Arginine methyltransferase inhibitors and uses thereof

• US 10,632,103 B2
• Filed: 01/26/2018
• Issued: 04/28/2020
• 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:
  US15/881,323
• Publication Number:
  US 20180289671A1
• Time in Patent Office: 823 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 compound of Formula (I):

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

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein -L₁-R^W is optionally substituted alkyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is hydrogen, C_1-4 alkyl, cyclopropyl, or cyclobutyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen or optionally substituted C_1-4 alkyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen, optionally substituted C_2-6 alkenyl, optionally substituted C_2-6 alkynyl, optionally substituted C_3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl;

or optionally substituted C_1-4 alkyl-Cy.

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

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

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

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

12. The method of claim 11, wherein the arginine methyl transferase is PRMT1, PRMT6, PRMT3, PRMT8, or CARM1.

13. 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.

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

15. A method of 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.

16. The method of claim 15, wherein the RMT-mediated disorder is a PRMT1-mediated disorder, a PRMT6-mediated disorder, a PRMT3-mediated disorder, a PRMT8-mediated disorder, or a CARM1-mediated disorder.

17. The method of claim 15, wherein the disorder is a proliferative disorder, a neurological disorder, a muscular dystrophy, an autoimmune disorder, a vascular disorder, or a metabolic disorder.

18. The method of claim 17, wherein the disorder is cancer.

19. The method of claim 17, wherein the disorder is amyotrophic lateral sclerosis.

20. The method of claim 17, wherein the disorder is selected from the group consisting of breast cancer, prostate cancer, lung cancer, colon cancer, bladder cancer, lymphoma, leukemia, diabetes mellitus, kidney failure, coronary heart disease, oculopharyngeal muscular dystrophy, and amyotrophic lateral sclerosis.