3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof

• US 10,640,489 B2
• Filed: 08/05/2019
• Issued: 05/05/2020
• Est. Priority Date: 08/23/2017
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Beckwith, Rohan Eric John, Bonazzi, Simone, Cernijenko, Artiom, Tichkule, Ritesh Bhanudasji, Visser, Michael Scott
• Primary Examiner(s): Cheng, Karen
• Application Number:
  US16/532,106
• Publication Number:
  US 20190367483A1
• Time in Patent Office: 274 Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/08 Bridged systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

The present disclosure provides a compound of Formula (I′):

• • or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R₁, R₂, R_x, X₁, n, n1, and q are as defined herein, and methods of making and using same.

Claims

1. A compound of Formula (Ic):

2. The compound according to claim 1, wherein R₄ is phenyl or (C₃-C₈)cycloalkyl optionally substituted with one to three R₇.

3. The compound according to claim 1, wherein R₄ is phenyl optionally substituted with one to three R₇.

4. The compound according to claim 1, wherein R₄ is (C₃-C₈)cycloalkyl optionally substituted with one to three R₇.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

14. The pharmaceutical composition of claim 13 further comprising at least one additional pharmaceutical agent.

15. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

16. A method of reducing proliferation of a cell, wherein the method comprises:

contacting the cell with a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.

17. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

18. The method of claim 17, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).

19. The method of claim 17, wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.

20. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt.

5. A compound selected from:

6. The compound of claim 5, wherein the compound is compound (I-156):

7. The compound of claim 5, wherein the compound is compound (I-57):

8. The compound of claim 5, wherein the compound is compound (I-87):

9. The compound of claim 5, wherein the compound is compound (I-88):

10. The compound of claim 5, wherein the compound is compound (I-112):

11. The compound of claim 5, wherein the compound is compound (I-303):

12. The compound of claim 5, wherein the compound is compound (I-11):

and

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 5, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

22. The pharmaceutical composition of claim 21 further comprising at least one additional pharmaceutical agent.

23. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 6, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

24. A method of reducing proliferation of a cell, wherein the method comprises:

contacting the cell with a compound according to claim 6, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.

25. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 6, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

26. The method of claim 25, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).

27. The method of claim 25, wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.

28. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 6, or a pharmaceutically acceptable salt.

29. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 7, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

30. A method of reducing proliferation of a cell, wherein the method comprises:

contacting the cell with a compound according to claim 7, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.

31. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 7, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

32. The method of claim 31, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).

33. The method of claim 31, wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.

34. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 7, or a pharmaceutically acceptable salt.

35. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

36. A method of reducing proliferation of a cell, wherein the method comprises:

contacting the cell with a compound according to claim 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.

37. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

38. The method of claim 37, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).

39. The method of claim 37, wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.

40. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 8, or a pharmaceutically acceptable salt.

41. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 9, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

42. A method of reducing proliferation of a cell, wherein the method comprises:

contacting the cell with a compound according to claim 9, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.

43. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 9, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

44. The method of claim 43, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).

45. The method of claim 43, wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.

46. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 9, or a pharmaceutically acceptable salt.

47. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 10, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

48. A method of reducing proliferation of a cell, wherein the method comprises:

contacting the cell with a compound according to claim 10, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.

49. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 10, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

50. The method of claim 49, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).

51. The method of claim 49, wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.

52. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 10, or a pharmaceutically acceptable salt.

53. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

54. A method of reducing proliferation of a cell, wherein the method comprises:

contacting the cell with a compound according to claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.

55. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

56. The method of claim 55, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).

57. The method of claim 55, wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.

58. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 11, or a pharmaceutically acceptable salt.

59. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

60. A method of reducing proliferation of a cell, wherein the method comprises:

contacting the cell with a compound according to claim 12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.

61. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

62. The method of claim 61, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).

63. The method of claim 61, wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.

64. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 12, or a pharmaceutically acceptable salt.