IP Library › Granted Patent US 11,634,407
Granted Patent B2
US 11,634,407 · App. 17/356,370 · Granted Apr 25, 2023

Cereblon binding compounds, compositions thereof, and methods of treatment therewith

Inventors: Matthew D. Alexander (San Diego, CA); Matthew D. Correa (San Diego, CA); Deepak Dalvie (Carlsbad, CA); Virginia Heather Sharron Grant (San Diego, CA); Joshua Hansen (La Jolla, CA); Roy L. Harris, III (San Diego, CA); Evan J. Horn (San Diego, CA); Dehua Huang (San Diego, CA); Christopher Mayne (Boulder, CO); Stephen Norris (San Diego, CA); Veronique Plantevin-Krenitsky (San Francisco, CA); John J. Sapienza (Chula Vista, CA); Lida Tehrani (San Diego, CA); Brandon W. Whitefield (San Diego, CA)
Assignee: Celgene Corporation
C07D401/14A61P35/00
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Quick Facts
Patent No.
US 11,634,407
App. No.
17/356,370
Granted
Apr 25, 2023
Kind
B2
Abstract

Provided herein are piperidine dione compounds having the following structure: wherein R N , R 1 , R 2 , R 3 , R 4 , R N , L, V, X, a, m, and n are as defined herein, compositions comprising an effective amount of a piperidine dione compound, and methods for treating or preventing an androgen receptor mediated disease.

Claims (76)

1. A compound selected from the group consisting of

2-((2R,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,

2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,

2-((2R,6S)-4-(2-((trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride,

2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride,

2-((2R,6S)-4-(3-(trans-4-(3-(5-Chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride,

2-((2R,6S)-4-(3-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride,

2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,

2-((R)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,

2-((2R,6S)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamide, and

2-(4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3 dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 , and a pharmaceutically acceptable carrier, excipient or vehicle.

3. A method for the treatment of an androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 , wherein the androgen mediated disease is prostate cancer.

4. The method of claim 3 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

5. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 2 , wherein the androgen mediated disease is prostate cancer.

6. The method of claim 5 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

7. A compound 2-((2R,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.

8. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 7 , and a pharmaceutically acceptable carrier, excipient or vehicle.

9. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 7 , wherein the androgen mediated disease is prostate cancer.

10. The method of claim 9 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

11. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically amount of the pharmaceutical composition of claim 8 , wherein the androgen mediated disease is prostate cancer.

12. The method of claim 11 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

13. A compound 2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 13 , and a pharmaceutically acceptable carrier, excipient or vehicle.

15. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 13 , wherein the androgen mediated disease is prostate cancer.

16. The method of claim 15 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

17. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 14 , wherein the androgen mediated disease is prostate cancer.

18. The method of claim 17 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

19. A compound 2-((2R,6S)-4-(2-((trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

20. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 19 , and a pharmaceutically acceptable carrier, excipient or vehicle.

21. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 19 , wherein the androgen mediated disease is prostate cancer.

22. The method of claim 21 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

23. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 20 , wherein the androgen mediated disease is prostate cancer.

24. The method of claim 23 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

25. A compound 2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

26. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 25 , and a pharmaceutically acceptable carrier, excipient or vehicle.

27. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 25 , wherein the androgen mediated disease is prostate cancer.

28. The method of claim 27 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

29. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 26 , wherein the androgen mediated disease is prostate cancer.

30. The method of claim 29 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

31. A compound 2-((2R,6S)-4-(3-(trans-4-(3-(5-Chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

32. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 31 , and a pharmaceutically acceptable carrier, excipient or vehicle.

33. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 31 , wherein the androgen mediated disease is prostate cancer.

34. The method of claim 33 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

35. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 32 , wherein the androgen mediated disease is prostate cancer.

36. The method of claim 35 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

37. A compound 2-((2R,6S)-4-(3-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

38. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 37 , and a pharmaceutically acceptable carrier, excipient or vehicle.

39. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 37 , wherein the androgen mediated disease is prostate cancer.

40. The method of claim 39 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

41. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 38 , wherein the androgen mediated disease is prostate cancer.

42. The method of claim 41 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

43. A compound 2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.

44. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 43 , and a pharmaceutically acceptable carrier, excipient or vehicle.

45. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 43 , wherein the androgen mediated disease is prostate cancer.

46. The method of claim 45 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

47. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 44 , wherein the androgen mediated disease is prostate cancer.

48. The method of claim 47 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

49. A compound 2-((R)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.

50. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 49 , and a pharmaceutically acceptable carrier, excipient or vehicle.

51. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 49 , wherein the androgen mediated disease is prostate cancer.

52. The method of claim 51 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

53. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 50 , wherein the androgen mediated disease is prostate cancer.

54. The method of claim 53 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

55. A compound 2-((2R,6 S)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamide.

56. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 55 , and a pharmaceutically acceptable carrier, excipient or vehicle.

57. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 55 , wherein the androgen mediated disease is prostate cancer.

58. The method of claim 57 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

59. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 56 , wherein the androgen mediated disease is prostate cancer.

60. The method of claim 59 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

61. A compound 2-(4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

62. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 61 , and a pharmaceutically acceptable carrier, excipient or vehicle.

63. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 61 , wherein the androgen mediated disease is prostate cancer.

64. The method of claim 63 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

65. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 62 , wherein the androgen mediated disease is prostate cancer.

66. The method of claim 65 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 9, 2023
From: ALEXANDER, MATTHEW D.; CORREA, MATTHEW D.; DALVIE, DEEPAK; SHARRON GRANT, VIRGINIA HEATHER; HANSEN, JOSHUA; HARRIS III, ROY L.; HORN, EVAN J.; HUANG, DEHUA; MAYNE, CHRISTOPHER; NORRIS, STEPHEN; PLANTEVIN-KRENITSKY, VERONIQUE; SAPIENZA, JOHN J.; TEHRANI, LIDA; WHITEFIELD, BRANDON W.
To: CELGENE CORPORATION
Reel/Frame 062930/0909 →
Continuity (2)
Provisional Application 63043555 · Jun 24, 2020
Related Publication 20210403454A1 · Dec 30, 2021
Cited By (2)
US 12,427,144 US 12,496,301