Dibenzo[b,f][1,4]oxazepin-11-yl-N-hydroxybenzamides as HDAC inhibitors

1. A compound of Formula (IV) or pharmaceutically acceptable salt thereof:

wherein:

R 140 is selected from the group consisting of: H, —OH, halo, —CN, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxyl, —O—C 2 -C 4 alkyl-O—C 1 -C 4 alkyl, —CF 3 , —OCF 3 , —NO 2 , —C 1 -C 6 alkyl-S(O) 0-2 R 53 , —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 and —N(C 1 -C 6 alkyl) 2 ;

xa and xb denote numbers that are each independently selected from 0, 1 and 2;

R 150 and a R 160 independently selected from the group consisting of H, halo, —CN, —CF 3 , —OCF 3 , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxyl, —O—C 2 -C 6 alkyl-O—R 53 , —OR 53 , —C 0 -C 6 alkyl-S(O) 0-2 —R 53 , —C 0 -C 6 alkyl-C(O)—R 53 , —C 0 -C 6 alkyl-C(O)NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 C(O)—R 53 , —C 0 -C 6 alkyl -S(O) 2 NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 S(O) 2 —R 53 , —C 0 -C 6 alkyl-OC(O)NR 50 R 51 , —C 0 -C 6 alkyl -NR 52 C(O)O—R 53 , —C 0 -C 6 alkyl-NR 52 C(O)NR 50 R 51 , —C 0 -C 6 alkyl-C(O)O—R 53 , —C 0 -C 6 alkyl -OC(O)—R 53 , —C 0 -C 6 alkyl-aryl, —C 0 -C 6 alkyl-heteroaryl, —C 0 -C 6 alkyl-cycloalkyl, —C 0 -C 6 alkyl -heterocyclyl, —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 , —O—C 2 -C 6 alkyl-NR 50 R 51 , —NR 53 —C 2 -C 6 alkyl-NR 50 R 51 and —O-heterocyclyl-R 53 , wherein each alkyl and heteroalkyl is optionally substituted with one or three substituents independently selected from the group consisting of F, —OH and oxo, and wherein each aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, —CN, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxyl, —O—C 2 -C 4 alkyl-O—C 1 -C 4 alkyl, —CF 3 , —OCF 3 , —NO 2 , —C 1 -C 6 alkyl-S(O) 0-2 R 53 , —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 and —N(C 1 -C 6 alkyl) 2 ;

R 50 and R 51 are independently selected from the group consisting of H, —C 1 -C 6 alkyl, —C 2 -C 6 alkyl -O—C 1 -C 6 alkyl, —C 0 -C 6 alkyl-C 3 -C 7 cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, amino, —CN or —C 1 -C 4 alkyl;

or

R 50 and R 51 , together with the N atom to which they are attached, optionally form a 3-10 membered heterocyclic ring, wherein the heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, —OH, amino, —CN or —C 1 -C 4 alkyl;

R 52 is independently selected from the group consisting of —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 0 -C 6 alkyl-C 3 -C 7 cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, amino, —CN or —C 1 -C 4 alkyl; and

R 53 is independently selected from the group consisting of —C 1 -C 6 alkyl, —C 0 -C 4 alkyl-C 3 -C 7 cycloalkyl, —C 0 -C 4 alkyl-aryl, —C 0 -C 4 alkyl-heteroaryl and —C 0 -C 4 alkyl-heterocyclyl, wherein each alkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one or three substituents independently selected from the group consisting of halo, —OH, amino, —CN or —C 1 -C 4 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof having Formula V:

wherein:

xc is 0 or 1; and

R 170 is selected from the group consisting of H, halo, —CN, —CF 3 , —OCF 3 , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxyl, —O—C 2 -C 6 alkyl-O—R 53 , —OR 53 , —C 0 -C 6 alkyl-S(O) 0-2 —R 53 , —C 0 -C 6 alkyl-C(O)—R 53 , —C 0 -C 6 alkyl-C(O)NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 C(O)—R 53 , —C 0 -C 6 alkyl-S(O) 2 NR 50 R 51 , —C 0 -C 6 alkyl -NR 52 S(O) 2 —R 53 , —C 0-6 alkyl-OC(O)NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 C(O)O—R 53 , —C 0 -C 6 alkyl -NR 52 C(O)NR 50 R 51 , —C 0 -C 6 alkyl-C(O)O—R 53 , —C 0 -C 6 alkyl-OC(O)—R 53 , —C 0 -C 6 alkyl-aryl, —C 0 -C 6 alkyl-heteroaryl, —C 0 -C 6 alkyl-cycloalkyl, —C 0 -C 6 alkyl-heterocyclyl, —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 , —O—C 2 -C 6 alkyl-NR 50 R 51 , —NR 53 —C 2 -C 6 alkyl-NR 50 R 51 and —O-heterocyclyl -R 53 , wherein each alkyl and heteroalkyl is optionally substituted with one or three substituents independently selected from the group consisting of F, —OH and oxo, wherein each aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, —CN, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxyl, —O—C 2 -C 4 alkyl-O—C 1 -C 4 alkyl, —CF 3 , —OCF 3 , —NO 2 , —C 1 -C 6 alkyl-S(O) 0-2 R 53 , —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 and —N(C 1 -C 6 alkyl) 2 .

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof having Formula (VI):

4. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:

(Z)-4-(dibenzo [b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

4-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

N-hydroxy-4-(10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)-4-(2-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

(Z)—N-hydroxy-4-(2-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)-4-(2-(2-(dimethylamino)ethoxy)dibenzo[b,f][1,4]oxazepin- 11-yl)-N-hydroxybenzamide,

(Z)—N-hydroxy-4-(8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11 -yl)benzamide,

(Z)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-2-fluoro-N-hydroxybenzamide,

(Z)—N-hydroxy-4-(3-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)-3-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

(Z)—N-hydroxy-4-(8-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)—N-hydroxy-4-(4-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)-4-(9-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

(Z)—N-hydroxy-4-(7-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11 -yl)benzamide,

(Z)-4-(7-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

(Z)-4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

(Z)-4-(8-cyanodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

(Z)—N-hydroxy-4-(4-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)—N-hydroxy-4-(3-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)-4-(3-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

(Z)-4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

(Z)—N-hydroxy-4-(3-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin- 11-yl)benzamide,

(Z)-4-(6-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

(Z)-4-(7-cyanodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

(Z)—N-hydroxy-4-(4-hydroxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)—N-hydroxy-4-(1-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)—N-hydroxy-4-(4-(2-methoxyethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)-4-(1-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

(Z)—N-hydroxy-4-(4-(2-morpholinoethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)-4-(2-fluoro-4-methoxydibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,

(Z)—N-hydroxy-4-(4-(methylthio)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)—N-hydroxy-4-(4-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin- 11-yl)benzamide,

(Z)—N-hydroxy-4-(4-(methylsulfinyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)—N-hydroxy-4-(4-(methylsulfonyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(E)-4-((dibenzo[b,f][1,4]oxazepin-11-ylamino)methyl)-N-hydroxybenzamide,

(Z)—N-hydroxy-4-(4-methoxy-8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)—N-hydroxy-4-(3-morpholinodibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)—N-hydroxy-4-(4-propyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(Z)—N-hydroxy-4-(4-(trifluoromethoxy)dibenzo[b,f][1,4]oxazepin- 11-yl)benzamide,

(Z)—N-hydroxy-4-(6-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,

(E)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-3-fluoro-N-hydroxybenzamide,

(Z)-4-(4-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, and

(E)-4-(2-(dibenzo[b,f][1,4]oxazepin-11-ylamino)ethyl)-N-hydroxybenzamide.

5. A pharmaceutical composition comprising the compound of any of claims 1 - 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

6. A method for alleviating one or more symptoms of Huntington's Disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of claims 1 - 4 or a pharmaceutically acceptable salt thereof.

7. A method for alleviating one or more symptoms of dentatorubralpallidoluysian atrophy comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of claims 1 - 4 or a pharmaceutically acceptable salt thereof.

8. A method for alleviating one or more symptoms of spinocerebellar ataxia type 3 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of claims 1 - 4 or a pharmaceutically acceptable salt thereof.

9. A method for alleviating one or more symptoms of spinal bulbar muscular atrophy comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of claims 1 - 4 or a pharmaceutically acceptable salt thereof.

10. The compound of claim 4 wherein the compound is (Z)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 4 wherein the compound is 4-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 4 wherein the compound is N-hydroxy-4-(10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 4 wherein the compound is (Z)-4-(2-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(2-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 4 wherein the compound is (Z)-4-(2-(2-(dimethylamino)ethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

16. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

17. The compound of claim 4 wherein the compound is (Z)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-2-fluoro-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(3-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 4 wherein the compound is (Z)-3-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

20. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(8-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

21. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(4-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

22. The compound of claim 4 wherein the compound is (Z)-4-(9- fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

23. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(7-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

24. The compound of claim 4 wherein the compound is (Z)4-(7-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

25. The compound of claim 4 wherein the compound is (Z)-4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

26. The compound of claim 4 wherein the compound is (Z)-4-(8-cyanodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

27. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(4-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

28. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(3-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

29. The compound of claim 4 wherein the compound is (Z)-4-(3-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

30. The compound of claim 4 wherein the compound is (Z)-4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

31. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(3-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

32. The compound of claim 4 wherein the compound is (Z)-4-(6-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

33. The compound of claim 4 wherein the compound is (Z)-4-(7-cyanodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

34. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(4-hydroxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

35. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(1-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

36. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(4-(2-methoxyethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

37. The compound of claim 4 wherein the compound is (Z)-4-(1-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

38. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(4-(2-morpholinoethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

39. The compound of claim 4 wherein the compound is (Z)-4-(2-fluoro-4-methoxydibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

40. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(4-(methylthio)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

41. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(4-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

42. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(4-(methylsulfinyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

43. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(4-(methylsulfonyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

44. The compound of claim 4 wherein the compound is (E)-4-((dibenzo[b,f][1,4]oxazepin-11-ylamino)methyl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

45. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(4-methoxy-8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

46. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(3-morpholinodibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

47. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(4-propyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

48. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(4-(trifluoromethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

49. The compound of claim 4 wherein the compound is (Z)-N-hydroxy-4-(6-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide, or a pharmaceutically acceptable salt thereof.

50. The compound of claim 4 wherein the compound is (E)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-3-fluoro-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

51. The compound of claim 4 wherein the compound is (Z)-4-(4-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide, or a pharmaceutically acceptable salt thereof.

52. The compound of claim 4 wherein the compound is (E)-4-(2-(dibenzo[b,f][1,4]oxazepin-11-ylamino)ethyl)-N-hydroxybenzamide or a pharmaceutically acceptable salt thereof.