Arginine methyltransferase inhibitors and uses thereof

• US 9,120,757 B2
• Filed: 03/14/2014
• Issued: 09/01/2015
• Est. Priority Date: 03/14/2013
• Status: Active Grant

• Current Assignee: Epizyme, Inc. (Ipsen Sa)
• Original Assignee: Epizyme, Inc. (Ipsen Sa)
• Inventors: Chesworth, Richard, Mitchell, Lorna Helen, Shapiro, Gideon
• Primary Examiner(s): SHTERENGARTS, SAMANTHA L
• Application Number:
  US14/212,543
• Publication Number:
  US 20140315904A1
• Time in Patent Office: 536 Days
• US Class Current: 1/1
• 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 compound of Formula (I):

2. The compound of claim 1, wherein the compound is of Formula (II) or (III):

3. The compound of claim 1, wherein the compound is of Formula (IV) or (V):

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

5. The compound of claim 4, wherein L₁ is a bond and R^W is optionally substituted cyclohexyl.

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

7. The compound of claim 6, wherein L₁ is a bond and R^W is optionally substituted piperidine.

8. The compound of claim 1, wherein R³ is C_1-4 alkyl.

9. The compound of claim 8, wherein R³ is methyl.

10. The compound of claim 1, wherein R³ is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, or cyclobutyl.

11. The compound of claim 1, wherein R⁴ is hydrogen.

12. The compound of claim 1, wherein R⁴ is optionally substituted C_1-6 alkyl.

13. The compound of claim 12, wherein R⁴ is unsubstituted C_1-6 alkyl.

14. The compound of claim 13, wherein R⁴ is methyl.

15. The compound of claim 1, wherein R⁵ is hydrogen.

16. The compound of claim 1, wherein R⁵ is optionally substituted C_1-4 alkyl.

17. The compound of claim 16, wherein R⁵ is unsubstituted C_1-4 alkyl.

18. The compound of claim 17, wherein R⁵ is methyl.

19. The compound of claim 1, wherein R^X is optionally substituted C_1-4 alkyl.

20. The compound of claim 19, wherein R^X is unsubstituted C_1-4 alkyl.

21. The compound of claim 20, wherein R^X is methyl.

22. The compound of claim 19, wherein R^X is ethyl, isopropyl, propyl, butyl, hydroxyethyl, methoxyethyl, cyclopropyl, or cyclobutyl.

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

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

25. A kit or packaged pharmaceutical comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and instructions for use thereof.

26. A method of inhibiting an arginine methyl tranferase (RMT) comprising contacting a cell with an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, wherein the arginine methyl transferase is PRMT1, PRMT3, PRMT6, PRMT8, or CARM1.

28. The method of claim 27, wherein the arginine methyl transferase is PRMT1.

29. A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

30. A method of modulating transcription comprising contacting a cell with an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

31. A method for therapeutically treating a RMT-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

32. The method of claims 31, wherein the RMT-mediated disorder is a PRMT1-mediated disorder, a PRMT3-mediated disorder, a PRMT6-mediated disorder, a PRMT8-mediated disorder, or a CARM1-mediated disorder.

33. The method of claim 32, wherein the RMT-mediated disorder is a PRMT1-mediated disorder.

34. The method of claim 31, wherein the disorder is a proliferative disorder, a neurological disorder, a muscular dystrophy, an autoimmune disorder, a vascular disorder, or a metabolic disorder.

35. The method of claim 34, wherein the proliferative disorder is cancer.

36. The method of claim 34, wherein the neurological disorder is amyotrophic lateral sclerosis.