Kinase inhibitors and methods of use thereof

• US 10,137,122 B2
• Filed: 07/14/2015
• Issued: 11/27/2018
• Est. Priority Date: 10/12/2012
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute, The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: Dana-Farber Cancer Institute, The General Hospital Corporation (Mass General Brigham, Inc.), The Broad Institute, Inc.
• Inventors: Wagner, Florence Fevrier, Pan, Jennifer Q., Dandapani, Sivaraman, Germain, Andrew, Holson, Edward, Munoz, Benito, Nag, Partha P., Lewis, Michael C., Haggarty, Stephen J., Bishop, Joshua A., Stegmaier, Kimberly, Weiwer, Michel, Banerji, Versha
• Primary Examiner(s): Desai, Rita J
• Application Number:
  US14/799,281
• Publication Number:
  US 20150313890A1
• Time in Patent Office: 1,232 Days
• Field of Search: 514293, 546 82
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/4747 spiro-condensed
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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
• CPC Class Codes: C07D 471/10 Spiro-condensed systems

Abstract

The present invention provides compounds of formula I, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting kinase (e.g., GSK3 (e.g., GSK3α or GSK3β) or CK1) activity. The present invention further provides methods of using the compounds described herein for treating kinase-mediated disorders, such as neurological diseases, psychiatric disorders, metabolic disorders, and cancer.

Claims

1. A method of treating Fragile X syndrome comprising administering to a subject suffering from Fragile X syndrome an effective amount of a compound of formula I:

2. The method of claim 1, wherein R¹ is optionally substituted phenyl.

3. The method of claim 1, wherein R^5a and R^5b are each unsubstituted methyl.

4. The method of claim 1, wherein the compound is of the formula:

9. The method of claim 1, wherein the compound is of formula:

10. The method of claim 1, wherein R¹ is optionally substituted heteroaryl.

11. The method of claim 1, wherein R¹ is optionally substituted pyridyl.

12. The method of claim 1, wherein R² is unsubstituted methyl.

13. The method of claim 1, wherein R² is substituted methyl or optionally substituted ethyl.

14. The method of claim 1, wherein R² is —

CF₃ or unsubstituted ethyl.

15. The method of claim 1, wherein R³ is hydrogen or fluoro.

16. The method of claim 1, wherein R^5a and R^5b are taken together with their intervening atoms to form unsubstituted, 3- to 7-membered, monocyclic, saturated, carbocyclyl or heterocyclyl.

17. The method of claim 1, wherein the compound is of the formula:

18. The method of claim 1, wherein the compound is of the formula:

19. The method of claim 1, wherein the compound is of the formula:

31. The method of claim 1, wherein R¹ and R² are taken together with their intervening atoms to form optionally substituted, 3- to 7-membered, monocyclic, saturated, carbocyclyl or heterocyclyl, wherein the carbocyclyl or heterocyclyl formed by taking together R¹ and R² is optionally fused to optionally substituted phenyl or optionally substituted heteroaryl.

5. A method of treating bipolar disorder comprising administering to a subject suffering from a mood disorder an effective amount of a compound of formula I:

20. The method of claim 5, wherein R² is unsubstituted methyl.

21. The method of claim 5, wherein R¹ and R² are taken together with their intervening atoms to form optionally substituted, 3- to 7-membered, monocyclic, saturated, carbocyclyl or heterocyclyl, wherein the carbocyclyl or heterocyclyl formed by taking together R¹ and R² is optionally fused to optionally substituted phenyl or optionally substituted heteroaryl.

22. The method of claim 5, wherein R³ is optionally substituted C_1-6 aliphatic.

23. The method of claim 5, wherein R³ is optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted iso-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted 3-methyl-2-butanyl, or optionally substituted tertiary amyl.

24. The method of claim 5, wherein R³ is optionally substituted neopentyl.

25. The method of claim 5, wherein R³ is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl.

26. The method of claim 5, wherein R³ is cyclobutyl substituted with one or more fluoro.

27. The method of claim 5, wherein R^5a and R^5b are each unsubstituted methyl.

28. The method of claim 5, wherein R^5a and R^5b are taken together with their intervening atoms to form unsubstituted, 3- to 7-membered, monocyclic, saturated, carbocyclyl or heterocyclyl.

29. The method of claim 5, wherein the compound is of the formula:

30. The method of claim 5, wherein the compound is of the formula:

32. The method of claim 5, wherein the compound is of formula:

33. The method of claim 5, wherein R¹ is optionally substituted phenyl.

34. The method of claim 5, wherein R¹ is optionally substituted heteroaryl.

35. The method of claim 5, wherein R¹ is optionally substituted pyridyl.

36. The method of claim 5 wherein R² is —

CF₃ or unsubstituted ethyl.

6. A method of treating autism comprising administering to a subject suffering from autism an effective amount of a compound of formula I:

37. The method of claim 6, wherein R¹ and R² are taken together with their intervening atoms to form optionally substituted, 3- to 7-membered, monocyclic, saturated, carbocyclyl or heterocyclyl, wherein the carbocyclyl or heterocyclyl formed by taking together R¹ and R² is optionally fused to optionally substituted phenyl or optionally substituted heteroaryl.

38. The method of claim 6, wherein the compound is of formula:

39. The method of claim 6, wherein R¹ is optionally substituted phenyl.

40. The method of claim 6, wherein R¹ is optionally substituted heteroaryl.

41. The method of claim 6, wherein R¹ is optionally substituted pyridyl.

42. The method of claim 6, wherein R² is unsubstituted methyl.

43. The method of claim 6, wherein R² is substituted methyl or optionally substituted ethyl.

44. The method of claim 6, wherein R² is —

CF₃ or unsubstituted ethyl.

45. The method of claim 6, wherein R³ is hydrogen or fluoro.

46. The method of claim 6, wherein R^5a and R^5b are each unsubstituted methyl.

47. The method of claim 6, wherein R^5a and R^5b are taken together with their intervening atoms to form unsubstituted, 3- to 7-membered, monocyclic, saturated, carbocyclyl or heterocyclyl.

48. The method of claim 6, wherein the compound is of the formula:

49. The method of claim 6, wherein the compound is of the formula:

50. The method of claim 6, wherein the compound is of the formula:

51. The method of claim 6, wherein the compound is of the formula:

7. A method of treating acute myeloid leukemia (AML) comprising administering to a subject suffering from AML an effective amount of a compound of formula I:

8. The method of claim 7, wherein the AML is acute promyelocytic leukemia.

52. The method of claim 7, wherein R¹ and R² are taken together with their intervening atoms to form optionally substituted, 3- to 7-membered, monocyclic, saturated, carbocyclyl or heterocyclyl, wherein the carbocyclyl or heterocyclyl formed by taking together R¹ and R² is optionally fused to optionally substituted phenyl or optionally substituted heteroaryl.

53. The method of claim 7, wherein the compound is of formula:

54. The method of claim 7, wherein R¹ is optionally substituted phenyl.

55. The method of claim 7, wherein R¹ is optionally substituted heteroaryl.

56. The method of claim 7 wherein R¹ is optionally substituted pyridyl.

57. The method of claim 7, wherein R² is unsubstituted methyl.

58. The method of claim 7, wherein R² is substituted methyl or optionally substituted ethyl.

59. The method of claim 7, wherein R² is —

CF₃ or unsubstituted ethyl.

60. The method of claim 7, wherein R³ is hydrogen or fluoro.

61. The method of claim 7, wherein R^5a and R^5b are each unsubstituted methyl.

62. The method of claim 7, wherein R^5a and R^5b are taken together with their intervening atoms to form unsubstituted, 3- to 7-membered, monocyclic, saturated, carbocyclyl or heterocyclyl.

63. The method of claim 7, wherein the compound is of the formula:

64. The method of claim 7, wherein the compound is of the formula:

65. The method of claim 7, wherein the compound is of the formula:

66. The method of claim 7, wherein the compound is of the formula: