Bone marrow on X chromosome kinase (BMX) inhibitors and uses thereof

• US 10,000,483 B2
• Filed: 10/18/2013
• Issued: 06/19/2018
• Est. Priority Date: 10/19/2012
• Status: Active Grant

• Current Assignee: Beth Israel Deaconess Medical Center, Inc. (Beth Israel Lahey Health, Inc.), Dana-Farber Cancer Institute
• Original Assignee: Beth Israel Deaconess Medical Center, Inc. (Beth Israel Lahey Health, Inc.), Dana-Farber Cancer Institute
• Inventors: Gray, Nathanael, Balk, Steven, Liu, Qingsong, Chen, Sen
• Primary Examiner(s): Desai, Rita J
• Application Number:
  US14/436,387
• Publication Number:
  US 20150246913A1
• Time in Patent Office: 1,705 Days
• Field of Search: 546 80, 514290
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the compounds of Formula (I) or (II), or compositions thereof, for treating or preventing a wide range of diseases (e.g., proliferative diseases (e.g., cancers, benign neoplasms, angiogenesis, inflammatory diseases, autoimmune diseases) and metabolic diseases (e.g., diabetes (e.g., type 2 diabetes, gestational diabetes)) in a subject. Treatment of a subject with a disease using a compound of Formula (I) or (II), or compositions thereof, may downregulate the expression and/or inhibit the activity of a kinase (e.g., a tyrosine kinase, such as a Tec kinase, in particular, bone marrow on X chromosome kinase (BMX)), and therefore, suppress tyrosine kinase singling in the subject.

Claims

1. A compound of Formula (I):

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^D is of Formula (i-1):

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring C is a phenyl ring optionally substituted with n instances of R^c.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a bond or —

CH₂—

.

5. The compound of claim 1, wherein the compound is of Formula (I-1):

6. The compound of claim 1, wherein the compound is of Formula (I-2):

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is a bond.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is trans-CH═

CH—

.

9. The compound of claim 1, wherein the compound is of Formula (I-3):

10. The compound of claim 1, wherein the compound is of Formula (I-4):

11. The compound of claim 1, wherein the compound is of Formula (I-5):

12. The compound of claim 1, wherein the compound is of Formula (I-6):

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

R^c is optionally substituted methyl; and

n is 1.

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

15. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

16. A method for treating a disease characterized by overexpression of bone marrow kinase on X chromosome (BMX) or associated with aberrant activity of BMX, the method comprising:

administering to a subject in need thereof a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the disease, wherein the disease is prostate cancer or lymphoma.

17. A method of suppressing kinase signaling in a biological sample or subject, the method comprising:

administering to the biological sample or subject a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to suppress the kinase signaling.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is an unsubstituted C₂ hydrocarbon chain.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^D is of the formula:

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^D is of the formula:

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

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

24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring C is a phenyl ring fused with a monocyclic, 5- or 6-membered heterocyclic ring and is optionally substituted with n instances of R^c.

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

26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R^A is —

NR^A1S(═

O)₂R^A1.

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

28. The pharmaceutical composition of claim 15, wherein the compound is of the formula:

29. The method of claim 16, wherein the compound is of the formula:

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

31. The method of claim 16, wherein the disease is prostate cancer.

32. The method of claim 16, wherein the disease is lymphoma.

33. The method of claim 32, wherein the lymphoma is Waldenströ

m'"'"'s macroglobulinemia.

34. The method of claim 32, wherein the lymphoma is Hodgkin'"'"'s lymphoma.

35. The method of claim 32, wherein the lymphoma is non-Hodgkin'"'"'s lymphoma.

36. The method of claim 32, wherein the lymphoma is B-cell lymphoma.

37. The method of claim 32, wherein the lymphoma is T-cell lymphoma.