USRE39850EExpiredUtility
Inhibitors of histone deacetylase
Est. expiryNov 23, 2019(expired)· nominal 20-yr term from priority
A61P 31/00A61P 43/00A61P 9/10A61P 35/00A61P 31/10C07C 259/10C07C 311/29C07D 215/36C07C 317/44C07C 311/13C07C 275/42C07C 259/06C07C 311/44C07D 213/76C07D 213/71C07D 307/54A61P 17/06C07D 285/135C07D 333/62C07D 307/46C07D 333/34C07C 311/21C07D 307/91A61K 31/4402
89
PatentIndex Score
34
Cited by
84
References
162
Claims
Abstract
The invention relates to the inhibition of histone deactylase. 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
exact text as granted — not AI-modified1. An inhibitor of histone deacetylase represented by the formula
Cy—L 1 —Ar—Y 1 —C(O)—NH—Z
wherein
Cy is cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted;
L 1 is —(CH 2 ) m —W—, where m is 0, 1, 2, 3, or 4, and W is selected from the group consisting of —C(O)NH—, —S(O) 2 NH—, —NHC( O )—, —NHS(O) 2 —, and —NH—C(O)—NH—;
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted;
Y 1 is a chemical bond or a straight- or branched-chain saturated alkylene, wherein said alkylene may be optionally substituted; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido;
provided that when L 1 is —C(O)NH—, Y 1 is an alklene alkylene of the formula —(CH 2 ) n —, n being 1, 2 or 3, and Z is —O—M, then Cy is not aminophenyl, dimethylaminophenyl, or hydroxyphenyl; and further provided that when L 1 is —C(O)NH— and Z is pyridyl, then Cy is not substituted indolinyl.
2. The inhibitor of claim 1 , wherein Z is selected from the group consisting of 2-anilinyl, 2-pyridyl, 1,3,4-thiadiazol-2-yl, and —O—M, M being H or a pharmaceutically acceptable cation.
3. The inhibitor of claim 2 claim 1 , wherein Z is 1,3,4 -thiadiazol-2-yl which is substituted at the 5-position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
4. The inhibitor of claim 1 , wherein Y 1 is C 1 -C 6 alkylene.
5. The inhibitor of claim 1 , wherein Y 1 is C 1 -C 3 alkylene.
6. The inhibitor of claim 1 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
7. The inhibitor of claim 6 , wherein the phenylene is 4-phenylene.
8. The inhibitor of claim 1 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
9. The inhibitor of claim 8 , herein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, halo, nitro, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, carboxy, and amino.
10. The inhibitor of claim 1 , wherein m is zero.
11. An inhibitor of histone deacetylase represented by the formula
Cy—L 2 —Ar—Y 2 —C(O)NH—Z
wherein
Cy is cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;
L 2 is C 1 -C 6 C 2 - C 8 saturated alkylene or C 2 -C 6 C 2 - C 8 alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 2 is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by a heteroatom moiety selected from the group consisting of O; NR′; R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 ;
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y 2 is a chemical bond or a straight- or branched-chain saturated alkylene, which may be optionally substituted, provided that the alkylene is not substituted with a substituent of the formula —C(O)R wherein R comprises an α-amino acyl moiety; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido;
provided that when the carbon atom to which Cy is attached is oxo substituted, then Cy and Z are not both pyridyl.
12. The inhibitor of claim 11 , wherein Z is selected from the group consisting of 2-anilinyl, 2-pyridyl, 1,3,4-thiadiazol-2-yl, and —O—M, M being H or a pharmaceutically acceptable cation.
13. The inhibitor of claim 12 , wherein Z is 1,3,4-thiadiazol-2-yl which is substituted at the 5-position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
14. The inhibitor of claim 11 , wherein Y 2 is a chemical bond.
15. The inhibitor of claim 11 , wherein Y 2 is C 1 -C 3 alkylene.
16. The inhibitor of claim 11 , wherein Y 2 is C 1 -C 2 alkylene.
17. The inhibitor of claim 11 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
18. The inhibitor of claim 17 , wherein the phenylene is 4-phenylene.
19. The inhibitor of claim 11 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
20. The inhibitor of claim 19 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, halo, nitro, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, carboxy, and amino.
21. The inhibitor of claim 11 , wherein one or two saturated carbons in L 2 are substituted with a substituent independently selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl, amino, oxo, hydroxy, C 1 -C 4 alkoxy, and C 6 -C 10 aryloxy.
22. The inhibitor of claim 21 , wherein the substituent is oxo or hydroxy.
23. The inhibitor of claim 11 , wherein L 2 is C 1 -C 6 C 2 - C 8 saturated alkylene, and no carbon atom of the alkylene is replaced by a heteroatom moiety.
24. The inhibitor of claim 11 , wherein one carbon atom of the Y 2 alkylene is replaced by a heteroatom moiety selected from the group consisting of O; NR′, R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 .
25. The inhibitor of claim 24 11 , wherein L 2 is selected from the group consisting of —S—(CH 2 ) n , —S(O)—(CH 2 ) n —, and —S(O) 2 —(CH 2 ) n —, wherein n is 0, 1, 2, 3, or 4.
26. An inhibitor of histone deacetylase represented by the formula
Cy—L 3 —Ar—Y 3 —C(O)NH—Z
wherein
Cy is cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;
L 3 is selected from the group consisting of
(a) —(CH 2 ) m —W—, where m is 0, 1, 2, 3, or 4, and W is selected from the group consisting of —C(O)NH—, —S(O) 2 NH—, —NHC(O)—, —NHS(O) 2 —, and —NH—C(O)—NH—; and
(b) C 1 -C 6 C 2 - C 8 alkylene or C 2 -C 6 C 2 - C 8 alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 3 is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by O; NR′; R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 ;
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y 3 is C 2 alkenylene or C 2 alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido;
provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L 3 and Y 3 are oriented ortho or meta to each other.
27. The inhibitor of claim 26 , wherein Z is selected from the group consisting of 2-anilinyl, 2-pyridyl, 1,3,4-thiadiazol-2-yl, and —O—M, M being H or a pharmaceutically acceptable cation.
28. The inhibitor of claim 27 , wherein Z is 1,3,4-thiadiazol-2-yl which is substituted at the 5-position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
29. The inhibitor of claim 26 , wherein Y 3 is selected from the group consisting of —CH═CH—, —C(CH 3 )═CH—, and —CH═C(CH 3 )—.
30. The inhibitor of claim 26 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
31. The inhibitor of claim 30 , wherein the phenylene is 4-phenylene.
32. The inhibitor of claim 26 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
33. The inhibitor of claim 32 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, halo, nitro, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, carboxy, and amino.
34. An inhibitor of histone deacetylase selected from the group consisting of
35. The inhibitor according to claim 11 selected from the group consisting of
36. An inhibitor of histone deacetylase represented by the formula
Cy—L 2 —Ar—Y 2 —C ( O ) NH—Z
Wherein
Cy is cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;
L 2 is C 1 - C 8 saturated alkylene or C 2 - C 8 alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 2 is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by a heteroatom moiety selected from the group consisting of NR′, R′ being alkyl, acyl, or hydrogen; S; or S(O); or L 2 is —S(O) 2 - (CH 2 ) n , wherein n is 1 , 2 , 3 or 4 ,
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y 2 is a straight - or branched - chain saturated alkylene, which may be optionally substituted, provided that the alkylene is not substituted with a substituent of the formula —C(O)R wherein R comprises an α - amino acyl moiety; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido;
provided that when the carbon atom to which Cy is attached is oxo substituted, then Cy and Z are not both pyridyl.
37. The inhibitor of claim 36 , wherein Z is selected from the group consisting of 2 - anilinyl, 2 - pyridyl, 1 , 3 , 4 - thiadiazol - 2 - yl, and —O—M, M being H or a pharmaceutically acceptable cation.
38. The inhibitor of claim 36 wherein Z is 1 , 3 , 4 - thiadiazol - 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
39. The inhibitor of claim 36 , wherein Y 2 is C 1 - C 3 alkylene.
40. The inhibitor of claim 36 , wherein Y 2 is C 1 - C 2 alkylene.
41. The inhibitor of claim 36 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
42. The inhibitor of claim 41 , wherein the phenylene is 4 - phenylene.
43. The inhibitor of claim 36 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
44. The inhibitor of claim 43 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 - C 10 aryl, (C 6 - C 10 )ar(C 1 - C 6 )alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
45. The inhibitor of claim 36 , wherein one or two saturated carbons in L 2 are substituted with a substituent independently selected from the group consisting of C 1 - C 6 alkyl, C 6 - C 10 aryl, amino, oxo, hydroxy, C 1 - C 4 alkoxy, and C 6 - C 10 aryloxy.
46. The inhibitor of claim 45 , wherein the substituent is oxo or hydroxy.
47. The inhibitor of claim 36 , wherein L 2 is C 2 - C 8 saturated alkylene, and no carbon atom of the alkylene is replaced by a heteroatom moiety.
48. The inhibitor of claim 36 , wherein one carbon atom of the Y 2 alkylene is replaced by a heteroatom moiety selected from the group consisting of O; NR′, R′ being alkyl, acyl, or hydrogen; S; or S(O); or S(O) 2 .
49. The inhibitor of claim 36 , wherein L 2 is selected from the group consisting of —S—(CH 2 ) n , —S(O)—(CH 2 ) n , —S(O) 2 —(CH 2 ) n and wherein n is 1 , 2 , 3 , or 4 .
50. An inhibitor of histone deacetylase represented by the formula
Cy—L 3 —Ar—Y 3 —C(O)NH—Z
wherein
Cy is cycloalkyl, aryl, heteroaryl,
or heterocyclyl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;
L
3
is selected from the group consisting of
(a) —(CH 2 ) m —W, where m is 0 , 1 , 2 , 3 , or 4 , and W is selected from the group consisting of —C(O)NH—, —S(O) 2 NH—, —NHC(O)—, —NHS(O) 2 —, and —NH—C(O)—NH—; and
(b) C 1 - C 8 alkylene or C 2 - C 8 alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 3 is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by NR′, R′ being alkyl, acyl, or hydrogen; S; or S(O);
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y
3
is C
2
alkenylene or C
2
alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido;
provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L
3
and Y
3
are oriented ortho or meta to each other.
51. The inhibitor of claim 50 , wherein Z is selected from the group consisting of 2 - anilinyl, 2 - pyridyl, l, 3 , 4 - thiadiazol - 2 - yl, and —O—M, M being H or a pharmaceutically acceptable cation.
52. The inhibitor of claim 51 , wherein Z is 1 , 3 , 4 - thiadiazol - 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
53. The inhibitor of claim 50 , wherein Y 3 is selected from the group consisting of —CH=CH—, —C(CH 3 )=CH—, and —CH=C(CH 3 )—.
54. The inhibitor of claim 50 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
55. The inhibitor of claim 54 , wherein the phenylene is 4 - phenylene.
56. An inhibitor of histone deacetylase represented by the formula
Cy—L 1 —Ar—Y 1 —C(O)—NH—Z
wherein
Cy is aryl or heteroaryl, either of which may be optionally substituted;
L
1
is —(CH
2
)m —W—, where m is 0 , 1 , 2 , 3 , or 4 , and W is selected from the group consisting of —C(O)NH—, —NHC(O)— and —NH—C(O)—NH—;
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted;
Y 1 is a straight - or branched - chain saturated alkylene, wherein said alkylene may be optionally substituted; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido;
provided that when L
1
is —C(O)NH—, Y
1
is an alkylene of the formula —(CH
2
)
n
—, being 1 , 2 , or 3 , and Z is —O—M, then Cy is not aminophenyl, dimethylaminophenyl, or hydroxyphenyl; and further provided that when L
1
is —C(O)NH— and Z is pyridyl, then Cy is not substituted indolinyl.
57. The inhibitor of claim 56 , wherein Z is selected from the group consisting of 2 -anilinyl, 2 -pyridyl, 1 , 3 , 4 -thiadiazol- 2 -yl, and —O—M, M being H or a pharmaceutically acceptable cation.
58. The inhibitor of claim 56 , wherein Z is 1 , 3 , 4 - thiadiazol - 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
59. The inhibitor of claim 56 , wherein Y 1 is C 1 -C 6 alkylene.
60. The inhibitor of claim 56 , wherein Y 1 is C 1 -C 3 alkylene.
61. The inhibitor of claim 56 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
62. The inhibitor of claim 61 , wherein the phenylene is 4 - phenylene.
63. The inhibitor of claim 56 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
64. The inhibitor of claim 63 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 - C 10 aryl, (C 6 - C 10 )ar(C 1 - C 6 )alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
65. The inhibitor of claim 56 , wherein m is zero.
66. An inhibitor of histone deacetylase represented by the formula
Cy—L 1 —Ar—Y 1 —C(O)—NH—Z
wherein
Cy is aryl or heteroaryl, any of which may be optionally substituted;
L
1
is —S(O)
2
NH—
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted;
Y 1 is a straight - or branched - chain saturated alkylene, wherein said alkylene may be optionally substituted; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamide.
67. The inhibitor of claim 66 , wherein Z is selected from the group consisting of 2 - anilinyl, 2 - pyridyl, 1 , 3 , 4 - thiadiazol - 2 - yl, and —O—M, M being H or a pharmaceutically acceptable cation.
68. The inhibitor of claim 66 , wherein Z is 1 , 3 , 4 - thiadiazol - 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
69. The inhibitor of claim 66 , wherein Y 1 is C 1 - C 6 alkylene.
70. The inhibitor of claim 66 , wherein Y 1 is C 1 - C 3 alkylene.
71. The inhibitor of claim 66 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
72. The inhibitor of claim 71 , wherein the phenylene is 4 - phenylene.
73. The inhibitor of claim 66 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
74. The inhibitor of claim 73 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 -C 10 aryl, (C 6 - C 10 )ar(C 1 - C 6 )alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
75. An inhibitor of histone deacetylase represented by the formula
Cy—L 1 —Ar—Y 1 —C(O)—NH—Z
wherein
Cy is aryl or heteroaryl, any of which may be optionally substituted;
L
1
is —(CH
2
)m —S(O)
2
NH—, where m is 1 , 2 , 3 , or 4 ,
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted;
Y 1 is a straight - or branched - chain saturated alkylene, wherein said alkylene may be optionally substituted; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamide.
76. The inhibitor of claim 75 , wherein Z is selected from the group consisting of 2 - anilinyl, 2 - pyridyl, 1 , 3 , 4 - thiadiazol - 2 - yl, and —O—M, M being a pharmaceutically acceptable cation.
77. The inhibitor of claim 75 , wherein Z is 1 , 3 , 4 - thiadiazol - 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonarnido.
78. The inhibitor of claim 75 , wherein Y 1 is C 1 - C 6 alkylene.
79. The inhibitor of claim 75 , wherein Y 1 is C 1 - C 3 alkylene.
80. The inhibitor of claim 75 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
81. The inhibitor of claim 80 , wherein the phenylene is 4 - phenylene.
82. The inhibitor of claim 75 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
83. The inhibitor of claim 82 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 - C 10 aryl, (C 6 - C 10 )ar(C 1 - C 6 )alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
84. An inhibitor of histone deacetylase represented by the formula
Cy—L 1 —Ar—Y 1 —C(O)—NH—Z
wherein
Cy is aryl or heteroaryl, either of which may be optionally substituted;
L
1
is —(CH
2
)
m
—NHS(O)
2
—, where m is 0 , 1 , 2 , 3 , or 4 ;
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted;
Y 1 is a straight - or branched - chain saturated alkylene, wherein said alkylene may be optionally substituted; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamide.
85. The inhibitor of claim 84 , wherein Z is selected from the group consisting of 2 - anilinyl, 2 - pyridyl, 1 , 3 , 4 -thiadiazol- 2 - yl, and —O—M, M being a pharmaceutically acceptable cation.
86. The inhibitor of claim 84 , wherein Z is 1 , 3 , 4 - thiadiazol - 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
87. The inhibitor of claim 84 , wherein Y 1 is C 1 - C 6 alkylene.
88. The inhibitor of claim 84 , wherein Y 1 is C 1 - C 3 alkylene.
89. The inhibitor of claim 84 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
90. The inhibitor of claim 89 , wherein the phenylene is 4 - phenylene.
91. The inhibitor of claim 84 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
92. The inhibitor of claim 91 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 - C 10 aryl, (C 6 - C 10 )ar(C 1 - C 6 )alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
93. The inhibitor of claim 84 , wherein m is zero.
94. An inhibitor of histone deacetylase represented by the formula
Cy—L 3 —Ar—Y 3 —C(O)NH—Z
wherein
Cy is aryl or heteroaryl, either of which may be optionally substituted;
L
3
is selected from the group consisting of
(a) —(CH
2
)
m
—W, where m is 0 , 1 , 2 , 3 , or 4 , and W is selected from the group consisting of —C(O)NH—,—NHC(O)—, and —NH—C(O)—NH—; and
(b) C 2 - C 8 alkylene or C 2 - C 8 alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 3 is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by NR′, R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 ;
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionalIy may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y
3
is C
2
alkenylene or C
2
alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido;
provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L
3
and Y
3
are oriented ortho or meta to each other.
95. The inhibitor of claim 94 , wherein Z is selected from the group consisting of 2 - anilinyl, 2 - pyridyl, 1 , 3 , 4 - thiadiazol - 2 - yl, and —O—M, M being H or a pharmaceutically acceptable cation.
96. The inhibitor of claim 95 , wherein Z is 1 , 3 , 4 - thiadiazol - 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonaniido.
97. The inhibitor of claim 94 , wherein Y 3 is selected from the group consisting of CH=CH—, —C(CH 3 )=CH—, and —CH=C(CH 3 )—.
98. The inhibitor of claim 94 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
99. The inhibitor of claim 98 , wherein the phenylene is 4 - phenylene.
100. The inhibitor of claim 94 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
101. The inhibitor of claim 100 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 - C 10 aryl, (C 6 - C 10 ) ar(C 1 - C 6 ) alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
102. An inhibitor of histone deacetylase represented by the formula
Cy—L 3 —Ar—Y 3 —C(O)NH—Z
wherein
Cy is aryl or heteroaryl, either of which may be optionally substituted;
L
3
is selected from the group consisting of
(a) —S(O)
2
NH—; and
(b) C 2 - C 8 alkylene or C 2 - C 8 alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 3 is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by NR′, R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 ;
Ar is arylene or heteroarylene wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y
3
is C
2
alkenylene or C
2
alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido;
provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L
3
and Y
3
are oriented ortho or meta to each other.
103. The inhibitor of claim 102 , wherein Z is selected from the group consisting of 2 - anilinyl, 2 - pyridyl, 1 , 3 , 4 - thiadiazol - 2 - yl, and —O—M, M being H or a pharmaceutically acceptable cation.
104. The inhibitor of claim 103 , wherein Z is 1 , 3 , 4 - thiadiazol - 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
105. The inhibitor of claim 102 , wherein Y 3 is selected from the group consisting of —CH═CH—, —C(CH 3 )═CH—, and —CH═C(CH 3 )—.
106. The inhibitor of claim 102 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
107. The inhibitor of claim 106 , wherein the phenylene is 4 - phenylene.
108. The inhibitor of claim 102 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
109. The inhibitor of claim 108 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 - C 10 aryl, (C 6 - C 10 )ar(C 1 - C 6 )alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
110. An inhibitor of histone deacetylase represented by the formula
Cy—L 3 —Ar—Y 3 —C(O)NH—Z
wherein
Cy is aryl or heteroaryl, either of which may be optionally substituted,
L
3
is selected from the group consisting of
(a) —(CH
2
)
m
—S(O)
2
NH—, where m is 1 , 2 , 3 , or 4 ; and
(b) C 2 - C 8 alkylene or C 2 - C 8 alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 3 is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by NR′, R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 ;
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y
3
is C
2
alkenylene or C
2
alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido;
provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L
3
and Y
3
are oriented ortho or meta to each other.
111. The inhibitor of claim 110 , wherein Z is selected from the group, consisting of 2 - anilinyl, 2 - pyridyl, 1 , 3 , 4 - thiadiazol - 2 - yl, and —O—M, M being a pharmaceutically acceptable cation.
112. The inhibitor of claim 111 , wherein Z is 1 , 3 , 4 - thiadiazol - 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
113. The inhibitor of claim 110 , wherein Y 3 is selected from the group consisting of—CH═CH—, —C(CH 3 )═CH—, and —CH═C(CH 3 )—.
114. The inhibitor of claim 110 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
115. The inhibitor of claim 114 , wherein the phenylene is 4 - phenylene.
116. The inhibitor of claim 110 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
117. The inhibitor of claim 116 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 - C 10 aryl, (C 6 - C 10 )ar(C 1 -C 6 )alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
118. An inhibitor of histone deacetylase represented by the formula
Cy—L 3 —Ar—Y 3 —C(O)NH—Z wherein Cy is aryl or heteroaryl, either of which may be optionally substituted; L 3 is selected from the group consisting of (a) —(CH 2 ) m —NHS(O) 2 —, where m is 0 , 1 , 2 , 3 , or 4 ; and (b) C 2 - C 8 alkylene or C 2 - C 8 alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 3 is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by NR′, R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 ; Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and Y 3 is C 2 alkenylene or C 2 alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl; and Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido: provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L 3 and Y 3 are oriented ortho or meta to each other.
119. The inhibitor of claim 118 , wherein Z is selected from the group consisting of 2 - anilinyl, 2 - pyridyl, 1 , 3 , 4 - thiadiazol - 2 - yl, and —O—M, M being a pharmaceutically acceptable cation.
120. The inhibitor of claim 119 , wherein Z is 1 , 3 , 4 -thiadiazol- 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
121. The inhibitor of claim 118 , wherein Y 3 is selected from the group consisting of—CH═CH—, —C(CH 3 )═CH—, and —CH═C(CH 3 )—.
122. The inhibitor of claim 118 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
123. The inhibitor of claim 122 , wherein the phenylene is 4 - phenylene.
124. The inhibitor of claim 118 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
125. The inhibitor of claim 124 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 - C 10 aryl, (C 6 - C 10 )ar(C 1 - C 6 )alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
126. An inhibitor of histone deacetylase represented by the formula
Cy—L 3 —Ar—Y 3 —C(O)NH—Z
wherein
Cy is aryl or heteroaryl, either of which may be optionally substituted;
L
3
is selected from the group consisting of
(a) —(CH
2
)
m
—W, where m is 0 , 1 , 2 , 3 , or 4 , and W is selected from the group consisting of —C(O)NH—, —NHC(O)—, and —NH—C(O)—NH—; and
(b) C 1 - C 8 alkylene or C 2 - C 8 alkenylene, wherein the alkylene or alkenylene ontionally may be substituted, provided that L 3 is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by NR′, R′ being alkyl, acyl, or hydrogen; S; or S(O);
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an arvl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y
3
is C
2
alkenylene or C
2
alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonarnido;
provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L
3
and Y
3
are oriented ortho or meta to each other.
127. The inhibitor of claim 126 , wherein Z is selected from the group consisting of 2 - anilinyl, 2 - pyridyl, 1 , 3 , 4 - thiadiazol - 2 - yl, and —O—M, M being H or a pharmaceutically acceptable cation.
128. The inhibitor of claim 127 , wherein Z is 1 , 3 , 4 - thiadiazol - 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
129. The inhibitor of claim 126 , wherein Y 3 is selected from the group consisting of—CH═CH—, —C(CH 3 )═CH—, and —CH═C(CH 3 )—.
130. The inhibitor of claim 126 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
131. The inhibitor of claim 130 , wherein the phenylene is 4 - phenylene.
132. The inhibitor of claim 126 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
133. The inhibitor of claim 132 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 - C 10 aryl, (C 6 - C 10 )ar(C 1 - C 6 )alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
134. An inhibitor of histone deacetylase represented by the formula
Cy—L 3 —Ar—Y 3 —C(O)NH—Z
wherein
Cy is aryl or heteroaryl, either of which may be optionally substituted;
L
3
is selected from the group consisting of
(a) —S(O)
2
NH—; and
(b) C 1 - C 8 alkylene or C 2 - C 8 alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 3 is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by NR′, R′ being alkyl, acyl, or hydrogen; S; or S(O);
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y
3
is C
2
alkenylene or C
2
alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being H or a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido;
provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L
3
and Y
3
are oriented ortho or meta to each other.
135. The inhibitor of claim 134 , wherein Z is selected from the group consisting of 2 - anilinyl, 2 - pyridyl, 1 , 3 , 4 -thiadiazol- 2 - yl, and —O—M, M being H or a pharmaceutically acceptable cation.
136. The inhibitor of claim 135 , wherein Z is 1 , 3 , 4 - thiadiazol - 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
137. The inhibitor of claim 134 , wherein Y 3 is selected from the group consisting of —CH═CH—, —C(CH 3 )═CH—, and —CH═C(CH 3 )—.
138. The inhibitor of claim 134 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
139. The inhibitor of claim 138 , wherein the phenylene is 4 - phenylene.
140. The inhibitor of claim 134 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
141. The inhibitor of claim 140 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 - C 10 aryl, (C 6 - C 10 )ar(C 1 - C 6 )alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
142. An inhibitor of histone deacetylase represented by the formula
Cy—L 3 —Ar—Y 3 —C(O)NH—Z
wherein
Cy is aryl or heteroaryl, either of which may be optionally substituted;
L
3
is selected from the group consisting of
(a) —(CH
2
)
m
—S(O)
2
NH—, where m is 1 , 2 , 3 , or 4 ; and
(b) C 1 - C 8 alkylene or C 2 - C 8 alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 3 is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by NR′, R′ being alkyl, acyl, or hydrogen; S; or S(O);
Ar is arylene or heteroarylene wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y
3
is C
2
alkenylene or C
2
alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido;
provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L
3
and Y
3
are oriented ortho or meta to each other.
143. The inhibitor of claim 142 , wherein Z is selected from the group consisting of 2 - anilinyl, 2 - pyridyl, 1 , 3 , 4 - thiadiazol - 2 - yl, and —O—M, M being a pharmaceutically acceptable cation.
144. The inhibitor of claim 143 , wherein Z is 1 , 3 , 4 -thiadiazol- 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl amino, and sulfonamido.
145. The inhibitor of claim 142 , wherein Y 3 is selected from the group consisting of —CH═CH—, —C(CH 3 )═CH—, and —CH═C(CH 3 )—.
146. The inhibitor of claim 142 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
147. The inhibitor of claim 146 , wherein the phenylene is 4 - phenylene.
148. The inhibitor of claim 142 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
149. The inhibitor of claim 148 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 - C 10 aryl, (C 6 - C 10 )ar(C 1 - C 6 )alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
150. An inhibitor of histone deacetylase represented by the formula
Cy—L 3 —Ar—Y 3 —C(O)NH—Z
wherein
Cy is aryl or heteroaryl, either of which may be optionally substituted;
L
3
is selected from the group consisting of
(a) —(CH
2
)
m
—NHS(O)
2
—, where m is 0 , 1 , 2 , 3 , or 4 ; and
(b) C 1 - C 8 alkylene or C 2 - C 8 alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 3 is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by NR′, R′ being alkyl, acyl, or hydrogen; S; or S(O);
Ar is arylene or heteroarylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
Y
3
is C
2
alkenylene or C
2
alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl; and
Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O—M, M being a pharmaceutically acceptable cation, wherein said thiadiazolyl may be optionally substituted with a substituent selected from the group consisting of thiol, trifluoromethyl, amino and sulfonamido;
provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L
3
and Y
3
are oriented ortho or meta to each other.
151. The inhibitor of claim 150 , wherein Z is selected from the group consisting of 2 - anilinyl, 2 - pyridyl, 1 , 3 , 4 - thiadiazol - 2 - yl, and —O—M, M being a pharmaceutically acceptable cation.
152. The inhibitor of claim 151 , wherein Z is 1 , 3 , 4 - thiadiazol - 2 - yl which is substituted at the 5 - position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.
153. The inhibitor of claim 150 , wherein Y 3 is selected from the group consisting of —CH═CH—, —C(CH 3 )═CH—, and —CH═C(CH 3 )—.
154. The inhibitor of claim 150 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.
155. The inhibitor of claim 154 , wherein the phenylene is 4 - phenylene.
156. The inhibitor of claim 150 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.
157. The inhibitor of claim 156 , wherein the phenvl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 - C 4 alkyl, C 1 - C 4 haloalkyl, C 6 - C 10 aryl, (C 6 - C 10 )ar(C 1 - C 6 )alkyl, halo, nitro, hydroxy, C 1 - C 6 alkoxy, C 1 - C 6 alkoxycarbonyl, carboxy, and amino.
158. The inhibitor according to claim 66 selected from the group consisting of
159. The inhibitor according to claim 11 selected from the group consisting of
160. The inhibitor according to claim 102 selected from the group consisting of
161. The inhibitor according to claim 118 selected from the group consisting of
162. The inhibitor according to claim 94 selected from the group consisting ofCited by (0)
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