.5, 545.3.

EXAMPLE 350: 'H NMR (DMSO-D5): # 2.15 (s, 6H), 2.39 (m, 8H), 3.51 (d, 4H), 4.22 (s, 2H), 7.03 (d, 1H), 7.43 (d, 1H), 7.64 (quintet, 2H), 7.77 (d, 1H), 7.87 (d, 1H), 7.99 (s, 1H), 8.02 (d, 1H), 8.83 (d, 1H), 9.08 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 522.2.

EXAMPLE 351: 'H NMR (DMSO-D6): # 3.93 (d, 2H), 4.10 (d, 2H), 4.23 (s, 2H), 5.20 (m, 4H), 5.79 (m, IH), 5.94 (m, 1H), 7.10 (d, IH), 7.78 (d, 1H), 7.63 (m, 2H), 7.80 (d, 1H), 7.83 (d, lH), 7.95 (d, 1H), 8.02 (d, 1H), 8.85 (d, 1H), 9.10 (s, 1H), 11 (brd s, 1H), 11.80 (brd s, 1H); MS(ACPI): 462.2

EXAMPLE 352: 1H NMR (DMSO-D5): 8 0.9 (t, 3H), 1.30 (sextet, 2H), 1.54 (sextet, 2H), 3.56 (t, 2H), 4.31 (s, 2H), 4.39 (s, 2H), 7.06 (d, 1H) 7.48 (d, 1H), 7.65 (quintet, 2H), 7.79 (dd, 1 H), 7.87 (d, 1H), 7.97 (d, 1H), 8.01 (d, 1H), 8.85 (d, 1H), 9.09 (s, 1 H), 11.79 (s, 1 H); MS (APCI): 477.01, 479.2.

EXAMPLE 353: 1H NMR (DMSO-D6): 81.17 (m, 4H), 1.54 (m, 4H), 2.68 (m, lH), 3.77 (d, 1H), 4.18 (s, 2H), 4.33 (m, 1H), 4.76 (brd, IH), 7.10 (d, IH), 7.43 (m, 1H), 7.65 (quintet, 2H), 7.81 (d, 1H), 7.88 (d, 1 H), 8.02 (s, 1H), 8.04 (d, 1 H), 8.84 (d, 1H), 9.09 (s, 1 H), 11.79 (s, 1 H); MS (APCI): 464.1, 466.2.

EXAMPLE 354: 1H NMR (DMSO-D6): # 0.85 (qt, 3H), 1.53 (m, 2H), 3.00 (dt, 2H), 3.29 (quintet, 2H), 3.77 (dt, 2H), 4.13 (d, 2H), 7.05 (d, 1H), 7.26 (m, 2H), 7.36 (d, 1H), 7.52 (qt, 1H), 7.69 (m, 2H), 7.87

(m, 2H), 7.95 (d, 1H), 8.00 (s, 1H), 7.87 (dd, 1H), 8.84 (t, 1H), 9.07 (brd, 1H), 11.76 (brd s, 1H); MS (APCI): 529.2, 529.7, 531.2.

EXAMPLE 355: 'H NMR (DMSO-D6): # 0.85 (qt, 3H), 1.33 (m, 1H), 1.65 (m, 7H), 2.60 (t, 0.5H), 3.10 (t, 0.5H) 3.80 (m, 1H), 4.21 (s, 2H), 4.24 (m, 1H), 7.11 (d, 1H), 7.45 (t, 1H), 7.65 (m, 2H), 7.75 (d, 1 H), 7.89 (d, 1H), 8.01 (d, 1H), 8.05 (d, 1H), 8.83 (d, 1 H), 9.09 (s, 1 H), 11.80 (s, 1 H); MS (APCI): 478.4, 480.3.

EXAMPLE 356: 'H NMR (DMSO-D6): # 2.36 (m, 4H), 2.97 (d, 2H), 3.50 (m, 2H), 3.60 (m, 2H), 4.23 (s, 2H), 5.17 (t, 2H), 5.86 (m, 1H), 7.08 (d, 1H), 7.43 (d, 1H), 7.64 (quintet, 2H), 7.79 (dd, 1H), 7.87 (d, 1H), 8.01 (s, 1H), 8.04 (d, 1H), 8.83 (d, 1H), 9.09 (d, 1H), 11.79 (brd s, 1H); MS (APCI): 4.91.2, 493.2.

EXAMPLE 357: 'H NMR (DMSO-D5): # 1.50 (m, 1H), 1.90 (m, 2H), 1.95 (m, 1H), 2.72 (t, 1H), 2.95 (t, 1H), 3.30 (m, 1H), 3.55 (m, 1H), 3.65 (t, 2H), 3.75 (m, IH), 3.92 (t, 1H), 4.12 (t, 1H) 4.35 (d, 2H), 7.11 (d, 1H), 7.48 (m, 1H), 7.65 (t, 1H),7.68 (t, 1H), 7.8 (dd, 1H), 7.87 (d, 1H), 8.00 (d, 1H), 8.03 (d, 1H), 8.83 (d, 1H), 9.10 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 519.5, 521.2, 522.2 EXAMPLE 358: 'H NMR (DMSO-D6): 8 2.19 (s, 3H), 2.30 (m, 4 H), 3.50 (T, 2H), 3.58 (T, 2H), 4.22 (S, 2H), 7.03 (D, 1H), 7.43 (D, 1H), 7.64 (quint, 2H) 7.77 (dd, 1H), 7.87 (d, 1H), 7.99 (d, 1H), 8.04 (s, 1H), 8.83 (d, 1H), 9.09 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 465.2, 467.3.

EXAMPLE 359: 1H NMR (DMSO-D6): # 2.38 (m, 4H), 3.51 (s, 4H), 3.61 (t, 2H), 4.22 (s, 2H), 7.08 (d, 1H), 7.31 (m, 5H), 7.43 (d, 1 H), 7.61 (quintet, 2H), 7.82 (dd, 1H), 7.88 (d, 1H), 8.00 (s, 1H), 8.02 (d, 1H), 8.85 (d, 1H), 9.10 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 541.4, 543.1.

EXAMPLE 360: 'H NMR (DMSO-D5): 8 1.33 (dd, 3H), 2.76 (s, 1.5H), 2.96 (s, 1.5H), 3.61 (d, 1H), 4.14 (quintet, 1H), 4.65 (m, 2H), 7.10 (m, 2H), 7.33 (s, 3H), 7.42 (m, 3H), 7.54 (m, 2H), 8.02 (t, 1H), 8.80 (m, 1H), 9.07 (brd, 1H), 11.80 (brd s, 1H); MS (APCI): 530.2, 532.2.

EXAMPLE 361: 1H NMR (DMSO-D5): [2.94 (s, 1.5H)+ 3.10 (s, 1.5H), 3H], 3.54 (m, 2H), 4.00 (d, 1H), 4.28 (d, 1H), 4.81 (t, 1H), 4.96 (t, 1H), 7.09 (d, 1H), 7.35 (m, 3H), 7.43 (m, 3H), 7.61 (m, 2H), 7.83 (m, 3H), 8.04 (s, 1H), 8.85 (t, 1H), 9.11 (d, 1H), 11.80 (brd s, 1H); MS (APCI): 516.3, 518.2.

EXAMPLE 362: 1H NMR (DMSO-D6): # 2.75 (t, 1H), 2.95 (t, 1H), 3.59 (t, 1H), 3.80 (t, 1H), 4.38 (brd s, 3H), 4.61 (s, 1H), 4.84 (s, 1H), 6.40 (d, 1H), 6.53 (d, 1 H), 7.05 (d, 1H), 7.45 (t, 1H), 7.58 (m, 3H), 7.81 (m, 3H), 8.00 (brd, 2H), 8.83 (d, 1H), 9.10 (s, 1H), 11.78 (brd s, 1H); MS (APCI, neg.): 513.3, 514.2.

EXAMPLE 363: 'H NMR (DMSO-D5): # .50 (m, 2H), 1.68, (d, 2H), 2.28 (t, 1H), 2.59 (t, 1H), 3.05 (t, 1H), 3.96 (d, lH), 4.16 (s, 2H), 4.32 (d, 1H), 6.74 (brd s, 1H), 6.95 (d, 1H), 7.22 (brd s, 1H), 7.36 (d, 1H), 7.57 (quintet, 2H), 7.71 (dd, 1H), 7.79 (d, 1H), 7.92 (dd, 1H), 7.96 (d, 1H), 8.76 (d, 1H), 9.0 (s, 1H), 11.80 (brd s, 1H); MS (ACPI): 493.1, 495.2.

EXAMPLE 364: 'H NMR (DMSO-D6): 82.10 (s, 3H), 2.15 (s, 3H), 2.29 (t, IH), 2.40 (t, 1H), 2.80 (s, 1H), 3.05 (s, 2H), 3.36 (t, 1H), 3.46 (t, 1H). 4.16 (d, 2H), 7.01 (d, lH), 7.38 (t, 1H), 7.56 (m, 2H), 7.72 (dd, 1H), 7.79 (d, 1H), 7.94 (m, 2H), 8.77 (d, 1H), 9.02 (s, 1H), 11.71 (brd s, 1 H); MS (ACPI): 467.3, 469.1.

EXAMPLE 365: 1H NMR (DMSO-D5): # 2.11 (s, 3H), 2.14 (s, 3H), 2.33 (t, 1H), 2.39 (t, 1H), 3.37 (t, 1H), 3.46 (t, 1H), 4.14 (s, 1H), 4.32 (s, 1H), 4.55 (s, 1H), 4.74 (s, 1H), 7.05 (d, 1H), 7.23 (d, 1H), 7.29 (m, 3H), 7.38 (t, 1H), 7.43 (d, 1H), 7.57 (m, 2H), 7.81 (m, 2H), 7.97 (s, 1H), 8.06 (d, 1 H), 8.79 (t, 1H), 9.05 (s, 1H), 11.75 (brd s, 1 H); MS (APCI): 543.2, 545.2.

EXAMPLE 366: EXAMPLE 367: EXAMPLE 368: EXAMPLE 369: EXAMPLE 370:

EXAMPLE 371: EXAMPLE 372: EXAMPLE 373: EXAMPLE 374: EXAMPLE 375:

EXAMPLE 376: EXAMPLE 377: EXAMPLE 378: EXAMPLE 379: EXAMPLE 380:

EXAMPLE 381: EXAMPLE 382: EXAMPLE 383: EXAMPLE 384: EXAMPLE 385:

EXAMPLE 386: EXAMPLE 387: EXAMPLE 388: EXAMPLE 389:

EXAMPLE 390: EXAMPLE 391: EXAMPLE 392: EXAMPLE 393:

EXAMPLE 394: EXAMPLE 395: EXAMPLE 396: EXAMPLE 397:

EXAMPLE 398: EXAMPLE 399: EXAMPLE 400: EXAMPLE 401:

EXAMPLE 402: EXAMPLE 403: EXAMPLE 404: EXAMPLE 405:

EXAMPLE 406: EXAMPLE 407: EXAMPLE 408: EXAMPLE 409:

EXAMPLE 410: EXAMPLE 411: EXAMPLE 412: EXAMPLE 413: EXAMPLE 414:

EXAMPLE 415: EXAMPLE 416: EXAMPLE 417: EXAMPLE 418: EXAMPLE 419:

EXAMPLE 420: EXAMPLE 421: EXAMPLE 422: EXAMPLE 423: EXAMPLE 424:

EXAMPLE 425: EXAMPLE 426: EXAMPLE 427: EXAMPLE 428: EXAMPLE 429:

EXAMPLE 430: EXAMPLE 431: EXAMPLE 432: EXAMPLE 433: EXAMPLE 434:

EXAMPLE 435: EXAMPLE 436: EXAMPLE 437: EXAMPLE 438:

EXAMPLE 439: EXAMPLE 440: EXAMPLE 441: EXAMPLE 442: EXAMPLE 443:

EXAMPLE 444: EXAMPLE 445: EXAMPLE 446: EXAMPLE 447: EXAMPLE 448:

EXAMPLE 449: EXAMPLE 450: EXAMPLE 451:

EXAMPLE 452: EXAMPLE 453: EXAMPLE 454:

General procedure for synthesis of compounds of the general formula XIII: formula XIII A and B are as defined for formula I and -NR5CR5d is where R5", R4a, R4b, c, q, d and D are as defined for for- mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.

Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyi alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloro- methane, DMSO, acetic acid, water or a compatible mixture of two or more of the above sol- vents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylort- hoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between 0°C to 140"C, preferably between 10°C to 80"C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystalli- zed if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloro- methane/methanol or chloroform/ethyl acetate.

Step B: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an an- hydride or an acid halide that can then react with the amine to give a compound of formula XIII.

The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XIII.

Specific examples illustrating the preparation of compounds of the general formula XIII accor- ding to the invention are provided below.

Preparation of 4-formylnaphthoic acid is depicted below: 4-Bromomethylnaphthoic acid: A mixture of 4-methyinaphthoic acid (10 g, 54 mmol), N-bromosuccinimide (10 g, 56 mmol) and AIBN (100 mg) in CCI4 (250 mL) was refluxed for 3 hr. The reaction mixture was con-

centrated and dissolved in ethyl acetate. The organic layer was washed with water, brine and dried over MgSO4. Evaporation of the solvent gave the desired product (16 g, 80%).

'H NMR (DMSO-D6): 85.24 (s, 2H), 7.73 (m, 3H), 8.03 (d, 1H), 8.28 (d, 1H), 8.86 (d, 1H), 13.29 (brd s, 1H).

4-Hydroxymethylnaphthoic acid: 4-Bromomethylnaphthoic acid (16 g, 60 mmol) in an aqueous solution of K2CO3 (10%, 100 mL) was stirred at 70 °C for 30 minutes. The reaction mixture was cooled and made acidic with conc. HCI. The resulting precipitate was filtered and dried to give the desired product as a yellow solid in quantitative yield. <BR> <BR> <BR> <BR> <BR> <BR> <P>'H NMR (DMSO-D5) ; 85.01 (s, 2H), 5.96 (s, 1H), 7.70 (m, 3H), 8.10 (m, 2H), 8.90 (d, 1H).

Methyl 4-hyd roxymethylnaphthoate: A mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 mL), and conc.

H2SO4 (2 mL) was refluxed overnight. The insolubles were filtered off and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with aqueous NaHCO3 (2x), brine, dried over MgSO4, and concentrated to give a yellow oil. Silica gel column chro- matography using ethyl acetate/hexane (1/3) gave the desired product as a yellow oil (3.3 g, 35%).

'H NMR (CDCl3): 6 2.05 (t, 1H), 4.01 (s, 3H), 5.22 (s, 2H), 7.66 (m, 3H), 8.09 (d, 1H), 8.16 (d, 1H), 8.96 (d, 1H).

Methyl 4-formylnaphthoate: To a solution of methyl 4-hydroxymethylnaphthoate above (3.3 g, 15.3 mmol) in dichloro- methane (20 mL) was added MnO2 (6.6 g, 76 mmol). After stirring the dark mixture for 16 hours, the insolubles were filtered through a bed of Celite. Evaporation of the solvent gave the desired product as a white solid in quantitative yield.

'H NMR (CDCl3): 84.06 (S, 3H), 7.75 (m, 2H), 8.03 (d, 1H), 8.20 (d, 1H), 8.80 (d, 1H), 9.27 (d, 10.50 (s, 1H).

4-Formylnaphthoic acid: A mixture of the methyl 4-formylnaphthoate above (2.3 g, 1 mmol) and Na2CO3 (1.25 g, 12 mmol) in water (30 mL) was heated in a water bath for approximately 2 hr until a clear soluti- on was obtained. The solution was cooled and filtered. The filtrate was acidified with conc.

HCI to give a yellow precipitate. The solids were collected and dried over night to give the desired product (1.86 g, 87%).

'H NMR (DMSO-D6): 87.76 (m, 2H), 8.22 (m, 2H), 8.71 (d, 1H), 9.20 (d, 1H). 10.49 (s, 1H).

4-F(3-Chloro-4-hydroxybenzoyl)hydrazonomethylinaphthoic acid (step A): To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (1.53 g, 8.23 mmol) in DMSO (20 mL) was added a solution of 4-formylnaphthoic acid (1.65 g, 8.23 mmol) in DMSO (2 mL).

After stirring the solution for 16 hr, the reaction was diluted with ethyl acetate (30 mL) and water (30 mL). A precipitate formed. The precipitate was collected washed with hexane and dried to give the product as a white solid in quantitative yield.

'H NMR (DMSO-D6): 84.70 (d, 1H), 7.70 (m, 2H), 7.83 (d, 1H), 8.03 (m, 2H), 8.18 (d, 1H), 8.72 (s, 1H),8.90 (d, 1H), 9.17 (s, 1H), 11.0 (brd s, 1H0, 11.94 (s, 1H), 13.4 (brd s, 1H); MS (APCI, neg): 368.5, 370.2).

General procedure Derivatives of 4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphthamides (step B): To a solution of a derivative of4-[(4-hydroxybenzoyl)-hydrazonomethyl]naphthoic acid in DMSO was added carbonyldiimidazole (1.2 eq). The solution was agitated for 5 minutes and diluted with DMSO to a concentration of 50 mM. The solution was then dispensed into 88 deep well plates containing solutions of amines in DMSO (50 mM). The plates were covered and agitated for 16 hours. The products were purified by HPLC.

The following compounds of formula XIII were prepared:

EXAMPLE 455: 'H NMR (DMSO-D6): 82.91 (t, 2H), 3.67 (t, 2H), 7.12 (d, 1H), 7.38 (qt, 4H), 7.58 (t, 2H), 7.70 (t, 1H), 7.50 (d, 1H), 7.95 (d, 2H), 8.03 (s, 1H), 8.69 (brd t. 1H), 8.81 (d. 1H), 9.12 (s, 1H), 11.02 (s, 1H), 11.89 (s, 1H); MS (APCI): 507.3, 508.5.

EXAMPLE 456: 1H NMR (DMSO-D6): # 2.20 (brd m, 1H), 2.30 (brd m, 1H), 2.55 (m, 2H), 3.10 (brd m, 2H), 3.50 (s, 2H), 3.72 (brd m, 1H), 3.85 (brd m, 1H), 7.10 (d, 1H), 7.36 (qt, 4H), 7.53 (d, 1H), 7.70 (m, 2H), 7.82 (m, 2H), 7.95 (d, 1H), 8.03 (s, 1H), 8.88 (d, 1H), 9.11 (s, 1H), 11.00 (brd s, 1H), 11.89 (s, 1H); MS (APCI, neg.): 559.2, 561.2.

EXAMPLE 457: EXAMPLE 458: EXAMPLE 459: EXAMPLE 460: EXAMPLE 461:

EXAMPLE 462: EXAMPLE 463: EXAMPLE 464: EXAMPLE 465: EXAMPLE 466:

EXAMPLE 467: EXAMPLE 468: EXAMPLE 469: EXAMPLE 470: EXAMPLE 471:

EXAMPLE 472: EXAMPLE 473: EXAMPLE 474: EXAMPLE 475: EXAMPLE 476:

EXAMPLE 477: EXAMPLE 478: EXAMPLE 479: EXAMPLE 480: EXAMPLE 481:

EXAMPLE 482: EXAMPLE 483: EXAMPLE 484: EXAMPLE 485: EXAMPLE 486:

EXAMPLE 487: EXAMPLE 488: EXAMPLE 489: EXAMPLE 490: EXAMPLE 491:

EXAMPLE 492: EXAMPLE 493: EXAMPLE 494: EXAMPLE 495: EXAMPLE 496:

EXAMPLE 497: EXAMPLE 498: EXAMPLE 499: EXAMPLE 500: EXAMPLE 501: EXAMPLE 502: EXAMPLE 503:

EXAMPLE 504: EXAMPLE 505: EXAMPLE 506: EXAMPLE 507: General procedure for synthesis of compounds of the general formula XIV: formula XIV A and B are as defined for formula I and -NR5CR5d is where R5", R4a, R4b, c, q, d and D are as defined for for- mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.

Step A: The acid is coupled to a primary or secondary amine using one of the methods well- known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an anhydride or

an acid halide that can then react with the amine to give a compound of formula XIV. The pro- duct can then be isolated either by filtration or by extraction using a solvent such as ethyl ace- tate, toluene, dichloromethane or diethylether and the solvent may then be removed by con- centration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Altematively, the product can be purified by column chromatography using dich- loromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a com- pound of formula XIV.

Step B: The carbonyl compounds are then treated with an acylhydrazide in a solvent. The sol- vent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl al- cohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dich- loromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethy- lorthoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between O"C to 140"C, preferably between 10°C to 80"C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recry- stallized if necessary from a solvent such as the above described reaction solvents. The pro- duct can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloro- methane/methanol or chloroform/ethyl acetate.

Specific examples illustrating the preparation of compounds of the general formula XIV accor- ding to the invention are provided below.

The preparation of 3-(4-formylnaphthalene)propanoic acid is depicted below:

4-Trifluoromethylsulfonyloxy naphthaldehyde: To a solution of 4-hydroxy naphthaldehyde (34.4 g, 0.20 moi) in dichloromethane (200 mL) and pyridine (19 mL, 18.58 9, 0.23 mol) was added dropwise at O"C trifluoromethane sulfo- nic anhydride (46.75 g, 0.16 mol). The mixture was stirred at O"C for 2 hr and at room tem- perature for 16 hr. It was poured into water (200 mL), and extracted with ether (3 x 100 mL).

The combined organic extracts were washed with water (100 mL), 0.1 N hydrochloric acid (2 x 100 mL), water (100 mL), brine (100 mL), dried (MgSO4), and concentrated.

1H NMR (CDCl3) # 7.89 - 7.97 (m, 3H), 8.09 (dd, J = 2.8, 6.5 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 9.24 (dd, J = 2.8, 6.5 Hz, 1H), 10.45 (s, 1H).

2-(4-Trifluoromethylsulfonyloxy naphthyl) dioxolane: A solution of 4-trifluoromethylsulfonyloxy naphthaldehyde (4.09 g, 13.4 mmol), ethylene gly- col (1.5 mL, 1.67 9, 26.9 mmol), and p-toluene sulfonic acid (250 mg) in toluene (250 mL) was refluxed for 16 hr using a Dean -Stark trap. The solution was allowed to reach room temperature, was washed with satd. NaHCO3-sol. (2x 80 mL), brine (80 mL), dried (MgSO4), and concentrated to give a yellow oil (4.79 g, quant).

'H NMR (CDCl3) 84.19 (m, 4H), 6.47 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.66- 7.70 (m, 2H), 7.81 (d, J = 8.0Hz, 1H), 8.13 (dd, J = 3.3, 6.3 Hz, lH), 8.30 (dd, J = 3.3,6.3Hz, 1H).

GCMS: 348.

2-[4-(2-ethoxycarbonylvinyl)naphthyl]dioxoiane: Nitrogen was passed through a solution of 2-(4-trifluoromethylsulfonyloxynaphthyl) dioxolane (2.46 g, 7.06 mmol), ethyl acrylate (2.3 mL, 2.1 g, 21.2 mmol), triethylamine (4.3 g, 42.3 mmol) in DMF (6 mL) for 15 min, and bis(triphenylphosphine)palladium dichloride was ad- ded. The well stirred solution was heated at 90°C for 8 hr, and concentrated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (2x 50 mL), dried (Na2SO4), and concentrated. Purification by flash chromatography using hexane /ethyl acetate 9:1 as elu- ent provided a yellow solid (1.13 g, 53%).

'H NMR (CDCl3) 8 1.38 (t, J = 7.0 Hz, 3H), 3.74 - 4.22 (m, 4H), 8.65 (q, J = 7.0 Hz, 2H), 6.50 (s, 1H), 6.53 (d, J = 16.7 Hz, 1H), 7.58-7.62 (m, 2H), 7.74 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 8.21-8.28 (m, 2H), 8.52 (d, J = 15.2 Hz, 1H).

2-[4-(2-ethoxycarbonylethyl)naphthyl]dioxolane: To a solution of 2-[4-(2-ethoxycarbonylvinyl)naphthyl]dioxolane (701 mg, 2.35 mmol) in ethyl acetate (15 mL) was added palladium (5% on BaCO3, 51 mg). The mixture was stirred under a hydrogen atmosphere for 16 hr, filtered by suction through Celite and concentrated to pro- vide 689 mg (98%) of a colorless oil.

H NMR (CDCl3) 8 1.25 (t, J = 7.0 Hz, 3H), 2.75 (t, J = 8.0 Hz, 2H), 3.43 (t, J = 8.0 Hz, 2H), 4.12-4.22 (m, 6H), 6.46 (s, 1H), 7.37 (d, J = 7.3 Hz, 1H), 7.54 - 7.70 (m, 2H), 7.70 (d, J = 7.3 Hz, 1H), 8.07 (dd, J = 3.3, 6.5 Hz, 1H), 8.26 (dd, J = 3.3, 6.5 Hz, 1H).

Ethyl 3-(4-formylnaphthalene)propanoic acid: To a solution of 2-[4-(2-ethoxycarbonylethyl)naphthyl]dioxolane (689 mg, 2.29 mmol) in THF (15 mL) was added 6N hydrochloric acid (2 mL). The mixture was stirred for 16 hr at room temperature, diluted with ethyl acetate (20 mL), washed with satd. NaHCO3solution (20 mL), dried (MgSO4), and concentrated to give the product as a colorless oil (407 mg, 68%) that crystallized upon sitting.

3-(4-formylnaphthalene)propanoic acid: Ethyl 3-(4-formylnaphthalene)propanoic acid (310 mg, 1.2 mmol) was suspended in water (10 mL), and Na2CO3 (130 mg, 1.2 mmol) was added. The mixture was refluxed for 5 hr, and allowed to cool to room temperature. After acidification with conc. hydrochloric acid, a preci- pitate was formed. The precipitate was collected by suction, and dried at 800C in vacuum for 16 hr to give a white solid (300 mg, 73%).

H NMR (DMSO-D5) 8 2.69 (t, J = 7.0 Hz, 2H), 3.39 (t, J = 7.0 Hz, 2H), 7.66-7.77 (m, 2H), 8.10 (d, J = 7.3Hz, 1H), 8.23 (dd, J = 1.1,8.0 Hz, 1H), 9.22 (dd, J = 1.1 ,9.OHz, 1H), 10.33 (s, 1H), 12.30 (br s, 1H).

General procedure (Step A): Preparation of 3-(4-formylnaphthalene)propanamides: To a solution of 3-(4-formylnaphthalene)propanoic acid (100 mg, 0.437 mmol) in DMF (3 mL) was added carbonyi diimidazole (140 mg, 0.863 mmol). The mixture was stirred at room temperature for 1 hr, and amine (1.3 equivalents) was added. After stirring at room tempe- rature for 16 hr, the mixture was diluted with ethylacetate (5 mL), extracted with water (5 mL), 1 N hydrochloric acid (5 mL), and water (3 x 5 mL), dried (MgSO4) and concentrated.

After flash chromatography using hexane/ethylacetate 1 1 pure amide was isolated.

Examples of amides: H NMR (CDCI3) 8 1.06 (t, J = 7.0Hz, 3H),l.12 (t, J = 7.0Hz, 3H), 2.79 (t, J = 8.0Hz, 2H), 3.50 (t, J = 8.0 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1 H), 7.64 - 7.71 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H), 8.18 (dd, J = 1.3, 8.0 Hz, 1H),9.34 (dd, J= 1.3, 8.0 Hz, 1H), 10.34 (s, 1H). MS (APCI, pos.) 284.1

1H NMR (CDCl3) # 0.77 (t, J = 7.0 Hz, 3 H), 0.86 (t, J = 7.0 Hz, 3 H), 1.15-1.82(m, 8 H), 2.58 (dt, 0.5 H), 2.65 - 2.88 (m, 2H), 2.92 (dt, 0.5H), 3.39 - 3.60 (m, 2.5H), 3.62- 3.73 (m, 0.5H), 4.58 (dd, 0.5H), 4.73 (m, 0.5H), 7.56 (d, J = 7.3 Hz, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.61 - 7.72 (m, 2H), 8.16 (d, J = 8.3 Hz, 1H), 9.33 (d, J = 8.0 Hz, 1H), 10.34 (s, 1H). MS (APCI, pos.) 325.2 Derivatives of 4-[(4-hydroxybenzoyl)hydrazonomethyl]naphthylpropanamides (step B): These compounds were prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 4-formyl-1-naphthyl propanamides (from step A) and 4-hydroxybenzoic acid hydrazide derivatives.

EXAMPLE 508: 1H NMR (DMSO-D5) # 0.95 - 1.02 (m, 6H), 2.69 (t, J = 7.3 Hz, 2H), 3.19 (q, J = 7.0 Hz, 2H), <BR> <BR> <BR> 3.25 (q, J = 7.0 Hz, 2H), 3.33 (t, J = 7.3 Hz, 2H), 7.08 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 7.5 HZ, 1H), 7.65 (m, 2H), 7.81 (m, 2H), 8.00 (d, J = 2.0 Hz, 1H), 9.17 (dd, J =2,4, 6.5 Hz, 1H), <BR> <BR> <BR> 8.87 (d, J = 7.6Hz, IH), 9.05 (s, 1H), 11.00 (s, 1H), 11.77 (s, 1H). MS (APCI, pos. ): 452.2, 454.2

EXAMPLE 509: H NMR (DMSO-D6) 8 0.68 (t, J = 7.5 Hz, 3H), 0.75 (t, J = 7.5 Hz, 3H), 0.76 (dd, 0.5 H), 0.90 (dd, 0.5 H), 1.02 - 1.68 (m, 8H), 2.49 (m. 0.5H), 2.75 (m, 2H), 2.90 (t, J = 14.0 Hz, 0.5H), 3.33 (m, 2H), 3.61 (d, J = 12.0, Hz, 0.5H), 3.75 (m, 0.5H), 4.36 (d, J = 12.0 Hz, 0.5H), 4.53 (m, 0.5H), 7.08 (d, J = 8.5 Hz, lH), 7.50 (d, J = 7.5 Hz, 1H), 7.64 - 7.66 (m, 2H), 7.80 (dd, J = 1.9, 8.5 Hz, 1), 7.83 (d, J =7.5 Hz, 1H0, 8.00 (d, J = 1,9, Hz, 1H), 8.17 (m 1H), 8.88 (d, J = 7.5 Hz, H), 7.25 (s, 1H), 11.0 (s, 1H), 11.76 (s, 1H). MS (APCI, pos.): 492.1,494.1 EXAMPLE 510: Ethyl 4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl propanate The compound was prepared according to the general procedure for the synthesis of alkyli- dene hydrazones from the condensation of ethyl 4-formyl-1-naphthylpropanate (from step E) and 3-chloro-4-hydroxy benzoic acid hydrazide.

1H NMR (DMSO-D6) 8 1.14 (t, J = 7.0 Hz, 3H), 2.73 (t, J = 7.5 Hz, 2H), 3.35 (t, J = 7.5 Hz, <BR> <BR> <BR> 2H), 4.02 (q, J = 7.0 Hz, 2H), 7.08 (d, J = 8.6 Hz, 1H), 7.66 (m, 2H), 7.79 (dd, J = 1.8, 8.6 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 8.85 (d, J = 7.7 Hz, 1H), 9.05 (s, 1H), 11.0 (brd s, 1H), 11.78 (s, 1 H). MS (APCI, pos.): 425.5,427.3 EXAMPLE 511: 3-Chloro-4-hydroxy benzoic acid (4-trifluoromethylsulfonyloxy naphthylidene) hydrazide The compound was prepared according to the general procedure for the synthesis of alkyli- dene hydrazones from the condensation of 4-trifluoromethylsulfonyloxy naphthaldehyde 3- chloro-4-hydroxy benzoic acid hydrazide.

1H NMR (DMSO-D5) 7.09 (d, J = 8.7 Hz, 1H), 7.68 - 7.95 (m, 4H), 8.00 - 8.10 (m, 3H), 8.90 (s, 1H), 9.10 (s, 1H). 11.02 (s, 1H), 11.86 9s, 1H). MS (APCI, pos.); 473,2, 475.1

General procedure for synthesis of compounds of the general formula XV: formula XV A and B are as defined for formula I and -NR5CR°d is where R5", R4a, R4b, c, q, d and D are as defined for for- mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.

Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloro- methane, DMSO, acetic acid, water or a compatible mixture of two or more of the above sol- vents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylort- hoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between O"C to 140°C, preferably between 10°C to 80"C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystalli- zed if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture in vacuo, followed by column

chromatography on silica gel using a solvent system such as chloroform/methanol or dichloro- methane/methanol or chloroform/ethyl acetate.

Step B: The epoxide is then ring opened by a primary or secondary amine using one of the methods well-known to those skilled in the art to give a compound of formula XV. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloro- methane, DMSO, DMF, NMP, water or a compatible mixture of two or more of the above sol- vents. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be rem- oved by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alco- hol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XV.

Specific examples illustrating the preparation of compounds of the general formula XV accor- ding to the invention are provided below.

The preparation of 4-(2,3-epoxypropanoxy)-l -naphthaldehyde is depicted below: 4-(2,3-epoxypropanoxy)-l -naphthaldehyde: To a solution of 4-hydroxy-l -naphthaldehyde (1 g, 5.8 mmol) in DMSO (20 mL) was added K2CO3 (1 g, 7.2 mmol). The mixture was stirred at room temperature for 30 min, and then 2,3-epoxypropyl bromide (0.96 g, 7 mmol) was added. After stirring for 24 hr, water (100

mL) was added. The mixture was extracted with ethyl acetate (3x80 mL), dried (MgSO4), and concentrated to give a brown solid (1.23 g, 93%).

1H NMR (CDCl3)# 2.88 (dd, J = 2.6, 4.8 Hz, 1H), 3.02 (dd, J = 4.0, 4.6 Hz, 1H), 3.51 - 3.57 (m, 1H), 4.22 (dd, J = 5.8, 11.1 Hz, IH), 4.55 (dd, J = 2.8, 11.1 Hz, lH), 6.94 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.92 d, J = 8.0 Hz, 1H), 8.89 (d, J = 8.4 Hz, 1H), 9.31 (d, J = 8.6 Hz, 1H), 10.22 (s, 1H).

General Procedure: 4-hyd roxybenzoic acid 4-(2,3-epoxypropanoxy)-l -naphthylidene hydrazide derivatives (step A): The compound was prepared according to the general procedure for the synthesis of alkyli- dene hydrazones from the condensation of the above epoxy-aldehyde with 4-hydroxy ben- zoic acid hydrazide derivatives.

1H NMR (DMSO-d6) # 2.84 (dd, J = 2.2, 4.9 Hz, 1H), 2.92 (dd, J = 4.5,4.5 Hz, 1H), 3.45 - 3.57 (m, 1H), 4.11 (dd, J = 6.4, 11.3 Hz, 1H), 4.60 (d, J = 11.3 Hz, 1H), 7.02 - 7.18 (m, 2H), 7.55 - 7.90 (m, 4H), 7.99 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.90 - 9.05 (d, 2H), 10.94 (s, 1 H), 11.66 (s, 1 H). MS (APCI, negative ): 395.

General procedure for epoxide ring opening (step B): A mixture of epoxide (0.2 mmol) and amine (0.3 mmol) in 10 mL ethanol was refluxed for 4 hr. A red oil was obtained after concentration. Products were purified by preparatory HPLC.

Examples of compounds of formula XV: EXAMPLE 512:

'H NMR (DMSO-d6) # 0.95 (t, J = 6.9 Hz, 6H), 1.90 (s, 3H), 2.50, 2.62 (2q, J = 6.6 Hz, 4H), 2.70 (dd, J = 6.6, 13.0 Hz, 1H), 2.88 (dd, J = 7.0, 14.2 Hz, 1H), 3.95 - 4.35 (m, 3H), 7.02 (d, J = 8.7Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 7.55 - 7.85 (m, 4H), 7.96 (dJ = 1.9 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.85 - 9.05 (d, 2H), 11.60 (s, 1H); MS (APCI, pos.): 470.

EXAMPLE 513: 1H NMR (DMSO-d6) # 1.67 (brd s, 4H), 1.88 (s, 3H), 2.50 - 2.85 (m, 6H), 4.0 - 4.3 (m, 3H), 7.00 - 7.12 (t, 2H), 7.55 - 7.85 (m, 4H), 7.97 (s, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.85 - 9.05 (d, 2H), 11.63 (s, 1 H); MS (APCI, pos.): 468.

EXAMPLE 514: 'H NMR (DMSO-d6) # 1.30-1.55 (m, 6H), 1.88 (s, 3H), 2.35 -2.60 (m, 6H), 4.05 - 4.30 (m, 3H), 7.04 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.55 - 7.85 (m, 4H), 7.97 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.85 - 9.05 (d, 2H), 11.62 (s, 1H); MS (APCI, pos.): 470.

EXAMPLE 515:

'H NMR (DMSO-d6) 8 1.25-1.82 (m, 8H), 1.88 (s, 3H), 2.68 -2.90 (m, 2H), 3.08 ( m, 1H), 4.0 - 4.25 (m, 3H), 7.03 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.52 - 7.85 (m, 4H), 7.97 (d, J = 1.4 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.85 - 9.0 (d, 2H), 11.61 (s, 1H); MS (APCI, pos.): 482.

EXAMPLE 516: 'H NMR (DMSO-d6) # 0.95 -1.80 ( m, 10H ), 1.88 (s, 3H ), 2.45 (m, 1H ), 2.70 -2.90 (m, 2H ), <BR> <BR> <BR> 3.984.30 (m, 3H), 7.02 (d, J = 8.52 Hz, 1H), 7.07 (d, J = 8.2 Hz, H ), 7.52 -- 7.75 (m, 4H), 7.97 (d, J = 2.05 Hz, 1H), 8.34 (d, J = 8.33 Hz, 1H), 8.87 - 9.00 (m, 2H), 1.61 (s, 1H); MS ( APCI, pos.): 496.

EXAMPLE 517: 3-Chloro-4-hydroxybenzoic acid 4-(3-hydroxypropyl)naphthylmethylene hydrazide 2-[4-(3-Hydroxypropyl)naphthyl]dioxolane (step A): To a solution of 2-[4-(2-ethoxycarbonylethyl)naphthyl]dioxolane (210 mg, 0.70 mmol) in an- hydrous THF (5 mL) was added at 0°C 1M lithium aluminum hydride in THF (0.5 mL). THF (5 mL) was added and the mixture was stirred at room temperature for 16 hr, diluted with water (10 mL), acidified with conc. hydrochloric acid, and extracted with ether (3x 10 mL).

The combined organic extracts were dried (Mg SO4), and concentrated. The residue was pu- rified by flash chromatography using hexane/ethyl acetate 2:1 as eluent to provide 67 mg (37 %) of a colorless oil.

1H NMR (CDCl3) 8 1.51 (brd s, 1H), 1.99 - 2.04 (m, 2H), 3.19 (t, J = 7.4 Hz, 2H), 3.75 (t, J = 6.3 Hz, 2H), 4.16 - 4.22 (m, 4H), 6.47 (s, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.52 - 7.70 (m, 2H), 7.70 (d, J = 7.3 Hz, 1H), 8.11 (d, J = 9.8 Hz, 1H), 8.25 (d, J = 9.8 Hz, 1H), GCMS: 258 1-Formyl-4-(3-hydroxypropyl)naphthalene (step B): To a solution of 2-[4-(3-hydroxypropyl)naphthyl]dioxolane (67 mg, 0.26 mmol) in anhydrous THF (5 mL) was added 1N hydrochloric acid (1 mL). The mixture was stirred at room tempe- rature for 48 hr, diluted with ethyl ether (20 mL), washed with satd. NaHCO3 solution (2x 10 mL), dried (MgSO4), concentrated and coevaporated with CHCI3 (3 x 10 mL) to yield 40 mg (72%) of a colorless oil.

'H NMR (CDCl3) # 1.56 (brd s, 1 H), 2.02 - 2.08 (m, 2H), 3.27 (t, J = 7.5 Hz, 2H), 3.78 (t, J = 6.4 Hz, 2H), 7.53 (d, J= 7.3 Hz, H), 7.62-7.70 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H), 9.17 (d, J = 8.3 Hz, 1H), 9.34 (d, J = 8.6 Hz, 1H), 10.34 (s, 1H).

3-Chloro-4-hydroxybenzoic acid 4-(3-hydroxypropyl)naphthylmethylene hydrazide (step C): This compound was prepared according to the general procedure for the synthesis of alkyli- <BR> <BR> <BR> dene hydrazones by condensation of 1 1-formyl-4-(3-hydroxypropyl) naphthalene from step B and 3-chloro4-hydroxy benzoic acid hydrazide.

'H NMR DMSO-D6) 8 1.83 (m, 2H), 3.12 (t, J = 7.5 Hz, 2H), 3.51 (dt, J = 4.9, 7.0 Hz, 2H), 7.09 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.65 (m, 2H), 7.80 (dd, J = 2.0, 8.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H).8.19 (dd, J = 2.5, 7.0 Hz, 1H), 8.84 (d, J = 8.4 Hz, 1H), 9.05 (s, 1H), 10.98 (s, 1H), 11.76 (s, 1H).

MS (APCI, pos.): 383.1, 385.1.

EXAMPLE 518: 4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyll naphthyl diethylacrylamide

Ethyl (4-hydroxymethyl) naphthalene acrylate (step A): To a suspension of sodium hydride (160 mg, 60% dispersion in mineral oil, 4.00mmol) in THF (10 mL) at 0°C was added triethylphosphonoacetate (0.77 mL, 670 mg, 3.88 mmol).

The mixture was stirred at 0°C for 1 hr, and 4-hydroxymethyl naphthaldehyde (600 mg, 3.2 mmol) in THF (5 mL) was added at the same temperature. The mixture was stirred at room temperature for 16 hr, diluted with satd. NH4CI-solution (10 mL), and extracted with ethyl acetate (3x 10 mL). The combined organic extracts were dried (MgSO4), and concentrated, to provide 900 mg of a colorless oil, which was used without further purification in the next step.

1H NMR (CDCl3) 8 1.37 (t, J = 7.1 Hz, 3H), 1.86 (brd s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 5.17 (s, 2H), 6.50 (d, J = 15.7 Hz, 1H), 7.54 - 7.62 (m, 2H), 7.70 (d, J = 7.4 Hz, 1H), 8.13 (dd, J = 2.8, 9.8 Hz, 1H), 8.21 (dd, J = 2.8, 9.8 Hz, 1H), 8.49 (d, J = 15.7 Hz, 1H).

Ethyl 4-formylnaphthalene acrylate (step B): The crude material (900 mg) from step A was dissolved in chloroform (10 mL), and manga- nese dioxide (1.5 g, 17 mmol) was added. After stirring at room temperature for 16 h, the suspension was filtered by suction through Celite, and the filtrate was concentrated.

Flash chromatography using hexane/ethyl acetate 5:1 provided 491 mg (60% over 2 steps) of a colorless oil.

1H NMR (CDCl3) # 1.39 (t, J = 7.1 Hz, 3H), 1.86 (brd s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 6.60 <BR> <BR> <BR> (d, J = 15.7 Hz, 1H), 7.68 - 7.75 (m, 2H), 7.85 (d, J = 7.4 Hz, 1H), 8.00 (d, J = 7.4 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.50 (d, J = 15.7 Hz, 1H), 9.31 (dd, J = 1.3, 8.1 Hz, 1H), 10.43 (s, 1H). MS (APCI, neg.): 254.1

4-Fopmylnaphthalene acrylic acid (step C): A suspension of ethyl 4-formylnaphthalene acrylate (391 mg, 1.53 mmol), sodium carbonate (195 mg, 1.84 mmol) in water (10 mL) was refluxed for 16 hr. The cold solution was filtered, and the filtrate was acidified with conc. hydrochloric acid. The precipitate was collected by suction and dried for 48 hr in vacuum to give the product (325 mg, 94%) as a yellow solid.

'H NMR (DMSO-D6) 86.72 (d, J = 15.7 Hz, 1H), 7.71 - 7.75 (m, 2H), 8.12 (d, J = 7.45Hz, 1H), 8.20 (d, J = 7.5 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 15.7 Hz, 1H), 9.21 (d, J = 8.0 Hz, 1H), 10.43 (s,1 H).

4-Formylnaphthalene diethyl acrylamide (step D): To a solution of 4-formylnaphthalene acrylic acid (210 mg, 0.92 mmol) in DMF (4 mL) was added carbonyl diimidazole (180 mg, 1.10 mmol). The mixture was stirred at room tempe- rature for 1 hr, and diethylamine (0.1 mL, 71 mg, 0.97 mmol) was added. After stirring at room temperature for 16 hr, the mixture was diluted with ethylacetate (5 mL), extracted with water (5 mL), 1 N hydrochloric acid (5 mL), and water (3 x 5 mL), dried (MgSO4) and con- centrated. After flash chromatography using hexane/ethylacetate 1:1, 115 mg (43%) of a yellow oil was obtained.

1H NMR (CDCl3) # 1.25 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 3.55 (m, 4H), 6.97 (d, J <BR> <BR> <BR> <BR> = 15.7 Hz, 1H), 7.63 - 7.76 (m, 2 H), 7.80 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 7.4 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.51 (d, J = 15.7 Hz, 1H), 9.30 (d, J = 8.3 Hz, 1H), 10.43 (s, 1H).

4-[(3-Chloro-4-hyd roxybenzoyl) hydrazonomethyl] naphthyl diethylacrylamide (step E): The compound was prepared according to the general procedure for the synthesis of alkyli- dene hydrazones from the condensation of 4-formyl-1-naphthyl diethylacrylamide (from step D) and 3-chloro-4-hydroxy benzoic acid hydrazide.

1H NMR (DMSO-D6) # 1.11 (t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.0 Hz, 3H), 3.42 (q, J = 7.0 Hz, 1H), 3.56 (q, J = 7.0 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 15.1 Hz, 1H), 7.67 - 7.72 (m, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.96-8.03 (m, 2H), 8.06 (d, J = 7.7 Hz, 1H), 8.26 (dd, J =

2.1, 7.2 Hz, 1H), 8.32 (d, J = 15.1 Hz, 1H), 8.83 (d, J = 7.0 Hz, 1H), 9.13 (s, 1H), 11.00 (s, 1H), 11.86 (s, 1 H). MS (APCI, pos.): 450.3 EXAMPLE 519: Ethyl 4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl acrylate The compound was prepared according to the general procedure for the synthesis of alkyli- dene hydrazones from the condensation of ethyl 4-formyl-I -naphthyl acrylate (from step B) and 3-chloro-4-hydroxy benzoic acid hydrazide.

1H NMR (DMSO-D6) # 1.29 (t, J = 7.1 Hz, 3H), 4.25 (q, J = 7.1 Hz, 2H), 6.75 (d, J 15.7 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.71 (m, 2H), 7.92 (d, J = 8,5 Hz, 1H), 8.01 (m, 2H), 8.07 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 15.7 Hz, 1H), 8.81 (d, J = 7.1 Hz, 1H), 9.13 (s, 1H), 11.00 (s, 1H), 11.89 (s, 1H), MS (APCI, pos.): 421.1, 423.0 EXAMPLE 520: 4-[(3-Chloro-4-hyd roxybenzoyl) hydrazonomethyl] naphthyl acrylate The compound was prepared according to the general procedure for the synthesis of alkyli- dene hydrazones from the condensation of 4-formyl -1-naphthyl acrylate (from step C) and 3-chloro-4-hydroxy benzoic acid hydrazide.

'H NMR (DMSO-D6) # 6.65 (d, J = 15.6 Hz, IH), 7.09 (d, J = 8.5 Hz, IH), 7.66 - 7.74 (m, 2H), 7.81 (d, J = 8.5 Hz, lH), 7.97 - 8.05 (m, 3H), 8.29 (dd, J = 2.2, 7.1 Hz, lH), 8.41 (d, J = 15.6 Hz, lH), 8.82 (d, J = 7.6 Hz, 1 H), 9.12 (s, 1 H), 10.92 (s, 1 H), 11.89 (s, 1H), 12.62 (s, 1H). MS (APCI, pos.): 394.1,395.3 General procedure for the synthesis of substituted piperazine-aryl-aldehydes followed by hy- drazone formation: The substituted piperazine-aryl-aldehydes may be prepared by N-alkylation of the correspon- ding unsubstituted piperazine-aryl-aldehydes using various electrophilic alkyiating agents that introduce the -(K)m-D moiety as defined above.

3a 3b 4b O H R j RR R14 Lx--(CH2)b (M),--(CH q (CH2)d D J R15 T Base, solvent H 14 3b R3b Razz 4b R R R R H NN- Oi5 (CH2)b (CH2)a (M)f (CH2)cgq (CH2)d D R H N-NH 0H A H R14R3aR3b R4b /\NN(CH2)bp(CH2)a (CH2)C4(CH2)d D N- N 0=( R5 A wherein Lx is a leaving group such as -Cl, -Br, -I, -OSO2CH3, -OSO2p-tolyl or -OSO2CF3; and A, R3a, R3b, R4a, R4b, a, b, c, d, f, p, q, D, M, R14 and R'5 are as defined for formula I.

According to the above scheme the substituted piperazine-aryl-aldehydes can be prepared by stirring piperazinylbenzaldehydes or piperazinylnaphthaldehydes in an organic solvent such as acetone, methylethyl ketone, dimethylformamide, DMSO, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or more of the above solvents with an equimolar amount of an alkyl halide or an aryl-lower alkyl halide and in the presence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydride, sodium or potassium methoxide, ethoxide or terf- butoxide, sodium, potassium or cesium carbonate, potassium or cesium fluoride, sodium or

potassium hydroxide or organic bases such as diisopropylethylamine, 2,4,6-collidine or benzyl- dimethyl- ammonium methoxide or hydroxide. The reaction can be performed at 0°C to 150"C, preferably at 20"C to 100"C and preferably in an inert atmosphere of N2 or Ar. When the reac- tion is complete the mixture is filtered, concentrated in vacuo and the resulting product optio- nally purified by column chromatography on silica gel using ethyl acetate/hexane as eluent.

The compound can also (when appropriate) be purified by recrystallization from a suitable sol- vent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture. Specific examples illustrating the preparation of unsubstituted piperazine- aryl-aldehydes are provided below.

The following step, the hydrazone formation is described above in general and below in detail.

Preparation of 4-piperazinyl-2.S-dimethylbenzaldehyde: 4-(2,5-dimethylphenyl)-1 -benzylpiperazine: A solution of 2,5-dimethylphenylpiperazine (20 g, 105 mmol) was prepared in acetonitrile (300 mL) and cooled to 0 OC. Benzyl bromide (19 g, 111 mmol) was added and the reaction mixture was stirred for 15 minutes before potassium carbonate (16 g, 116 mmol) was added.

After stirring the mixture for two hours, the acetonitrile was evaporated and the residue taken up in water and ethyl acetate. The organic layer was separated and washed with brine and dried over magnesium sulfate. The benzylated product was purified by silica gel column chromatography using gradient hexane/ethyl acetate (10/0 to 8/2). The product (21 g, 71%) was obtained as an oil.

1H NMR (CDCl3) 8 2.24 (s, 3H), 2.29 (s, 3H), 2.60 (brd s, 4H), 2.92 (brd s, 4H), 3.55 (s, 2H), 6.78 (m, 1H), 6.84 (s, 1H), 7.04 (m, 1H), 7.30 (m, 5H).

4-(2,5-dimethyl-4-formylphenyl)-l -benzylpiperazine: The 4-(2,5-dimethyiphenyl)-1-benzylpiperazine (10 g, 36 mmol) was dissolved in anhydrous DMF (30 mL, 390 mmol) and cooled to 0 oC. Fresh POC13 (70 mL, 750 mmol) was added drop wise with stirring. Once the addition was completed the dark mixture was warmed to 75 OC for five hours or until TLC analysis indicated the disappearance of the starting materi-

al. The excess phosphorous oxychloride was distilled off and the entire mixture was diluted with ethyl acetate and added slowly to 500 mL of ice-chips. The solution was neutralized and made basic with concentrated NaOH. The neutralization and basification must be done at low temperatures to avoid creating by-products. The formylated product was extracted with ethyl acetate (5x). The organic layer was washed with water (2x), brine, dried over magnesium sulfate and purified by silica gel column chromatography using gradient hexa- ne/ethyl acetate (10/0 to 8/2). The product (9 g, 81%) was obtained as an oil.

1H NMR (CDCl3) 8 2.29 (s, 3H), 2.28 (s + t, 7H), 3.03 (t, 4H), 3.59 (s, 2H), 6.75 (s, 1H), 7.31 (m, 5H), 7.58 (s, 1H), 10.12 (s, 1H).

4-(2,5-dimethyl-4-formyiphenyl)-l -(1 -chloroethoxycarbonyl)piperazine: The 4-(2,5-dimethyl-4-formylphenyl)-l -benzylpiperazine (9 g, 29 mmol) was dissolved in an- hydrous 1,2-dichloroethane (100 mL) and 1-chloroethyl chloroformate (4.5 g, 31.5 mmol) was added. The solution was refluxed for 30 minutes or until TLC analysis indicated the disappearance of the starting material. The product was just slightly less polar than the star- ting material by TLC using hexane/EtOAc (3/1). Dichloroethane was evaporated and the residue was chromatographed using gradient hexane/EtOAc (10/0 to 8/2) to give the product (6 g, 64%) as an oil.

'H NMR (CDCl3) 8 1.84 (d, 3H), 2.32 (s, 3H), 2.61 (s, 3H), 2.99 (brd m, 4H), 3.70 (brd m, 4H), 6.62 (qt, 1H), 6.76 (s, 1H), 7.62 (s, 1H), 10.14 (s, 1H).

4-piperazinyl-2,5-dimethylbenzaldehyde: To a solution of the dimethylphenylpiperazinylcarbamate above (6 g, 18.5 mmol) in THF (50 mL) was added 1 N HCI (50 mL, 50 mmol). The mixture was warmed to approximately 80 OC until the evolution of CO2 stopped. Most of the THF was removed by rotary evaporation and the residue was lyophilized to give the product as the dihydrochloride salt (5.5 g, 99%).

1H NMR (DMSO-D6) 8 2.2 (s, 3H), 2.50 (s, 3H), 3.13 (brd s, 8H), 6.85 (s, 1H), 7.54 (s, 1H), 9.49 (brd s, 2H), 10.02 (s, 1H).

4-piperazinyl-2.3-dimethylbenzaldehyde: 4-Piperazinyl-2,3-dimethylbenzaldehyde was prepared in the same fashion as above. For- mylation of the N-benzyl-piperazinyl-2,3-dimethylbenzene was much slower and required overnight heating at 70 OC. All other steps were otherwise very similar and the yields were comparable.

'H NMR (DMSO-D5) 8 2.15 (s, 3H), 2.47 (s, 3H), 3.07 (brd m, 4H), 3.17 (brd m, 4H), 5.90 (brd s, 1H, NH), 7.02 (d, 1H), 7.50 (d, 1H), 9.54 (brd s, 2H, NH2), 10.10 (s, 1H).

4-piperazinyl-3.5-dimethylbenzaldehyde.

4-Piperazinyl-3,5-dimethylbenzaldehyde was prepared in the same manner as above.

General library procedure for N-alkylation and hydrazone formation: To a solution of the unsubstituted piperazinyl-aryl-aldehyde in DMSO dispensed into 88 deep well plates were added solutions of desired alkylating agents (1 eq) in DMSO followed by diisopropylethylamine (5 eq). Solid potasssium carbonate (5 eq) may also be substituted.

After stirring the solutions for 16 hours, a solution of 4-hydroxybenzoic acid hydrazide deri- vative (1 eq) in DMSO and a solution of acetic acid (catalytic) in DMSO were added into e- ach well. The reaction mixtures were agitated for 16 hours to give the crude products which were purified by HPLC.

Examples of products: EXAMPLE 521:

'H NMR (DMSO-D5): 8 2.26 (s, 3H), 2.38 (s, 3H), 2.65 (brd s, 4H), 2.73 (t, 2H), 2.89 (brd s, 4H), 4.07 (t, 2H), 6.03 (d, 2H), 6.84 (t, 2H), 7.02 (d, 1H), 7.13 (d, 1H), 7.72 (d, 1H), 7.82 (dd, 1H), 8.01 (s, 1H), 8.86 (brd s, 1H), 11.68 (brd s, 1H); MS (APCI): 480.7, 482.3.

EXAMPLE 522: 1H NMR (DMSO-D6): 8 2.49 (s, 6H), 2.68 (brd s 4H), 3.22 (brd s, 4H), 3.72 (s, 2H), 7.22 (d, 1H), 7.4 (m, 1H),7.52 (m, 6H), 7.92 (dd, 1H), 8.13 (s, 1H), 8.46 (s, 1H), 11.12 (brd s, 1H), 11.80 (s, 1H); MS (APCI): 477.5, 479.2.

EXAMPLE 523: 1H NMR (DMSO-D6): # 1.25 (s, 3H), 1.27 (s, 3H), 2.26 (s, 3H), 2.38 (s, 3H), 2.57 (brd s, 4H), 2.95 (brd s, 4H), 3.56 (s, 2H), 7.02 (d, 1H),7.12 (d, 1H), 7.30 (qt, 4H), 7.72 (d, 1H), 7.82 (d, 1H), 8.01 (s, 1H), 8.83 (s, 1H),11.0 (brd s, 1H), 11.1 (s, 1H); MS (APCI): 519.7, 521.5.

EXAMPLE 524: 'H NMR (DMSO-D5): 8 2.22 (s, 3H), 2.33 (s, 3H), 3.17 (brd s, 4H), 3.23 (m, 2H), 3.36 (m, 2H), 4.41 (s, 2H), 6.98 (d, 1H), 7.10 (d, 1H), 7.48 (m, 3H), 7.68 (m, 3H), 7.71 (d, 1H), 7.97 (s, 1H), 8.83 (s, 1H), 11.00 (s, 1H), 11.02 (brd s, 1H), 11.69 (s, 1H); MS (APCI): 477.4, 479.2.

EXAMPLE 525: 1H NMR (DMSO-D6): 8 2.20 (s, 3H), 2.31 (s, 3H), 2.59 (s, 4H), 2.87 (s, 4H), 3.69 (s, 2H), 6.98 (d, 1H), 7.02 (d, 1H), 7.64 (m, 2H), 7.75 (dd, 1H), 7.82 (d, 1H), 7.94 (d, 1H), 8.12 (dd, 1H), 8.19 (s, 1H), 8.74 (s, 1H), 10.94 (brd s, 1H), 11.54 (s, 1H); MS (APCI): 522.2, 524.3.

EXAMPLE 526: 'H NMR (DMSO-D6): 8 2.20 (s, 3H), 2.31 (s, 3H), 2.62 (brd s, 4H), 2.87 (brd s, 4H), 3.68 (s, 2H), 6.98 (d, 1 H), 7.04 (d, 1H), 7.55 (d, 1H), 7.61 (d, 1 H), 7.74 (dd, 1 H), 7.91 (s, 1H), 7.92 (d, 1H), 8.01 (d, 1H), 8.74 (s, 1H), 10.93 (brd s, 1H), 11.54 (s, 1H); MS (APCI): 519.2, 521.3.

EXAMPLE 527: 1H NMR (DMSO-D6): 8 2.21 (s, 3H), 2.37 (s, 3H), 2.66 (brd s, 4H), 2.91 (brd s, 4H), 3.76 (s, 2H), 6.83 (s, 1H), 7.05 (d, 1H), 7.62 (s, 1H), 7.69 (s, 1H), 7.75 (dd, 1H), 7.86 (d, 2H), 7.94 (s, 1H), 8.15 (d, 2H), 8.60 (s, 1H), 10.92 (brd s, 1H), 11.55 (s, 1H); MS (APCI): 628.3, 630.2, 631.2.

General procedure for the synthesis of N-substituted indole aldehydes followed by hydrazo- ne formation: The N-substituted indole aldehydes may be prepared by N-alkylation of the corresponding un- substituted indole aldehydes using various electrophilic alkylating agents that introduce the - (K)m-D moiety as defined above.

OH R3aR3bR4aR4b R1 LX(CH2)b (CH2)a-(M) (CH2)c<(cH2)d D R15 H Base, solvent STEP A 0< H R R3a Rab R4a R4b 12)b. p(CH2)a(M)(CH2)q(CH2) D 1;1-NH, STEP B A o=( STEP B A 0yNH2 STE PB A H R 3 \ R4\ R4b 15N(CH2)bp(CH2)(M)(CH2)q(CH2) D wherein Lx is a leaving group such as -Cl, -Br, -I, -OSO2CH3, -OSO2p-tolyl or -OSO2CF3; and A, R3", R3b, R4a, R4b, a, b, c, d, f, p, q, D, M, R'4 and R15 are as defined for formula I.

According to the above scheme the N-substituted indole aldehydes can be prepared by stir- ring formyiindoles in an organic solvent such as acetone, methylethyl ketone, dimethylforma- mide, DMSO, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, di- ethylether, water or a compatible mixture of two or more of the above solvents with an e- quimolar amount of an alkyl halide or an aryl-lower alkyl halide and in the presence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydri- de, sodium or potassium methoxide, ethoxide or tert-butoxide, sodium, potassium or cesium carbonate, potassium or cesium fluoride, sodium or potassium hydroxide or organic bases such as diisopropylethylamine, 2,4,6-collidine or benzyldimethyl- ammonium methoxide or hy- droxide. The reaction can be performed at 0°C to 1 500C, preferably at 20"C to 1 00°C and

preferably in an inert atmosphere of N2 or Ar. When the reaction is complete the mixture is fil- tered, concentrated in vacuo and the resulting product optionally purified by column chromato- graphy on silica gel using ethyl acetate/hexane as eluent. The compound can also (when ap- propriate) be purified by recrystallization from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture.

The following step, the hydrazone formation is described above in general and below in detail.

Library Procedure for Indole Alkylation (Step A): Preparation of the sodium salt of the indole: Indole-3-carboxaldehyde (1.45 g) was dissolved into 8.6 mL of dry DMF in a dried and cooled 3 100 mL 3-necked roundbottom flask.

Evolution of large amounts of hydrogen gas occurs during this step. Care should be taken to keep the flow of inert gas steady and maintain adequate venting to accommodate the hydrogen gas evolution.

While maintaining a steady flow of nitrogen or argon through the 3-necked round bottomed flask, 1.1 equivalent of sodium hydride (0.27 g of dry 95% reagent) was transferred to the indole solution. The mixture was stirred for 15 minutes, while maintaining flow of inert gas.

Proceeded promptly to the next step.

Preparation of the alkyl halide solutions: Amber glass vials (for preparing stock solutions) were dried for at least four hours at 110 "C, then were allowed to cool under an argon atmosphere in a desiccator. Alkyl halides solutions (1.0 M) were prepared in anhydrous DMF in the dried vials. Each alkyl halide solution (100 pL) was added to its corresponding well of a deep-well plate (1 x 88 x 1 for- mat).

Alkylation of the indole sodium salt: 100 µL of the 1.0 M indole salt solution was quickly delivered to each alkyl halide in the de- ep-well plates. The plates were vortexed briefly to mix, then allowed to react for two hours.

Library Procedure for Hydrazone Formation (Step B): Acyl Hydrazone formation: 3-Chloro-4-hydroxybenzoic acid hydrazide (1.86 g) was dissolved in 5 mL of dry DMSO, followed by trifluoroacetic acid (0.77mL). The resulting solution was diluted to a final volu- me of 10.0 mL. 100 pL of the 1.0 M acid hydrazide TFA salt solution was added to each well of the deep-well plate. The plate was vortexed for one minute to mix, then allowed to react for 30 minutes.

The products were purified by chromatography on silica gel with ethyl acetate/hexane elu- ent.

The following compounds were prepared: EXAMPLE 528: 1H NMR (DMSO-D6): # 5.46 (s, 2H), 7.10 (d, J = 8.7, 2H), 7.20 (m, 2H), 7.28 (m, 5H), 7.51 (d, J = 7.53, 1H), 7.79 (d, J = 7.9, 1H), 7.99 (s, 1H), 8.01 (s, 1H) 8.33 (d, J = 6.96, 1H), 8.62 (s, 1 H), 10.9 (s, 1H), 11.5 (s, 1H); LRMS calcd for C26 H24 Cl1 N3 O2 (M - H) 402, found 402.1.

EXAMPLE 529: 1H NMR (DMSO-D6): # 1.14 (d, J = 6.8, 6H), 2.81 (sept, J = 6.9, 1H), 5.41 (s, 2H), 7.07 (d, J = 8.3 1H), 7.20 (m, 6H), 7.54 (d, J = 7.6, 1H), 7.77 (d, J = 7.9, 1H), 7.97 (s, 1H), 8.01 (s, 1H), 8.29 (d, J = 7.2,1 H), 8.59 (s, 1H), 10.88 (s, 1H), 11.44 (s, 1H). LRMS calcd for C26 H24 Cl1 N3 O2 (M - H) 445, found 445.9 EXAMPLE 530: 'H NMR (DMSO-D6): 6 5.47 (s, 2H), 7.08, (d, J = 8.7, 1H), 7.13-7.25 (m, 5H), 7.18 (t, J = 74.2, 1H), 7.35 (d, J = 8.7, 1H), 7.54 (d, J = 7.9, 1H), 7.77 (dd, J = 8.7, 1.7, 1H), 7.97 (d, J = 1.7, 1H), 8.02 (s, 1H), 8.30 (d, J = 7.2, 1H), 8.59 (s, 1H), 10.89 (s, 1H), 11.45 (s, 1H). LRMS calcd for C24 H,8 Cl1 F2 N3 O3 (M - H) 468, found 468.1.

EXAMPLE 531: 'H NMR (DMSO-D6): 80.94 (d, J = 6.2, 6H), 1.54 (sept, J = 6.2, 1H), 1.66-1.73 (m, 2H), 4.23 (t, J = 7.0, 2H), 7.08 (d, J = 8.7, 1H), 7.16-7.29 (m, 2H), 7.54 (d, J = 7.95, 1H), 7.77 (d,

J = 8.7, 1H), 7.88 (s, 1H), 7.97 (s, 1H), 8.29 (d, J = 7.5, 1H), 8.57 (s, 1H), 10.88 (s, 1H).

11.42 (s, 1H). LRMS calcd for C21 H, Cl1 N3 O2 (M + H) 384, found 384.2.

EXAMPLE 532: 1H NMR (DMSO-D5): 87.06 (d, J = 8.5, 1H), 7.12-7.26 (m,3H), 7.46-7.49 (M,2H), 7.78 (d, J = 8.1,1 H), 7.99 (s, 1H), 11.33 (s, 1H), 11.65 (s, 1H). LRMS calcd for C,6 H,2 Cl1 N3 O2 (M - H) 312, found 312.0.

General procedure for the synthesis of alkyl/aryl-sulfonyloxy aryl-aldehydes followed by hy- drazone formation: The alkyl/aryl-sulfonyloxy aryl-aldehydes may be prepared by 0-sulfonylation of the corre- sponding phenolic compounds using various electrophilic sulfonylating agents that introduce the -(K)m-D moiety as defined above.

H RR3bR4aR4t) e LX-SO2 - :CH2)a.(M>t (CH:9 b(CH2)D Base, or Base, solvent R OH H 14 R 3a 3b 4a4b RR R R 2)a- (CH2)a-(M)f (CH2)c (CH2)d D 0 0 NNH H H 2 HN ,4 \CH I RR3b 4b R R OSO,- ) (CH2)a-(M)f (CH2)c (CH2)d D wherein Lx is a leaving group such as -Cl, -Br, -I, -OSO2CH3, -OSO2p-tolyl or -OSO2CF3; and A, R3a, R3b, R4a, R4b, a, b, c, d, f, p, q, D, M, R14 and R15 are as defined for formula According to the above scheme an alkyl/aryl-sulfonyioxyaryl aldehyde can be prepared by stir- ring hydroxybenzaldehydes or hydroxynaphthaldehydes in an organic solvent such as aceto- ne, methylethyl ketone, dimethylformamide, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or more of the above solvents with an equimolar amount of an alkylsulfonylhalide, arylsulfonylhalide or an a- ryl-lower alkyl sulfonylhalide and in the presence of 1 to 15 equivalents (preferably 1 to 5 equi- valents) of a base such as sodium hydride, potassium hydride, sodium or potassium methoxi- de, ethoxide or tert-butoxide, sodium, potassium or cesium carbonate, potassium or cesium fluoride, sodium or potassium hydroxide or organic bases such as diisopropylethylamine, 2,4,6-

collidine or benzyldimethyl- ammonium methoxide or hydroxide. The reaction can be perfor- med at 0°C to 150°C, preferably at 20°C to 100°C and preferably in an inert atmosphere of N2 or Ar. When the reaction is complete the mixture is filtered, concentrated in vacuo and the re- sulting product optionally purified by column chromatography on silica gel using ethyl aceta- te/hexane as eluent. The compound can also (when appropriate) be purified by recrystallizati- on from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexa- ne, toluene or their compatible mixture.

The following hydrazone formation step is described above in general.

Examples of compounds synthesized using the methodology described are given below: EXAMPLE 533: 'H NMR (DMSO-D5): # 7.03 (d, 1H), 7.28 (d, 1H), 7.39 (d, 1H), 7.61 (t, 1H), 7.67 (t, 1H), 7.75 (m, 2H), 7.87 (d, 2H), 7.95 (s, 1H), 8.75 (d, 1H), 9.02 (s, 1H), 11.00 (s, 1H), 11.88 (s, 1H); MS (APCI): 521.0, 523.0.

EXAMPLE 534: 1H NMR (DMSO-D5): 81.38 (d, 6H), 3.91 (septet, 1H), 6.97 (d, 1H), 7.46 (d, 1H), 7.61 (m, 2H), 7.71 (d, 1H), 7.81 (d, 1H), 7.89 (s, 1H), 8.01 (d, 1H), 8.69 (d, 1H), 9.11 (s, 1H), 11.00 (brd s, 1H), 11.98 (s, 1H); MS (APCI, neg.): 445.0, 487.0, 339 - iprso2.

General procedures for the preparation of alkylidene hydrazides according to the invention involving parallel synthesis on a solid support The compounds of Examples 535 to 614 were prepared according to the following equation Resin [Building block 1] Resin [Building block 1] [Building block 2] Resin [Building block 1] [Building block 2] [Building block 3] and were simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula [Building block l]----[Building block 2] [Building block 3].

The following 80 compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block l]-[Building block 2] was done manually, whereas the attachment of [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS.

The starting resins, Resin-[Building block l]-[Building block 2], were all prepared as de- scribed below.

The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g.

All 80 compounds are based on attachment of [Building block 3] to Resin-[Building block 1]- [Building block 2] in a fully combinatorial way using a Heck reaction according to the follow- ing scheme: [Building block 3] cl 23Jt N * N <, B Lea 0 Resin Pd m½ catalyst oI Pd catatyst Resin-[Building block 1]-[Building block 2] Resin[Building block 1]-[Building block 2]-[Building block 3] where BLea is wherein Lea is a leaving group and preferably is selected from bromo, iodo and trifluoromethanesulfonyloxy, and R'4 and R'5 are as defined for formula I.

The following resin, here depicted as Resin-[Building block 1] was used: o IINH, where PS is where PS is ) polystyrene polystyrene. In the following "Resin" is the resin with the Wang linker: where = Resin The following building blocks were used: [Building block 2: 3,4-dimethoxy-5-iodobenzaldehyde Trifluoromethanesulfonic acid 4-formyl-l - naphthyl ester 3-Bromobenzaldehyde 4-Bromobenzaldehyde [Buiiding block 3]: 1 -Ethynylcyclohexylamine N-Methyl-N-propargylbenzylamine N, N-Diethylpropargylamine 3-Phenyl-l -propyne 2-Amino-4-pentynoic acid Propargylamine Phenyl propargyl ether Ethynyl p-tolyl sulfone 1 -Chloro-4-ethynylbenzene 5-Phenyl-l -pentyne 5-Phenyl-2-(2-propynylamino)-2-oxazolin-4- one 4-Pentynoic acid 3-Ethynylphenol 2-Ethynylpyridine tert-Butyl propiolate tert-Butyl 1-methyl-2-propynyl ether

3-Butyn-l -ol O-Trimethylsilylpropargyl alcohol 5-Hexyn-3-ol 3-(2,6-Dichlorophenoxy)prop-l -yne By combination of these building blocks in a fully combinatorial way 1x4x20 = 80 compounds were prepared.

Preparation of [Building block 2]: Preparation of 3,4-dimethoxy-5-iodobenzaldehyde: lodomethane (2.5 mL, 40 mmoles) was added to a mixture of 5-iodovanillin (10 g, 36 mmoles), potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mix- ture was stirred at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed with water (200 mL), dried over MgSO4 and evaporated in vacuo to afford 9.78 g (93%) of 3,4-dimethoxy-5-iodobenzaldehyde, m.p. 58-63 "C.

Preparation of trifluoromethanesulfonic acid 4-formyl-l-naphthyl ester: 4-Hydroxy-l -naphthaldehyde (10 g, 58 mmoles) was dissolved in pyridine (50 ml) and the mixture was cooled to 0 OC. Trifluoromethanesulfonic anhydride (11.7 mL, 70 mmoles) was added dropwise while maintaining the temperature below 5 "C. When the addition was com- pleted the mixture was stirred at room temperature for 30 minutes. Diethyl ether (200 mL) was added and the mixture was successively washed with water (2 x 250 mL), 3 N hydro- chloric acid (200 mL), and saturated NaCI (200 mL). The organic phase was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1 :4). Pure fractions

eluting with Rf = 0.46 were pooled and evaporated in vacuo to afford 8.35 g (47 %) of trifluoromethanesulfonic acid 4-formyl-l-naphthyl ester, m.p. 44-47 OC.

The other [Building block 2]'s (3-Bromobenzaldehyde and 4-bromobenzaldehyde) are com- mercially available.

Preparation of Resin-[Building block 1]: (Resin bound 3-chloro-4-hydroxybenzoic acid hydrazide) Polystyrene resin (15 g) loaded with the Wang linker (0.92 mmoles/g), was successively washed with DMF (3 x 40 mL) and CH2CI2 (3 x 40 mL). The resin was suspended in CH2CI2 (80 mL) and diisopropylethylamine (60 mL) was added. The mixture was cooled to 0°C and methanesulfonyl chloride (5.8 mL) dissolved in CH2CI2 (30 mL) was added drop wise while maintaining the temperature below 5 "C. When addition was complete the mixture was stirred at 0 OC for 30 minutes and at room temperature for 30 minutes. The resin was suc- cessively washed with CH2CI2 (3 x 80 mL) and N-methylpyrrollidone (NMP) (3 x 80 mL). This resin and cesium carbonate (12.3 g) were added to ethyl 3-chloro-4-hydroxybenzoate (15 g) dissolved in NMP (200 mL) and the mixture was stirred at 80 OC for 4 hours. After cooling the resin was successively washed with NMP (3 x 80 mL) and methanol (3 x 80 mL).

The above resin was suspended in 1,4-dioxane (150 mL) and water (36 mL). Lithium hy- droxide (2.6 g) was added and the mixture was stirred at 60 OC under N2 for 16 hours. After cooling the resin was successively washed with DMF (3 x 80 mL), CH2CI2 (3 x 80 mL) and methanol (80 mL) and dried in vacuo at 50 OC for 3 days.

The above resin (3.0 g) was suspended in CH2CI2 (20 mL) and I-hydroxybenzotriazole (0.6 g), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, hydrochloride (0.9 g) and DMF (10 mL) were added. The mixture was shaken at room temperature for 45 minutes, hydrazine hy- drate (300 pL) was added, and the mixture was shaken overnight at room temperature. The resin was successively washed with DMF (3 x 20 mL) and CH2Cl2 (3 x 20 mL) to afford resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (Resin-[Building block 1]).

Preparation of Resin-[Building block 1]-[Building block 2]: Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (3,4-dimethoxy-5-iodobenzyli- dene)hydrazide:

The above resin (Resin-[Building block 1]) (4 g) was suspended in DMF (50 mL) and 3,4-dimethoxy-5-iodobenzaldehyde (5.8 g) and triethyl orthoformate (25 mL) were added and the mixture was shaken for 16 hours at room temperature. The resin was suc- cessively washed with DMF (4 x 40 mL) and CH2CI2 (6 x 40 mL), and dried in vacuo at 50 "C for 16 hours to afford resin bound 3-chloro-4-hydroxybenzoic acid (3,4-dimethoxy-5- iodobenzylidene)hydrazide.

Preparation of resin bound trifluoromethanesulfonic acid 4-[(3-chloro-4-hydroxybenzoyl)- hydrazonomethyl]naphthalen-I -yl ester: Similarly as described above but using trifluoromethanesulfonic acid 4-formyl-1-naphthyl ester instead of 3,4-dimethoxy-5-iodobenzaldehyde resin bound was trifluoromethanesulfo- nic acid 4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]naphthalen-I -yl ester obtained.

Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydrazide: Similarly as described above but using 3-bromobenzaldehyde instead of 3,4-dimethoxy-5- iodobenzaldehyde resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydra- zide) was obtained.

Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (4-bromobenzylidene)hydrazide: Similarly as described above but using 4-bromobenzaldehyde instead of 3,4-dimethoxy-5- iodobenzaldehyde resin bound 3-chloro-4-hydroxybenzoic acid (4-bromobenzylidene)- hydrazide) was obtained.

EXAMPLE 535: 3-Chloro-4-hydroxybenzoic acid [3-(1-aminocyciohexylethynyl!-4.5-dimethoxybenzylidene]- hyd razide To the resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydrazide (0.05 mmoles) was added copper (I) iodide (10 mg). Diisopropylethylamine (0.2 mL), a solution of triphenylphosphine in NMP (0.4 M, 0.5 mL), a solution of tetrabutylammonium chloride in water (0.66 M, 0.3 mL), a solution of palladium (II) acetate in NMP (0.16 M, 0.25 mL) and a solution of 1-ethynylcyclohexylamine ([Building block 3]) in NMP (1 M, 0.5 mL) were added successively, and the mixture was shaken at 90 "C for 15 hours. The resin was repeatedly washed with NMP (1.5 mL, 3 times), 50% water in DMF (1.5 mL, 3 times), NMP (1.5 mL, 2 times), 1% sodium diethylaminodithiocarbamate trihydrate (1.5 mL, 9 times), NMP (1.5 mL, 5 times), and CH2Cl2 (1.5 mL, 6 times) for 2 minutes and filtered.

The compound was cleaved off the resin by shaking for 45 minutes at room temperature with a 50% solution of trifluoroacetic acid in CH2CI2 (1.5 mL). The mixture was filtered and the resin was extracted with CH2CI2 (0.5 mL). The combined CH2CI2 extracts were concentrated in vacuo. The residue was dissolved in a 1:1 mixture of methanol and CH2CI2 (1 mL) and concentrated invacuo to give the title compound.

The final product obtained was characterized by analytical RP-HPLC (retention time) and by LC-MS (molecular mass).

The RP-HPLC analysis was performed on a Waters HPLC system consisting of Waters 600S Controller, Waters 996 Photodiode Array Detector, Waters 717 Autosampler, Wa- tersTM 616 Pump, Waters 3 mm x 150 mm 3.5 ij C-18 Symmetry column and Millenium

QuickSet Control Ver. 2.15 using UV detection at 214 nm. A gradient of 5% to 90% acetoni- trile/0.1% trifluoroacetic acid/water during 15 minutes at 1 mL/minute.

The LC-MS analysis was performed on a PE Sciex API 100 LC/MS System using a Waters 3 mm x 150 mm 3.5 p C-18 Symmetry column and positive ionspray with a flow rate at 20 minute.

Examples 536 to 614: A library of the following 79 compounds can be prepared in parallel as individual entities analogously to example 535 on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer. The 4 resins of type Resin-[Building block 1]-[Building block 2] are equally distributed in the 80 wells in the syntheziser prior to the initialization of the device.

ChemFile C:\ACT\90250004.CHM Page 1 1 Empty RBHeatingAll~1to36 for 2.000 minute(s) 2 REM Addition of DIPEA 3 Transfer 2OOpl from Monomers~1to36 [25] () to RBHeating~All~1to96 [1-80] using DCE 4 Mix for 1.00 minutes at 600 rpm(s) 5 REM Addition of Ph3P in NMP 6 Transfer 500µl from Monomers~1to36 [21] () to RB Heating~All~1to96 [1-80] using DCE 7 REM Addition of Bu4NCl in water 8 Transfer 300,ul from MonomersDto36 [22] () to RB Heating~All~1to96 [1-80] using DCE 9 Mix for 1.00 minutes at 600 rpm(s) 10 REM Addition of Pd(OAc)2 in NMP 11 Transfer 250,ul from Monomers~1to36 [22] () to RB~Heating~All~1to96 [1-80] using DCE 12 Mix for 2.00 minutes at 600 rpm(s) 13 Dispense Sequence C:\ACT\ALKYNES.DSP with 500µl to RB~Heating~All~1to96 rack 14 Set Temperature to 90.0 degrees Celsius 15 Mix for 15.00 minutes at 600 rpm(s) 16 Wait for 15.000 minute(s) 17 Repeat from step 15, 47 times 18 Turn Temperature Controller Off 19 Mix for 15.00 minutes at 600 rpm(s) 20 Wait for 15.000 minute(s) 21 Repeat from step 19, 7 times 22 Empty RBHeating~All~1to96 for 2.000 minute(s) 23 Dispense System Fluid NMP1 1500µl to RB~Cleavage~All~1to96 [1-80] 24 Mix for 3.00 minutes at 600 rpm(s) 25 Empty RB~Heating~All~1to96 for 2.000 minute(s) 26 Repeat from step 23, 2 times 27 REM Wash with 50% H20/NMP

28 Transfer 1500µl from Reagent3 [I] () to RB~Heating~AI1~1to96 [1-80] using NMP1 29 Mix for 3.00 minutes at 600 rpm(s) 30 Empty RB~Heating~All~1to96 for 2.000 minute(s) 31 Repeat from step 28, 2 times 32 Dispense System Fluid NMP1 1500µl to RB~Cleavage~All~1to96 [1-80] 33 Mix for 3.00 minutes at 600 rpm(s) 34 Empty RB~Heating~All~1to96 for 2.000 minute(s) 35 Repeat from step 32, 1 times 36 REM Wash with Sodium diethylaminodithiocarbamate 37 Transfer 1500µl from Reagent~3 [1] () to RB~Heating~All~1to96 [1-80] using NMP1 38 Mix for 3.00 minutes at 600 rpm(s) 39 Empty RB~Heating~All~1to96 for 2.000 minute(s) 40 Repeat from step 37, 2 times 41 Transfer 1500µl from REAGENT~4 [1] () to RB~Heating~All~1to96 [1-80] using NMP1 42 Mix for 3.00 minutes at 600 rpm(s) 43 Empty RB~Heating~All~1to96 for 2.000 minute(s) 44 Repeat from step 41, 2 times 45 Transfer 1500µl from REAGENT~5 [1] () to RB~Heating~All~1to96 [1-80] using NMP1 46 Mix for 2.00 minutes at 600 rpm(s) 47 Empty RB~Heating~All~1to96 for 2.000 minute(s) 48 Repeat from step 45, 2 times 49 Dispense System Fluid NMP1 1500,ul to RB~Cleavage~All~1to96 [1-80] 50 Mix for 3.00 minutes at 600 rpm(s) 51 Empty RB~Heating~All~1to96 for 2.000 minute(s) 52 Repeat from step 49, 4 times 53 Dispense System Fluid DCE1 1500µl to RB~Cleavage~All~1to96 [1-80] 54 Mix for 3.00 minutes at 600 rpm(s) 55 Empty RBHeating~All~1to96 for 2.000 minute(s) 56 Repeat from step 53, 5 times 57 REM Cleavage from Resin 58 REM with 50% TFA/DCM 59 Transfer 1500µl from Reagent~3 [1] () to RB~Cleavage~AI1~1to96 [1-80] using DCM1 60 Mix for 45.00 minutes at 600 rpm(s) 61 Empty RB~Cleavage~AI1~1to96 for 1.000 minute(s) 62 Dispense System Fluid DCM1 500µl to RB~CleavageAlLIto96 [1-80] 63 Mix for 1.00 minutes at 300 rpm(s) 64 Empty RB~Cleavage~AI1~1to96 for 1.000 minute(s) 65 66 Dispense Sequence C:\ACT\ALKYNES.DSP is a subroutine that controls the combinatorial addition of the solutions of the 20 alkynes of type [Building block 3] into the 80 wells in the synthesizer.

The library containing the compounds listed below was synthesized. A subset of the library obtained was characterized by analytical RP-HPLC (retention time) and by LC-MS (molecular mass).

EXAMPLE 536: 2-Amino-5-(5-[(3-chloro-4- hydroxybenzoyl)hydrazonomethyl]-2,3- dimethoxyphenyl)-4-pentynoic acid EXAMPLE 537: 3-Chloro-4-hyd roxybenzoic acid [3-(3- diethylamino-l -propynyl)-4,5- dimethoxybenzylidene]hydrazide EXAMPLE 538: 3-Chloro-4-hydroxybenzoic acid(3-[3- (benzylmethylamino)-1-propynyl]-4,5- dimethoxybenzylidene)hydrazide EXAMPLE 539: 3-Chloro-4-hydroxybenzoic acid [3,4- dimethoxy-5-(3-phenyl-1 - propynyl)benzylidene]hydrazide EXAMPLE 540: 3-ChloroA-hydroxybenzoic acid [3-(3-amino-1- propynyl)-4,5-dimethoxybenzylidene]hydrazide EXAMPLE 541: 3-Chloro-4-hydroxybenzoic acid [3,4- dimethoxy-5-(3-phenoxy-l - propynyl)benzylidene]hydrazide EXAMPLE 542: 3-Chloro-4-hydroxybenzoic acid [3,4- <BR> <BR> <BR> dimethoxy-5-(toluene-4-sulfonylethynyl)- benzylidene]hydrazide EXAMPLE 543: 3-Chloro-4-hydroxybenzoic acid [3-(3- hyd roxyph enylethynyl)-4,5- dimethoxybenzylidene]hydrazide EXAMPLE 544: 3-Chloro-4-hyd roxybenzoic acid [3-(4- chlorophenylethynyl)-4,5- dimethoxybenzylidene]hydrazide EXAMPLE 545: 3-Chloro-4-hydroxybenzoic acid [3,4- dimethoxy-5-(2-pyridylethynyl]- benzylidene]hydrazide EXAMPLE 546: 3-Chloro-4-hydroxybenzoic acid [3,4- dimethoxy-5-(5-phenyl-1 - pentynyl)benzylidene]hydrazide EXAMPLE 547: 3-Chloro-4-hydroxybenzoic acid (3,4- dimethoxy-5-[3-(4-oxo-5-phenyl-4,5-dihydro- 2-oxazolylamino)-1-propynyl]- benzylidene)hyd razide EXAMPLE 548: <BR> <BR> <BR> (5-[(3-Chloro-4-hyd roxybenzoyl)- hydrazonomethyl]-2,3-dimethoxy- phenyl)propynoic acid EXAMPLE 549: 5-{5-[(3-Chloro-4-hydroxybenzoyl)- <BR> <BR> hydrazonomethyl]-2,3-d imethoxyphenyl)-4- pentynoic acid EXAMPLE 550: 3-Chloro-4-hydroxybenzoic acid [3-(3- hydroxy -butynyl)-4,5-dimethoxy- benzylidene]hydrazide EXAMPLE 551: 3-Chloro-4-hydroxybenzoic acid [3-(4- hydroxy -butynyl)-4,5-dimethoxy- benzylidene]hydrazide EXAMPLE 552: 3-Chloro-4-hydroxybenzoic acid [3-(4- hydroxy-1-hexynyl)-4,5-dimethoxy- benzylidene]hydrazide EXAMPLE 553: 3-Chloro-4-hydroxybenzoic acid [3-(3- hydroxy-1-propynyl)-4,5-dimethoxy- benzylidene]hydrazide EXAMPLE 554: 3-Chloro-4-hyd roxybenzoic acid (3-[3-(2,6- dichlorophenoxy)-1-propynyl]-4,5- dimethoxybenzylidene}hydrazide EXAMPLE 555: 3-Chloro-4-hydroxybenzoic acid [4-(1- aminocyclohexylethynyl)-1 - naphthylmethylene]hydrazide EXAMPLE 556: 3-Chloro-4-hydroxy benzoic acid [4-(3- benzylmethylamino-1-propynyl)-1- naphthylmethylene] hydrazide EXAMPLE 557: 3-Chloro-4-hydroxybenzoic acid [4-(3-amino- 1-propynyl)-1-naphthylmethylene]hydrazide EXAMPLE 558: <BR> <BR> <BR> 2-Amino-5-(4-[(3-chloro-4-hydroxybenzoyl <BR> <BR> <BR> hydrazonomethyl]- I -naphthyl)-4-pentynoic acid EXAMPLE 559: 3-Chloro-4-hydroxybenzoic acid[4-(3- diethylamino-1-propynyl)-1-naphthyl- methylene]hydrazide EXAMPLE 560: 3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 1 -propynyl)-l -naphthylmethylene]hydrazide EXAMPLE 561: 3-Chlorod-hyd roxybenzoic acid [4-(toluene- 4-sulfonylethynyl)-l - naphthylmethylene]hydrazide EXAMPLE 562: 3-Chloro-4-hydroxybenzoic acid [4-(3- phenoxy-1-propynyl)-1-naphthylmethylene]- hyd razide EXAMPLE 563: 3-Chloro-4-hydroxybenzoic acid [4-(4- chlorophenylethynyl)-1 -naphthyl- methylene]hydrazide EXAMPLE 564: 3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 1-pentynyl)-1-naphthylmethylene]hydrazide EXAMPLE 565: 3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- 5-phenyl4,5-dihydro-(2-oxazolylamino)-l - propynyl]-1-naphthylmethylene}hydrazide EXAMPLE 566: 3-Chloro-4-hydroxybenzoic acid [4-(3- hydroxyphenylethynyl)-1 -naphthyl- methylene] hyd razide EXAMPLE 567: 5-(4-[(3-Chloro-4-hydroxybenzoyl)- hydrazonomethyl]-1-naphthyl}-4-pentoic acid EXAMPLE 568: 3-Chloro-4-hyd roxybenzoic acid [4-(2- pyridyl)ethynyl-l -naphthylmethylene)- hydrazide EXAMPLE 569: (4-[(3-Chloro-4-hyd roxybenzoyl)- hydrazonomethyl]-1-naphthyl}propynoic acid EXAMPLE 570: 3-Chloro-4-hydroxybenzoic acid [4-(3- hydroxy-1-butynyl)-1-naphthylmethylene]- hydrazide EXAMPLE 571: 3-Chloro-4-hydroxybenzoic acid [4-(3- hy- droxy-1 -propynyl)-1 -naphthylmethylene]- hyd razide EXAMPLE 572: 3-Chloro-4-hydroxybenzoic acid [4-(4- hydroxy-1-butynyl)-1-npahthylmethylene]- hydrazide EXAMPLE 573: 3-Chloro-4-hydroxybenzoic acid [4-(4- hydroxy-1-hexynyl)-1-naphthylmethylene]- hydrazide EXAMPLE 574: 3-Chloro-4-hydroxybenzoic acid (4-[3-(2,6- dichlorophenoxy)-1-propynyl]-1- naphthylmethylene}hydrazide EXAMPLE 575: 2-Amino-5-{3-[(3-chloro-4-hydroxy- benzoyl)hyd razonomethyl]phenyl)-4- pentynoic acid EXAMPLE 576: 3-Chloro-4-hydroxybenzoic acid [3-(1- aminocyclohexylethynyl)benzylidene]- hyd razide EXAMPLE 577: 3-Chloro-4-hydroxybenzoic acid (3-[3- (benzylmethylamino)-l - propynyl]benzylidene}hydrazide EXAMPLE 578: 3-Chloro-4-hydroxybenzoic acid [3-(3-amino- 1 -propynyl)benzylidene]hydrazide EXAMPLE 579: 3-Chloro-4-hydroxybenzoic acid [3-(3- <BR> <BR> <BR> diethylamino-l -propynyl)benzylidene]- hydrazide EXAMPLE 580: 3-Chloro-4-hydroxybenzoic acid [3-(toluene- 4-sulfonylethynyl)benzylidene]hydrazide EXAMPLE 581: 3-Chloro-4-hydroxybenzoic acid [3-(3-phenyl- 1 -propynyl)benzylidene]hydrazide EXAMPLE 582: 3-Chloro-4-hydroxybenzoic acid [3-(4- chlorophenylethynyl)benzylidene]hydrazide EXAMPLE 583: 3-ChloroA-hydrnxybenzoic acid [3-(3- phenoxy-l -propynyl)benzylidene]hydrazide EXAMPLE 584: 3-Chloro-4-hydroxybenzoic acid [3-(5-phenyl- 1 -pentynyl)benzylidene]hydrazide EXAMPLE 585: 3-Chloro4-hydroxybenzoic acid [3-(3- <BR> <BR> <BR> hydroxyphenylethynyl)benzylidene] hyd razide EXAMPLE 586: 5-{3-[(3-Chloro-4-hydroxybenzoyl)-hydrazo- nomethyl]phenyl}-4-pentynoic acid EXAMPLE 587: 3-Chloro-4-hydroxybenzoic acid [3-(2- pyridylethynyl)benzylidene]hydrazide EXAMPLE 588: {3-[(3-chloro-4-hydroxybenzoyl)- hydrazonomethyl]phenyl)propynoic acid EXAMPLE 589: 3-Chloro-4-hydroxybenzoic acid (3-[3-(4-oxo- 5-phenyl-4,5-dihydro-(2-oxazolylamino))- - propynyl] benzylidene)hydrazide EXAMPLE 590: 3-Chloro-4-hydroxybenzoic acid [3-(3- hydroxy -butynyl)benzylidene]hydrazide EXAMPLE 591: 3-Chloro-4-hydroxybenzoic acid [3-(4- <BR> <BR> hydroxy -butynyl)benzylidene] hyd razide EXAMPLE 592: 3-Chloro-4-hydroxybenzoic acid [3-(4- <BR> <BR> hydroxy -hexynyl)benzyl idene]hyd razide EXAMPLE 593: 3-Chloro4-hydroxybenzoic acid [3-(3- <BR> <BR> <BR> hydroxy -propynyl)benzylidene]hydrazide EXAMPLE 594: 3-Chloro-4-hydroxybenzoic acid {3-[3-(2,6- dichlorophenoxy)-l -propynyl]benzylidene}- hydrazide EXAMPLE 595: 3-Chloro-4-hyd roxybenzoic acid [4-(1- aminocyclohexylethynyl)benzylidene]- hyd razide EXAMPLE 596: 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl)- hydrazonomethyl]phenyl)-4-pentynoic acid EXAMPLE 597: 3-Chloro-4-hydroxybenzoic acid (4-[3- (benzylmethylamino)-1 -propynyl]- benzylidene}hydrazide EXAMPLE 598: 3-Chloro-4-hydroxybenzoic acid [4-(3-amino- 1 -propynyl)benzylidene]hydrazide EXAMPLE 599: 3-Chloro-4-hydroxybenzoic acid [4-(3- diethylamino-1-propynyl)benzylidene]- hyd razide EXAMPLE 600: 3-Chloro-4-hydroxybenzoic acid [4-(3- phenoxy-1 -propynyl]benzylidene]hydrazide EXAMPLE 601: 3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 1 -propynyl)benzylidene]hydrazide EXAMPLE 602: 3-Chloro-4-hydroxybenzoic acid [4-(toluene- 4-sulfonylethynyl)benzylidene]hydrazide EXAMPLE 603: 3-Chloro-4-hydroxybenzoic acid [4-(4- chlorophenylethynyl)benzylidene]hydrazide EXAMPLE 604: 3-Chloro-4-hydroxybenzoic acid [4-(3- hydroxyphenylethynyl)benzylidene]hydrazide EXAMPLE 605: 3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 1-pentynyl)benzylidene]hydrazide EXAMPLE 606: 3-Chloro-4-hydroxybenzoic acid [4-(2- pyridylethynyl)benzylidene]hydrazide EXAMPLE 607: 3-Chloro-4-hydroxybenzoic acid (4-[3-(4-oxo- 5-phenyl-4,5-dihydro-(2-oxazolylamino)-l - propynyl]benzylidene}hydrazide EXAMPLE 608: <BR> <BR> <BR> (4-[(3-ChlornA- <BR> <BR> <BR> hydroxybenzoyl)hydrazonomethyl]- phenyl)propynoic acid EXAMPLE 609: 5-{4-[(3-Chloro-4-hydroxybenzoyl)- hydrazonomethyl]phenyl)-4-pentynoic acid EXAMPLE 610: 3-Chloro-4-hyd roxybenzoic acid [4-(3- hydroxy-l -butynyl)benzylidene]hydrazide EXAMPLE 611: 3-Chloro-4-hyd roxybenzoic acid [4-(4- hydroxy -butynyl)benzylidene]hydrazide EXAMPLE 612: -Chloro-4-hydroxybenzoic acid [4-(4- hydroxy-1 -hexynyl)benzylidene]hydrazide EXAMPLE 613: 3-Chloro-4-hydroxybenzoic acid [4-(3- <BR> <BR> hydroxy -propynyl)benzylidene]hydrazide EXAMPLE 614: 3-Chloro-4-hydroxybenzoic acid (4-[3-(2,6- dichlorophenoxy)-1-propynyl]benzylidene}- hydrazide

General procedure for the preparation of Examples 615 to 694: The following 80 compounds were prepared as single entities by parallel synthesis on a solid support. The attachment of [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS.

The compounds were prepared according to the following equation: Resin [Building block 1] Resin [Building block 1] [Building block 2] Resin [Building block I] [Building block 2] [Building block 3] and were simultaneously cleaved (and deprotected when protected) from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula: [Building block l]---[Building block 2] [Building block 3].

The starting resins, Resin-[Building block 1]-[Building block 2], were all prepared as de- scribed above.

The resin used was a polystyrene resin loaded with a Wang linker and the substitution ca- pacity was 0.9 mmol/g.

All 80 compounds are based on attachment of [Building block 3] to Resin-[Building block 1]- [Building block 2] in a fully combinatorial way using a Suzuki reaction according to the fol- lowing scheme. =- R [Building block 3] Catecholborane c10. NB-Lea fB'R 0 N B esinI)HN Resin cli) \\ R Pd catalyst 0 Resin-[Building block 1]-[Building block 2] Resin-[Building block 1]-[Building block 2]-lBuilding block 3] where B-Lea is wherein Lea is a leaving group and R'4 and R'5 are as defined for formula The starting materials used were the same as those use in examples 535 to 614, i.e.

Resin-[Building block 1], [Building block 2] and [Building block 3] were the same as those used in examples 535 to 614, the only difference being the products in examples 615 to 694 are having double bonds as compared to the products in examples 535 to 614 having triple bonds.

EXAMPLE 615: 3-Chloro-4-hydroxybenzoic acid {3-[2-(1 -aminocyclohexyl)vinyli-4. S-dimethoxybenzylidene)- hyd razide Preparation of a 1 ,4-dioxane/THF solution of I -(2-Benzo[I ,3,2]dioxaborol-2-ylvinyl)cyclo hexylamine: To a solution of 1-ethynylcyclohexylamine ([Building block 3]) in 1,4-dioxane (1 M, 0.5 mL) was added a solution of catecholborane in THF (1 M, 0.5 mL) and the mixture was heated at 60 °C for 4 hours. The solution was cooled to room temperature and used directly in the Suzuki coupling reaction.

To the resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydrazide (0.05 mmoles) was added a solution of cesium carbonate in water (1.25 M, 0.2 mL), a solution of triphenylphosphine and tetrabutylammonium chloride in NMP (both 0.4 M, 0.5 mL), a solu- tion of palladium (II) acetate in NMP (0.16 M, 0.25 mL), was mixed and the solution of 1-(2- benzo[l ,3,2]dioxaborol-2-ylvinyl)cyclohexylamine in 1,4-dioxane/THF (prepared as described above) was added and the mixture was shaken at 70 °C for 15 hours. The resin was repeat- edly washed with NMP (1.5 mL, 3 times), 50% water in DMF (1.5 mL, 3 times), NMP (1.5 mL, 2 times), 1% sodium diethylaminodithiocarbamate trihydrate (1.5 mL, 9 times), NMP (1.5 mL, 5 times) and CH2CI2 (1.5 mL, 6 times) for 2 minutes and filtered.

The compound was cleaved off the resin by shaking for 45 minutes at room temperature with a 50% solution of trifluoroacetic acid in CH2CI2 (1.5 mL). The mixture was filtered and the resin was extracted with CH2CI2 (0.5 mL). The combined CH2CI2 extracts were concentrated

in vacuo. The residue was dissolved in a 1:1 mixture of methanol and CH2CI2 (1 mL) and concentrated in vacuo to give the title compound.

The final product obtained was characterized by analytical RP-HPLC (retention time) and by LC-MS (molecular mass).

The RP-HPLC analysis was performed on a Waters HPLC system consisting of Waters 600S Controller, Waters 996 Photodiode Array Detector, Waters 717 Autosampler, Wa- tersTM 616 Pump, Waters 3 mm x 150 mm 3.5 p C-18 Symmetry column and Millenium QuickSet Control Ver. 2.15 using UV detection at 214 nm. A gradient of 5% to 90% acetoni- trile/0.I% trifluoroacetic acid/water at 15 minutes at 1 mL/minute.

The LC-MS analysis was performed on a PE Sciex API 100 LC/MS System using a Waters 3 mm x 150 mm 3.5 p C-18 Symmetry column and positive ionspray with a flow rate at 20 uL/minute.

EXAMPLES 616 to 694: A library of the following 79 compounds can be prepared in parallel as individual entities analogously to example 615 on an Advanced ChemTech Model 496 HTS using the following ChemFile to control the operation of the synthesizer. The 4 resins of type Resin-[Building block l]-[Building block 2] are equally distributed in the 80 wells in the synthesizer prior to the initialization of device.

ChemFile C:\ACT\90250003.CHM Page 1 1 Empty RBHeatingAll~1to96 for 2.000 minute(s) 2 3 REM Addition of Cs2C03 in water 4 5 Transfer 200µl from Monomers~1to36 [25] () to RB~Heating~All~1to96 [1-80] using DCE 6 Mix for 1.00 minutes at 600 rpm(s) 7 8 REM Addition of Ph3P + Bu4NCI in NMP 9 10 Transfer 500µl from Monomers~1to36 [21] () to RB~Heating~All~1to96 [1-80] using DCE 11 Mix for 1.00 minutes at 600 rpm(s) 12 13 REM Addition of Pd(OAc)2 in NMP 14 15 Transfer 500ul from Monomers~1to36 [22] () to RB~Heating~All~1to96 [1-80] using DCE

16 Mix for 2.00 minutes at 600 rpm(s) 17 Dispense Sequence C:\ACT\ALKYNES.DSP with 500µl to RB~Heating~All~1to96 rack 18 Set Temperature to 70.0 degrees Celsius 19 Mix for 15.00 minutes at 600 rpm(s) 20 Wait for 15.000 minute(s) 21 Repeat from step 19, 29 times 22 Turn Temperature Controller Off 23 Mix for 15.00 minutes at 600 rpm(s) 24 Wait for 15.000 minute(s) 25 Repeat from step 23, 7 times 26 Empty RB~Heating~All 1to96 for 2.000 minute(s) 27 Dispense System Fluid NMP1 1500p1 to RB~Cleavage~AI1~1to96 [1-80] 28 Mix for 3.00 minutes at 600 rpm(s) 29 Empty RBHeating~All~1to96 for 2.000 minute(s) 30 Repeat from step 27, 2 times 31 32 REM Wash with 50% H20/NMP 33 34 Transfer 1500Xul from Reagent 3 [1] () to RB~Heating~All~1to96 [1-80] using NMP1 35 Mix for 3.00 minutes at 600 rpm(s) 36 Empty RB~Heating~All~1to96 for 2.000 minute(s) 37 Repeat from step 34, 2 times 38 Dispense System Fluid NMP1 1500,ul to RB~Cheavage~All~1to96 [1-80] 39 Mix for 3.00 minutes at 600 rpm(s) 40 Empty RBHeating~All~1to96 for 2.000 minute(s) 41 Repeat from step 38,1 times 42 43 REM Wash with Sodium diethylaminodithiocarbamate 44 45 Transfer 1 1500µl from Reagent~3 [1] () to RB~Heating~All~1to96 [1-80] using NMP1 46 Mix for 3.00 minutes at 600 rpm(s) 47 Empty RBHeating~All~1to96 for 2.000 minute(s) 48 Repeat from step 45, 2 times 49 Transfer 1500µl from REAGENT 4 [1] () to RB~Heating~All~1to96 [1-80] using NMP1 50 Mix for 3.00 minutes at 600 rpm(s) 51 Empty RB~Heating~All~1to96 for 2.000 minute(s) 52 Repeat from step 49, 2 times 53 Transfer 1500µl from REAGENT~5 [1] () to RB~Heating~All~1to96[ 1-80] using NMP1 54 Mix for 2.00 minutes at 600 rpm(s) 55 Empty RB~Heating~All~1to96 for 2.000 minute(s) 56 Repeat from step 53, 2 times 57 Dispense System Fluid NMP1 1500µl to RB~Cleavage~All~1to96 [1-80] 58 Mix for 3.00 minutes at 600 rpm(s) 59 Empty RB~Heating~All~1to96 for 2.000 minute(s) 60 Repeat from step 57, 4 times 61 Dispense System Fluid DCE1 1500µl to RB~Cleavage~All~1to96 [1-80] 62 Mix for 3.00 minutes at 600 rpm(s) 63 Empty RB~Heating~All~1to96 for 2.000 minute(s) 64 Repeat from step 61, 5 times

65 66 REM Cleavage from Resin 67 REM with 50% TFA/DCM 68 69 Transfer 1500µl from Reagent [1] () to RB~Cleavage~All~1to96 [1-80] using DCM1 70 Mix for 45.00 minutes at 600 rpm(s) 71 Empty RB~Cleavage~All~1to96 for 1.000 minute(s) 72 Dispense System Fluid DCM1 500,ul to RB~Cleavage~All~1to96 [1-80] 73 Mix for 1.00 minutes at 300 rpm(s) 74 Empty RB~Cleavage~All~1to96 for 1.000 minute(s) 75 Dispense Sequence C:\ACT\ALKYNES.DSP is a subroutine that controls the combinatorial addition of the solutions of the 20 2-vinyl-benzo[1,3,2]dioxaboroles of type [Building block 3] into the 80 wells in the synthesizer.

The library containing the compounds listed below was synthesized. A subset of the library obtained was characterized by analytical RP-HPLC (retention time) and by LC-MS (molecular mass).

EXAMPLE 616: <BR> <BR> <BR> 2-Amino-5-(5-[(3-chloro-4-hydroxybenzoyl hydrazonomethyl]-2,3-dimethoxyphenyl}-4- pentenoic acid EXAMPLE 617: 3-Chloro-4-hydroxybenzoic acid [3-(3- amino-l -propenyl)-4,5-dimethoxy- benzylidene]hydrazide EXAMPLE 618: 3-Chloro-4-hyd roxybenzoic acid (3-[3- (benzylmethylamino)propenyl]-4,5- dimethoxybenzylidene)hydrazide EXAMPLE 619: 3-Chloro-4-hydroxybenzoic acid [3-(3- diethylamino-l -propenyl)-4,5- dimethoxybenzylidene]hydrazide EXAMPLE 620: 3-Chloro-4-hydroxybenzoic acid [3,4- dimethoxy-5-(3-phenoxy-1 -propenyl)- benzylidene]hydrazide EXAMPLE 621: 3-Chioro-4-hydroxybenzoic acid [3,4- dimethoxy-5-(3-phenyl-1 -propenyl)- benzylidene]hydrazide EXAMPLE 622: 3-Chloro-4-hydroxybenzoic acid (3,4- <BR> <BR> <BR> dimethoxy-5-[2-(toluene-4-sulfonyl)vinyl]- benzylidene}hydrazide EXAMPLE 623: 3-Chloro4-hyd roxybenzoic acid (3-[2-(4- <BR> <BR> chlorophenyl)vinyl]-4,5- <BR> <BR> <BR> dimethoxybenzylidene)hydrazide EXAMPLE 624: 3-Chloro-4-hydroxybenzoic acid (3-[2-(3- hyd roxyphenyl)vinyl]-4,S-dimethoxy- benzylidene}hydrazide EXAMPLE 625: 3-Chloro-4-hydroxybenzoic acid [3,4- dimethoxy-5-(5-phenyl-1 -pentenyl)- benzylidene]hydrazide EXAMPLE 626: 3-Chloro-4-hydroxybenzoic acid [3,4- dimethoxy-5-(2-(2-pyridyl)vinyl)- benzylidene]hydrazide EXAMPLE 627: 3-Chloro-4-hydroxybenzoic acid (3,4- <BR> <BR> <BR> dimethoxy-5-[3-(4-oxo-5-phenyl-4, 5-d ihydro-2- oxazolylamino)-1propenyl]- benzyiidene)hyd razide EXAMPLE 628: <BR> <BR> <BR> 3-(5-[(3-Chloro-4-hydroxybenzoyl)- <BR> <BR> <BR> hydrazonomethyl]-2,3-d imethoxyphenyl)- acrylic acid EXAMPLE 629: <BR> <BR> <BR> 5-(5-[(3-Chloro-4-hydroxybenzoyl)- <BR> <BR> <BR> hydrazonomethyl]-2, 3-d imethoxyphenyl)-4- pentenoic acid EXAMPLE 630: 3-Chloro-4-hydroxybenzoic acid [3-(3- hydroxy -b utenyl)-4,5-d i methoxy- benzylidene]hydrazide EXAMPLE 631: 3-Chloro-4-hyd roxybenzoic acid [3-(4- hydroxy-1-butenyl)-4,5-dimethoxy- benzylidene]hydrazide EXAMPLE 632: 3-Chloro-4-hyd roxybenzoic acid [3-(4- <BR> <BR> <BR> hydroxy -hexenyl)-4 , 5-d imethoxy- benzylidene]hydrazide EXAMPLE 633: 3-Chloro-4-hydroxybenzoic acid [3-(3- hydroxy-1-propenyl)-4,5-dimethoxy- benzylidene]hydrazide EXAMPLE 634: 3-Chloro-4-hydroxybenzoic acid (3-[3-(2,6- dichlorophenoxy)-1-propenyl]-4,5- dimethoxybenzylidene)hydrazide EXAMPLE 635: 3-chloro-4-hydroxybenzoic acid {4-[2-(1- aminocyclohexyl)vinyl]-1 -naphthyl- methylene}hydrazide EXAMPLE 636: 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl]-1-naphthyl}-4-pentenoic acid EXAMPLE 637: 3-Chloro-4-hydroxybenzoic acid {4-[3- <BR> <BR> (benzylmethylamino)propenyl]-l- <BR> <BR> <BR> naphthylmethylene}hydrazide EXAMPLE 638: 3-Chloro-4-hydroxybenzoic acid [4-(3-amino- 1-propenyl)-1-naphthylmethylene]hydrazide EXAMPLE 639: 3-Chloro-4-hydroxybenzoic acid[4-(3- diethylamino-l -propenyl)-l -naphthyl- methylene]hydrazide EXAMPLE 640: 3-Chloro-4-hydroxybenzoic acid [4-(3- phenoxy-1-propenyl)-1-naphthyl- methylene]hydrazide EXAMPLE 641: 3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 1 -propenyl)-1 -naphthylmethylene]hydrazide EXAMPLE 642: 3-Chloro-4-hydroxybenzoic acid (4-[2- (toluene-4-sulfonyl)vinyl]-l- naphthyl- methylene)hyd razide EXAMPLE 643: 3-Chloro-4-hydroxybenzoic acid (4-[2-(4- chlorophenyl)vinyl]-1 -naphthylmethylene)- hydrazide EXAMPLE 644: 3-Chloro-4-hydroxybenzoic acid (4-[2-(3- hydroxyphenyl)vinyl]-1 -naphthyl- methylene)hydrazide EXAMPLE 645: 3-Chloro-4-hydroxybenzoic acid [4-(5-phenyi- 1-pentenyl)-1-naphthylmethylene]hydrazide EXAMPLE 646: 3-Chloro-4-hydroxy-benzoic acid [4-(2-(2- pyridyl)vinyl)-l -naphthylmethylene]- hydrazide EXAMPLE 647: 3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- 5-phenyl-4,5-dihydro-(2-oxazolylamino)-1- propenyl]-1-naphthylmethylene}hydrazide EXAMPLE 648: 3-{4-[(3-Chloro-4-hydroxybenzoyl)- hydrazonomethyl]-1-naphthyl}acrylic acid EXAMPLE 649: 5-(4-[(3-Chioro-4-hydroxybenzoyl)- hydrazonomethyl]-l -naphthyl)-4-pentenoic acid EXAMPLE 650: 3-Chloro-4-hydroxybenzoic acid [4-(3- hydroxy-1-butenyl)-1-naphthylmethylene]- hydrazide EXAMPLE 651: 3-Chloro-4-hydroxybenzoic acid [4-(4- hydroxy -butenyl)-l -naphthylmethylene]- hydrazide EXAMPLE 652: 3-Chloro-4-hydroxybenzoic acid [4-(4- hydroxy-1-hexenyl)-1-naphthyl- methylene]hydrazide EXAMPLE 653: 3-Chloro-4-hydroxybenzoic acid [4-(3- hydroxy-1-propenyl)-1- naphthylmethylene]hydrazide EXAMPLE 654: 3-Chloro-4-hydroxybenzoic acid (4-[3-(2,6- dichlorophenoxy)-1-propenyl]-1- naphthylmethylene)hydrazide EXAMPLE 655: 3-Chloro-4-hydroxybenzoic acid (3-[2-(I - <BR> <BR> aminocyclohexyl)vinyl]benzylidene)hydrazide EXAMPLE 656: 2-Amino-5-{3-[(3-chloro-4-hydroxy- benzoyl)hydrazonomethyl]phenyl)-4- pentenoic acid EXAMPLE 657: 3-Chloro-4-hydroxybenzoic acid (3-[3- (benzylmethylamino)-1 -propenyl]- benzylidene)hydrazide EXAMPLE 658: 3-Chloro-4-hydroxybenzoic acid [3-(3-amino- 1-propenyl)benzylidene]hydrazide EXAMPLE 659: 3-Chloro-4-hydroxybenzoic acid [3-(3- diethylamino-l -propenyl)benzylidene]- hyd razide EXAMPLE 660: 3-Chloro-4-hydroxybenzoic acid [3-(3- phenoxy-l -propenyl)benzylidene]hydrazide EXAMPLE 661: 3-Chloro-4-hydroxybenzoic acid [3-(3-phenyl- 1 -propenyl)benzylidene]hydrazide EXAMPLE 662: 3-Chloro-4-hydroxybenzoic acid {3-[2- (toluene-4-sulfonyl)vinyl]benzylidene)- hydrazide EXAMPLE 663: 3-Chloro4-hydroxybenzoic acid (3-[2-(4- chlorophenyl)vinyi]benzylidene)hyd razide EXAMPLE 664: 3-Chloro-4-hydroxybenzoic acid (3-[2-(3- <BR> <BR> hydroxyphenyl)vinyl]benzylidene)hyd razide EXAMPLE 665: 3-Chloro-4-hydroxybenzoic acid [3-(5-phenyl- 1 -pentenyl)benzylidene]hydrazide EXAMPLE 666: 3-Chloro-4-hydroxybenzoic acid [3-(2-(2- pyridyl)vinyl)benzylidene]hydrazide EXAMPLE 667: 3-Chloro-4-hydroxybenzoic acid (3-[3-(4-oxo- 5-phenyl-4,5-dihydro-(2-oxazolylamino))-1- propenyl]benzylidene)hydrazide EXAMPLE 668: <BR> <BR> <BR> 3-(3-[(3-Chloro-4-hydroxybenzoyl)- hydrazonomethyl]phenyl)acrylic acid EXAMPLE 669: 5-(3-[(3-C h loro4- hyd roxybe nzoyl)- hydrazonomethyl]phenyl)-4-pentenoic acid EXAMPLE 670: 3-Chloro-4-hyd roxybenzoic acid [3-(3- hydroxy-1-buenyl)benzylidene]hydrazide EXAMPLE 671: 3-Chloro-4-hydroxybenzoic acid [3-(4- hydroxy-1 -butenyl)benzylidene] hydrazide EXAMPLE 672: 3-Chloro-4-hydroxybenzoic acid [3-(4- hydroxy-l -hexenyl)benzylidene]hydrazide EXAMPLE 673: 3-ChloroA-hydroxybenzoic acid [3-(3- hydroxy-l -propenyl)benzylidene]hydrazide EXAMPLE 674: 3-Chloro-4-hydroxybenzoic acid {3-[3-(2,6- dichlorophenoxy)-l -propenyl]- benzylidene}hydrazide EXAMPLE 675: 3-Chloro-4-hydroxybenzoic acid (4-[2-(1- aminocyclohexyl)vinyl]benzylidene}hydrazide EXAMPLE 676: 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl)- hydrazonomethyl]phenyl}-4-pentenoic acid EXAMPLE 677: 3-Chloro-4-hydroxybenzoic acid (4-[3-( ben- zylmethylamino)-I -propenyl]- benzylidene}hydrazide EXAMPLE 678: 3-Chloro-4-hydroxybenzoic acid [4-(3-amino- 1 -propenyl)benzylidene]hydrazide EXAMPLE 679: 3-Chloro-4-hydroxybenzoic acid [4-(3- diethylaminopropenyl)benzylidene]hydrazide EXAMPLE 680: 3-ChloroA-hyd roxybenzoic acid [4-(3- phenoxy-l -propenyl]benzylidene]hydrazide EXAMPLE 681: 3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 1 -propenyl)benzylidene]hydrazide EXAMPLE 682: 3-Chloro-4-hydroxybenzoic acid (4-[2- <BR> <BR> <BR> (toluene4-sulfonyl )vinyl]benzylidene)- hyd razide EXAMPLE 683: 3-Chloro-4-hydroxybenzoic acid (4-[2-(4- <BR> <BR> chlorophenyl)vinyl] benzylidene)hydrazide EXAMPLE 684: 3-Chloro-4-hydroxybenzoic acid (4-[2-(3- <BR> <BR> hydroxyphenyl)vinyl] benzylidene)hyd razide EXAMPLE 685: 3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 1-pentenyl)benzylidene]hydrazide EXAMPLE 686: 3-Chloro-4-hyd roxybenzoic acid (4-[2-(2- pyridinyl)vinyl]benzylidene}hydrazide EXAMPLE 687: 3-Chloro-4-hydroxybenzoic acid (4-[3-(4-oxo- 5-phenyl-4,5-dihydro-(2-oxazolylamino)-1- propenyl] benzylidene)hyd razide EXAMPLE 688: <BR> <BR> <BR> (4-[(3-Chloro-4-hydroxybenzoyl)- hydrazonomethyl]phenyl)acrylic acid EXAMPLE 689: 5-(4-[(3-Chloro-4-hydroxybenzoyl)- hyd razonomethyl]phenyl)4-pentenoic acid EXAMPLE 690: 3-Chloro-4-hydroxybenzoic acid [4-(4- hydroxy-1-hexenyl)benzylidene]hydrazide EXAMPLE 691: 3-Chloro-4-hydroxybenzoic acid [4-(4- hydroxy -butenyl)benzylidene]hydrazide EXAMPLE 692: 3-Chloro-4-hydroxybenzoic acid [4-(3- hydroxy-l -propenyl)benzylidene]hydrazide EXAMPLE 693: 3-Chloro-4-hydroxybenzoic acid [4-(3- hydroxy -butenyl)benzylidene]hydrazide EXAMPLE 694: 3-Chloro-4-hydroxybenzoic acid (4-[3-(2,6- dichlorophenoxy)-l -propenyl]- benzylidene)hydrazide

General Procedure for Examples 695 to 701: The compounds were prepared as single entities according to the following equation Resin [Building block 1] Resin [Building block 1] [Building block 2] Resin [Building block 1] [Building block 2] [Building block 3] and were simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula [Building block Ii [Building block 2] [Building block 3].

The following compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block 1] was done manually, whereas the attachment of [Building block 2] and [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS.

The starting resin, Resin-[Building block 1], was prepared as described above.

The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g.

All compounds are based on successive attachment of [Building block 2] and [Building block 3] to Resin-[Building block 1] in a combinatorial way using a nucleophilic substitution reaction according to the following formulae, which are included in the general formula II:

0 R14 R14 esin0lI)NHNH2 + H$4I1{Br ResinO<N NJ°~Br Resin-[Building block 1] [Building block 2] Resin-[Building block 1]-[Building block 2] HNRSeRM [Building [Building block 3] RltNRSC R14 HO<N NJt R5d ResinsO<N NJS, Rsd [Building block 1]-[Building block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2]-[Building block 3] and 15 15 0 R10 0 Resin O<N NH2 ~Br Resin14 HN R14 Resin-[Building block 1] [Building block 2] Resin-[Building block 1]-[Building block 2] HNR5415d [Building block 3] 15 R R Sc °N Rs Resin>OX o - N-R5c esin'c0l)½Th0NHN114R5d HOI NH RI4 R [Building block 1]-[Building @ block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2]-[Building @ block 3] wherein R'4, R15 are as defined for formula I and -NR5CR5d is where R5a, R4a, R4b, c, q, d, and D are as defined for formula I or

-D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.

The following resin, here depicted as Resin-[Building block 1] was used: where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker: = Resin The following building blocks were used: [Building block 2]: 4-(2-bromoethoxy)-2-methoxybenzaldehyde 4-(2-bromoethoxy)-3-methoxybenzaldehyde Br Br ¼M0H ¼M0H p PH H3c 4-(2-b romoethoxy)-3-ch loro-5 4-(2-bromoethoxy)-l -naphthaldehyde methoxybenzaldehyde Br 0 H3C - O 4-(2-bromoethoxy)-3,5- 4-(2-bromoethoxy)-3,5- dimethylbenzaldehyde dibromobenzaldehyde Br H C Br Br H XH H3C Br 4-(2-bromoethoxy)-3-methoxy-5- 4-(2-bromoethoxy)-3,5- phenylbenzaldehyde dimethoxybenzaldehyde - Br MeO Br \/o ¼M0H Me0 H,C-O 4-(2-bromoethoxy)-3-bromo-5- 3-(2-bromoethoxy)-4-methoxybenzaldehyde methoxybenzaldehyde HSC /-7 0 Br Br BrM0 H H3C-O 2-(2-bromoethoxy)-l -naphthaldehyde 4-(2-bromoethoxy)-3-methoxyacetophenone o H Br g ~ Br MeO Me0 [Building block 3]: N-isopropylbenzylamine 4-amino-1 -benzylpiperidine 1 -(4-methoxyphenyl)- H3c H2Ny razz piperazine H,CYN HNTh - CH3 o oO CH, 'CH, N-benzyl-ethanolamine 4-methoxybenzylamine N'-benzyl-N ,N- H N or H2NJ3t° CH3 dimethylethylenediamine 'CH, H3C N~NJ3 CH3 1 -(4-acetylphenyl)- 1 -benzylpiperazine 2-phenylpiperidine piperazine HN/10 HN N--V cH3 I -(3,4- 3-benzylaminopyrrolidine 2-amino-2-phenylethanol methylenedioxyphenyl)- H l q piperazine /Y NY H2N N HO / \ /=\ H HNN\/30 0 1 ,2,3,4- 1 -(3,4- 4-chloro-a- tetrahydroisoquinoline methylenedioxybenzyl)- methylbenzylamine piperazine rf\ C' HtDiG piperazine H2Ne HN, cH3 4-(trifluoromethyl)- 4-(4-chlorophenyl)-4,5,6,7- 4-(4-chlorophenyl)-4- benzylamine tetrahydro- hydroxypiperidine F thieno[3,2-c]pyridine Ho H2N J F tS CI vCNH /--7 3,4-dichlorophenethylamine 3,4-dichlorobenzylamine 4-methoxyphenethylamine jI1)i¼NH2 CI NH2 MeOJ>NH2 4-aminobenzylamine 4-chlorophenethylamine 4-bromophenethylamine NH2 NH2 If NH2 H cI :<Hz Brm 2-amino-l -phenylethanol 2-amino-3-(4-chlorophenyl)- 2-amino-1 -phenyl-1,3- OH 1-propanol propanediol ¼ NH2 I) zNH2 OH 4-fluorobenzyiamine 1 -(4-chlorophenyl)-piperazine 2-(2-thienyl)ethylamine 3NH2 Cl<NUNH NH2 4-chlorobenzylamine 1 -(3-methoxyphenyl)- 6,7-dimethoxy-I ,2,3,4- NH2 piperazine tetrahydroisoquinoline Cl R N no N3NH MeO 4-trifluoromethoxybenzyl- 4-benzylpiperidine 2-(3,4-dimethoxyphenyl)-N- amine NH methylethylamine - H cINH2 MeOym1) N MeO 1 ,2,3,4-tetrahydro-I - 1 -(3,4-dichlorophenyl)- 1 ,4-bis(aminomethyl)- naphthylamine piperazine benzene cI NH2 cI NNH H2N NH2 4-(aminomethyl)pyridine f NH, NH2

Preparation of resin-[Building block 1]: This resin was prepared as described above.

Preparation of [Building block 2]: Preparation of 4-(2-bromoethoxy)-2-methoxybenzaldehyde: 1,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-2- methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in

DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.8 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride (400 mL), dried over MgSO4 and evaporated in vacuo to afford 17.4 g (99%) of 4-(2-bromoethoxy)-2- methoxybenzaldehyde, M.p. 78 - 79 °C.

Preparation of 4-(2-bromoethoxy)-3-methoxybenzaldehyde: 1,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-3- methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (1.2 L) and extracted with ethyl acetate (500 + 4 x 300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo to afford 16.3 g (95%) of 4-(2- bromoethoxy)-3-methoxybenzaldehyde. M.p. 61 - 64 °C.

Preparation of 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde: 1,2-Dibromoethane (46 mL, 0.54 moles) was added to a mixture of 3-chloro-4-hydroxy-5- methoxybenzaldehyde (10 g, 54 mmoles) and potassium carbonate (37 g, 0.27 moles) in DMF (180 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with saturated sodium chloride (150 mL), dried over MgSO4 and evaporated in vacuo to afford 9.33 g (59%) of 4-(2-bromoethoxy)-3- chloro-5-methoxybenzaldehyde. M.p. 52 - 54 °C.

Preparation of 4-(2-bromoethoxy)-3,5-dimethylbenzaldehyde: 1,2-Dibromoethane (26 mL, 0.3 moles) was added to a mixture of 3,5-dimethyl-4- hydroxybenzaldehyde (4.57 g, 30 mmoles) and potassium carbonate (21 g, 150 mmoles) in DMF (90 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.3 L), added saturated sodium chloride (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed

with saturated sodium chloride (300 mL), dried over MgSO4 and evaporated in vacuo to af- ford 8.2 g (95%) of 4-(2-bromoethoxy)-3,5-dimethylbenzaldehyde as an oil.

'H-NMR (300 MHz, CDCI3): 6 = 2.33 (6H, s), 3.83 (2H, t), 4.18 (2H, t), 7.60 (2H, s), 9.88 (1H, s).

Preparation of 4-(2-bromoethoxy)-3,5-dibromobenzaldehyde: 1,2-Dibromoethane (62 mL, 0.72 moles) was added to a mixture of 3,5-dibromo4- hydroxybenzaldehyde (10 g, 36 mmoles) and potassium carbonate (25 g, 180 mmoles) in DMF (100 mi) and the resulting mixture was stirred vigorously at 70 "C for 16 hours. After cooling, the mixture was poured into water (300 mL) and extracted with ethyl acetate (400 mL). Water (200 mL) was added to the aqueous phase and this was extracted with ethyl acetate (150 mL). The combined organic phases were washed with saturated sodium chlo- ride (3 x 150 mL), dried over MgSO4 and evaporated in vacuo. The residue was dissolved in refluxing 96% ethanol (60 mL). Water (15 mL) was added and after cooling, filtration, wash- ing with 60% ethanol and drying 10.7 g (77%) of 4-(2-bromoethoxy)-3,5- dibromobenzaldehyde was isolated in two crops. M.p. 84 - 85 "C.

Preparation of 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde: A mixture of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (20 g, 72 mmoles), ethylene glycol (8.0 mL, 144 mmoles), and chlorotrimethylsilane 36.5 mL, 0.29 moles) in dichloromethane (300 mL) was heated at reflux for 16 hours. The mixture was cooled to room temperature and washed with saturated sodium hydrogencarbonate (3 x 200 mL). The combined aque- ous phases were extracted with dichloromethane (3 x 150 mL). The combined organic ex- tracts were washed with saturated sodium chloride (200 mL), dried over MgSO4 and evapo- rated in vacuo to afford 22.1 g (95%) of 4-[I ,3]dioxolan-2-yl-2-iodo-6-methoxy-phenol. M.p.

120- 121 °C.

Under N2, tetrakis-triphenylphosphinepalladium(0) was added to a mixture of the above di- oxolane (10 g, 31 mmoles), benzeneboronic acid (4.5 g, 37 mmoles), toluene (67 mL), 2 M aqueous sodium carbonate (33 mL) and methanol (20 mL). The resulting mixture was

heated at reflux under N2 for 16 hours. After cooling the mixture was diluted with water (150 mL) and washed with heptane (400 mL) . The aqueous phase was made acidic with 3N hy- drochloric acid and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were dried over Mg SO4 and evaporated invacuo. The residue was purified by column chro- matography over silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1 :2) to afford 5.49 g (77%) of 4-hydroxy-3-methoxy-5-phenylbenzaldehyde. M.p. 107 - 108 "C.

1,2-Dibromoethane (41 mL, 0.48 moles) was added to a mixture of the above 4-hydroxy-3- methoxy-5-phenylbenzaldehyde (5.49 g, 24 mmoles) and potassium carbonate (17 g, 123 mmoles) in DMF (80 ml) and the resulting mixture was stirred vigorously at room tempera- ture for 16 hours. The mixture was poured into water (1 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride (200 mL), dried over MgSO4 and evaporated in vacuo to afford 8.1 g (100%) of 4-(2- bromoethoxy)-3-methoxy-5-phenylbenzaldehyde as an oil.

'H-NMR (300 MHz, DMSO-d6): 8 = 3.50 (2H, t), 3.96 (3H, s), 4.19 (2H, t), 7.4-7.6 (11H, m).

Preparation of 4-(2-bromoethoxy)-l -naphthaldehyde: 1,2-Dibromoethane (30 mL, 0.35 moles) was added to a mixture of 4-hydroxy-1- naphthaldehyde (6 g, 35 mmoles) and potassium carbonate (24 g, 175 mmoles) in DMF (110 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours.

The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over Mg SO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:1) to afford 8.5 g (88%) of 4-(2-bromoethoxy)-l -naphthaldehyde as a solid. M.p.: 83 - 84 "C.

Calculated for C,3H1,BrO2: C, 55.94%; H, 3.97%.

Found: C, 56.10%; H, 3.98%; C, 56.30%; H, 3.97%.

Preparation of 4-(2-bromoethoxy)-3,5-dimethoxybenzaldehyde:

1,2-Dibromoethane (47 mL, 0.55 moles) was added to a mixture of syringaldehyde (10 g, 55 mmoles) and potassium carbonate (38 g, 275 mmoles) in DMF (150 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated invacuo to afford 3.44 g (22%) of 4-(2-bromoethoxy)-3,5- dimethoxybenzaldehyde.

'H-NMR (300 MHz, DMSO-d5): 8 = 3.70 (2H, t), 3.88 (3H, s), 4.27 (2H, t), 7.27 (2H, s).

Preparation of 3-(2-bromoethoxy)-4-methoxybenzaldehyde: 1,2-Dibromoethane (56 mL, 0.66 moles) was added to a mixture of 3-hydroxy4- methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 328 mmoles) in DMF (170 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatog- raphy on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:1) to af- ford 9.8 g (58%) of 3-(2-bromoethoxy)-4-methoxybenzaldehyde.

'H-NMR (300 MHz, DMSO-d6): 6 = 3.82 (2H, t), 3.90 (3H, s), 4.40 (2H, t), 7.22 (1H, d), 7.44 (1H, d), 7.59 (1H, dd).

Preparation of 4-(2-bromoethoxy)-3-bromo-5-methoxybenzaldehyde: 1,2-Dibromoethane (37 mL, 0.43 moles) was added to a mixture of 5-bromovaniilin (10 g, 43 mmoles) and potassium carbonate (30 g, 216 mmoles) in DMF (150 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours followed by vigorously stir- ring at 60 "C for 16 hours. The cooled mixture was poured into water L) and extracted with ethyl acetate (3 x 250 mL). The combined organic phases were washed with saturated so- dium chloride (300 mL), dried over MgSO4 and evaporated in vacuo to afford 13.7 g (94%) of 4-(2-bromoethoxy)-3-bromo-5-methoxybenzaldehyde .

1H-NMR (300 MHz, DMSO-d6): 8 = 3.79 (2H, t), 3.93 (3H, s), 4.40 (2H, t), 7.55 (1H, d), 7.79 (1H, d).

EXAMPLE 695: Preparation of 3-Chloro-4-hydroxybenzoic acid (4-[2-(I .2.3.4-tetrahydroisoquinolin-2- yl)ethoxy]-2-methoxybenzylidene)hydrazide The resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building blockl]) (3 g, 3 mmoles) was swelled in DMF (35 mL) for 30 minutes. Then 4-(2-bromoethoxy)-2- methoxybenzaldehyde (2.33 g, 9 mmoles) and triethyl orthoformate (18 mL) were added and the mixture was shaken at room temperature for 16 hours. The resin was repeatedly swelled in DMF (35 ml, 4 times), CH2CI2 (35 mL, 6 times) and N-methyl-2-pyrrolidinone (NMP) (35 mL, 2 times) and filtered. The resin was swelled in NMP (40 mL) and 1,2,3,4- tetrahydroisoquinoiine (3.75 mL, 30 mmoles) and potassium iodide (1.0 g, 6 mmoles) were added. The resin was shaken at room temperature for 16 hours and filtered. The resin was repeatedly swelled in DMF (40 ml, 5 times), CH2Ci2 (40 mL, 10 times) and filtered. The com- pound was cleaved off the resin by shaking for 1 hour at room temperature with a 50% solu- tion of trifluoroacetic acid in CH2Cl2 (40 mL). The mixture was filtered and the resin was ex- tracted with CH2Cl2 (40 mL, 2 times). The combined CH2Cl2 extracts were concentrated in vacuo. The residue was dissolved in CH2Cl2 (40 mL) and concentrated in vacuo. The residue was dissolved in methanol (40 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium hydrogencarbonate (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL), and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by coloumn chromatography over silica gel (200 mL) eluting with a mixture of CH2Cl2and methanol (9:1).

This afforded 280 mg of the title compound.

HPLC-MS (METHOD A): Rt = 8.44 min; m/z = 480 (M+1).

1H-NMR (300 MHz, DMSO-d,)G = 2.80 (4H, m), 2.90 (2H, t), 3.69 (2H, s), 3.86 (3H, s), 4.25 (2H, t), 6.68 (2H, m), 7.04 (1H, d), 7.07-7.14 (5H, m), 7.75 (1H, dd), 7.80 (1H, bs), 7.96 (1H, d), 8.58 (1H, s), 11.6(1H, s).

HR-MS: Calcd. for C26H25ClN3O4: 479.1611; Found: 479.1604.

EXAMPLE 696: 3-Chloro-4-hydroxybenzoic acid {2-methOxy-4-[2-(4-trifluoromethylbenzylamino)ethOxy]- benzylidene)hydrazide This compound was prepared analogously to the compound described in the previous ex- ample starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, -2 mmoles), 4-(2-bromoethoxy)-2-methoxybenzaldehyde ([building block 2]) (0.73 g, 1.5 equivs.), and 4-trifluoromethylbenzylamine ([building block 3]) (3.3 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1 g) was purified by col- umn chromatography on silica gel (20 g) eluting with a mixture of 25% aq. ammonia, ethanol and dichloromethane (1:9:115). This afforded 130 mg of the title compound.

HPLC-MS (METHOD A): Rt = 9.4 min; m/z = 522 (M+1).

EXAMPLE 697: 3-Chloro-4-hydroxybenzoic acid {4-[2-(4-benzylpiperazin-1-yl)ethoxy]-2- methoxvbenzylidene}hydrazide

This compound was prepared analogously to the compound described in the previous ex- ample starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, -2 mmoles), 4-(2-bromoethoxy)-2-methoxybenzaldehyde ([building block 2]) (0.73 g, 1.5 equivs.), and l-benzylpiperazine ([building block 3]) (3.3 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.4 g) was dissolved in 2-propanol (50 ml) and concentrated to 20 ml. The mixture was allowed to stand at 5 °C for 1 h and filtered.

The mother liquor was concentrated in vacuo and the residue was purified by column chro- matography on silica gel (20 g) eluting with a mixture of methanol and dichloromethane (1 :9). This afforded 0.98 g of the title compound.

'H-NMR (400 MHz, DMSO-d5): 8H = 2.4 (2H, bs), 2.55 (2H, bs), 2.62 (2H, bs), 3.50 (2H, bs), <BR> <BR> <BR> 3.85 (3H, s), 4.15 (2H, t), 6.62 (2H, m), 7.05 (1H, d), 7.30 (5H, m), 7.75 (2H, t), 7.97 (1H, s), 8.67 (1H, s),11 (1H, bs), 11.5(1H, s).

HPLC-MS (METHOD A): Rt = 7.7 min; m/z = 523 (M+1).

EXAMPLE 698: 3-Chloro-4-hydroxybenzoic acid {2-methoxy-4-[2-(2-phenylpiperidin-1- yl)ethoxyi benzylidene)hyd razide This compound was prepared analogously to the compound described in the previous ex- ample starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, -2 mmoles), 4-(2-bromoethoxy)-2-methoxybenzaldehyde ([building block 2])

(0.73 g, 1.5 equivs.), and 2-phenylpiperidine ([building block 3]) (3.0 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.0 g) was purified by column chroma- tography on silica gel (28 g) eluting with a mixture of methanol and dichloromethane (1:13).

This afforded 0.24 g of the title compound.

'H-NMR (400 MHz, DMSO-d5): 8H = 1.4 (2H, m), 1.65 (4H, m), 2.25 (2H, m), 2.75 (1H, m), <BR> <BR> <BR> 3.16 (1H, d), 3.25 (2H, d), 3.83 (3H, s), 4.0 (2H, m), 6.50 (1H, d), 6.54 (1H, s), 7.07 (1H, d), <BR> <BR> <BR> <BR> <BR> 7.23 (1H, t), 7.35 (4H, m), 7.73 (1H, d), 7.77 (1H, dd), 7.96 (1H, d), 8.65 (1H, s), 10.9 (1H, s), 11.6 (1H, s).

HPLC-MS (METHOD A): R, = 9.1 min; m/z = 508 (M+1).

EXAMPLE 699: <BR> <BR> <BR> 3-Chloro-4-hydroxybenzoic acid (3-chloro-4-[2-(l .2.3.4-tetrahydro-isoauinolin-2-yl)ethoxy]-S <BR> <BR> <BR> <BR> <BR> methoxybenzylidene)hydrazide This compound was prepared analogously to the compound described in the previous ex- ample starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, -2 mmoles), 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde ([building block 2]) (0.81 g, 1.5 equivs.), and 1,2,3,4-tetrahydroisoquinoline ([building block 3]) (2.5 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.0 g) was dissolved in 15 ml of a mixture of 25% aq. ammonia, methanol and dichloromethane (1:9:90) and purified by column chromatography on silica gel (25 g) eluting with a mixture of methanol and di- chloromethane (1:12). This afforded 0.11 g of the title compound.

1H-NMR (400 MHz, DMSO-d6): #H = 1.9 (1H, p), 2.18 (1H, t), 2.90 (2H, t), 3.70 (2H, s), 3.90 (3H, s), 4.19 (2H, t), 7.05 (5H, m), 7.37 (2H, s), 7.78 (1H, d), 7.95 (1H, s), 8.33 (1H, s), 11 (1H, bs), 11.8 (1H, s).

HPLC-MS (METHOD A): R, = 9.0 min; m/z = 514 (M+1).

EXAMPLE 700: 3-Chloro-4-hydroxybenzoic acid {6-[2-(1,2,3,4-tetrahydro-isoquinolin-2-yl)ethoxy]-5- methoxybiphenyl-3-ylmethylene}hydrazide This compound was prepared analogously to the compound described in the previous ex- ample starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, -2 mmoles), 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde ([building block 2]) (0.93 g, 1.5 equivs.), and 1,2,3,4-tetrahydroisoquinoline ([buiiding block 3]) (2.5 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue was dissolved in 15 ml of a mixture of 25% aq. ammonia, methanol and dichloromethane (1:9:90) and purified by column chromatography on silica gel (25 9) eluting with a mixture of methanol and di- chloromethane (1:12). This afforded 0.31 g of the title compound.

1H-NMR (400 MHz, DMSO-d5): #H = 2.60 (4H, m), 2.70 (2H, m), 3.48 (2H, s), 3.92 (3H, s), <BR> <BR> <BR> 3.96 (2H, t), 6.98 (1H, m), 7.10 (4H, m), 7.22 (1H, s), 7.40 (4H, m), 7.55 (2H, d), 7.78 (1H, d), 8.00 (1H, s), 8.40 (1H, s), 11 (1H, bs), 11.7 (1H, s).

HPLC-MS (METHOD A): R, = 9.6 min; m/z = 557 (M+1).

EXAMPLE 701:

3-Chloro-4-hydroxybenzoic acid (3,5-dibromo-4-{2-[4-(4-chlorophenyl)piperazin-1-yl]- ethoxy)benzylidene)hydrazide A solution of 4-(2-bromoethoxy)-3,5-dibromobenzaldehyde ([building block 2]) in DMF (0.6 M, 1 mL) was added to the resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1]) (0.05 mmoles) followed by addition of triethyl orthoformate (0.5 mL) and the mixture was shaken at room temperature for 15 hours. The resin was repeatedly swelled in DMF (1.5 mL, 3 times), CH2CI2 (1.5 mL, 2 times) and NMP (1.5 mL, 2 times) for 5 minutes and filtered. The resulting resin (resin-[building block 1]-[building block 2]) was added a solu- tion of 1-(4-chlorophenyl)piperazine (0.4 M, 1 mL) and a solution of potassium iodide in NMP (0.08 M, 0.5 mL) were added and the mixture was shaken at room temperature for 16 hours.

The resin was repeatedly swelled in DMF (1.5 mL, 3 times) and CH2CI2 (1.5 mL, 6 times) for 2 minutes and filtered.

The compound was cleaved off the resin by shaking for 1 hour at room temperature with a 50% solution of trifluoroacetic acid in CH2Cl2 (1.5 mL). The mixture was filtered and the resin was extracted with CH2Cl2 (0.5 mL). The combined CH2Cl2 extracts were concentrated in vacuo. The residue was dissolved in methanol (1 mL) and concentrated in vacuo. The resi- due was dissolved in a 1:1 mixture of methanol and CH2Cl2 (1 mL) and concentrated in vacuo to give the title compound.

HPLC-MS (METHOD B): R, = 15.02 min; m/z = 671.

EXAMPLES 702 TO 791: The following 90 compounds were prepared in parallel as individual entities analogously to the previous example on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer.

Further, a library of compounds of all the possible combinations of the above listed building blocks ([building block 1], [building block 2] and [building block 3]) was prepared in parallel as individual entities analogously to the previous example on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer. The com- pounds are all expected to be present in the respective wells.

The resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) is equally distributed in the wells in the synthesizer prior to the initialization of the device.

ChemFile C:\ACT~1328\90250012.CHM: 1 REM Filtration of resin 2 Empty RB1~1to96 for 5.000 minute(s) 3 Empty RB2~1to96 for 5.000 minute(s) 4 Empty RB3~1to96 for 5.000 minute(s) 5 Empty RB4~1to96 for 5.000 minute(s) 6 Pause 7 8 REM Washing of resin 9 10 Dispense System Fluid Disdu 1~4* 1500ul to RB1~1to96[1-96] 11 Dispense System Fluid Disdu1~4* 1500µl to RB2~1to96[1-96] 12 Dispense System Fluid Disdu1~4* 1500ul to RB3~1to96[1-96] 13 Dispense System Fluid Disdu1~4* 1500ul to RB4lto96[I-96] 14 Start mixing "RB1~1to96" for 5.00 minutes at 600 rpm(s) and continue.

15 Start mixing "RB2~1to96" for 5.00 minutes at 600 rpm(s) and continue.

16 Start mixing "RB3~1to96" for 5.00 minutes at 600 rpm(s) and continue.

17 Mix "RB4~1to96" for 5.00 minutes at 600 rpm(s) and wait.

18 Wait for 25.000 minute(s) 19 Repeat from step 14,1000 times 20 Empty RB1~1to96 for 5.000 minute(s) 21 Empty RB2~1to96 for 5.000 minute(s) 22 Empty RB3~1to96 for 5.000 minute(s) 23 Empty RB4~1to96 for 5.000 minute(s) 24 Pause 25 26 REM Coupling with aldehydes 27 28 Dispense System Fluid Disdu2~3* 1500µl to RB1~1to96[1-96] 29 Dispense System Fluid Disdu2~3* 1500ul to RB2lto96[1-96] 30 Dispense System Fluid Disdu2~3* 1500ul to RB3~1to96[1-96] 31 Dispense System Fluid Disdu2~3* 1500ul to RB4~1to96[1-96]

32 Start mixing "RB1~1to96" for 5.00 minutes at 600 rpm(s) and continue.

33 Start mixing "RB2~1to96" for 5.00 minutes at 600 rpm(s) and continue.

34 Start mixing "RB3~1to96" for 5.00 minutes at 600 rpm(s) and continue.

35 Mix "RB4~1to96" for 5.00 minutes at 600 rpm(s) and wait.

36 Empty RB1~1to96 for 5.000 minute(s) 37 Empty RB2~1to96 for 5.000 minute(s) 38 Empty RB3~1to96 for 5.000 minute(s) 39 Empty RB4~1to96 for 5.000 minute(s) 40 Pause 41 42 Dispense Sequence c:\ACT13~28\R2-A.DSP with 1000µl to RB1~1to96 rack using DMF 43 Mix "RB1~1to96" for 2.00 minutes at 600 rpm(s) and wait.

44 Dispense Sequence c:\ACT13~28\R2-B.DSP with 1000ul to RB2~1to96 rack using DMF 45 Start mixing "RB1~1to96" for 2.00 minutes at 600 rpm(s) and continue.

46 Mix "RB2~1to96" for 2.00 minutes at 600 rpm(s) and wait.

47 Dispense Sequence c:\ACT13~28\R2-C.DSP with 1000ul to RB3~1to96 rack using DMF 48 Start mixing "RB1~1to96" for 2.00 minutes at 600 rpm(s) and continue.

49 Start mixing "RB2~1to96" for 2.00 minutes at 600 rpm(s) and continue.

50 Mix "RB3~1to96" for 2.00 minutes at 600 rpm(s) and wait.

51 Dispense Sequence c:\ACT13~28\R2-D.DSP with 1000ul to RB4~1to96 rack using DMF 52 Start mixing "RB1~1to96" for 2.00 minutes at 600 rpm(s) and continue.

53 Start mixing "RB2~1to96" for 2.00 minutes at 600 rpm(s) and continue.

54 Start mixing "RB3~1to96" for 2.00 minutes at 600 rpm(s) and continue.

55 Mix "RB4~1to96" for 2.00 minutes at 600 rpm(s) and wait.

56 57 Pause 58 REM Manual addition of CH(OC2H5)3 59 Start mixing "RB1~1to96" for 5.00 minutes at 600 rpm(s) and continue.

60 Start mixing "RB2~1to96" for 5.00 minutes at 600 rpm(s) and continue.

61 Start mixing "RB3~1to96" for 5.00 minutes at 600 rpm(s) and continue.

62 Mix "RB4~1to96" for 5.00 minutes at 600 rpm(s) and wait.

63 Wait for 25.000 minute(s) 64 Repeat from step 59, 200 times 65 Empty RB1~1to96 for 5.000 minute(s) 66 Empty RB2~1to96 for 5.000 minute(s) 67 Empty RB3~1to96 for 5.000 minute(s) 68 Empty RB4~1to96 for 5.000 minute(s) 69 Pause 70 71 REM Wash after coupling with aldehydes 72 73 Flush Arm1 with Flush Diluterl and Flush Diluter 2, Arm2 with Flush Diluter 74 Dispense System Fluid Disdu2~3* 1500ul to RB1~1to96[1-96] 75 Dispense System Fluid Disdu2~3* 1500ul to RB2Ito96[l-96] 76 Dispense System Fluid Disdu2~3* 1500ul to RB3Ito96[I-96] 77 Dispense System Fluid Disdu2~3* 1500ul to RB4~1to96[1-96] 78 Start mixing "RB1~1to96" for 5.00 minutes at 600 rpm(s) and continue.

79 Start mixing "RB2~1to96" for 5.00 minutes at 600 rpm(s) and continue.

80 Start mixing "RB3Ito96" for 5.00 minutes at 600 rpm(s) and continue.

81 Mix "RB4~1to96" for 5.00 minutes at 600 rpm(s) and wait.

82 Empty RB1~1to96 for 5.000 minute(s) 83-Empty RB2~1to96 for 5.000 minute(s) 84 Empty RB3~1to96 for 5.000 minute(s) 85 Empty RB4~1to96 for 5.000 minute(s) 86 Repeat from step 74, 2 times 87 Pause 88 Dispense System Fluid Disdu1~4* ISOOul to RB1~1to96[1-96] 89 Dispense System Fluid Disdu1~4* 1500ul to RB2~1to96[1-96] 90 Dispense System Fluid Disdu1~4* ISOOul to RB3~1to96[1-96] 91 Dispense System Fluid Disdu1~4* ISOOul to RB4~1to96[1-96] 92 Start mixing "RB1~1to96" for 5.00 minutes at 600 rpm(s) and continue.

93 Start mixing "RB2~1to96" for 5.00 minutes at 600 rpm(s) and continue.

94 Start mixing "RB3Ito96" for 5.00 minutes at 600 rpm(s) and continue.

95 Mix "RB4~1to96" for 5.00 minutes at 600 rpm(s) and wait.

96 Empty RB1~1to96 for 5.000 minute(s) 97 Empty RB2~1to96 for 5.000 minute(s) 98 Empty RB3~1to96 for 5.000 minute(s) 99 Empty RB4~1to96 for 5.000 minute(s) 100 Repeat from step 88,1 times 101 Dispense System Fluid Disdu2~3* 1500ul to RB1~1to96[1-96] 102 Dispense System Fluid Disdu2~3* 1500ul to RB2~1to96[1-96] 103 Dispense System Fluid Disdu2~3* 1500ul to RB3~1to96[1-96] 104 Dispense System Fluid Disdu2~3* 1500ul to RB4~1to96[1-96] 105 Start mixing "RB1~1to96" for 5.00 minutes at 600 rpm(s) and continue.

106 Start mixing "RB2~1to96" for 5.00 minutes at 600 rpm(s) and continue.

107 Start mixing "RB3~1to96" for 5.00 minutes at 600 rpm(s) and continue.

108 Mix "RB4~1to96" for 5.00 minutes at 600 rpm(s) and wait.

109 Wait for 25.000 minute(s) 110 Repeat from step 105, 1000 times 111 Pause 112 Empty RB1~1to96 for 5.000 minute(s) 113 Empty RB2~1 to96 for 5.000 minute(s) 114 Empty RB3~1to96 for 5.000 minute(s) 115 Empty RB4~1to96 for 5.000 minute(s) 116 Repeat from step 101, times 117 118 REM Coupling with amines 119 Flush Arm1 with Disdu2~3*, Arm2 with Disdu2 3* 120 Dispense Sequence c:\ACT13~28\R3-A.DSP with 1000µl to RB1~1to96 rack using NMP 121 Mix "RB1~1to96" for 2.00 minutes at 600 rpm(s) and wait.

122 Dispense Sequence c:\ACT13~28\R3-B.DSP with 1000µl to RB2~1to96 rack using NMP 123 Start mixing "RB1~1to96" for 2.00 minutes at 600 rpm(s) and continue.

124 Mix "RB2~1to96" for 2.00 minutes at 600 rpm(s) and wait.

125 Dispense Sequence c:\ACT13~28\R3-C.DSP with 1000µl to RB3~1to96 rack using NMP 126 Start mixing "RB1~1to96" for 2.00 minutes at 600 rpm(s) and continue.

127 Start mixing "RB2~1to96" for 2.00 minutes at 600 rpm(s) and continue.

128 Mix "RB3~1to96" for 2.00 minutes at 600 rpm(s) and wait.

129 Dispense Sequence c:\ACTl3~28\R3-D.DSP with 1000ul to RB4~1to96 rack using NMP

130 Start mixing "RB1~1to96" for 2.00 minutes at 600 rpm(s) and continue.

131 Start mixing "RB2~1to96" for 2.00 minutes at 600 rpm(s) and continue.

132 Start mixing "RB3~1to96" for 2.00 minutes at 600 rpm(s) and continue.

133 Mix "RB4~1to96" for 2.00 minutes at 600 rpm(s) and wait.

134 Pause 135 Transfer 500ul from REAGENT~3[1]() to RB1~1to96[1-96] using NMP 136 Mix "RB1~1to96" for 2.00 minutes at 600 rpm(s) and wait.

137 Pause 138 Transfer 500ul from REAGENT~3[1]() to RB2~1to96[1-96] using NMP 139 Start mixing "RB1 1to96" for 2.00 minutes at 600 rpm(s) and continue.

140 Mix "RB2~1to96" for 2.00 minutes at 600 rpm(s) and wait.

141 Pause 142 Transfer 500ul from REAGENT~3[1]() to RB3~1to96[1-96] using NMP 143 Start mixing "RB1~1to96" for 2.00 minutes at 600 rpm(s) and continue.

144 Start mixing "RB2~1to96" for 2.00 minutes at 600 rpm(s) and continue.

145 Mix "RB3~1to96" for 2.00 minutes at 600 rpm(s) and wait.

146 Pause 147 Transfer 500ul from REAGENT~3[1]() to RB4~1to96[1-96] using NMP 148 Start mixing "RB1~1to96" for 5.00 minutes at 600 rpm(s) and continue.

149 Start mixing "RB2~1to96" for 5.00 minutes at 600 rpm(s) and continue.

150 Start mixing "RB3~1to96" for 5.00 minutes at 600 rpm(s) and continue.

151 Mix "RB4~1to96" for 5.00 minutes at 600 rpm(s) and wait.

152 Wait for 25.000 minute(s) 153 Repeat from step 148, 200 times 154 Pause 155 156 Empty RB1 1to96 for 5.000 minute(s) 157 Empty RB2~1to96 for 5.000 minute(s) 158 Empty RB3~1to96 for 5.000 minute(s) 159 Empty RB4~1to96 for 5.000 minute(s) 160 161 162 REM Wash after coupling with amines 163 164 Flush Arm1 with Flush Diluterl and Flush Diluter 2, Arm2 with Flush Diluter 165 166 Dispense System Fluid Disdu2~3* 1500ul to RB1~1to96[1-96] 167 Dispense System Fluid Disdu2~3* 1500ul to RB2~1to96[1-96] 168 Dispense System Fluid Disdu2~3* 1500ul to RB3Ito96[l-96] 169 Dispense System Fluid Disdu2~3* 1500ul to RB4Ito96[l-96] 170 Start mixing "RB1~1to96" for 5.00 minutes at 600 rpm(s) and continue.

171 Start mixing "RB2~1to96" for 5.00 minutes at 600 rpm(s) and continue.

172 Start mixing "RB3~1to96" for 5.00 minutes at 600 rpm(s) and continue.

173 Mix "RB4~1to96" for 5.00 minutes at 600 rpm(s) and wait.

174 Empty RB1~1to96 for 5.000 minute(s) 175 Empty RB2~1to96 for 5.000 minute(s) 176 Empty RB3~1to96 for 5.000 minute(s) 177 Empty RB4~1to96 for 5.000 minute(s) 178 Repeat from step 166, 2 times

179 Pause 180 Dispense System Fluid Disdu1~4* 1500ul to RB1~1to96[1-96] 181 Dispense System Fluid Disdu1~4* 1500ul to RB2~1to96[1-96] 182 Dispense System Fluid Disdu1~4* 1500ul to RB3~1to96[1-96] 183 Dispense System Fluid Disdu1~4* 1500ul to RB4~1to96[1-96] 184 Start mixing "RB1~1to96" for 5.00 minutes at 600 rpm(s) and continue.

185 Start mixing "RB2~1to96" for 5.00 minutes at 600 rpm(s) and continue.

186 Start mixing "RB3~1to96" for 5.00 minutes at 600 rpm(s) and continue.

187 Mix "RB4~1to96" for 5.00 minutes at 600 rpm(s) and wait.

188 Empty RB1~1to96 for 5.000 minute(s) 189 Empty RB2~1to96 for 5.000 minute(s) 190 Empty RB3~1to96 for 5.000 minute(s) 191 Empty RB4~1to96 for 5.000 minute(s) 192 193 Repeat from step 180, 5 times 194 195 Dispense System Fluid Disdu1~4* 1500ul to RB1~1to96[1-96] 196 Dispense System Fluid Disdul 4* 1500µl to RB2Ito96[I-96] 197 Dispense System Fluid Disdu1~4* 1500µl to RB3Ito96[l-96] 198 Dispense System Fluid Disdu1~4* 1500ul to RB4Ito96[I-96] 199 Start mixing "RB1~1to96" for 5.00 minutes at 600 rpm(s) and continue.

200 Start mixing "RB2~1to96" for 5.00 minutes at 600 rpm(s) and continue.

201 Start mixing "RB3~1to96" for 5.00 minutes at 600 rpm(s) and continue.

202 Mix "RB4~1to96" for 5.00 minutes at 600 rpm(s) and wait.

203 Wait for 25.000 minute(s) 204 Repeat from step 199, 1000 times 205 206 Flush Arm1 with Flush Diluterl and Flush Diluter 2, Arm2 with Flush Diluter 3 207 Empty RB4~1to96 for 5.000 minute(s) 208 Pause 209 210 REM Clevage (50%TFA/DCM manually added, one rack at a time) 211 Flush Arm1 with Flush Diluterl, Arm2 with Flush Diluter 4 212 Mix "RB1~1to96" for 5.00 minutes at 600 rpm(s) and wait.

213 Wait for 5.000 minute(s) 214 Repeat from step 7, 5 times 215 Empty RB1~1to96 for 1 second(s) 216 Wait for 4 second(s) 217 Repeat from step 10, 25 times 218 Empty RB1~1to96 for 5.000 minute(s) 219 220 Dispense System Fluid Disdul 4* 500µl to RB1~1to96[1-96] 221 Wait for 1.000 minute(s) 222 Empty RB1~1to96 for 1 second(s) 223 Wait for 4 second(s) 224 Repeat from step 17, 25 times 225 Empty RB1~1to96 for 5.000 minute(s) 226 Dispense sequence files C:\ACT13~28\R3-A.DSP, C:-ACT13~28\R3-B.DSP, C:\ACT 13~28\R3-C.DSP and C:\ACT13~28\R3-D.DSP are subroutines that control the combinato- rial addition of the amines into the 4 reaction blocks each containing 96 wells in the syn- theziser.

The library containing the following compounds was synthesized, and the products were characterised by HPLC-MS (molecular mass & retention time).

Ex Structure HPLC-MS HPLC-MS No. (METHOD B) (METHOD B) m/z R, (minutes) 702 0 O HOY 1/ 0 M$l$1}yN5 596 15.9 cl cl 703 < MeO 2/ 0 Xl 522 8.82 HOo"""0 Cl 704 <<CI 502 6.62 O MeOO JT H N HO ci 705 < HO ~< ONH $Nci 488 6.68 HO/ N H CI Cl 706 0 MeO 543 10.93 HO/ HO H Mcl ci 707 0N)$½½'0 NH¼j$ji 522 9.40 HO IH HOX H Cl 708 HO )½¼OHNMN$)½iONH)½ 494 7.87 MeON' O H ci

EXAMPLE 792: 3-Amino-4-hydroxybenzoic acid (4-[2-(I .2.3.4-tetrahydro-isoquinolin-2-yI)ethoxy]-2- methoxybenzylidene}hydrazide The above 4-(2-bromoethoxy)-2-methoxybenzaldehyde (16.8 g, 65 mmol) ([building block 2]) was dissolved in acetone (300 ml) and potassium carbonate (44.9 g, 0.33 mol), potassium iodide (2 g) were added followed by addition of 1,2,3,4- tetrahydroisoquinoline (9.07 g, 72 mmol). The resulting mixture was stirred vigorously at reflux temperature for 16 hours. After cooling, the mixture was filtered and the inor- ganic precipitate was washed with acetone (100 ml). The combined acetone filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water (2 x 20 ml) saturated sodium chloride (20 ml), dried over MgSO4 and concentrated in vacuo. The residue (23 g) was purified by column chromatography on silica gel (400 g) eluting first with a mixture of ethyl acetate and heptane (1 :1, 2 liters) then with a mixture of ethyl acetate and heptane (2:1, 5 liters) to afford 12 g (60%) of 4- [2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenz aldehyde as a solid. M.p.: 69 - 71 °C.

Calculated for C,9H21NO3.0.25H2O: C, 72.24%; H, 6.86%; N, 4.43%.

Found: C, 72.79%; H, 6.86%; N, 4.46%; C, 72.65%; H, 6.88%; N, 4.47%.

Methyl 3-amino-4-hydroxybenzoate (5.0 g, 30 mmol) was dissolved in ethanol (50 ml) and hydrazine hydrate (4.4 ml, 90 mmol) was added and the resulting mixture was heated at re- flux temperature for 16 hours. After cooling the mixture was filtered and solid was washed with ethanol to afford after drying 1.4 g (28%) of 3-amino-4-hydroxybenzoic acid hydrazide as a solid. M.p.: 242-243 "C.

Calculated for C7H9N3O2: C, 50.30%; H, 5.43%; N, 25.14%.

Found: C, 50.27%; H, 5.46%; N, 24.35%; C, 50.41%; H, 5.47%; N, 24.38%.

The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above 4-[2- (1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenzald ehyde (93 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2 x 4 ml) and dried by suction to afford 66 mg (48%) of the title compound as a solid. M.p.: 162 - 164 "C.

HPLC -MS (METHOD B): Rt = 6.50 minutes. m/z = 461.

EXAMPLE 793: 3-Amino-4-hydroxybenzoic acid F4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzylidene]- hydrazide Syringaldehyde (4-hydroxy-3,5-dimethoxybenzaldehyde) (10.2 g, 55 mmol) was dissolved in DMF (45 ml), and 4-isopropylbenzylchloride (9.7 g, 55 mmol) and potassium carbonate (11.5 g) were added successively. The resulting mixture was heated at 60 "C for 16 hours. After cooling, the mixture was partitioned between water (150 ml) and ethyl acetate (3 x 100 ml).

The combined organic extracts were washed with water (100 ml), saturated NaCI (100 ml),

dried (MgSO4), treated with activated carbon, filtered and concentrated in vacuo to afford 15 g (100%) of 4-(4-isopropylbenzyloxy)-3,5-dimethoxybenzaldehyde as an oil.

'H-NMR (400 MHz, DMSO-d5): 8H = 1.20 (9H, d), 2.89 (1H, h), 3.86 (6H, s), 4.98 (2H, s), 7.23 (2H, d), 7.27 (2H, s), 7.36 (2H, d).

The above 3-amino4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above 4-(4- isopropylbenzyloxy)-3,5-dimethoxybenzaldehyde(93 mg, 0.3 mmol) were dissolved in 2- propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2 x 4 ml) and dried by suction to afford 144 mg (100%) of the title compound as a solid. M.p.: 174 - 175 "C.

HPLC-MS (METHOD B): R, = 10.40 minutes. m/z = 464.

EXAMPLE 794: <BR> <BR> <BR> (R)-2-(4-F(3-Amino-4-hydroxybenzoyl)hyd razonomethyl]-3-methoxyphenoxy)-N-( I - <BR> <BR> <BR> <BR> <BR> benzylpyrrolidin-3-yl)acetamide (R)-(-)-l -Benzyl-3-aminopyrrolidine (5 g, 28 mmol) was dissolved in dichloromethane (10 ml). To this solution, a solution of bromoacetyl chloride (4.55 g, 28 mmol) in dichloromethane (5 ml) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 6.8 g (72%) of (3R)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid which was used directly in the next step.

4-Hydroxy-2-methoxybenzaldehyde (2.05 g, 13 mmol) was dissolved in DMF (7 ml) and potassium carbonate (6.2 g, 45 mmol) was added followed by a suspension of the above (3R)-N-(1-Benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 9 mmol) in DMF (16 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was

then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with saturated sodium chloride (3 x 15 ml), dried (MgSO4) and concentrated in vacuo. The resi- due was crystallized from diethyi ether to afford 2.11 g (64%) (R)-N-(1-benzylpyrrolidin-3-yl)- 2-(4-formyl-3-methoxyphenoxy)acetamide as a solid. M.p.: 98 - 101 "C.

Calculated for C21 H24N2O4.0.SH2O: C, 66.83%; H, 6.68%; N, 7.42%.

Found: C, 67.15%; H, 6.57%; N, 7.75%; C, 66.96%; H, 6.57%; N, 7.77%.

The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (R)- N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)ace tamide (110 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2 x 3 ml) and dried by suction to afford 109 mg (70%) of the title compound as a solid. M.p.: 157 - 160 "C.

HPLC-MS (METHOD B): R, = 3.10 minutes. m/z = 518.

EXAMPLE 795: <BR> <BR> <BR> (R)-2-{4-[(3-Amino-4-hydroxybenzoyl)hydrazonomethyl]naphthyl -1 -yloxy}-N-(1 - <BR> <BR> <BR> <BR> <BR> <BR> benzylpyrrolidin-3-yl)acetamide 4-Hydroxy-1-naphthaldehyde (2.32 g, 13 mmol) was dissolved in DMF (7 ml) and potassium carbonate (6.2 g, 45 mmol) was added followed by a suspension of the above (3R)-N-(1- Benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 9 mmol) in DMF (16 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then parti-

tioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with saturated sodium chloride (3 x 15 ml), dried (MgSO4) and concentrated in vacuo. The residue was pu- rified by column chromatography on silica gel (110 g) eluting with ethyl acetate to afford 1.7 g (49%) (R)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy) acetamide as a solid.

M.p.: 105-107"C.

Calculated for C24H24N203.0.25H2O: C, 73.36%; H, 6.28%; N, 7.13%.

Found: C, 73.81%; H, 6.22%; N, 7.11%; C, 73.92%; H, 6.23%; N, 7.11%.

The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (R)- N-(I -benzylpyrrolidin-3-yl)-2-(44ormylnaphthyl-l -yloxy)acetamide (116 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (6 x 2 ml) and dried by suction to afford 140 mg (87%) of the title compound as a solid. M.p.: 187 - 192 "C.

HPLC-MS (METHOD B): Rut = 5.72 minutes. m/z = 538.

EXAMPLE 796: (S)-2-{4-[(3-Amino-4-hydroxybenzoyl)-hydrazonomethyl]-3-meth oxyphenoxy)-N-(1- benzylpyrrolidin-3-yl)acetamlde (S)-(+)-l-Benzyl-3-aminopyrrolidine (6 g, 34 mmoi) was dissolved in dichloromethane (12 ml). To this solution, a solution of bromoacetyl chloride (5.46 g, 34 mmol) in dichloromethane

(5 ml) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 7.3 g (64%) of (3S)-N-(1-benzyipyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid which was used directly in the next step.

4-Hydroxy-2-methoxybenzaldehyde (2.39 g, 16 mmol) was dissolved in DMF (10 ml) and potassium carbonate (7.3 g, 52 mmol) was added followed by a suspension of the above (3S)-N-(l -benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.5 g, 10 mmol) in DMF (20 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with saturated sodium chloride (3 x 15 ml), dried (MgSO4) and concentrated in vacuo. The resi- due (4 g) was crystallised from a mixture of diethyl ether and heptane, filtered and dried in vacuo to afford 2.7 g (71%) (S)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methOxyphenoxy )- acetamide as a solid. M.p.: 96 - 100 "C.

Calculated for C2,H24N204.0.25H2O: C, 67.63%; H, 6.62%; N, 7.51%.

Found: C, 67.35%; H, 6.61%; N, 7.85%; C, 67.24%; H, 6.59%; N, 7.82%.

The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (S)- N-(1-benzyipyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)ace tamide (110 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (6 x 2 ml) and dried by suction to afford 109 mg (70%) of the title compound as a solid. M.p.: 139 - 141 °C.

HPLC-MS (METHOD B): Rt = 3.15 minutes. m/z = 518.

EXAMPLE 797:

(S)-2-{4-[(3-Amino-4-hydroxybenzoyl)hydrazonomethyi]naphthyl -1 -yloxy}-N-(1 - <BR> <BR> <BR> benzylpyrrolidin-3-yl)acetamide 4-Hydroxy-1-naphthaldehyde (2.71 g, 16 mmol) was dissolved in DMF (10 ml) and potas- sium carbonate (7.25 g, 52 mmol) was added followed by a suspension of the above (3S)-N- (1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 10 mmol) in DMF (20 ml).

The resulting mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was ex- tracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with saturated sodium chloride (3 x 15 ml), dried (MgSO4) and concentrated in vacuo. The resi- due (4 g) was purified by column chromatography on silica gel (110 g) eluting with ethyl acetate to give an oil (2 g), which was crystallized from a mixture of diethyl ether and hep- tane to afford 1.8 g (45%) (S)-N-(l-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-l-yloxy) - acetamide as a solid. M.p.: 96 - 97 "C.

Calculated for C24H24N203.0.25H2O: C, 73.36%; H, 6.28%; N, 7.13%.

Found: C, 73.58%; H, 6.28%; N, 7.05%; C, 73.55%; H, 6.27%; N, 7.03%.

The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (S)- N-(1-benzylpyrrolidin-3-yl)-2-(4-formyinaphthyl-1-ylOxy)acet amide (116 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (3 x 3 ml) and dried by suction to afford 143 mg (89%) of the title compound as a solid. M.p.: 192 - 193 "C.

HPLC-MS (METHOD B): Rt = 5.18 minutes. m/z = 538.

EXAMPLE 798: (S)-2-{4-[(3-Fluoro-4-hydroxybenzoyl)hydrazonomethyl]naphthy l-1 -yloxy}-N-(1 - <BR> <BR> <BR> benzylpyrrolidin-3-yl)acetamide This compound was prepared on solid phase using resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide, prepared similarly as described above for the resin bound 3-chloro-4- hydroxybenzoic acid hydrazide. Thus, methyl 3-fluoro-4-hydroxybenzoate was attached to the resin. Hydrolysis of the methyl ester (aq. LiOH, dioxane, 60 "C) followed by reaction with hydrazine (PyBOP, hydrazine, DMF) afforded resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide.

The resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) was swelled in DMF (10 ml) for 30 minutes and filtered. This was repeated once more. DMF (4 ml) and the above (S)-N-(I -benzylpyrrolidin-3-yl)-2-(44ormylnaphthyl-I -yloxy)acetamide (0.4 g, 0.94 mmol) were added followed by triethyl orthoformate (1.5 ml) and the resulting mixture was shaken at room temperature for 16 hours. The mixture was filtered and the resin was suc- cessively washed with DMF (5 x 4 ml) and dichioromethane (5 x 4 ml). The compound was cleaved off the resin by addition of 50% TFA in dichloromethane (6 ml) and shaking at room temperature for 1 hour. Filtration followed by extraction of the resin with a mixture of metha- nol and dichloromethanne (4:6) (2 x 4 ml) followed by extraction with dichloromethane (4 ml).

The combined filtrates were concentrated in vacuo, stripped successively with wet methanol, dichloromethane, methanol and dichloromethane. The residue (0.39 g) was purified by col- umn chromatography on silica gel (40 g) eluting first with a mixture of dichloromethane, ethanol and 25% aq. ammonia (90:9:1), then with (85:13.5:1.5) and finally with (80:18:2).

Pure fractions were pooled and concentrated in vacuo to afford 0.15 g of the title compound.

HPLC-MS (METHOD B): Rt = 8.82 minutes. m/z = 541.

Calculated for C31H29N4O4F.0.25CH2Cl2: C, 66.81%; H, 5.29%; N, 9.97%. Found: C, 67.30%; H, 5.48%; N, 10.03%;

C, 67.33%; H, 5.49%; N, 10.02%.

EXAMPLE 799: <BR> <BR> (R)-2-{4-[(3-Fluoro-4-hydroxybenzoyl)hydrazonomethyl]naphthy l-1 -yloxy}-N-(1 - <BR> <BR> <BR> benzylpyrrolidin-3-yl!acetamide This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above (R)-N- (I -benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-I -yloxy)acetamide (0.4 g, 0.94 mmol). After cleavage the compound was purified by column chromatography to afford 0.14 g of the title compound.

HPLC-MS (METHOD B): R1 = 9.02 minutes. m/z = 541.

Calculated for C31H29N4O4F.0.25CH2CI2: C, 66.81%; H, 5.29%; N, 9.97%.

Found: C, 66.77%; H, 5.46%; N, 10.02%; C, 67.14%; H, 5.42%; N, 9.97%.

EXAMPLE 800: (S)-2-{4-[(3-Fluoro-4-hydroxybenzoyl)hydrazonomethyl]-3-meth oxyphenoxy}-N-(1- benzylpyrrolidin-3-yl)acetamide This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above (S)-N- (1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)aceta mide (0.4 g, 0.94 mmol). After

cleavage the compound was purified by column chromatography to afford 0.13 g of the title compound.

HPLC-MS (METHOD B): Rt = 3.68 minutes. m/z = 521.

Calculated for C25H29N4O5F.0.25CH2Cl2: C, 62.63%; H, 5.49%; N, 10.34%.

Found: C, 62.92%; H, 5.83%; N, 10.15%; C, 62.71%; H, 5.81%; N, 10.16%.

EXAMPLE 801: (R)-2-(4-[(3-Fluoro-4-hydroxybenzoyl)-hydrazonomethyll-3-met hoxyphenoxy}-N-(I - benzylpyrrolidin-3-yl)acetamide This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above (R)-N- (I -benzylpyrrolidin-3-yl)-2-(44ormyl-3-methoxyphenoxy)acetamid e (0.4 g, 0.94 mmol). After cleavage the compound was purified by column chromatography to afford 0.16 g of the title compound.

HPLC-MS (METHOD B): Rut=4.18 minutes. m/z = 521.

Calculated for C25H29N4O5F.0.25CH2Cl2: C, 62.63%; H, 5.49%; N, 10.34%.

Found: C, 62.65%; H, 5.73%; N, 10.31%; C, 62.84%; H, 5.81%; N, 10.30%.

EXAMPLE 802:

3-Fluoro-4-hydroxybenzoic acid {4-t2-(1.2.3.4-tetrahydro-isoquinolin-2-yl)ethOxy]-2- methoxybenzylidene)hydrazide This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above 4-[2- (1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methOxybenzald ehyde (0.4 g, 0.94 mmol). After cleavage the compound was purified by column chromatography to afford 0.13 g of the title compound.

HPLC-MS (METHOD B): Rt = 7.60 minutes. m/z = 464.

Calculated for C25H25N3O4F.0.SCH2Cl2: C, 62.91%; H, 5.38%; N, 8.30%.

Found: C, 62.68%; H, 5.47%; N, 8.02%; C, 62.48%; H, 5.43%; N, 8.01%.

The HPLC-MS (METHOD A) analyses were performed on a PE Sciex API 100 LC/MS Sys- tem using a Waters 3 mm x 150 mm 3.5 p C-18 Symmetry column and positive ionspray with a flow rate of 20 pLiminute. The column was eluted with a linear gradient of 5-90% A, 85-0% B and 10% C in 15 minutes at a flow rate of 1 ml/min (solvent A = acetonitrile, solvent B = water and solvent C = 0.1% trifluoroacetic acid in water).

The HPLC-MS (METHOD B) analyses were performed on a system identical to the one de- scribed above, the only difference being the eluent. The column was eluted with a linear gra- dient of 30-80% A, 60-10% B and 10% D in 15 minutes at a flow rate of 1 ml/min (solvent A = acetonitrile, solvent B = water and solvent D =20 mM ammonium acetate in water, pH 7).

EXAMPLE 803:

3-Chloro-4-hydroxy-benzoic acid (4-[2-(I .2.3.4-tetrahydro-isoquinolin-2-yl)-ethoxy]-8- methoxy-naphthalen- 1 -ylmethylene}-hyd razide 4-hydroxy-8-methoxynaphthalene-l -carbaldehyde (1 g, 5 mmol) was dissolved in DMF (15 mL). To this mixture potassium carbonate (3.4 g, 25 mmol) and 1,2-dibromoethane (4 mL, 50 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water (150 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 90 mL). The combined organic extracts were washed with saturated sodium chloride (100 mL), dried (MgSO4) and evaporated in vacuo to afford 1.13 g (74%) of 4-(2- bromoethoxy)-8-methoxynaphthalene-l -carbaldehyde.

HPLC-MS (Method A): Rt = 14.1 minutes. m/z = 309.

1H-NMR (300 MHz, DMSO-d5): 8H = 3.99 (3H, s), 7.00 (1H, d), 7.20 (1H, d), 7.47 (1H, t), 7.88 (2H, m), 10.9 (1H, s).

The above resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (2 g, 1.8 mmol) was swelled in DMF (25 mL) for 30 minutes and the above 4-(2-bromoethoxy)-8- methoxynaphthalene-l -carbaldehyde (1.7 g, 5.4 mmol) was added followed by triethyl ort- hoformate (1.2 mL) and the resulting mixture was shaken at room temperature for 16 hours.

The mixture was filtered and the resin was successively washed with DMF (3 x 25 mL), dichloromethane (4 x 25 mL) and N-methyl pyrrolidin-2-one (NMP) (2 x 25 mL). NMP (25 mL) was added followed by potassium iodide (0.6 g) and 1,2,3,4-tetrahydro-isoquinoline (2.25 mL, 18 mmol) and the resulting mixture was shaken at room temperature for 16 hours.

The mixture was filtered and the resin was successively washed with NMP (2 x 25 mL) and dichloromethane (6 x 25 mL). The compound was cleaved off the resin by addition of 50% TFA in dichloromethane (30 mL) and shaking at room temperature for 1 hour. After filtration followed by extraction of the resin with dichloromethane (2 x 30 mL) the combined filtrates were concentrated in vacuo. The residue was partitioned between ethyl acetate (80 mL) and saturated sodium hydrogen carbonate (100 mL). The aqueous phase was extracted with ethyl acetate (2 x 80 mL) and the combined organic extracts were dried (MgSO4) and con- centrated in vacuo. The residue was purified by column chromatography on silica gel (200 mL) eluting with a mixture of dichloromethane and methanol (9:1). This afforded 217 mg of the title compound.

HPLC-MS (Method A): Rt = 9.14 minutes. m/z = 530.

General Procedure for Examples 804 to 824: The compounds were prepared as single entities according to the following equation Resin [Building block 1] Resin [Building block 1] [Building block 2] Resin [Building block 1] [Building block 2] [Building block 3] and were simultaneously deprotected (when required) and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula [Building block 1] [Building block 2] [Building block 3].

The following compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block 1] and attachment of [Building block 2] was done manually, whereas the attachment of [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 496 HTS in several runs.

The starting resin, Resin-[Building block 1], was prepared as described above.

The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g.

All compounds are based on successive attachment of [Building block 2] and [Building block 3] to Resin-[Building block 1] in a combinatorial way according to the following formulae, which are included in the general formula II: 15 R15 R R801 1 Resin,(k" lc NHFmoc O Resin>O s 3salt Resin, R14 H 0 Resin-[Building block 1] [Building block 2] Resin-[Building block 1]-[Building block 2] R R3b R a R4 R4a Hooc-(cH4$(cH2)7(M (cH2((cH2)7D RIS H [Building block 3] AN 1N ),E (CH2)dD o Resin O H R4 Resin-[Building block i]Buildin9 block Building block 3] R33 R3b R44 R4b R AHN il {CH2) (CH2) (M)r(CH24«CH2)d D K NH' R R9N.N@g I NH IA R HO [Building block Building block 2].[Building block 3]

wherein R8, R9, R14, R15 and are as defined for formula I.

The following resin, here depicted as Resin-[Building block 1] was used: where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker: = Resin

The following building blocks were used: [Building block 2] (4-Formyl-3-methoxyphenyl)carbamic acid (4-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester: 9H-fluoren-9-ylmethyl ester 0 0#½NHFmoc NHFmoc p 9 H3CO CH3 3-(tert-Butyidimethylsilanyloxy)-4- (5-Formyl-2-methoxyphenyl)carbamic acid formylphenyl)carbamic acid 9H-fluoren-9- 9H-fluoren-9-ylmethyl ester: yimethyl ester: NHFmoc 'q 3NHFmoc 3 H TBDMSO [Building block 3]@ 4-Methoxy-2- N-Methylpyrrole-2-carboxylic Succinylsulfathiazole quinoiinecarboxylic acid acid H Ne N<N3 $½l3OH n71. H3O 7-Ethoxybenzofuran-2- 4-Toluenesulfonylacetic acid 3-(2-Thienoyl)propionic acid carboxylic acid 0 CH3 R OH3 - HO 010$m 0 OH c, OH OH CH3 Boc-Hyp-OH N-fmoc-O-t-butyl-L-serine Fmoc-His(Boc)-OH OH that3 XoH3XOH HO 0 OH aq 3 H3C OH3 0 /0 Foc-beta-(3-pyridyl)-D-Ala- Methanesulfonylacetic acid Fmoc-Trp(Boc)-OH OH oO;;MO CH3 OH OH O ¼½HOHN$I OH o O 3 Fmoc-L-Methionine 5-Methoxy-I -indanone-3- 4-Hydroxycinnamic acid acetic acid I NH OH 0 3 OH ,NH H 0 Fmoc-Arg(Boc)-2-OH 5-Oxopryrrolidine-2- 4-Bromo-2,5-dimethyl-1 -H- carboxylic acid pyrrole-3-carboxylic acid HOPH Br 00H own, HO 0 H3C NH OH3 HN N O CH3 H C 0 CONCH, 3)r H3C CH Acetic acid Hippuric acid 2-Methylpropenoic acid HO4H3 O½ONHH OH F 3 Cyano-acetic acid O-Anisic acid 4-Acetamidobenzoic acid H3C H HO OH 01NO3 H Trifluoroacetic acid 2-Amino-4-thiazole acetic p-Anisic acid F0 acid H3 F F OH HO $ ¼N NH2 HO 0 Alfa-Methoxyphenylacetic Benzoylformic acid Oxamic acid acid R H2N½O OH HO 0 Quinolin-2-carboxylic acid Benzofuran-2-carboxylic acid Monomethyl malonate 0 0 ¼½j)(OH H3CO°$O° OH 3-Cyanobenzoic acid 3-(3-Pyridyl)acrylic acid Cyclopentanecarboxylic acid 'OH OH IOH 0 OH N-Acetylglycine DL-Glyceric acid 2-Chloro-3- O OH HO methoxythiophene-4- 0 1 carboxylic acid H3C H 0 HO OH HO H3C-O OH 01/s\ 5-Fluoroindole-2-carboxylic 3-(4,5-Methylenedioxy-2- 3- Acid nitrophenyl)acrylic acid (Formyiaminomethyl)benzoic F OH acid OH I H <O HO 0 0 5-Bromo-2-furoic Acid 3-Methylthiophene-2- Methylmalonic acid Br z c OH carboxylic acid H ¼3OH H0 OH30 4-Thioureido-benzoic acid (4-Trifluoromethoxy)phenoxy (4-Chlorophenoxy)acetic acid NWOH acetic acid ,QH F0 Cl Isoquinoline-1-carboxylic a- 6-Methylnicotinic acid 3H-lndene-1-carboxylic acid cid H3CY^N OH 1/ o Benzo[b]thien-3-yl acetic a- 2-methyl-2-phenoxypropionic 3-Benzo[I ,3]dioxol-5-yl- cid acid acrylic acid oH o;OH OH 6/7(CH3 O 3 3-(3-Trifluoromethylphenyl) 2-Fluoro-3-phenylacrylic acid 2-Oxo-3-phenylpropionic acid acrylic acid F ,O, F' P F¼iIOH OH OH 3-Methoxybenzo[b]thio- Benzo[b]thiophene-2- Fmoc-phenylalanine phene-2-carboxylic acid carboxylic acid O O 0 OH O CH3 V (2,4-Dichlorophenoxy)acetic 3-(4-Trifluoromethylphenyi)- (3-Trifluoromethylphenyl)- acid propionic acid acetic acid 0H H FF ClClO FFI)0 OH F Preparation of resin-[Building block 1]: This resin was prepared as described above.

Preparation of [Building block 2]: (4-Formyl-3-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester: Methyl 4-amino-2-methoxybenzoate (14.7 g, 7.3 mmol) and Fmoc-Osu (26.1 g, 77.3 mmol) were stirred in a mixture of acetonitrile and water (1:1, 320 mL) at reflux for 16 hr. The reac- tion mixture was concentrated to half the volume and the precipitate isolated by filtration.

The isolated solid was dissolved in ethyl acetate (300 mL) and washed with 0.4 N hydrochlo- ric acid (200 mL), 0.2 N hydrochloric acid (200 mL), water (200 mL) and a 20 % saturated solution of sodium chloride (200 mL). After drying (magnesium sulphate) the organic phase was concentrated in vacuo. and the solid residue was washed with methanol and dried.

The crude product (12g) was dissolved in dichloromethane (1 L) under nitrogen and a solu- tion of diisobutylaluminium hydride (90 mL, 1.2 M in toluene) was dropwise added at 0-50C.

The reaction mixture was stirred at 200C for 16 hr and quenched by dropwise addition of water (58 mL) at 0-5 OC. The reaction mixture was stirred at 200C for 3 hr and filtered. The filtrate was concentrated in vacuo. The crude product (6.8 g) was suspended in di- chloromethane (400 mL) and manganese dioxide (15.6 g, 180 mmol) was added. The mix- ture was stirred for 16 hr at 200C and filtered. The filtrate was concentrated in vacuo to give 5.1 g of the title compound. m.p. 187-1880C HPLC-MS (METHOD A): Rt = 15.1 min, m/z= 374.

Micro analysis: calculated: C, 73.98; H, 5.13; N, 3.75% found: C, 73.44; H, 5.20; N, 3.56% (4-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester:

Thionylchloride (12.8 g, 108 mmol) was dropwise added to an ice cold suspension of 4- amino-3-methoxybenzoic acid (12.3 g, 72 mmol) in methanol (250 mL). The reaction mixture was stirred at 200C for 16 hr and concentrated in vacuo. Ethyl acetate (250 mL) and a satu- rated solution of sodium hydrogen carbonate (150 mL) were added and the organic phase was washed with saturated solutions of sodium hydrogen carbonate (2x50 mL), dried (magnesium sulphate) and concentrated in vacuo. The crude product (12.5 g) and Fmoc- Osu (28 g, 83 mmoi) was stirred in a mixture of acetonitrile and water (1:1, 240 mL) at 900C for 16 hr. The reaction mixture was concentrated to half the volume. Ethyl acetate (200 mL) was added together with 0.4N hydrochloric acid (150 mL). The organic phase was washed with 0.2N hydrochloric acid (100 mL), water (100 mL) and a saturated solution of sodium chloride (2x100 mL). After drying (magnesium sulphate) the organic phase was concentrated in vacuo, and the residue was crystallized from methanol and dried. m.p. 96-980C HPLC (Method 1) R,= 32.4 min Micro analysis: calculated: C, 71.45; H, 5.25; N, 3.47% found: C, 71.32; H, 5.24; N, 3.41% The product (12 g, 29.7 mmol)) was dissolved in dichloromethane (800 mL) under nitrogen and a solution of diisobutylaluminium hydride (90 mL, I .2M in toluene) was dropwise added at 0-50C. The reaction mixture was stirred at 200C for 16 hr and quenched by dropwise addi- tion of water (58 mL) at 0-50C. The reaction mixture was stirred at 200C for 3 hr and filtered.

The filtrate was concentrated in vacuo to give 5.5 g of product (m.p. 169-1710C). The prod- uct (5.5 g) was suspended in dichloromethane (325 mL) and manganese dioxide (12.8 g, 148 mmol) was added. The mixture was stirred for 16 hr at 200C and filtered. The filtrate was concentrated in vacuo to give 3.5 g of the title compound. Recrystallization from ethyl ace- tate.

m.p. 150-1520C HPLC (Method 1) Rt = 30.6 min Micro analysis: calculated: C, 73.98; H, 5.13; N, 3.75% found: C, 73.54; H, 5.18; N, 3.65% 3-(tert-Butyldimethylsilanyloxy)-4-formylphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester: 4-(9H-Fluoren-9-yI methoxycarbonylamino)-2-hydroxybenzoic acid methyl ester: Thionylchloride (19.49, 163 mmol) was dropwise added to an ice cold solution of 4-amino salicylic acid (10.0g, 65.3 mmol) in methanol (200 mL). The reaction mixture was hereafter heated to 650C for 6 days. The reaction mixture was concentrated in vacuo and the crude product was dissolved in a mixture of acetonitrile and water (1 :1, 220 mL). Fmoc-Osu (22.0 g, 65.3 mmol) was added and the reaction mixture was stirred at 900C for 16 hr. The reaction mixture was concentrated to 100 mL in vacuo, and water (50 mL) and ethyl acetate (250 mL) added. The organic phase was isolated and washed with water (2x50 mL), a saturated solu- tion of sodium chloride (2x50 mL), dried (magnesium sulphate) and concentrated in vacuo.

The residue was purified on silica (300 g) using ethyl acetate and n-heptane (1 :2) as eluent.

The product was recrystallized from methanol to give 4-(9H-fluoren-9- ylmethoxycarbonylamino)-2-hydroxybenzoic acid methyl ester. m. p.156-90C HPLC (Method 1) Rt = 31.7 min Micro analysis: calculated: C, 70.94; H, 4.92; N, 3.60% found: C, 70.73; H, 4.98; N, 3.37%

4-(9H-Fluoren-9-ylmethoxycarbonylamino)-2-hydroxybenzOic acid methyl ester (4.36 g, 11.2 mmol) was dissolved in dimethylformamide (20 mL) and imidazole (1.92 g, 28 mmol) was added. tert-Butyldimethylsilylchloride (2.09 g, 13.4 mmol) dissolved in dimethylformamide (10 mL) was dropwise added and the reaction mixture was stirred at 200C for 16 hr. The re- action mixture was poured into water (160 mL) and extracted with ethyl acetate (4x50 mL).

The collected organic phases were washed with a saturated solution of sodium chloride (4x50 mL), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified on silica (150 g) using ethyl acetate and n-heptane (15:85) as eluent. The isolated product (3.10 g, 6.15 mmol) was dissolved in dichloromethane (200 mL) under nitrogen. A solution of diisobutylaluminiumhydride (18.5 mL, I .2M in toluene) was dropwise added 0-50C. The mix- ture was stirred at 200C for 3.5 hr, and quenched by dropwise addition of water at 0-50C. Af- ter 2.5 hr at 200C the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on silica using ethyl acetate and n-heptane (1:3) as eluent. The isolated product (2.40 g) was dissolved in dichloromethane (120 mL) and manganese dioxide (4.39 g, 50.5 mmol) was added. The reaction mixture was stirred at OOC for 16 hr and filtered. The filtrate was concentrated in vacuo and the residue purified on silica using ethyl acetate and n-heptane (15:85) as eluent to give 1.0 g of the title compound.

HPLC (Method 1) Rt = 30.7 min and 36.8 min (5-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester: Thionylchloride (10.3 g, 85 mmol) was dropwise added to an ice cold suspension of 3- amino-4-methoxybenzoic acid (9.48 g, 56.7 mmol) in methanol (180 mL). The reaction mix- ture was stirred at 200C for 16 hr and concentrated in vacuo. Ethyl acetate (100 mL) and a saturated solution of sodium hydrogen carbonate (100 mL) were added and the organic phase was washed with saturated solutions of sodium hydrogen carbonate (2x40 mL), dried

(magnesium sulphate) and concentrated in vacuo. The crude product (7.7 g) and Fmoc-Osu (12.9 g, 38.2 mmol) were stirred in a mixture of acetonitrile and water (1:1, 75 mL) at 200C for 16 hr, and at reflux for 3.5 hr. The reaction mixture was concentrated to half the volume and the precipitate isolated by filtering the mixture to give 15 g of intermediate crude product.

The product (5 g, 12 mmol) was dissolved in dichloromethane (400 mL) under nitrogen and a solution of diisobutylaluminium hydride (38 mL, I .2M in toluene) was dropwise added at 0- 50C. The reaction mixture was stirred at 200C for 16 hr and quenched by dropwise addition of water (23 mL) at 0-50C. The reaction mixture was stirred at 200C for 1.5 hr and filtered. The filtrate was concentrated in vacuo to give 4.9 g of intermediate product. The product (4.9 g) was suspended in dichloromethane (180 mL) and manganese dioxide (11.2 g, 129 mmol) was added. The mixture was stirred for 16 hr at 200C and filtered. The filtrate was concen- trated in vacuo to give 4.3 g crude product that was purified on silica (150 g) using ethyl acetate and n-heptane (3:7) as eluent to give 1.9 g of the title compound. m.p. 139-1420C HPLC (Method 1) Rt = 29.8 min Micro analysis: calculated: C, 73.98; H, 5.13; N, 3.75% found: C, 73.45; H, 5.17; N, 3.72% EXAMPLE 804: N-(4-[3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methOxyph enyl!-2-(4- trifluoromethoxyphenoxy)acetamide

Step 1: Coupling of aldehyde [building block 2] to resin[buildingblock 1] 0.75 g resin (Wang resin loaded with 3-chloro-4-hydroxybenzoic acid hydrazide) was swelled in dimethylformamide (6 mL) for 30 min and drained. The aldehyde (4-formyl-3- methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester, 0.5 g, 1.36 mmol) dissolved in dimethylformamide (3 mL) was added followed by addition of triethylorthoformate (1.5 mL).

The mixture was shaken for 16 hr at 200C and drained. The resin was washed with di- methylformamide (5x4 mL), dichloromethane (5x4 mL) and dimethylformamide (5x4 mL).

The coupling of the aldehyde was repeated twice.

Step 2: Deprotection of aniline The resin was swelled in dimethylformamide (5 mL) and piperidine added (1.25 mL). After shaking for 30 min, the resin was drained and washed with dimethylformamide (5x4 mL), N- methylpyrrolidinone (5x4 mL) and dimethylformamide (5x4 mL).

Step 3: Coupling of acid [building block 3] to resin[building block 1][building block 2] The resin[building block 1][building block 2] was swelled in dimethylformamide (2.5 mL) and the acid (4-trifluoromethoxy)phenoxy acetic acid (0.64 g, 2.7 mmol) was added together with diisopropylcarbodiimide (0.21 mL). After 5 min of shaking dimethylaminopyridine (0.34 mL) was added and the mixture was shaken for 3 hr and drained. The resin was washed with di- methylformamide (5x4 mL), dichloromethane (5x4 mL) and dimethylformamide (5x4 mL).

The coupling of the acid was repeated twice, but with 16 hr reaction time for the repetition.

Step 4: Cleavage from the resin The resin was swelled in dichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL) was added. After shaking for 1 hr the resin was drained. The eluent was collected and concen- trated in vacuo. The residue was crystallized from methanol to give 0.2 g of the title com- pound. m.p. 235-236.50C HPLC-MS (METHOD A) Rt = 13.5 min m/z = 538 Micro analysis: calculated: C, 53.59; H, 3.56; N, 7.81% found: C, 53.57; H, 3.58; N, 7.51%

Further, a library of compounds of all the possible combinations of the above listed building blocks ([building block 1], [building block 2] and [building block 3]) was prepared in parallel as individual entities analogously to the previous example on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer. The com- pounds are all expected to be present in the respective wells.

The four [building block 2] aldehydes, (4-Formyl-3-methoxyphenyl)carbamic acid 9H-fluoren- 9-ylmethyl ester, (4-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester, 3- (tert-Butyidimethylsilanyloxy)-4-formylphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester and (5-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester, were coupled to four individually batches of the resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1]) using the same procedure as described for step 1 in the example above.

Subsequently the Fmoc deprotection of the anilino group was carried out as described in step 2 in the example above.

The four different examples of resin[building block 1][building block 2] thus prepared were equally distributed in the wells in the synthesizer prior to the initialization of the device.

The attachment of the array of [building block 3] mentioned above was carried out in a fully combinatorial way with the four types of resin[building block 1][building block 2] using the general procedure as described in step 3 in the example above. The final cleavage was performed using the same general procedure as described in step 4 in the example above.

During this cleavage step deprotection of acid sensible protection groups was also taken place. These two steps 3 and 4 were carried out (in several runs) on an ACT 496 HTS automated synthesizer using the following ChemFile to control the device.

ChemFile: C:\DATA\90250017.CHM 1 Empty RBlto96 for 2.000 minute(s) 2 Flush Arm1 with NMParml and DCMarml 3 4 REM Adding acids 1 to 36 5

6 Dispense Sequence C:\act\ACID1-36.DSP with 1000ul to RB1to96 rack using NMParm1 7 Mix for 2.00 minutes at 600 rpm(s) 8 Pause 9 Mix for 2.00 minutes at 600 rpm(s) 10 11 REM Adding acids 37 to 48 12 13 Dispense Sequence ACI37-48.DSP with 1000ul to RB1to96 rack using NMParml 14 Mix for 2.00 minutes at 600 rpm(s) 15 16 Pause 17 18 REM Adding DIC 19 20 Transfer 300ul from Monomer1to36[12]() to RBlto96[2-48] using NMParm1 21 Mix for 2.00 minutes at 600 rpm(s) 22 Transfer 300ul from Monomer1to36[13]() to RB1to96[50-96] using NMParml 23 Mix for 10.00 minutes at 600 rpm(s) 24 25 REM Adding DMAP 26 27 Transfer 200ul from Monomer1to36[14]() to RB1to96[2-48] using NMParml 28 Transfer 200ui from Monomer1to36[14]() to RB1to96[50-96] using NMParml 29 30 REM Mixing overnight 31 32 Mix for 10.00 minutes at 600 rpm(s) 33 Wait for 20.000 minute(s) 34 Repeat from step 32, 150 times 35 36 REM wash 37 38 Empty RB1to96 for 2.000 minute(s) 39 Dispense System Fluid NMPdualarms* 1000ul to RB1to96[1-96] 40 Mix for 3.00 minutes at 600 rpm(s) 41 Empty RB1to96 for 2.000 minute(s) 42 Repeat from step 39, 5 times 43 44 REM de fmoc 45 Mix for 3.00 minutes at 600 rpm(s) 46 Dispense Sequence C:\act\DEFMOC.DSP with 1500ul to RB1to96 rack using NMParml 47 Mix for 15.00 minutes at 600 rpm(s) 48 Empty RB1to96 for 3.000 minute(s) 49 Empty RB1to24 for 3.000 minute(s) 50 Empty RB49to72 for 2.000 minute(s) 51 Pause 52 53 REM wash 54 Dispense System Fluid NMPdualarms* 1000ul to RB1to96[1-96]

55 Mix for 3.00 minutes at 600 rpm(s) 56 Empty RB1to96 for 3.000 minute(s) 57 Repeat from step 54, 2 times 58 Flush Arm1 with NMParml and DCMarm1, Arm2 with DCMarm2 59 Dispense System Fluid DCMdualarm* 1000µl to RB1to96[1-96] 60 Mix for 3.00 minutes at 600 rpm(s) 61 Empty RB1to96 for 3.000 minute(s) 62 Repeat from step 59, 5 times 63 64 REM TFA CLEAVAGE 65 66 Mix for 1.00 minutes at 300 rpm(s) 67 Transfer 1000µl from Reagent2[1]() to RBcleavage1to96[1-96] using DCMarml 68 Mix for 1.00 hours at 600 rpm(s) 69 Empty RBcleavagelto96 for 30 second(s) 70 Dispense System Fluid DCMdualarm* 500ul to RBcleavage 1to96[1-96] 71 Mix for 5.00 minutes at 300 rpm(s) 72 Empty RBcleavagelto96 for 30 second(s) 73 Dispense sequence files C:\act\ACID1-36.DSP are subroutines that control the combinatorial addition of the amines into the 4 reaction blocks each containing 96 wells in the syntheziser.

Examples of compounds from this library were characterized by HPLC-MS (molecular mass & retention time) and includes: EXAMPLE 805.

Quinoline-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3- methoxyphenyl)amide m.p. 236-238°C HPLC (Method 1) Rt=26.2 min EXAMPLE 806:

N-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-2-methoxyp henyl}-2-(4- trifluoromethoxyphenoy)acetamide m.p. 216-218"C HPLC (Method 1) Rt=26.6 min EXAMPLE 807: Quinoline-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-2- methoxyphenyl}amide m.p. 159-1620C HPLC (Method 1 ) Rt=27.7 min EXAMPLE 808: N-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyp henyl}-2-(4- chlorophenoxy)acetamide m.p. 216-218"C HPLC-MS (METHOD A) Rt=13.4 min, m/z=488

EXAMPLE 809: <BR> <BR> N-(4-[(3-Chloro-4-hydroxybenzoyl)hyd razonomethyl]-3-methoxyphenyl}-6- <BR> <BR> <BR> <BR> <BR> methylnicotinamide HPLC-MS (METHOD A) Rt=8.2 min, m/z=439 EXAMPLE 810: N-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyp henyl}-2-(3- trifluoromethylphenyl)acetamlde HPLC-MS (METHOD A) Rt=13.4 min, m/z=506 EXAMPLE 811: N-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyp henyl}-2-(2,4- dichlorophenoxy)acetamide HPLC-MS (METHOD A) Rt=14.3 min, m/z=524 EXAMPLE 812: <BR> <BR> N-(4-[(3-Chloro-4-hyd roxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-3-(4- <BR> <BR> <BR> <BR> trifluoromethylphenyl)propionamide HPLC-MS (METHOD A) Rt=14.0 min, m/z=520 EXAMPLE 813: Isoquinoline-I -carboxylic acid (4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3- methoxyphenyl}amide HPLC-MS (METHOD A) Rt=13.0 min, m/z=475

EXAMPLE 814: 7-Ethoxybenzofu ran-2-carboxylic acid (4-(3-ch loro-4-hyd roxybenzoyl)hydrazonomethyl]-3- methoxyphenyl)amide HPLC-MS (METHOD A) Rt=13.3 min, m/z=508 EXAMPLE 815: N-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyp henyl}-2-(toluene-4 sulonyl)acetamide HPLC-MS (METHOD A) Rt=10.8 min, m/z=517 EXAMPLE 816: Benzofuran-2-carboxylic acid {4-[(3-Chloro-4-hyd roxybenzoyl)hydrazonomethyl]-3- methoxyphenyl)-amide

HPLC-MS (METHOD A) Rt=12.3 min, m/z=465 EXAMPLE 817: N-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyp henyl}-3-cyanobenzamide HPLC-MS (METHOD A) Rt=10.8 min, m/z=450 EXAMPLE 818: 5-Chloro-4-methoxythiophene-3-carboxylic acid {4-[(3-Chloro-4- hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl)amide HPLC-MS (METHOD A) Rt=9.8 min, m/z=495

EXAMPLE 819: 5-Bromofuran-2-carboxylic acid {4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3- methoxyphenyl}amide HPLC-MS (METHOD A) Rt=11.4 min, m/z=494 EXAMPLE 820: 2-Benzo[b]thien-3-yl-N-{4-[(3-chloro-4-hydroxybenzoyl)hydraz onomethyl]-2- methoxyphenyl}acetamide HPLC-MS (METHOD A) Rt=13.4 min, m/z=494 EXAMPLE 821: N-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-2-methoxyp henyl}-2-(4-chlorophenoxy)- 2-methylpropionamide HPLC-MS (METHOD A) Rt=14.7 min, m/z=516

EXAMPLE 822: <BR> <BR> <BR> <BR> N-(4-[(3-Ch loro-4-hyd roxybenzoyl)hydrazonomethyl]-2-methoxyphenyl}-3-(3- trifluoromethylphenyl)acrylamide HPLC-MS (METHOD A) Rt=14.3 min, m/z=518 EXAMPLE 823: N-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-2-methoxyp henyl}-2-fluoro-3- phenylacrylamide HPLC-MS (METHOD A) Rt=14.3 min, m/z=468 EXAMPLE 824: 2-Benzo[b]thieophene-2-carboxylic acid (4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-2- methoxyphenyl)amide

HPLC-MS (METHOD A) Rt=13.8 min, m/z=480 HPLC Method 1.

The RP-HPLC analysis was performed using UV detection at 254 nm and a Merck Hibar LiChrosorb RP-18 (5 ptm) prepacked column (Cat. No. 50333), which was eluted at 1 mL/minute. Two solvent systems were used: Solvent system I: 0.1% Trifluoroacetic acid in acetonitrile. Solvent system II: 0.1% Trifluoroacetic acid in water.

The column was equilibrated with a mixture composed of 20% of solvent system I and 80% of solvent system II. After injection of the sample a gradient of 20% to 80% of solvent system I in solvent system II was run over 30 minutes. The gradient was then extended to 100% of solvent system I over 5 minutes followed by isocratic elution with 100% of this system for 6 minutes.

General Procedure for Examples 825 to 875: The compounds were prepared as single entities according to the following equation Resin - [Building block 1] Resin [Building block 1] [Building block 2] Resin [Building block 1] [Building block 2] [Building block 3] and were simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula

[Building block l]---[Building block 2] [Building block 3].

The following compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block l]-[Building block 2] was done manually, whereas the attachment of [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS.

The starting resin, Resin-[Building block 1], was prepared as described above.

The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g.

All compounds are based on successive attachment of [Building block 2] and [Building block 3] to Resin-[Building block 1] in a combinatorial way using a nucleophilic substitution reaction according to the following formulae, which are included in the general formula II: R15 IS R1s R:s cX N-NH2 BuzzCl N.NX Resin H NH2 H H 14 Resin > HN R14 Resin-[Building block 1] [Building block 2] Resin-[Building block 1]-[Building block 2] 0 O IS R o Resin OCN N HR14 R HNRSCRM [Building block 3] ci N XR5d I Ot; tN-IsISNR5dR5c H.0lHRl' Resin0 R [Building block 1]-[Building block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2]-[Building block 3] and

15 0 0 R OH VNNH,C OH N>OH H + cl HNNI4 0 Resin Resin-[Building block 1] [Building block 2] Resin-[Building block l]-[Building block 2] 0 ClS- CH3 0 R15 R Yl;OsicH --CH, 0 NHN R HSR5e [Building block 3] IS IS R R Rsc Cl 0Ni N N>sR5c H^ H r4 ResinO R R esin01)NH [Building block 1]-[Building block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2]-[Building block 3] wherein R'4, R15 are as defined for formula I and -NR5cR5d is where R5a R4a, R4b, C, q, d, and D are as defined for formula I or -D' where -D' is defined as a subset of -D that contains a primary or a secondary amine that can react as a nucleophile; and -SR5c is

where R4a, R4b, c, q, d, and D are as defined for formula I or -D' where -D' is defined as a subset of -D that contains a thiol that can react as a nu- cleophile.

The following resin, here depicted as Resin-[Building block 1] was used: where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker: = Resin The following building blocks were used: rBuilding block 2]: 4-Hydroxymethylnaphthalene-l - carbaldehyde [Building block 3]: (1P'-Bipiperidine)- 2-Thiophenemethylamine 5-Methyl-2-furanmethylamine 4'carboxamide NH2 N Cs NH2 1 -Pyrrolidinocarbonylmethyl)- 1 -(2-Furoyi)piperazine 2-Amino-2-phenylethanol piperázine ONfX3 NH2 HNDNND 0 L-Methionine ethyl ester DL-Serine methyl ester 4-Acetyl-4-phenylpiperidine 0 0 H3C' vO CH3 HO+oCH3 OO NH2 NH2 H3C)t H 4-Piperidinopiperidine N-Ethylpiperazine I -Acetylpiperazine HN(}ND HN>N CH3 H3C>O Piperazine 2-(Aminomethyl)pyridine 4-(Aminomethyl)piperidine HNSNH H2N HNSNH2 HNw 1 ,3-Diaminocyclohexane Pyrrolidine H2NXNH2 HNt> 4-(2-Aminoethyl)pyridine - 4-(Hydroxymethyl)piperidine Thiomorphoiine N NH2 XjOH HNtpS H 2-(2-Methylaminoethyl)- (s)-2-Amino-3-cyclohexyl-l- 3-lsopropylamino-n- pyridine propanol propylamine N .CH, O^r"" HYNH¼NH2 cH, CH3 L-Prolinol 4-Hydroxypiperidine 1 -Amino-2-propanol ( OH HN9OH CH3 CH, Furfurylamine 2-Methoxyisopropylamine L-lsoleucinol HN'½o1 HO'LICH, CH, 'LCH, cK3 H2N 3-Aminopentane 2-Piperidineethanol 3-Amino-l ,2-propanediol N, NH HoNH2 NH2 HO m OH Cyclopropylamine Ethylenediamine 1 -Benzyl-3-Aminopyrrolidine H2N H2N HN N 3Pyrroiidinol 2-Aminocyclohexanol Morpholine HN }OH F2 H 3-Mercaptopropionic acid Glycine tert butylester 3-Mercaptopropionic acid H H3c cH3 ethyl ester )LcH3 NH2 0 Ethylamine Methylamine 2-Aminoethanol cH H3C NH2 OH NH2 F - YN Isopropylamine Isopentylamine Dimethylamine CH3 H3Cv I CH, H1N/\CH, NH cH H2NCH3 H3c H2N CH3 Propylamine Cyclopentylamine 2-Furanylmethylamine cHI 7 NH2 F y mi H2N NH2 2-Methylimidazole 3-Amino-5-mercapto-l ,2,4- Captopril (N,yCH3 F#N0 HSNNH tHiS 0 OH 30 NH2 HS 2,2-Dimethylpropylamine N,N-Dimethylethylene- 2,4-Dimethylimidazole 0HaNH diamine H3c 2 d iam $1N H3C NH2 H cH3 3-M erca pto-l H-l ,2,4-triazol Cyclopropyimethylamine Cyclobutylamine NH2 H 4-Mercaptopyridine Thiazolidine Isopropylmercaptane sH I \ sH S,NH H3C cH3 4-(4-Trifluoromethylphenyl)- 4-(2-Thienyl)-4-piperidinol 4-(3-Trifluoromethylphenyl)- 4-piperidinol HOS 3-piperidinol HO F S FF N F OH 1OH tH H XF N H Glutamic Acid di tert butyle- 2,2,2-Trifluoroethylamine S-l-amino-2-propanol ster FNH2 HO.NH2 CH3 O F F cH3 H3C0 NH2 H c00 ycH2 Hay cho 4-(Aminomethyl)-piperidine D-Valinol Thiophene-2-ethylamine N CH3 HO NH2 kNH2 Tetrahydro-3-thiophenamine 1,1-dioxide NH2 ò,S NH2 2,3-Dimethoxybenzylamine Alfa-methylbenzylamine 1,2,3,4- H2N H,N Tetrahydroisoquinoline ¼oOcHa CH3 1 ,2,3,4-Tetrahydro-l - N-Benzylethanolamine 4-Methoxybenzyiamine naphthylamine HO I H2N v ,CH3 NH2 N'-Benzyl-N,Nn- 2-Benzylamino-1 -propanol dimethylethylenediamine HONH H3C H H3C N-lsopropylbenzylamine 1 ,2-Dimethylpropylamine D-(-)-apha-Phenylglycinol H H HaN CHO H3C3cNH¼i HOS HOHaN\/ 4-Fluorobenzylamine N-Ethylbenzylamine N-(n-propyl) Benzylamine H2NF H3C Nx (3 H3C~Nx 2-Amino-2-methyl-l -propanol Piperonylamine 4-(Trifluoromethyl)benzyl- HOH O amine H3C CH3 (0/NHa H2N#y\/FF (-)-Norephedrine 2-Methylaminoethanol 2-Butylamine H2N> HNCHiH H3CtNHC2H3 Ho OH Benzylmethylamine Diisobutylamine Cyclohexylamine H3C H,C.CH, Q N-Benzylhydroxylamine Methylaminoacetonitril N,N-Diethyl nipecotamide H 4-Aminocyclohexanol 2-lsopropylaminoethanol 1 ,3-Dimethylbutanamine NH A m i n o CHa CHa 0 HaCa)½ NH2 OH 4-Methylcyclohexylamine Alfa-methyl-4-chlorobenzyl- 4-Methoxybenzylhydroxyl- H3C) amine CHa amine Ha 2 /NH CH3 2 H CI HO 2-Phenylglycinonitrile 3-(Benzylamino)propionitrile 3-Methoxybenzylamine NHa CHa MN ThHNN y6 NHa 1 -Methyl-2- 3-Fluorobenzylamine 1 -Aminoindan phenoxyethylamine NH2 NH2 %,CH3 NH, 3-Piperidinemethanol 3,4-Dimethoxybenzylamine 2-Mercapto-5- OH CH3 methylthiadiazole HaN H N X° NH 9 CHa CHa 1 -Methyl-5-mercaptotetra- 3-Methylaminopropionitril Isopropylmethylamine zole 3 NV HaC H -N HS Y,N N H HaC CH3 N-N HaC 2-Mercaptothiazole 2-Amino-l-propanol exo-2-Aminonorbornane H3C 0/5NM\ SH NH2 OH NHa 4-Aminobenzylamine 2-Mercaptoimidazol 2-Mercapto-1 -methylimidazol H2N (NOSH NWSH HN H cHa 3-Mercapto-4-methyl-1 ,2,4- 2-Methyl-4-amino-5- 2-Phenylpiperidine triazol aminomethylpyrimidine N-N CHa HN$I /?-CH, '#"0 CH3 NH2 3-benzylamino-l -propanol 4-Aminomethylpyridine 3-Aminomethylpyridine H D iA NH2 R-2-Amino-l-propanol 4-(Ethylaminomethyl)pyridine 4-Trifluoromethoxybenzyl- HO¼Nc lCHa amine H F N 12 F 0 4-tert-Butylbenzylamine 3-Aminobenzylamine 3-(Methylaminomethyl)- NH NH2 pyridine Ha H,CIL%J NH2 INH DL-Phenylalanine methyl ester H2NS CH3 o

Preparation of resin-[Building block 11: This resin was prepared as described above.

Preparation of 4-hydroxymethylnaphtaldehyde ([Building block 2]): The preparation of this compound is described above.

Preparation of resin-[Building block 1]-[Building block 2]: Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (4- hydroxymethylnaphthylmethylene)hydrazide: Resin-[Building block 1] (4 g) was suspended in DMF (40 mL) and was allowed to swell for 15 min. and then washed with DMF (2 x 40 mL), DCM (3 x 40 mL) and DMSO (2 x 40 mL).

The solvent was removed by filtration. 1.488 g (8 mmol) 4-hydroxymethylnaphtaldehyde was dissolved in 40 mL DMSO and was added to the resin followed by 4 mL glacial acetic acid.

The suspension was shaken for 16 hours at 25 OC. The resin was successively washed with DMSO (2 x 40 mL), THF (3 x 40 mL), CH3OH (40 mL), CH2Cl2 (40 mL), CH3OH (40 mL), CH2Cl2 (40 mL) and dried in vacuo at 40 °C for 16 hours to afford resin bound 3-chloro-4- hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide.

EXAMPLE 825 3-chloro-4-hydroxybenzoic acid (4-( I H-l .2.4-Triazol-3-ylsulfanylmethyl)naphthyl- <BR> <BR> <BR> methylene)hydrazide

The resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethyl naphthylmethylene)- hydrazide (resin-[Building block 1]-[Building block 2]) (2 g, - 2 mmoles) was swelled in CH2CI2 (20 mL) for 15 min, then washed twice with CH2CI2 (20 mL). 8 mL CH2CI2 and 8 ml diisopropylethylamine was subsequently added and the suspension was cooled to 0 OC.

Methanesulfonylchioride (2 mL) was dissolved in CH2CI2 (6 mL) and added to the suspen- sion. The mixture was allowed to react at 0 °C for 30 min, then at 25 °C for 1 hour. The resin was isolated by filtration and washed with CH2CI2 (2 x 20 mL) and N-methyl-2-pyrroiidone (2 x 20 mL). lH-I,2,4-Triazole-3-thiol (0.8 g) and KI (0.4 g) was dissolved in a mixture of 10 mL N-methyl-2-pyrrolidone and 10 mL dimethylsulfoxide and was added to the resin. Then 4 mL diisopropylethylamine was added and the mixture was shaken at 25 °C for 2 days. The solvent was removed by suction and the resin was washed with N-methyl-2-pyrrolidone (3 x 20 mL) THF (3 x 20 mL), CH3OH (20 mL), CH2CI2 (20 mL), CH3OH (20 mL), CH2CI2 (4 x 20 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 °C with a 50% solution of trifluoroacetic acid in CH2CI2 (20 mL). The mixture was filtered and the resin was extracted with acetonitrile (20 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH30H (10 mL) and acetonitrile (10 mL) and con- centrated invacuo. The residue was treated with CH30H (4 mL) at 25 °C providing an off- white precipitate which was isolated by filtration. The solid was washed with CH3OH (3 x 2 mL) and dried in vacuo at 40 OC.

This afforded 275 mg of the title compound.

HPLC-MS (METHOD B): Rt = 2.48 min; m/z = 438 (M+1).

1H-NMR (300 MHz, DMSO-d,)G = 4.9 (2H, s), 7.1 (1H, d),7.5-7.9 (5H, m), 8.0 (1H, s), 8.25 (1H, d), 8.9 (1H, d), 9.1 (1H, s), 11.0 (1H, s), 11.8 (1H, s) EXAMPLE 826: 3-Chloro-4-hydroxybenzoic acid (4-(isobutylaminomethyl)naphthylmethylene)hydrazide

The resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthyl- methylene)hydrazide (resin-[Building block 1]-[Building block 2]) (50 mg, - 0.05 mmoles) was swelled in CH2CI2 (1 mL) for 15 min, then washed with CH2Cl2(2 x 0.5 mL). 0.4 mL CH2CI2 and 0.4 mL diisopropylethylamine was subsequently added and the suspension was cooled to 0 OC. Methanesulfonylchioride (0.1 mL) was dissolved in CH2CI2 (0.3 mL) and added to the suspension. The mixture was allowed to react at 0 °C for 30 min, then at 25 °C for 1 hour. The resin was isolated by filtration and washed with CH2CI2 (2 x 0.5 mL) and DMSO (0.5 mL). DMSO (0.5 mL) was added followed by 50 pL isobutylamine and 100 pL diisopropylethylamine. The mixture was shaken at 25 °C for 16 hours, filtered and washed successively with DMSO (2 x 0.5 mL), THF (3 x 0.5 mL), CH30H (0.5 mL), CH2CI2 (0.5 mL), CH30H (0.5 mL), CH2Cl2 (4 x 0.5 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 °C with a 50% solution of trifluoroacetic acid in CH2CI2 (1 mL). The mixture was filtered and the resin was extracted with acetonitrile (1 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH30H (0.5 mL) and acetonitrile (0.5mL) and concentrated in vacuo to give the title compound.

HPLC-MS (METHOD B): Rt = 4.20 min; m/z = 410 (M+1) EXAMPLE 826: 3-Chloro-4-hydroxybenzoic acid ((4-(4-trifluoromethoxybenzylamino)methyl)naphthyl- methylene)hydrazide Resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide: (resin-[building block 1]-[building block 2]) (50 mg) was swelled in a 1:1 mixture of CH2CI2 and N-methyl-2-pyrrolidone (0.5 mL) for 15 minutes and then washed with CH2CI2 (3 x 0.5 mL). 800 pL of a 1:1 mixture of CH2CI2 and diisopropylethylamine was added to the resin

which subsequently was cooled to -3 OC. A solution of 100 pL methanesulfonylchloride dis- solved in 300 pL was added and allowed to react at -3 OC for 30 minutes then at 25 OC for 1 hour. Filtration of the resin was followed by washing with CH2CI2 (2 x 1 mL) and N-methyl-2- pyrrolidone (2 x 0.5 mL). 600 pL of a solution of 4-trifluoromethoxybenzylamine (45.8 mg, 0.24 mmol, 0.4M) and KI (10 mg, 0.06 mmol, 0.1M) in N-methyl-2-pyrrolidone (0.5 mL) and diisopropylethylamine (0.1 mL) was added and allowed to react at 25 OC for 16 hours. The resin was isolated by filtration and washed successively with N-methyl-2-pyrrolidone (5 x 0.5 mL), THF (3 x 0.8 mL), CH,OH (0.8 mL), CH2Cl2 (0.8 mL), CH30H (0.8 mL) and CH2CI2 (3 x 0.8 mL). The compound was cleaved from the resin by shaking 1 hour at 25 OC with a solu- tion of 50% trifluoroacetic acid in CH2CI2 (1 mL) The mixture was filtered and the resin was extracted with acetonitrile (1 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH30H (0.5 mL) and acetonitrile (0.5mL) and con- centrated in vacuo to give the title compound.

HPLC-MS (METHOD A): Rt = 10.07 min; m/z = 528 (M+1) EXAMPLES 828 TO 875: A library of compounds of all the possible combinations of the above listed building blocks ([building block 1], [building block 2] and [building block 3]) was prepared in parallel as indi- vidual entities analogously to the previous example on an Advanced ChemTech Model 384 HTS using the following ChemFiie to control the operation of the synthesizer. The com- pounds are all expected to be present in the respective wells.

A suspension of the resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethyl- naphthylmethylene)hydrazide: (resin-[building block 1]-[building block 2]) (50 mg) in a 1:1 mixture of CH2CI2 and N-methyl-2-pyrrolidone (0.5 mL) is equally distributed in the wells in the synthesizer prior to the initialization of the device.

ChemFile C:\ACT~1328\MAIN.CHM 1 REM Nucleophilic displacement of benzylic alcohol

2 REM via mesylation 3 4 5 REM Dipense resin bound benzylic alchohol to wells 6 7 8 REM Setup Diluterl=DCM, D2=NMP (N-methyl-2-pyrrolidone), D3=NMP, D4=DCM 9 REM Adjust pressure 10 REM Add 100 mL DIEA/DCM 1:1 mixture to Reagentl 11 REM Add 70 mL MsCI/DCM 1:3 mixture to Reagent2 12 REM Add 100 mL TFA/DCM 1:1 mixture to Reagent3 13 REM Add 100 mL CH3CN to Reagent4 14 REM Nitrogen for cooling 15 16 Pause 17 REM Initialising...

18 19 REM Subroutine Empty 1~72~3min is called twice to remove DCM/NMP from dispensed resin 20 Go to ChemFile MTY72~3M.CHM, line 1 21 Go to ChemFile MTY72~3M.CHM, line 1 22 23 Flush Arm1 with Flush Diluter1 and Flush Diluter 2, Arm2 with Flush Dilter 3 and with Flush Diluter 4 24 25 REM Washing with DCM, 3 times 26 Dispense System Fluid Disdu14* 500ul to RB1lto96[I-72] 27 Mix "RB1 1to96" for 3.00 minutes at 300 rpm(s) and wait.

28 REM Subroutine Empty 1~72~3min 29 Go to ChemFile MTY72~3M.CHM, line 1 30 Repeat from step 26, 2 times 31 32 REM Adding DCM/DIEA mixture from Reagent 33 Transfer 800µl from REAGENT~1[1](DCM/DIEA) to RB1~1to96[1-72] using Flush Diluter1 34 Mix "RB1~1to96" for 1.00 minutes at 300 rpm(s) and wait.

35 Set Temperature of rack "RB1~1to96" to -3.0 degrees Celsius and wait for Temperera- ture to reach setpoint 36 Mix "RB1 1to96" for 1.00 minutes at 300 rpm(s) and wait.

37 REM Ensure complete cooling 38 Wait for 15.000 minute(s) 39 40 REM Adding mesylchloride 41 Transfer 400µl from REAGENT~2[1](MsCl/DCM) to RB1~1to96[1-72] using Flush Diluter1 42 REM Reacts 30 min @ -3 °C 43 Mix "RB1~1to96" for 1.00 minutes at 300 rpm(s) and wait.

44 Wait for 4.000 minute(s) 45 Repeat from step 43, 5 times 46 47 REM Reacts 60 min @ 25 C

48 Set Temperature of rack "RB1~1to96" to 25.0 degrees Celsius and wait for Temperera- ture to reach setpoint 49 Mix "RB1~1to96" for 1.00 minutes at 300 rpm(s) and wait.

50 Wait for 4.000 minute(s) 51 Repeat from step 46, 11 times 52 53 REM Subroutine Empty1~72~3min 54 Go to ChemFile MTY72~3M.CHM, line 1 55 56 REM Initiate washing procedure, 2XDCM 57 Dispense System Fluid Disdu1~4* 1000ul to RB1~1to96[1-72] 58 Mix "RB1~1to96" for 3.00 minutes at 300 rpm(s) and wait.

59 Go to ChemFile MTY72~3M.CHM, line 1 60 Repeat from step 57, 1 times 61 62 REM NMP wash 63 64 Dispense System Fluid Disdu2~3* 500ul to RB1~1to96[1-72] 65 Mix "RB1~1to96" for 5.00 minutes at 300 rpm(s) and wait.

66 Go to ChemFile MTY72~3M.CHM, line 1 67 68 Go to ChemFile MTY72~3M.CHM, line 1 69 Repeat from step 64, 1 times 70 71 REM Make sure that nucleophiles are dissolved and ready for addition 72 Pause 73 74 Dispense Sequence C:\ACT~1328\R2-A.DSP with 600µl to RB1~1to96 rack using Flush Diluter2 75 REM Nucleophiles react @ 25 C for 16 hr 76 Mix "RB1~1to96" for 1.00 minutes at 300 rpm(s) and wait.

77 Wait for 4.000 minute(s) 78 Repeat from step 76, 11 times 79 Repeat from step 76, 15 times 80 81 REM End of reaction 82 Go to ChemFile MTY72~3M.CHM, line 1 83 Go to ChemFile MTY72~3M.CHM, line 1 84 85 REM Commence final washing procedure 86 Dispense System Fluid Disdu2~3* 500ul to RB1~1to96[1-72] 87 Mix "RB1~1to96" for 10.00 minutes at 300 rpm(s) and wait.

88 Go to ChemFile MTY72~3M.CHM, line 1 89 Go to ChemFile MTY72~3M.CHM, line 1 90 Repeat from step 86, 4 times 91 92 REM Change systemfluids: 93 REM * Diluter2: THF 94 REM * Diiuter3: MeOH

95 Pause 96 97 Flush Arm1 with Flush Diluter1 and Flush Diluter 2, Arm2 with Flush Diluter 3 and Flush Diluter 4 98 REM THF wash 3 times 99 Dispense System Fluid Flush Diluter 2 800µl to RB1~1to96[1-72] 100 Mix "RB1~1to96" for 10.00 minutes at 300 rpm(s) and wait.

101 Go to ChemFile MTY72~3M.CHM, line 1 102 Go to ChemFile MTY72~3M.CHM, line 1 103 Repeat from step 99, 2 times 104 105 REM Alternating MeOH/DCM wash, 2 cycles 106 Dispense System Fluid Flush Diluter 3 800µl to RB1~1to96[1-72] 107 Mix "RB1~1to96" for 3.00 minutes at 300 rpm(s) and wait.

108 Go to ChemFile MTY72~3M.CHM, line 1 109 110 Dispense System Fluid Disdu1~4* 800ul to RBllto96[I-72] 111 Mix "RB1~1to96" for 10.00 minutes at 300 rpm(s) and wait.

112 Go to ChemFile MTY72~3M.CHM, line 1 113 Go to ChemFile MTY72~3M.CHM, line 1 114 115 Repeat from step 106, 1 times 116 117 Dispense System Fluid Disdul 4* 800µl to RB1~1to96[1-72] 118 Mix "RB1~1to96" for 10.00 minutes at 300 rpm(s) and wait.

119 Go to ChemFile MTY72~3M.CHM, line 1 120 Repeat from step 117,1 times 121 122 REM Washing procedure has ended 123 124 REM Setup for cleavage: 125 REM * Cleavage vials 126 REM * Lower pressure 127 REM * Add 100 mL TFA/DCM 1:1 mixture to Reagent3 128 REM * Add 100 mL CH3CN to Reagent4 129 Pause 130 131 REM Adding cleavage solution, 1hr 132 Transfer 1000ul from REAGENT~3[1](TFA/DCM) to RB1~1to96[1-72] using Flush Di- luterl 133 Mix "RB1~1to96" for 1.00 minutes at 300 rpm(s) and wait.

134 Wait for 4.000 minute(s) 135 Repeat from step 133,11 times 136 REM PULSE EMPTY! 137 Go to ChemFile PULSEMP1.CHM, line 1 138 139 REM Washing with CH3CN 140 Transfer 500µl from REAGENT~4[1](CH3CN) to RB1~1to96[1-72] using Flush Diluterl 141 Mix "RB1~1to96" for 10.00 minutes at 300 rpm(s) and wait.

142 REM PULSE EMPTY! 143 Go to ChemFile PULSEMP1.CHM, line 1 144 145 REM The End 146 The following chemfile is called to empty the wells of the reaction block.: ChemFile C:\ACT~1328\MTY72~3M.CHM 1 REM Subroutine Empty 1~72~3min 2 Empty RB1~~1to96 for 5.000 minute(s) 3 Return The following chemfile is called to empty the wells of the reaction block into the cleavage vi- als containing the final product in a controlled manner.

ChemFile C:\ACT~1328\PULSEMP1.CHM 1 Empty RB1~1to96 for 1 second(s) 2 Wait for 4 second(s) 3 Repeat from step 1, 11 times 4 Empty RB1~1to96 for 5.000 minute(s) 5 Return Dispense sequence C:\ACT~1328\R2-A.DSP is a subroutine that controls the combinatorial addition of the amines into the reaction block in the syntheziser.

Examples of compounds from this library were characterised by HPLC-MS (molecular mass & retention time) including the following examples 828 to 875: Ex No. Structure HPLC-MS HPLC-MS (METHOD (METHOD B) B) m/z (M+1 ) Rt (minutes) 8283 422 6.10 829 o NH 410 4.20 HO'gJ NN\J H C , gNN)95 QCH cH3 831 CH3 508 13.30 OOCH, 832 ao X 450 7.87 CI -V 833 H N-Nt\N 448 7.07 H cHa Ex No. Structure HPLC-MS HPLC-MS (METHOD (METHOD A) A) m/z (M+1) Rt (minutes) 848 H N-Nt\H 3 484 9.80 849 , zN NhtH<F 462 9.38 F EXAMPLE 874:

'H NMR (DMSO-D6) d 2.37 (m, 8H), 3.44 (s, 2H), 3.90 (s, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 7.4 Hz, 1H), 7.67 (m, 2H), 7.81 (d, J = 8.7Hz, 1H), 7.86 (d, J = 7.3 Hz, 1H), 8.02 (d, J = 1.8Hz, IH), 8.36 (dd, J = 1.7,7.0 Hz, 1H), 8.83 (d, J = 8.0 Hz, 1H), 9.08 (s, 1H), 10.99 (s, 1H), 11.78 (s, 1H). MS (APCI, pos.): 547.1, 550.1 EXAMPLE 875: 1H NMR (DMSO-D5) d 2.66 - 2.75 (m, 4H), 3.69 (s, 2H), 4.06 (s, 2H), 6.36 (m, 1H), 6.40 (m, 1H), 7.06 (d, J = 8.5 Hz, 1H), 7.51 - 7.66 (m, 4H), 7.77 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.1 Hz, 1H), 7.98 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.80 (d, J = 8.5 Hz, 1H), 9.04 (s, 1H), 10.94 (s, 1H), 11.77 (s, 1H). MS (APCI, pos.): 485.1,487.1 General Procedure for Examples 876 to 877: The compounds were prepared as single entities according to the following equation Resin-[Building block 1] Resin-[Building block 1]-[Building block 2] Resin-[Building block 1]-[Building block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2] [Building block 3] [Building block 4] and were simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula

[Building block 1] [Building block 2] [Building block 3] [Building block 4].

The following compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block l]-[Building block 2] was done manually, whereas the attachment of [Building block 3], attachment of [Building block 4] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS.

The starting resin, Resin-[Building block 1], was prepared as described above.

The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g.

All compounds are based on successive attachment of [Building block 2] and [Building block 3] to Resin-[Building block 1] in a combinatorial way using a nucleophilic substitution reaction followed by an acylation reaction attaching [Building block 4] according to the following for- mulae, which are included in the general formula II:

R15 R15 N1OH Resin1 + H})$OH Resin 0 R Resin-[Building block 1] [Building block 2] Resin-[Building block ll-[Building block 2] 0 ClS- CH3 0 R1s H2NR5a R15 o X [%u)lding block -OS, - CH3 Cl><NeNw Cl+tN N>e Resin zO4j H Ra4 Resin 0lHRI4 Resin-[Building block l]-[Building block 2]-[Building block 3] 0 Lea [Building block 4] 0 c R15 N I. R55 Resin lRc 0 RIC Cl NH NN9 Cl N N' NN0 Resin R14 R H. H R14 Resin-[Building block 1]-[Building block 2]-[Building block 3]-[Building block 4] [Building block 1]-[Building block 2]-[Building block 3]-[Building block 4] wherein R6a, R14, R15 are as defined for formula I and R5C is where R4a, R4b, c, q, d, and D are as defined for formula I or -D' where -D' is defined as a subset of -D that contains an activated carboxylic acid capable of reacting as an electrophile and Lea is a leaving group such as chloro, bromo, iodo, carboxylate,

The following resin, here depicted as Resin-[Building block 1] was used: where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker: = Resin The following building blocks were used: [Building block 2]: 4-Hydroxymethylnaphthalene-l - carbaldehyde [Building block 3] 2-Thiophenemethylamine S-Methyl-2-furanmethylamine L-Methionine ethyl ester H2N#j H3CmNH2 H3C' H NH, 2-(Aminomethyl)pyridine 4-(2-Aminoethyl)pyridine 3-Aminopentane H2N%N\ N(3 NH2 HaC¼7cHa Furfurylamine 2-Methoxyisopropylamine Cyclopropylamine H,NO-CH, H2N H2N½j/ cHa Glycine 2-Furanylmethylamine N ,N-Dimethylethylenedi- O OH NH2 amine NH2 0 Ha0 NH2 Ethylamine Methylamine Propylamine HaC. CHa NH2 CHa NH2 H2N Isopropyiamine Isopentylamine Cyclopentylamine cHa CH H2N cHa NH2 H2Na 3 NH2 CH3 Cyclopropylmethylamine Cyclobutylamine Thiophene-2-ethylamine NH2 q ff¼S/ NH2 NH, Glutamic Acid di tert butyle- 2,2,2-Trifluoroethylamine Tetrahydro-3-thiophenamine ster F>¼NH ,1dioxide H,C O F 2 NH, NH2 )½NH2 0 0 HaC 0Ha

[Building block 4]: Acetic anhy- N-tert Butoxycarbonyl- dride proline anhydride H3Ct CH3 0#wN CH3 H3CO H3Cvio ° ° O+CHH3 0 CH3 3 Preparation of resin-[Building block 1]: This resin was prepared as described above.

Preparation of resin-[Building block 1]-[Building block 2]: This resin was prepared as described above.

EXAMPLE 876: N-{4-[(3-Chloro-4-hydroxybenzoyl)-hydrazonomethyl]naphthylme thyl}-N-isobutylprolinamide The resin bound 3-chloro-4-hydroxybenzoic acid (4-hyd roxymethylnaphthyl- methylene)hydrazide (resin-[Building block 1]-[Building block 2]) (50 mg, - 50 µmoles) was swelled in CH2Ci2 (0.5 mL) for 15 min, then washed twice with CH2CI2 (0.5 mL). 0.4 mL CH2CI2 and 0.4 mL diisopropylethylamine were subsequently added and the suspension was cooled to 0 OC. Methanesulfonylchloride (0.1 mL) was dissolved in CH2CI2 (0.3 mL) and added to the suspension. The mixture was allowed to react at 0 °C for 30 min, then at 25 °C for 1 hour. The resin was isolated by filtration and washed with CH2CI2 (2 x 0.5 mL) and DMSO (0.5 mL). 0.5 mL DMSO was added to the resin followed by isobutylamine (50 pL)

and diisopropylethylamine (100 pL). The mixture was shaken at 25 OC for 16 hours. The sol- vent was removed by suction and the resin was washed with DMSO (2 x 0.5 mL) andTHF (3 x 0.5 mL). To a solution of N-tert- butoxycarbonyl-proiine (46 mg, 0.21 mmol) in THF (0.5 mL) was added diisopropylcarbodiimide (16 pL, 0.2 mmol). This solution was allowed to re- act at 25 °C for 10 minutes and then added to the resin. The suspension was shaken at 25 °C for 16 hours after which the resin was isolated by suction and washed with THF (3 x 0.5 mL), DMF (3 x 0.5 mL) THF (3 x 0.5 mL), CH30H (0.5 mL), CH2CI2 (0.5 mL), CH30H (0.5 mL), CH2CI2 (4 x 0.5 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 °C with a 50% solution of trifluoroacetic acid in CH2CI2 (1 mL). The mixture was filtered and the resin was extracted with acetonitrile (1 mL). The combined extracts were concen- trated in vacuo. The residue was redissolved in a mixture of CH30H (0.5 mL) and acetonitrile (0.5 mL) and concentrated in vacuo to give the title compound.

HPLC-MS (METHOD B): R, = 3.90 min; m/z = 507 (M+1).

EXAMPLE 877: 3-Chloro-4-hydroxybenzoic acid ((4-(4-trifluoromethoxybenzylamino)methyl)naphthyl- methylene)hydrazide Resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide (resin-[building block l]-[building block 2]) (50 mg) was swelled in a 1:1 mixture of CH2CI2 and N-methyl-2-pyrrolidone (0.5 mL) for 15 minutes and then washed with CH2CI2 (3 x 0.5 mL). 800 pL of a 1:1 mixture of CH2CI2 and diisopropylethylamine was added to the resin which subsequently was cooled to -3 OC. A solution of 100 pL methanesulfonylchloride dis- solved in 300 pL was added and allowed to react at -3 °C for 30 minutes then at 25 °C for 1 hour. Filtration of the resin was followed by washing with CH2Cl2 (2 x 1 mL) and N-methyl-2- pyrrolidone (2 x 0.5 mL). 600 pL of a solution of 4-trifluoromethoxybenzylamine (45.8 mg, 0.24 mmol, 0.4M) and Kl (10 mg, 0.06 mmol, 0.1M) in N-methyl-2-pyrrolidone (0.5 mL) and

diisopropylethylamine (0.1 mL) was added and allowed to react at 25 °C for 16 hours. The resin was isolated by filtration and washed successively with N-methyl-2-pyrrolidone (5 x 0.5 mL) and THF (3 x 0.5 mL). 600 pL of a solution of acetic anhydride (120 pL, 130 mg, 1.27 mmol) in THF (480 pL) was added to the resin. The mixture was allowed to react at 25 °C for 16 hr. The resin was filtered and washed successively with THF (2 x 0.8 mL), CH30H (0.8 mL), CH2Cl2 (0.8 mL), CH3OH (0.8 mL) and CH2Cl2 (3 x 0.8 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 °C with a solution of 50% trifluoroacetic acid in CH2Cl2 (1 mL). The mixture was filtered and the resin was extracted with acetonitrile (1 mL).

The combined extracts were concentrated in vacuo. The residue was redissolved in a mix- ture of CH30H (0.5 mL) and acetonitrile (0.5mL) and concentrated in vacuo to give the title compound.

HPLC-MS (METHOD B): Rt = 6.42 min; m/z = 492 (M+1) EXAMPLES 878 TO 881: A library of compounds of all the possible combinations of the above listed building blocks ([building block 1], [building block 2], [building block 3] and acetic anhydride as [building block 4]) was prepared in parallel as individual entities analogously to the previous example on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the op- eration of the synthesizer. The compounds are all expected to be present in the respective wells.

A suspension of the resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethyl- naphthylmethylene)hydrazide (resin-[building block 1]-[building block 2]) (50 mg) in a 1:1 mixture of CH2Cl2 and N-methyl-2-pyrrolidone (0.5 mL) is equally distributed in the wells in the synthesizer prior to the initialization of the device.

ChemFile C:\ACT~1328\MAIN.CHM 1 REM Nucleophilic displacement of benzylic alcohol 2 REM via mesylation 3 4

5 REM Dipense resin bound benzylic alchohol to wells 6 7 8 REM Setup Diluterl=DCM, D2=NMP (N-methyl-2-pyrrolidone), D3=NMP, D4=DCM 9 REM Adjust pressure 10 REM Add 100 mL DIEA/DCM 1:1 mixture to Reagentl 11 REM Add 70 mL MsCI/DCM 1:3 mixture to Reagent2 12 REM Add 100 mL TFA/DCM 1:1 mixture to Reagent3 13 REM Add 100 mL CH3CN to Reagent4 14 REM Nitrogen for cooling 15 16 Pause 17 REM Initialising...

18 19 REM Subroutine Empty 1~72~3min is called twice to remove DCM/NMP from dispensed resin 20 Go to ChemFile MTY72~3M.CHM, line 1 21 Go to ChemFile MTY72~3M.CHM, line 1 22 23 Flush Arm1 with Flush Diluterl and Flush Diluter 2, Arm2 with Flush Diluter 3 and with Flush Diluter 4 24 25 REM Washing with DCM, 3 times 26 Dispense System Fluid Disdu1~4* 500ul to RB1~1to96[1-72] 27 Mix "RB1~1to96" for 3.00 minutes at 300 rpm(s) and wait.

28 REM Subroutine Empty1~72~3min 29 Go to ChemFile MTY72~3M.CHM, line 1 30 Repeat from step 26, 2 times 31 32 REM Adding DCM/DIEA mixture from Reagent1 33 Transfer 800µl from REAGENT~1[1](DCM/DIEA) to RB1~1to96[1-72] using Flush Diluter1 34 Mix "RB1 1to96" for 1.00 minutes at 300 rpm(s) and wait.

35 Set Temperature of rack "RB1~1to96" to -3.0 degrees Celsius and wait for Temperature to reach setpoint 36 Mix "RB1 1to96" for 1.00 minutes at 300 rpm(s) and wait.

37 REM Ensure complete cooling 38 Wait for 15.000 minute(s) 39 40 REM Adding mesyichloride 41 Transfer 400µl from REAGENT~2[1](MsCl/DCM) to RB1~1to96[1-72] using Flush Diluter1 42 REM Reacts 30 min @ -3 °C 43 Mix "RB1~1to96" for 1.00 minutes at 300 rpm(s) and wait.

44 Wait for 4.000 minute(s) 45 Repeat from step 43, 5 times 46 47 REM Reacts 60 min @ 25 C 48 Set Temperature of rack "RB1~1to96" to 25.0 degrees Celsius and wait for Temperature to reach setpoint 49 Mix "RB1~1to96" for 1.00 minutes at 300 rpm(s) and wait.

50 Wait for 4.000 minute(s) 51 Repeat from step 46, 11 times 52 53 REM Subroutine Empty1~72~3min 54 Go to ChemFile MTY72~3M.CHM, line 1 55 56 REM Initiate washing procedure, 2XDCM 57 Dispense System Fluid Disdu1~4* 1000ul to RB1~1to96[1-72] 58 Mix "RBl~1to96" for 3.00 minutes at 300 rpm(s) and wait.

59 Go to ChemFile MTY72~3M.CHM, line 1 60 Repeat from step 57, 1 times 61 62 REM NMP wash 63 64 Dispense System Fluid Disdu2~3* 500ul to RB1~1to96[1-72] 65 Mix "RB1~1to96" for 5.00 minutes at 300 rpm(s) and wait.

66 Go to ChemFile MTY72~3M.CHM, line 1 67 68 Go to ChemFile MTY72~3M.CHM, line 1 69 Repeat from step 64, 1 times 70 71 REM Make sure that nucleophiles are dissolved and ready for addition 72 Pause 73 74 Dispense Sequence C:\ACT~1328\R2-A.DSP with 600ul to RB1~1to96 rack using Flush Diluter 2 75 REM Nucleophiles react @ 25 C for 16 hr 76 Mix "RB1~1to96" for 1.00 minutes at 300 rpm(s) and wait.

77 Wait for 4.000 minute(s) 78 Repeat from step 76, 11 times 79 Repeat from step 76, 15 times 80 81 REM End of nucleophilic substitution reaction 82 Go to ChemFile MTY72~3M.CHM, line 1 83 Go to ChemFile MTY72~3M.CHM, line 1 84 85 REM Commence washing procedure 86 Dispense System Fluid Disdu2~3* 500ul to RB1~1to96[1-72] 87 Mix "RB1~1to96" for 10.00 minutes at 300 rpm(s) and wait.

88 Go to ChemFile MTY72~3M.CHM, line 1 89 Go to ChemFile MTY72~3M.CHM, line 1 90 Repeat from step 86, 4 times 91 92 REM Change systemfluids: 93 REM * Diluter2: THF 94 REM * Diiuter3: MeOH 95 Pause 96

97 Flush Arm1 with Flush Diluterl and Flush Diluter 2 , Arm2 with Flush Diluter 3 and Flush Diluter 4 98 REM THF wash 3 times 99 Dispense System Fluid Flush Diluter 2 500µl to RB1~1to96[1-72] 100 Mix "RB1~1to96" for 10.00 minutes at 300 rpm(s) and wait.

101 Go to ChemFile MTY72~3M.CHM, line 1 102 Go to ChemFile MTY72~3M.CHM, line 1 103 Repeat from step 99, 2 times 104 Go to ChemFile Acylation.CHM, line 1 105 Go to ChemFile WASH.CHM, line 1 106 Go to ChemFile Cleavage.CHM, line 1 107 REM The End The following chemfile is called to acylate the amines: ChemFile C:\ACT~1328\Acetyl.CHM 1 REM Acetylation procedure 2 REM Charge REAGENT~S with 100 mL Acetic anhydride/THF 1:4 v/v 3 REM * Diiuter2: THF 4 REM Addition of acylation reagent 5 Dispense Sequence C:\R3-A.DSP with 600 pL to RB1to96 rack using Flush Diluter 2 6 Mix for 1.00 minutes at 300 rpm(s) 7 Wait for 5.000 minute(s) 8 Repeat from step 6, 60 times 9 Go to ChemFile MTY72~3M.CHM, line 1 10 Go to ChemFile MTY72~3M.CHM, line 1 11 Retrun The following chemfile is called to wash the resin bound products: ChemFile C:\ACT~1328\WASH.CHM 1 REM Washing procedure 2 REM Systemfluids: 3 4 REM * Diluter2: THF 5 REM * Diluter3: MeOH 6 7 Flush Arm1 with Flush Diluter1 and Flush Diluter 2, Arm2 with Flush Diluter 3 and Flush Diluter 4 8 REM THF wash 3 times 9 Dispense System Fluid Flush Diluter 2 800ul to RBl~1to96[I-72] 10 Mix "RB1~1to96" for 10.00 minutes at 300 rpm(s) and wait.

11 Go to ChemFile MTY72~3M.CHM, iine 1 12 Go to ChemFile MTY72~3M.CHM, line 1 13 Repeat from step 9, 2 times 14 15 REM Alternating MeOH/DCM wash, 2 cycles 16 Dispense System Fluid Flush Diluter 3 800ul to RB1~1to96[1-72] 17 Mix "RB1~1to96" for 3.00 minutes at 300 rpm(s) and wait.

18 Go to ChemFile MTY72~3M.CHM, line 1 19 20 Dispense System Fluid Disdu1~4* 800ul to RB1~1to96[1-72] 21 Mix "RB1~1to96" for 10.00 minutes at 300 rpm(s) and wait.

22 Go to ChemFile MTY72~3M.CHM, line 1 23 Go to ChemFiie MTY72~3M.CHM, line 1 24 25 Repeat from step 16, 1 times 26 27 Dispense System Fluid Disdu1~4* 800ul to RB1~1to96[1-72] 28 Mix "RB1~1to96" for 10.00 minutes at 300 rpm(s) and wait.

29 Go to ChemFile MTY72~3M.CHM, line 1 30 Repeat from step 117, 1 times 31 32 REM Washing procedure has ended 33 Return The following chemfile is called to cleave the products from the resin: ChemFile C:\ACT~1328\Cleavage.CHM 1 REM Setup for cleavage: 2 REM * Cleavage vials 3 REM * Lower pressure 4 REM * Add 100 mL TFA/DCM 1:1 mixture to Reagent3 5 REM * Add 100 mL CH3CN to Reagent4 6 Pause 7 8 REM Adding cleavage solution, Ihr 9 Transfer 1000ul from REAGENT 3[1](TFA/DCM) to RB1~1to96[1-72] using Flush Diluterl 10 Mix "RB1~1to96" for 1.00 minutes at 300 rpm(s) and wait.

11 Wait for 4.000 minute(s) 12 Repeat from step 133, 11 times 13 REM PULSE EMPTY! 14 Go to ChemFile PULSEMP1.CHM, line 1 15 16 REM Washing with CH3CN 17 Transfer 500µl from FEAGENT~4[1](CH3CN) to RB1~1to96[1-72] using Flush Diluter1 18 Mix "RB1~1to96" for 10.00 minutes at 300 rpm(s) and wait.

19 REM PULSE EMPTY! 20 Go to ChemFile PULSEMP1.CHM, line 1 21 Return The following chemfile is called to empty the wells of the reaction block.: ChemFile C:\ACT~1328\MTY72~3M.CHM Page 1 1 REM Subroutine Empty1~72~3min 2 Empty RB1~1to96 for 5.000 minute(s) 3 Return The following chemfile is called to empty the wells of the reaction block into the cleavage vi- als containing the final product in a controlled manner.

ChemFile C:\ACT~1328\PULSEMP1.CHM Page 1 1 Empty RB1~1to96 for 1 second(s) 2 Wait for 4 second(s) 3 Repeat from step 1, 11 times 4 Empty RB1~1to96 for 5.000 minute(s) 5 Return Dispense sequence C:\ACT~1328\R2-A.DSP is a subroutines that control the combinatorial addition of the amines into the reaction block in the syntheziser.

Dispense sequence C:\ACT~1328\R3-A.DSP is a subroutines that control the combinatorial addition of the acylating agents into reaction block in the syntheziser.

Examples of compounds from this library were characterised by HPLC-MS (molecular mass & retention time) including the following examples 878 to 881. Ex No. Structure HPLC-MS HPLC-MS (METHOD (METHOD B) B) m/z (M+1) Rt (minutes) 878 H O CH3 490 6.22 N-NXJNR3 879 HO/\ O OcHa 454 1.05 N-N<> N \/H90 880 H.0#4 H 464 6.33 CI HNN; o)r-CHa 881 HCH, o=C3 450 5.30 N- NNb

EXAMPLE 882: N-{4-[3-chloro-4-hydroxybenzoyl)-hydrazonemethyl]-1-naphthyl }methyl iso-propyl amide Preparation of N-4-Formylnaphthylmethyl isopropyl amide: A mixture of 4-bromomethyl-1-naphthaldehyde ethyleneacetal (447 mg, 1.52 mmol) and NaN3 (221 mg, 3.4 mmol) in 10 mL DMF was warmed up to 100 °C and stirred for 30 min.

Solution turned orange. The reaction was filtered and the clear solution was concentrated to 391 mg of yellow oil. This oil (249 mg) together with triphenylphosphine (260 mg, 0.99 mmol) was dissolved in 10 mL of THF. The reaction mixture was left overnight followed by the addition of water. Ninhydrin test revealed the formation of an amine. This amine was extracted into ethyl acetate layer, dried to give an oil. This oil was dissolved in CH2CI2, EDC, DMAP and 2-methylpropionic acid were added. The reaction mixture was left for 2 days.

Column chromatography eluted with ethyl acetate afforded the amide. Deprotection of di- ethyleneacetal was achieved by 10% HCI in THF to give the title compound (50 mg).

'H NMR (CDCl3): d 1.2 (d, 6H), 2.4 (m, 1H), 4.9 (d, 2H), 6.1 (b, 1H), 7.5 (d, 1H), 7.6 (m, 2H), 7.8 (d, 1H), 8.0 (d, 1H), 9.2 (d, 1H), 10.3 (s, 1H).

The title compound was prepared similarly as described above.

1H NMR (DMSO-D5): d 1.0 (d, 6H), 2.4 (m, 1H), 4.7 (s, 2H), 7.0 (d, 1H), 7.4 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 7.8 (d, 1H), 7.9 (s, 1H), 8.1 (d, 1H), 8.3 (s, 1H), 8.8 (d, 1H), 9.0 (s, 1H) 10.9 (s, 1 H), 11.7 (s, 1 H); ms (APCI negative); 422.

EXAMPLE 883: 4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthylmet hll iso-propylsulfoxide:

4-Ethyleneacetal-4-formyl-naphthyimethyl iso-propylthioether: A mixture of 4-bromomethyl naphthaldehyde ethyleneacetal (232 mg, 0.79 mmol) and iso- propyl thioalcohol (0.08 mL, 0.81 mmol) and 0.12 mL of triethylamine was left at room tem- perature for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography eluted with ethyl acetate Ihexane (1/5) to afford 93 mg of the desi- red product as pale radish oil.

'H NMR (CDCl3): d 1.3 (d, 6H), 2.9 (m, 1H), 4.2 (m, 6H), 6.5 (s, 1H), 7.4 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 8.2 (m, 1H).

4-Ethyleneacetal-naphthylmethyl iso-propylsulfoxide: To a mixture of the above 4-ethyleneacetal-naphthylmethyl iso-propylthioether (79 mg, 0.27 mmol) in 5 mL of dichloromethane at -78 °C was added m-chloro perbenzoic acid (82 mg, 55% purity, 0.28 mmol). The reaction mixture was left for 1 hour and 40 min. Then, NaHSO3 solution was added followed by NaHCO3. The mixture was extracted with water and dichloromethane. The organic layer was combined and dried over MgSO4. Solvent was removed and the residue was purified by column chromatography eluted with ethyl acetate to yield 56 mg of desired product as an oil.

'H NMR (CDCl3): d 1.3 (d, 3H), 1.4 (d, 3H), 2.7 (m, 1H), 4.2 (m, 4H), 4.4 (dd, 2H), 6.5 (s, 1H), 7.5 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 8.1 (m, 1H), 8.2 (m, 1H). This compound was hy- drolyzed in aqueous 10% HCI in THF for 1 hr to give the corresponding aldehyde.

4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthyl methyl iso-propylsulfoxide: The title compound was prepared similarly as described above.

'H NMR (DMSO-D6): d 1.3 (dd, 6H), 3.0 (m, 1H), 4.3 (d, 1H), 4.7 (d, 1H), 7.1 (d, 1H), 7.6 (m, 3H), 7.8 (d, 1H), 7.9 (d, 1H), 8.0 (s, 1H), 8.2 (d, 1H), 8.8 (d, 1H), 9.1 (s, 1H), 11.0 (s, 1H), 11.8 (s, 1H); ms (APCI negative); 427, 337.

EXAMPLE 884: 4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthylmet hyl iso-propylsulfone Similarly, the title compound was prepared.

'H NMR (DMSO-D6): d 1.3 (d, 6H), 3.4 (m, 1H), 5.0 (s, 2H), 7.0 (d, 1H), 7.6 (m, 3H), 7.7 (d, 1H), 7.9 (d, 2H), 8.2 (d, 1H), 8.7 (d, 1H), 9.0 (s, 1H), 10.9 (s, 1H), 11.8 (s, 1H); ms (APCI negative); 443, 336.

EXAMPLE 885: 4-[3-chloro-4-hyd roxybenzoyl)-hydrazonomethyl]-1 -naphthylmethyl iso-propylsulfide Similarly, the title compound was prepared.

Further examples of the invention are the following compounds: EXAMPLE 886: EXAMPLE 887: EXAMPLE 888: EXAMPLE 889:

EXAMPLE 890: EXAMPLE 891: EXAMPLE 892: EXAMPLE 893: EXAMPLE 894:

It should be apparent from the foregoing that other starting materials and other intermediate compounds can be substituted in the above procedures to prepare all of the compounds of the invention. The methods disclosed herein are based on established chemical techniques, as will be apparent to those skilled in the art, and therefore all of the compounds of the invention are broadly enabled by the preceding disclosure.

Accordingly, the invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all re- spects only as illustrative and not restrictive, and the scope of the invention is, therefore, indi- cated by the appended claims rather than by the foregoing description. All modifications which come within the meaning and range of the lawful equivalency of the claims are to be embraced within their scope.