PRMT1 inhibitors and uses thereof

• US 10,039,748 B2
• Filed: 08/08/2016
• Issued: 08/07/2018
• 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, Shapiro, Gideon, Chesworth, Richard, Boriack-Sjodin, Paula Ann, Moradei, Oscar Miguel, Kuntz, Kevin Wayne
• Primary Examiner(s): Jackson, Shawquia
• Application Number:
  US15/231,651
• Publication Number:
  US 20170182005A1
• Time in Patent Office: 729 Days
• 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 31/455 Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

Described herein are compounds of Formula (I-a) and (I-b), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT1 activity. Methods of using the compounds for treating PRMT1-mediated disorders are also described.

Claims

1. A method of therapeutic treatment of a PRMT1-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I-a) or (I-b):

2. The method of claim 1 wherein R¹ is hydrogen, —

OR^A, —

CN, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclic.

3. The method of claim 1, wherein R² is hydrogen, —

OR^A, —

CN, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclic.

4. The method of claim 1, wherein R⁷ is hydrogen and R⁸ is not hydrogen or wherein R⁷ is not hydrogen and R⁸ is hydrogen.

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

6. The method of claim 1, wherein R⁴ is hydrogen or optionally substituted C_1-6 alkyl.

7. The method of claim 1, wherein R⁵ is hydrogen or optionally substituted C_1-4 alkyl.

8. The method of claim 1, wherein R^x is methyl, ethyl, propyl, butyl, isopropyl, hydroxyethyl, methoxyethyl, cyclopropyl, or cyclobutyl.

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

10. The method of claim 1, wherein the PRMT1-mediated disorder is selected from breast cancer, prostate cancer, lung cancer, colon cancer, bladder cancer, leukemia, and lymphoma.

11. The method of claim 10, wherein the PRMT1-mediated disorder is leukemia.

12. The method of claim 10, wherein the PRMT1-mediated disorder is lymphoma.

13. The method of claim 1, wherein the PRMT1-mediated disorder is selected from diabetes mellitus, kidney failure, coronary heart disease, oculopharyngeal muscular dystrophy, and amyotrophic lateral sclerosis.