Inhibitors of histone deacetylase

• US 7,838,520 B2
• Filed: 03/15/2005
• Issued: 11/23/2010
• Est. Priority Date: 09/14/2001
• Status: Expired due to Term

• Current Assignee: 92229129 Quebec Inc.
• Original Assignee: MethylGene, Inc. (Bristol-Myers Squibb Company)
• Inventors: Frechette, Sylvie, Bouchain, Giliane, Woo, Soon Hyung, Zhou, Zhihong, Vaisburg, Arkadii, Raeppel, Stephane, Leit, Silvana, Delorme, Daniel, Moradei, Oscar
• Primary Examiner(s): Balasubramanian; Venkataraman
• Application Number:
  US11/081,095
• Publication Number:
  US 20060058298A1
• Time in Patent Office: 2,079 Days
• Field of Search: 564/155, 564/161, 544/113, 544/196, 544/264, 544/283, 544/353, 544/358, 514/617, 514/231.5, 514/252.01, 514/252.1, 514/256, 514/269, 514/359
• US Class Current: 514/231.5
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/537 spiro-condensed or forming part of bridged ring systems
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 233/44 having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
• CPC Class Codes: C07C 233/80 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/38 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/42 having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 235/56 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/84 with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/20 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 237/22 : having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 237/40 : having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/42 : having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07C 255/58 : containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
• CPC Class Codes: C07C 255/59 : the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 275/34 : having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 275/36 : with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
• CPC Class Codes: C07C 311/42 : to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 323/32 : having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
• CPC Class Codes: C07C 323/36 : the sulfur atom of the sulfide group being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 323/44 : X or Y being nitrogen atoms
• CPC Class Codes: C07C 323/60 : with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07C 381/00 : Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 239/91 : with aryl or aralkyl radicals attached in position 2 or 3
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 251/18 : with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
• CPC Class Codes: C07D 251/52 : with an oxygen or sulfur atom attached to the third ring carbon atom
• CPC Class Codes: C07D 251/54 : Three nitrogen atoms
• CPC Class Codes: C07D 263/14 : with radicals substituted by oxygen atoms
• CPC Class Codes: C07D 263/24 : with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
• CPC Class Codes: C07D 265/36 : condensed with one six-membered ring
• CPC Class Codes: C07D 271/06 : 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 277/42 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 277/74 : Sulfur atoms substituted by carbon atoms
• CPC Class Codes: C07D 277/82 : Nitrogen atoms
• CPC Class Codes: C07D 295/155 : with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/12 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 307/28 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 311/56 : without hydrogen atoms in position 3
• CPC Class Codes: C07D 311/58 : other than with oxygen or sulphur atoms in position 2 or 4
• CPC Class Codes: C07D 333/36 : Nitrogen atoms
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 473/40 : with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems
• CPC Class Codes: C07F 7/081 : comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
• CPC Class Codes: C07F 7/0812 : comprising a heterocyclic ring

Abstract

The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

Claims

1. A histone deacetylase inhibitor of formula (3):

2. The compound according to claim 1 wherein Ar³ has the structure:

3. The compound according to claim 1 wherein when X² is a chemical bond, then Ar³ is not

4. The compound according to claim 2 wherein Q at each occurrence is C(R⁸), where R⁸ is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy.

5. The compound according to claim 2 wherein from one to about three Q are nitrogen.

6. The compound according to claim 1 wherein Ar³ is selected from the group consisting of phenylene, pyridylene, thiazolylene, and quinolylene.

7. The compound according to claim 1 wherein X² is a chemical bond.

8. The compound according to claim 1 wherein X² is C₁-C₄ alkylene, C₂-C₄ alkenylene, or C₂-C₄ alkynylene.

9. The compound according to claim 1 wherein X² is C₁C₄ alkylene.

10. The compound according to claim 1 wherein X² is methylene or ethylene.

11. The compound according to claim 1 wherein X² is C₂-C₄ alkenylene or C₂-C₄ alkynylene.

13. The compound according to claim 1 wherein Cy₃ is heteroaryl which is optionally substituted and is optionally fused to one or two aryl rings.

14. The compound according to claim 1 wherein Cy³ is pyridyl, pyrimidinyl, imidazolyl, thiazolyl, oxadiazolyl, or quinolyl, each of which is optionally substituted and is optionally fused to one or two aryl rings.

15. The compound according to the claim 1 wherein Cy³ is fused to a benzene ring.

16. The compound according to claim 1 wherein Cy³ has from one to three substituents independently selected from the group consisting of alkyl, alkoxy, aryl, aralkyl, amino, halo, haloalkyl, and hydroxyalkyl.

17. The compound according to claim 16 wherein the substituents are selected from methyl, methoxy, fluoro, trifluoromethyl, amino, aminomethyl, hydroxymethyl, and phenyl.

18. The compound according to claim 1 wherein Cy³ has from one to three substituents of the formula —

K¹—

N(H)(R¹⁰), wherein

K¹ is a chemical bond or C₁-C₄ alkylene;

R¹⁰ is selected from the group consisting of Z′ and

-Ak²-Z′

, wherein

Ak² is C₁-C₄ alkylene; and

Z′

is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted, and each of which is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings.

19. The compound according to claim 18 wherein the substituent is selected from

20. The compound of claim 1 wherein when Ar³ is quinoxalinylene, then X² is not —

CH(OH)—

.

21. The compound of claim 1 wherein Ar³ is

22. The compound of claim 1 wherein Ar³ is

24. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

25. A method of treating colon cancer, lung cancer or pancreatic cancer in a human, the method comprising administering to a human in need of such treatment a compound according to claim 1.

27. A method of treating colon cancer, lung cancer or pancreatic cancer in a human, the method comprising administering to a human in need of such treatment a compound according to claim 24.

36. The compound according to claim 24 wherein Cy²-X¹- is collectively selected from the group consisting of

a) D₂-E₂-F₂-, wherein D₂ is optionally substituted heteroaryl wherein E₂ is —

NH(CH₂)_0-2—

; and

wherein F₂ is a covalent bond; and

b) D₄-E₄-F₄-, wherein D₄ is an optionally substituted heteroaryl wherein E₄ is —

S(CH₂)_0-2—

; and

wherein F₄ is a covalent bond.

12. A histone deacetylase inhibitor of formula (3):

23. A compound of formula

26. A composition comprising a compound according to claim 23 and a pharmaceutically acceptable carrier.

28. A compound of formula

29. A composition comprising a compound according to claim 28 and a pharmaceutically acceptable carrier.

30. A method of treating colon cancer, lung cancer or pancreatic cancer in a human, the method comprising administering to a human in need of such treatment a compound according to claim 28.

31. A histone deacetylase inhibitor selected from the group consisting of

N-(2-Amino-phenyl)-4-{[4-amino-6-(4-phenyl-piperazin-1-yl)-[1,3,5]triazin-2-ylamino]-methyl}-benzamide;

4-{[4-amino-6-(2-pyridinyl-methyl-amino)-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

N-(2-Amino-phenyl)-4-{[4-amino-6-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-methyl}-benzamide;

4-({4-Amino-6-[2-(2-methoxy-phenyl)-ethylamino][1,3,5]triazin-2-ylamino}-methyl)-N-(2-amino-phenyl)-benzamide;

4-{[6-(2-indanyl-amino)-4-(3-pyridinyl-methyl-amino)-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

N-(2-Amino-phenyl)-4-{[2-piperidin-1-yl-6-(2-pyrrolidin-1-yl-ethylamino)-pyrimidin-4-ylamino]-methyl}-benzamide;

N-(2-Amino-phenyl)-4-{[2-piperidin-1-yl-6-(2-pyrrolidin-1-yl-ethylamino)-pyrimidin-4-ylamino]-methyl}-benzamide;

N-(2-amino-phenyl)-4-{[4-cyclopropyl-methylamino-6-(2-indanyl-amino)- [1,3,5]-triazin-2-yl-amino]-methyl}-benzamide;

N-(2-amino-phenyl)-4-{[4-(2-methoxy-ethyl-1-amino)-6-phenethyl-amino-[1,3,5]-triazin-2-yl-amino]-methyl}-benzamide;

N-(2-amino-phenyl)-4-{[6-cyclopropyl-amino-4-(4-methoxy-phenethyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-benzamide;

N-(2-amino-phenyl)-4-{[6-cyclopropyl-amino-4-(3,4-dimethoxy-phenethyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-benzamide;

N-(2-amino-phenyl)-4-{[6-cyclopropyl-amino-4-(3-methoxy-phenethyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-benzamide;

N-(2-amino-phenyl)-4-{[6-cyclopropyl-amino-4-(2-pyridin-2-yl-ethyl-1-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-benzamide;

N-(2-amino-phenyl)-4-{[6-cyclopropyl-amino-4-(3-pyridin-2-yl-ethyl-1-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-benzamide;

N-(2-amino-phenyl)-4-[(4-cyclopropyl-amino-6-phenethyl-oxy-[1,3,5]triazin-2-yl-amino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-{5-[(3,4,5-trimethoxy-phenylamino)-methyl]-thiophen-2-ylmethyl}-benzamide;

N-(2-Amino-phenyl)-4-{6-[(pyridin-3-ylmethyl)-amino]-benzothiazol-2-ylsulfanylmethyl}-benzamide;

N-(2-Amino-phenyl)-4-{6-[(pyridin-2-ylmethyl)-amino]-benzothiazol-2-ylsulfanylmethyl}-benzamide;

N-(2-Amino-phenyl)-4-[4-cyano-3-methyl-5-(3-phenyl-ureido)-thiophen-2-ylmethyl]-benzamide;

N-(2-Amino-phenyl)-4-({4-chloro-6-[(pyridin-3-ylmethyl)-amino]-pyrimidin-2-ylamino}-methyl)-benzamide;

N-(2-Amino-phenyl)-4-{[4-chloro-6-(3,4,5-trimethoxy-benzylamino)-pyrimidin-2-ylamino]-methyl}-benzamide;

N-(2-Amino-phenyl)-4-{[4-chloro-6-(3,4,5-trimethoxy-phenylamino)-pyrimidin-2-ylamino]-methyl}-benzamide;

N-(2-Amino-phenyl)-4-{[4-(3,4-dimethoxy-phenylamino)-pyrimidin-2-ylamino]-methyl}-benzamide;

N-(2-Amino-phenyl)-4-[5-(pyridin-2-ylaminomethyl)-thiophen-2-ylmethyl]-benzamide;

N-(2-Amino-phenyl)-4-{[4-(6-methoxy-pyridin-3-yl)-pyrimidin-2-ylamino]-methyl}-benzamide;

4-((4-amino-6-(2-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)-2-oxoethyl)-1,3,5-triazin-2-ylamino)methyl)-N-(2-aminophenyl)benzamide;

N-(2-aminophenyl)-4-((6-(2-morpholinoethylamino)benzo[d]thiazol-2-ylthio)methyl)benzamide;

N-(2-aminophenyl)-4-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-2-ylthio)methyl)benzamide;

N-(2-aminophenyl)-4-((6-(2-morpholinoethoxy)benzo[d]thiazol-2-ylamino)methyl)benzamide;

and pharmaceutically acceptable salts thereof.

32. A histone deacetylase inhibitor selected from the group consisting of

4-[(4-amino-6-morpholin-4-yl-[1,3,5]-triazin-2-ylamino)-methyl]-N-(2-amino-phenyl)-benzamide;

4-{[4-amino-6-(1-indanyl-amino)-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

4-{[4,6-bis-(2-indanyl-amino)-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

4-{[4-Amino-6-(9H-fluoren-9-ylamino)-[1,3,5]triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

N-(2-amino-phenyl)-4- [(4-amino-6-piperidin- l-yl-[l ,3 ,5 ]-triazin-2-ylamino)-methyl]-benzamide;

4-[(4-amino-6-cyclopentyl-amino-[1,3,5]-triazin-2-yl-amino)-methyl]-N-(2-amino-phenyl)-benzamide;

(1R)-4-{[4-amino-6-(2-exo-fenchyl-amino)-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

4-{[4-allyl-amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

4-{[4-cyclopropyl-amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

4-[(4-Amino-6-phenethylamino-[1,3,5]triazin-2-ylamino)-methyl]-N-(2-amino-phenyl)-benzamide;

4-{[4-Amino-6-(2,3 -dihydro-indol-1-yl)-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

4-({4-Amino-6-[2-(2-fluoro-phenyl)-ethylamino]-[1,3,5]triazin-2-ylamino}-methyl)-N-(2-amino-phenyl)-benzamide;

4-{[4-benzyl-amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

N-(2-Amino-phenyl)-4-[(4,6-di-piperidin-1-yl-[1,3,5]triazin-2-ylamino)-methyl]-benzamide;

4-{[6-(2-indanyl-amino)-4-phenethyl-amino-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

4-{[4-benzyl-amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

4-[(4-Amino-6-benzylamino-[1,3,5]triazin-2-ylamino)-methyl]-N-(2-amino-phenyl)-benzamide;

N-(2-Amino-phenyl)-4-[(4-piperidin-1-yl-6-pyrrolidin-1-yl-[1,3,5]triazin-2-ylamino)-methyl]-benzamide;

4-{[6-(2-indanyl-amino)-4-morpholin-4-yl-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2-amino-phenyl)-benzamide;

4-({4-Amino-6-[2-(1H-indol-3-yl)-ethylamino]-[1,3,5]triazin-2-ylamino}-methyl)-amino-phenyl)-benzamide;

4-{[4-amino-6-(3-phenyl-propyl-1-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-benzamide;

N-(2-amino-phenyl)-4-[(4-cyclopropyl-amino-6-phenethyl-amino-[1,3,5]triazin-2-yl-amino)-methyl]-benzamide;

N-(2-amino-phenyl)-4-[(4-n-butyl-amino-6-phenethyl-amino-[1,3,5]triazin-2-yl-amino)-methyl]-benzamide;

N-(2-amino-phenyl)-4-{[4-(4-chloro-phenethyl-amino)-6-cyclopropyl-amino-[1,3,5]triazin-2-yl-amino]-methyl}-benzamide;

N-(2-amino-phenyl)-4-{[4-(3-chloro-phenethyl-amino)-6-cyclopropyl-amino-[1,3,5]triazin-2-yl-amino]-methyl}-benzamide;

N-(2-amino-phenyl)-4-[(6-methyl-4-phenethylamino-[1,3,5 ]triazin-2-yl-amino)-methyl]-benzamide;

N-(2-amino-phenyl)-4-{[4-amino-6-phenyl-[1,3,5]-triazin-2-yl-amino]-methyl}-benzamide;

N-(2-amino-phenyl)-4-{[6-(2-indanyl-amino)-4-phenyl-[1,3,5]-triazin-2-yl-amino]-methyl}-benzamide;

N-(2-Amino-phenyl)-4-[(4,6-dimethoxy-pyrimidin-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-(quinolin-2-ylsulfanylmethyl)-benzamide;

N-(2-Amino-phenyl)-4-(benzothiazol-2-ylsulfanylmethyl]-benzamide;

N-(2-Amino-phenyl)-4-(5-phenyl-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-benzamide;

N-(2-Amino-phenyl)-4-(4,6-dimethyl-pyrimidin-2-ylsulfanylmethyl)-benzamide;

N-(2-Amino-phenyl)-4-(4-trifluoromethyl-pyrimidin-2-ylsulfanylmethyl)benzamide;

N-(2-Amino-phenyl)-4-[(5 -chloro-benzooxazol-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-{[4-(4-chloro-phenyl)-thiazol-2-ylamino]-methyl}-benzamide;

N-(2-Amino-phenyl)-4-[(5-bromo-benzothiazol-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-(1H-imidazol-2-ylsulfanylmethyl)-benzamide;

4-[(2-Amino-9-butyl-9H-purin-6-ylamino)-methyl]-N-(2-amino-phenyl)-benzamide;

N-(2-Amino-phenyl)-4-[(2-amino-9H-purin-6-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(2-chloro-9H-purin-6-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(9-butyl-2-chloro-9H-purin-6-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(3-fluoro-2-pyridinyl-amino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(3,4,5-trifluoro-2-pyridinyl-amino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-(5-phenyl-[1,2,4]oxadiazol-3-yl)-benzamide;

N-(2-Amino-phenyl)-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzamide;

N-(2-Amino-phenyl)-4-(5-piperidin-1-ylmethyl-[1 ,2,4]oxadiazol-3-yl)-benzamide;

N-(2-Amino-phenyl)-4-(5-morpholin-4-ylmethyl-[1 ,2,4]oxadiazol-3-yl)-benzamide;

N-(2-Amino-phenyl)-4-(5-propyl-[1,2,4]oxadiazol-3-ylmethyl)-benzamide;

N-(2-Amino-phenyl)-4-(5-pyridin-3-yl-[1,2,4]oxadiazol-3-ylmethyl)-benzamide;

N-(2-Amino-phenyl)-4-(5-pyridin-4-yl-[1,2,4]oxadiazol-3-ylmethyl)-benzamide;

4-(5-Acetylamino-4-cyano-thiophen-2-ylmethyl)-N-(2-amino-phenyl)-benzamide;

4-(5-Benzoylamino-4-cyano-3-methyl-thiophen-2-ylmethyl)-N-(2-amino-phenyl)-benzamide;

N-(2-Amino-phenyl)-4-(pyrimidin-2-ylaminomethyl)-benzamide;

N-(2-Amino-phenyl)-4-(4,6-dimethyl-pyrimidin-2-ylsulfanylmethyl)-benzamide;

N-(2-Amino-phenyl)-4-(4-trifluoromethyl-pyrimidin-2-ylsulfanylmethyl)-benzamide;

N-(2-Amino-phenyl)-4-(pyridin-2-ylsulfanylmethyl)-benzamide;

N-(2-Amino-phenyl)-4-[(4,6-dimethyl-pyrimidin-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(4,6-dimethyl-pyridin-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-(4,6-dimethyl-pyrimidin-2-yloxymethyl)-benzamide;

N-(2-Amino-phenyl)-4-[(6-methoxy-pyrimidin-4-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(4-chloro-6-methoxy-pyrimidin-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(2,6-dimethoxy-pyridin-3-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(1H-benzoimidazol-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(6-methoxy-pyridin-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(2,6-dimethoxy-pyrimidin-4-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-(quinolin-2-yloxymethyl)-benzamide;

N-(2-Amino-phenyl)-4-(isoquinolin-1-ylaminomethyl)-benzamide;

N-(2-Amino-phenyl)-4-[(4-chloro-6-morpholin-4-yl-pyrimidin-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(4-chloro-6-methyl-pyrimidin-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(4,6-dichloro-pyrimidin-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(6-methoxy-pyridin-3-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(4-morpholin-4-yl-pyrimidin-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-{[4-chloro-6-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylamino]-methyl}-benzamide;

N-(2-Amino-phenyl)-4-{[4-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylamino]-methyl}-benzamide;

N-(2-Amino-phenyl)-4-[5-(indan-2-ylaminomethyl)-thiophen-2-ylmethyl]-benzamide;

N-(2-Amino-phenyl)-4-[(5-bromo-thiazol-2-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(5-phenyl-1H-pyrazol-3-ylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-(3-cyano-6-methyl-pyridin-2-yloxymethyl)-benzamide;

2-Acetylamino-5-[4-(2-amino-phenylcarbamoyl)-benzyl]-thiophene-3-carboxamide;

5-(5-Methoxy-1H-benzoimidazol-2-ylsulfanylmethyl)-benzofuran-2-carboxylic acid (2-amino-phenyl)amide;

4-((4-amino-6-(2,3-dihydro-1H-inden-2-ylamino)-1,3,5-triazin-2-ylamino)methyl)-N-(2-aminophenyl)benzamide;

4-(4-amino-6-(2,3-dihydro-1H-inden-2-ylamino)-1,3,5-triazin-2-ylamino)-N-(2-aminophenyl)benzamide;

4-((4-amino-6-(2,3-dihydro-1H-inden-2-ylamino)-1,3,5-triazin-2-yloxy)methyl)-N-(2-aminophenyl)benzamide;

N-(2-aminophenyl)-4-((4-(phenethylamino)-1,3,5-triazin-2-ylamino)methyl)benzamide;

N-(2-aminophenyl)-4-((4,6-dimethoxy-1,3,5-triazin-2-ylamino)methyl)benzamide;

N-(2-aminophenyl)-4-((4-(2,3-dihydro-1H-inden-2-ylamino)-6-methoxy-1,3,5-triazin-2-ylamino)methyl)benzamide;

4-(((4-amino-6-(2,3-dihydro-1H-inden-2-ylamino)-1,3,5-triazin-2-yl)(methyl)amino)methyl)-N-(2-aminophenyl)benzamide;

N-(2-aminophenyl)-4-((4-(2,3-dihydro-1H-inden-2-ylamino)-6-methyl-1,3,5-triazin-2-ylamino)methyl)benzamide;

(E)-N-(2-aminophenyl)-4-(2-(4,6-diamino-1,3,5-triazin-2-yl)vinyl)benzamide;

(E)-4-(2-(4-amino-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)vinyl)-N-(2-aminophenyl)benzamide;

4-(2-(4-amino-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)ethyl)-N-(2-aminophenyl)benzamide;

4-((1H-benzo[d]imidazol-2-ylthio)methyl)-N-(2-aminophenyl)benzamide;

N-(2-aminophenyl)-4-((quinolin-2-ylthio)methyl)benzamide;

N-(2-aminophenyl)-4-((1-methyl-1H-imidazol-2-ylthio)methyl)benzamide;

N-(2-aminophenyl)-6-(3-methoxyphenyl)nicotinamide;

N-(2-aminophenyl)-4-((5-(3,4,5-trimethoxyphenyl)benzo[d]thiazol-2-ylamino)methyl)benzamide;

N-(2-aminophenyl)-4-((6-methoxybenzo[d]thiazol-2-ylamino)methyl)benzamide;

N-(2-aminophenyl)-4-((2-chloro-9-(2-methoxyethyl)-9H-purin-6-ylamino)methyl)benzamide;

N-(2-aminophenyl)-4-(1H-imidazol-2-yl)benzamide;

N-(2-aminophenyl)-4-((4-(morpholinomethyl)thiazol-2-yl)methyl)benzamide;

N-(2-aminophenyl)-4-((3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl)benzamide;

4-((5-acetamido-4-cyano-3-methylthiophen-2-yl)methyl)-N-(2-aminophenyl)benzamide;

N-(2-aminophenyl)-4-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)benzamide;

N-(2-aminophenyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)benzamide;

N-(2-aminophenyl)-6-(quinolin-2-ylthio)nicotinamide;

N-(2-aminophenyl)-4-((5-methoxy-1H-benzo[d]imidazol-2-ylthio)methyl)benzamide;

and pharmaceutically acceptable salts thereof.

33. A histone deacetylase inhibitor of formula (3):

40. A composition comprising a compound according to claim 33 and a pharmaceutically acceptable carrier.

41. A method of treating colon cancer, lung cancer or pancreatic cancer in a human, the method comprising administering to a human in need of such treatment a compound according to claim 33.

34. A compound of formula

35. The compound according to claim 34 wherein Ar² is aryl or heteroaryl;

and Cy²-X¹- is collectively selected from the group consisting of

a) A₁-L₁-B₁-, wherein A₁ is an optionally substituted heteroaryl wherein L₁ is NH(CH₂)_0-1—

or —

NHCH₂—

; and

wherein B₁ is phenyl or a covalent bond;

b) A₅-L₅-B₅-, wherein A₅ is an optionally substituted heteroaryl wherein L₅ is a covalent bond; and

wherein B₅ is —

SCH₂—

;

c) A₆-L₆-B₆-, wherein A₆ is an optionally substituted heteroaryl wherein L₆ is a covalent bond; and

wherein B₆ is —

NHCH₂—

;

d) optionally substituted heteroaryl;

p1 e) A₁₁-L₁₁-B₁₁-, wherein A₁₁ is an optionally substituted heteroaryl wherein L₁₁ is a covalent bond; and

wherein B₁₁ is —

OCH₂—

; and

f) A₁₆-L₁₆-B₁₆-, wherein A₁₆ is an optionally substituted heteroaryl wherein L₁₆ is a covalent bond; and

wherein B₁₆ is —

N(optionally substituted alkyl)CH₂.

42. A composition comprising a compound according to claim 34 and a pharmaceutically acceptable carrier.

43. A method of treating colon cancer, lung cancer or pancreatic cancer in a human, the method comprising administering to a human in need of such treatment a compound according to claim 34.

37. A compound of formula

44. A composition comprising a compound according to claim 37 and a pharmaceutically acceptable carrier.

45. A method of treating colon cancer, lung cancer or pancreatic cancer in a human, the method comprising administering to a human in need of such treatment a compound according to claim 37.

38. A compound of formula

46. A composition comprising a compound according to claim 38 and a pharmaceutically acceptable carrier.

47. A method of treating colon cancer, lung cancer or pancreatic cancer in a human, the method comprising administering to a human in need of such treatment a compound according to claim 38.

39. A compound of formula

48. A composition comprising a compound according to claim 39 and a pharmaceutically acceptable carrier.

49. A method of treating colon cancer, lung cancer or pancreatic cancer in a human, the method comprising administering to a human in need of such treatment a compound according to claim 39.