Inhibitors of Histone Deacetylase

• US 20070213330A1
• Filed: 03/16/2007
• Published: 09/13/2007
• Est. Priority Date: 03/26/2004
• Status: Active Grant

• Current Assignee: 92229129 Quebec Inc.
• Original Assignee: MethylGene, Inc.
• Inventors: Frechette, Sylvie, Leit, Silvana, Vaisburg, Arkadii, Raeppel, Stephane, Paquin, Isabelle, Delorme, Daniel, Isakovic, Ljubomir, Bouchain, Giliane, Moradei, Oscar, Gaudette, Frederic, Zhou, Zhihong
• Granted Patent: US 8,088,805 B2
• Time in Patent Office: Days
• US Class Current: 514/235.500
• 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 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/39 having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07D 209/42 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 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 231/38 Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 235/16 Radicals substituted by 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 237/20 Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 263/58 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 271/06 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 307/84 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• 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 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

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 compound of formula (1):

2. A compound according to claim 1 wherein q is 1, and T is NH₂.

3. A compound according to claim 2 wherein Ar is phenylene, and Cy-X—

is

4. A compound according to claim 1 wherein q is 0.

5. A compound according to claim 4, of the formula (1a)

6. A compound according to claim 5 wherein Cy is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, benzothiazolyl, benzoimidazolyl, and benzotriazolyl, each of which is optionally substituted.

7. A compound according to claim 5 of the formula 1a-1:

8. A compound according to claim 5 of the formula 1a-2:

9. A compound according to claim 5 of the formula 1a-3:

10. A compound according to claim 9 wherein W is NH.

11. A compound according to claim 5 of the formula 1a-4:

12. A compound according to claim 11 wherein W is NH.

13. A compound according to claim 7 of the formula 1a-5:

14. A compound according to claim 13 wherein W is NH.

15. A compound according to claim 5 wherein W is NH and Cy is quinoxalinyl, phthalimidyl, or benzodioxolyl, each of which is optionally substituted with A and/or B, wherein

groups A and B are the same or different and are independently selected from H, halogen, C₁-C₄ alkyl, optionally substituted alkoxy including aminoalkoxy, haloalkoxy and heteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio, acylamino, carbamoyl,

16. A compound according to claim 1, of the formula (1b):

17. A compound according to claim 16 wherein T is NH₂.

18. A compound according to claim 16 wherein X is —

S—

CH₂—

, —

NH—

CH₂—

or —

CH₂—

NH—

.

19. A compound according to claim 16 wherein Cy is aryl or heteroaryl, each of which is optionally substituted.

20. A compound according to claim 16 wherein Cy is phenyl, pyridyl, pyrimidinyl, or benzothiazolyl, each of which is optionally substituted.

21. A compound according to claim 16 wherein Cy is substituted with A and/or B, wherein

groups A and B are the same or different and are independently selected from H, halogen, C₁-C₄ alkyl, optionally substituted alkoxy including aminoalkoxy, haloalkoxy and heteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio, acylamino, carbamoyl,

22. A compound according to claim 16 wherein Cy is optionally substituted with one, two or three groups independently selected from alkoxy, acyl, morpholino, and phenyl optionally substituted with alkoxy.

23. A compound according to claim 1 of the formula (1c):

24. A compound according to claim 23 wherein T is NH₂.

25. A compound according to claim 23 wherein X is —

S—

CH₂—

, —

NH—

CH₂—

or —

CH₂—

NH—

.

26. A compound according to claim 23 wherein Cy is aryl or heteroaryl, each of which is optionally substituted.

27. A compound according to claim 23 wherein Cy is phenyl, pyridyl, pyrimidinyl, or benzothiazolyl, each of which is optionally substituted.

28. A compound according to claim 23 wherein Cy is substituted with A and/or B, wherein

groups A and B are the same or different and are independently selected from H, halogen, C₁-C₄ alkyl, optionally substituted alkoxy including aminoalkoxy, haloalkoxy and heteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio, acylamino, carbamoyl,

29. A compound according to claim 23 wherein Cy is optionally substituted with one two or three groups independently selected from alkoxy, haloalkoxy, acyl, morpholino, or phenyl optionally substituted with alkoxy.

30. A compound according to claim 1, of the formula (1d):

31. A compound according to claim 30 wherein T is NH₂.

32. A compound according to claim 30 wherein Cy is:

33. A compound according to claim 1, of the formula (1e):

34. A compound according to claim 33 wherein T is NH₂.

35. A compound according to claim 33 wherein Cy is heterocyclyl or heteroaryl, each of which is optionally substituted, and each of which contains at least one nitrogen atom as part of the ring.

36. A compound according to claim 34 wherein Cy is optionally substituted with one or two substituents independently selected from A and B, wherein

groups A and B are the same or different and are independently selected from H, halogen, C₁-C₄ alkyl, optionally substituted alkoxy including aminoalkoxy, haloalkoxy and heteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio, acylamino, carbamoyl,

37. A compound according to claim 33 wherein Cy is optionally substituted with one or two substituents independently selected from:

38. A compound according to claim 4 wherein Ar is phenylene, indolyl or indolinyl, each of which is optionally substituted, and X is absent, CH₂, —

O—

CH₂—

, —

S—

CH₂—

, —

S—

C(CH₃)(H)—

, or —

N(R₉)—

CH₂.

39. A compound according to claim 38 wherein Ar is an indolyl or indolinyl group, X is CH₂ or —

N(R₉)—

CH₂—

, and Cy is;

40. A compound according to claim 38 wherein Ar is phenylene, X is —

S—

CH₂—

, or —

S—

C(CH₃)(H)—

, and Cy is;

41. A compound according to claim 1, of the formula (1f):

42. A compound according to claim 41 wherein Cy is heterocyclyl or heteroaryl, each of which is optionally substituted, and each of which contains at least one nitrogen atom as part of the ring.

43. A compound according to claim 42 wherein Cy is bound to the phenyl through a nitrogen atom.

44. A compound according to claim 41 wherein Cy is:

45. A compound according to claim 41 of the formula (1f-1):

46. A compound according to claim 45 wherein T is NH₂.

47. A compound according to claim 38 wherein Ar is phenylene, X is —

O—

CH₂—

, and Cy is;

48. A compound according to claim 1 of the formula (1 g):

49. A compound according to claim 48 wherein Cy is optionally substituted heteroaryl.

50. A compound according to claim 48 wherein Cy is optionally substituted pyrimidinyl.

51. A compound according to claim 48 wherein X is —

NH—

CH₂—

.

52. A compound according to claim 48 wherein T is NH₂.

53. A compound according to claim 1 of the formula (1 h):

54. A compound according to claim 53 wherein W is NH.

55. A compound according to claim 53 wherein A is optionally substituted pyridyl or optionally substituted phenyl.

56. A compound according to claim 53 wherein B is H or halo.

57. A compound according to claim 1 of the formula (1i):

58. A compound according to claim 57 wherein W is NH.

59. A compound according to claim 57 wherein R₄₀ is H.

60. A compound according to claim 57 wherein R₄₀ is methyl.