HISTONE DEMETHYLASE INHIBITORS

• US 20160039808A1
• Filed: 03/12/2014
• Published: 02/11/2016
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Celgene Quanticel Research, Inc. (Bristol-Myers Squibb Company)
• Original Assignee: Quanticel Pharmaceuticals, Inc. (Bristol-Myers Squibb Company)
• Inventors: Kanouni, Toufike, Stafford, Jeffrey Alan, Veal, James Marvin, Wallace, Michael Brennan
• Granted Patent: US 9,994,562 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted pyrido[3,4-d]pyrimidin-4-one derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

Claims

1. A compound of Formula (I), or pharmaceutically acceptable salt thereof,

2. The compound of claim 1, wherein Y is hydrogen.

3. The compound of claim 1, wherein Y is

4. The compound of claim 1, wherein X is alkyl.

5. The compound of claim 1, wherein X is -L-R¹.

6. The compound of claim 2, wherein X is alkyl.

7. The compound of claim 3, wherein X is alkyl.

8. The compound of claim 2, wherein X is -L-R¹.

9. The compound of claim 3, wherein X is -L-R¹.

10. The compound of claim 6 or 7, wherein the alkyl is a C1-C6 alkyl.

11. The compound of claim 10, wherein the alkyl is substituted with at least one fluoro substituent.

12. The compound of claim 10, wherein the alkyl is substituted with at least one group selected from hydroxy, alkoxy, aryloxy, amino, alkylamino, arylamino, or diakylamino.

13. The compound of claim 10, wherein the alkyl is substituted with at least one group selected from —

NHCOR³, —

NHCO₂R³, —

NHCONHR³, —

N(R⁴)COR³, —

N(R⁴)CO₂R³, —

N(R⁴)CONHR³, —

N(R⁴)CON(R⁴)R³, —

NHSO₂R³, or —

NR⁴SO₂R³, wherein each R³ is independently selected from alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and each R⁴ is an alkyl.

14. The compound of claim 10, wherein the alkyl is substituted with at least one group selected from —

CONH₂, —

CONHR³, —

CON(R³)₂, —

COR³, —

SO₂NH₂, —

SO₂NHR³, —

SO₂N(R³)₂, or —

SO₂R³, wherein each R³ is independently selected from alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl.

15. The compound of claim 8 or 9, wherein L is a bond.

16. The compound of claim 15, wherein R¹ is carbocyclyl.

17. The compound of claim 15, wherein R¹ is aryl.

18. The compound of claim 15, wherein R¹ is heterocyclyl.

19. The compound of claim 15, wherein R¹ is heteroaryl.

20. The compound of claim 17, wherein the aryl is a phenyl group.

21. The compound of claim 20, wherein the phenyl is substituted with at least one halogen substituent.

22. The compound of claim 20, wherein the phenyl is substituted with at least one alkyl substituent.

23. The compound of claim 20, wherein the phenyl is substituted with at least one group selected from hydroxy, alkoxy, aryloxy, amino, alkylamino, arylamino, or diakylamino.

24. The compound of claim 20, wherein the phenyl is substituted with at least one group selected from —

NHCOR³, —

NHCO₂R³, —

NHCONHR³, —

N(R⁴)COR³, —

N(R⁴)CO₂R³, —

N(R⁴)CONHR³, —

N(R⁴)CON(R⁴)R³, —

NHSO₂R³, or —

NR⁴SO₂R³, wherein each R³ is independently selected from alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and each R⁴ is an alkyl.

25. The compound of claim 20, wherein the phenyl is substituted with at least one group selected from —

CONH₂, —

CONHR³, —

CON(R³)₂, —

COR³, —

SO₂NH₂, —

SO₂NHR³, —

SO₂N(R³)₂, or —

SO₂R³, wherein each R³ is independently selected from alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl.

26. The compound of claim 20, wherein the phenyl is substituted with a group selected from aryl, heteroaryl, carbocyclyl, or heterocyclyl.

27. The compound of claim 19, wherein the heteroaryl is a group selected from benzimidazolyl, benzofuranyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl or thiophenyl.

28. The compound of claim 27, wherein the heteroaryl group is substituted with at least one halogen substituent.

29. The compound of claim 27, wherein the heteroaryl group is substituted with at least one alkyl substituent.

30. The compound of claim 27, wherein the heteroaryl group is substituted with at least one group selected from hydroxy, alkoxy, aryloxy, amino, alkylamino, arylamino, or diakylamino.

31. The compound of claim 27, wherein the heteroaryl group is substituted with at least one group selected from —

NHCOR³, —

NHCO₂R³, —

NHCONHR³, —

N(R⁴)COR³, —

N(R⁴)CO₂R³, —

N(R⁴)CONHR³, —

N(R⁴)CON(R⁴)R³, —

NHSO₂R³, or —

NR⁴SO₂R³, wherein each R³ is independently selected from alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and each R⁴ is an alkyl.

32. The compound of claim 27, wherein the heteroaryl group is substituted with at least one group selected from —

CONH₂, —

CONHR³, —

CON(R³)₂, —

COR³, —

SO₂NH₂, —

SO₂NHR³, —

SO₂N(R³)₂, or —

SO₂R³, wherein each R³ is independently selected from alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl.

33. The compound of claim 27, wherein the heteroaryl group is substituted with a group selected from aryl, heteroaryl, carbocyclyl, or heterocyclyl.

34. The compound of claim 27, wherein the heteroaryl is a pyrazolyl having the structure

35. The compound of claim 34, wherein the R⁵ group is a C1-C6 alkyl, optionally substituted with at least one group selected from hydroxy, C1-C4 alkoxy, amino, C1-C4 alkylamino, C1-C4 diakylamino, piperdinyl, pyrrolidnyl, or morpholinyl.

36. The compound of claim 34, wherein the R⁵ group is a heterocyclyl selected from 4-tetrahydropyranyl, 1-morpholinyl, or 4-piperdinyl having the structure

37. The compound of claim 8 or 9, wherein L is a C1-C6 alkylene.

38. The compound of claim 8 or 9, wherein L is a C1-C4 alkylene.

39. The compound of claim 37, wherein R¹ is 3- to 7-membered carbocyclyl.

40. The compound of claim 37, wherein R¹ is phenyl.

41. The compound of claim 37, wherein R¹ is a 5- or 6-membered heteroaryl.

42. The compound of claim 37, wherein R¹ is a 4- to 6-membered oxygen containing heterocyclyl.

43. The compound of claim 3, wherein R² is alkyl.

44. The compound of claim 3, wherein R² is heterocyclyl.

45. The compound of claim 3, wherein R² is heterocyclylalkyl.

46. The compound of claim 3, wherein R² is carbocyclylalkyl.

47. The compound of claim 43, wherein the alkyl is methyl.

48. The compound of claim 43, wherein the alkyl is C2-C4 alkyl.

49. The compound of claim 47 or 48, wherein the alkyl is substituted with at least one fluoro substituent.

50. The compound of claim 48, wherein the alkyl is substituted with at least one group selected from hydroxy, alkoxy, amino, alkylamino, or diakylamino.

51. The compound of claim 44, wherein the heterocyclyl is a 4- to 6-membered oxygen or nitrogen containing heterocyclyl.

52. The compound of claim 45, wherein the heterocyclylalkyl consists of a 4- to 6-membered oxygen or nitrogen containing heterocyclyl, and a C1-C3 alkylene.

53. The compound of claim 46, wherein the carbocyclylalkyl consists of a 3- to 7-membered carbocyclyl, and a C1-C3 alkylene.

54. A pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

55. A method for inhibiting a histone demethylase enzyme comprising contacting a histone demethylase enzyme with a compound of Formula (I).

56. A method for treating cancer in subject comprising administering to the subject in need thereof a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof.