PRMT1 inhibitors and uses thereof

• US 10,227,307 B2
• Filed: 12/21/2017
• Issued: 03/12/2019
• Est. Priority Date: 03/14/2013
• Status: Active Grant

• Current Assignee: Epizyme, Inc. (Ipsen Sa)
• Original Assignee: Epizyme, Inc. (Ipsen Sa)
• Inventors: Kuntz, Kevin Wayne, Mitchell, Lorna Helen, Shapiro, Gideon, Chesworth, Richard, Boriack-Sjodin, Paula Ann
• Primary Examiner(s): Barker, Michael
• Application Number:
  US15/850,367
• Publication Number:
  US 20180265478A1
• Time in Patent Office: 446 Days
• Field of Search: None
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

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

Claims

1. A pharmaceutical composition comprising a compound selected from the following, or a pharmaceutically acceptable salt thereof,

2. A kit or packaged pharmaceutical comprising a compound selected from the following, or a pharmaceutically acceptable salt thereof,

3. A method of treating a disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I,

4. The method of claim 3, wherein the disorder is a proliferative disorder, a neurological disorder, a muscular dystrophy, an autoimmune disorder, a vascular disorder, or a metabolic disorder.

5. The method of claim 4, wherein the disorder is cancer.

6. The method of claim 4, wherein the disorder is amyotrophic lateral sclerosis.

7. The method of claim 3, wherein R^y is —

NHC(O)R^A, —

NHSO₂R^A, or —

CH₂C(O)N(R^B)₂.

8. The method of claim 3, wherein the compound is of Formula (II) or (III):

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

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

OR^A, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, or —

CN.

11. The method of claim 3, wherein R⁶ is hydrogen, —

OR^A, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, or —

CN.

12. The method of claim 3, wherein R³ is hydrogen or C_1-4 alkyl.

13. The method of claim 3, wherein R³ is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, or cyclobutyl.

14. The method of claim 3, wherein R⁴ is hydrogen or optionally substituted C_1-6 alkyl.

15. The method of claim 3, wherein R⁵ is hydrogen or optionally substituted C_1-4 alkyl.

16. The method of claim 3, wherein R^x is optionally substituted C_1-4 alkyl.

17. The method of claim 3, wherein R^x is methyl, ethyl, propyl, butyl, isopropyl, hydroxyethyl, methoxyethyl, cyclopropyl, or cyclobutyl.

18. The method of claim 3, wherein the compound is selected from the group consisting of: