PRMT1 inhibitors and uses thereof

• US 8,952,026 B2
• Filed: 03/14/2014
• Issued: 02/10/2015
• 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
• Primary Examiner(s): BARKER, MICHAEL P
• Application Number:
  US14/212,057
• Publication Number:
  US 20140288140A1
• Time in Patent Office: 333 Days
• Field of Search: None
• US Class Current: 514/269
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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

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 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:

R¹ is —

NR^BC(O)R^A, —

NR^BSO₂R^A, or —

(CR_zR^z)_nC(O)N(R^B)₂;

each R^z is independently hydrogen or fluoro; and

n is 0, 1, 2, 3, or 4.

5. The compound of claim 1, wherein R² is hydrogen, —

OR^A, halo, —

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

6. The compound of claim 1, wherein R¹ is hydrogen, —

OR^A, halo, —

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

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

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

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

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

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

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

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

14. A method of inhibiting protein arginine methyl tranferase 1 (PRMT1) comprising contacting a cell with an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

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

16. 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.

17. A method of treating a PRMT1-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.

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

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

20. The method of claim 18, wherein the neurological disorder is amyotrophic lateral sclerosis.