Arginine methyltransferase inhibitors and uses thereof

• US 9,724,332 B2
• Filed: 07/24/2015
• Issued: 08/08/2017
• Est. Priority Date: 03/14/2013
• Status: Active Grant

• Current Assignee: Epizyme, Inc. (Ipsen Sa)
• Original Assignee: Epizyme, Inc. (Ipsen Sa)
• Inventors: Mitchell, Lorna Helen, Chesworth, Richard, Shapiro, Gideon
• Primary Examiner(s): SHTERENGARTS, SAMANTHA L
• Application Number:
  US14/808,290
• Publication Number:
  US 20160184267A1
• Time in Patent Office: 746 Days
• Field of Search: None
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: C07D 231/10 having two or three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/02 containing two hetero rings
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/02 containing two hetero rings
• CPC Class Codes: C07D 413/08 linked by a carbon chain containing alicyclic rings
• CPC Class Codes: C12N 9/1007 Methyltransferases (general) (2.1.1.)
• CPC Class Codes: C12Y 201/01125 Histone-arginine N-methyltransferase (2.1.1.125)

Abstract

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.

Claims

1. A method of therapeutically treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

2. The method of claim 1, wherein the cancer is leukemia.

3. The method of claim 2, wherein the leukemia is acute lymphocytic leukemia.

4. The method of claim 2, wherein the leukemia is acute myelocytic leukemia.

5. The method of claim 2, wherein the leukemia is chronic myelocytic leukemia.

6. The method of claim 2, wherein the leukemia is chronic lymphocytic leukemia.

7. The method of claim 1, wherein the compound inhibits PRMT1 at an IC₅₀ less than or equal to 10 μ

M.

8. The method of claim 1, wherein the compound inhibits PRMT1 at an IC₅₀ less than or equal to 1 μ

M.

9. The method of claim 1, wherein the compound inhibits PRMT1 at an IC₅₀ less than or equal to 0.1 μ

M.

10. The method of claim 1, wherein the compound is of Formula (II):

11. The method of claim 1, wherein the compound is of Formula (III):

12. The method of claim 1, wherein L₁ is a bond, and R^W is optionally substituted carbocyclyl.

13. The method of claim 1, wherein L₁ is a bond, and R^W is optionally substituted cyclohexyl.

14. The method of claim 1, wherein L₁ is a bond, and R^W is optionally substituted heterocyclyl.

15. The method of claim 1, wherein R³ is C_1-4 alkyl.

16. The method of claim 15, wherein R³ is methyl.

17. The method of claim 1, wherein R⁴ and R⁵ are hydrogen.

18. The method of claim 1, wherein R^x is optionally substituted C_1-4 alkyl.

19. The method of claim 18, wherein R^x is methyl.

20. The method of claim 1, wherein the compound is selected from the group consisting of:

21. A method of therapeutically treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

22. The method of claim 21, wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, lung cancer, colorectal cancer, bladder cancer, and leukemia.

23. The method of claim 22, wherein the cancer is leukemia.

24. The method of claim 23, wherein the leukemia is acute lymphocytic leukemia.

25. The method of claim 23, wherein the leukemia is acute myelocytic leukemia.

26. The method of claim 23, wherein the leukemia is chronic myelocytic leukemia.

27. The method of claim 23, wherein the leukemia is chronic lymphocytic leukemia.

28. The method of claim 21, wherein the compound inhibits PRMT1 at an IC₅₀ less than or equal to 10 μ

M.

29. The method of claim 21, wherein the compound is selected from the group consisting of: