Arginine methyltransferase inhibitors and uses thereof

• US 9,943,504 B2
• Filed: 06/10/2016
• Issued: 04/17/2018
• 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, Kuntz, Kevin Wayne
• Primary Examiner(s): Solola, Taofiq A
• Application Number:
  US15/178,696
• Publication Number:
  US 20170119735A1
• Time in Patent Office: 676 Days
• Field of Search: None
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention 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 ameliorating a disorder 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, 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 compound is of Formula (II-a):

3. The method of claim 2, wherein R₄ is optionally substituted C_1-3 alkyl, optionally substituted C₅ carbocyclyl, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl or optionally substituted C_1-3 alkyl-Cy, wherein Cy is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl.

4. The method of claim 1, wherein the compound is of Formula (II-a1):

5. The method of claim 1, wherein the compound is of Formula (II-a2):

6. The method of claim 1, wherein X is NR₂ and Y is N.

7. The method of claim 1, wherein X is N and Y is NR₂.

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

9. The method of claim 1, wherein R_x is methyl, ethyl, isopropyl, isopropyl, propyl, butyl, hydroxyethyl, methoxyethyl, cyclopropyl, or cyclobutyl.

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

11. The method of claim 1, wherein the disorder is breast cancer, prostate cancer, lung cancer, colon cancer, bladder cancer, or a leukemia.

12. The method of claim 1, wherein the disorder is a leukemia.

13. The method of claim 12, wherein the leukemia is acute myelocytic leukemia.

14. The method of claim 1, wherein the disorder is a lymphoma.

15. The method of claim 1, wherein the disorder is amyotrophic lateral sclerosis.

16. The method of claim 1, wherein the disorder is oculopharyngeal muscular dystrophy.

17. The method of claim 1, wherein the disorder is diabetes.