Arginine methyltransferase inhibitors and uses thereof

• US 9,346,761 B2
• Filed: 03/14/2014
• Issued: 05/24/2016
• 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, Boriack-Sjodin, Paula Ann, Moradei, Oscar Miguel, Jin, Lei, Duncan, Kenneth W.
• Primary Examiner(s): SAEED, KAMAL A
• Application Number:
  US14/212,102
• Publication Number:
  US 20140323537A1
• Time in Patent Office: 802 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• 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 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond

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):

3. The compound of claim 1, wherein the compound is of Formula (I-a):

4. The compound of claim 1, wherein the compound is of Formula (I-b):

5. The compound of claim 1, wherein R¹ is halo, —

CN, —

NO₂, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —

OR^A, —

N(R^B)₂, —

SR^A, —

C(=O)R^A, —

C(O)OR^A, —

C(O)SR^A, —

C(O)N(R^B)₂, —

C(O)N(R^B)N(R^B)₂, —

OC(O)R^A, —

OC(O)N(R^B)₂, —

NR^BC(O)R^A, —

NR^BC(O)N(R^B)₂, —

NR^BC(O)N(R^B)N(R^B)₂, —

NR^BC(O)OR^A, —

SC(O)R^A, —

C(=NR^B)R^A, —

C(=NNR^B)R^A, —

C(=NOR^A)R^A, —

C(=NR^B)N(R^B)₂, —

NR^BC(=NR^B)R^B, —

C(=S)R^A, —

C(=S)N(R^B)₂, —

NR^BC(=S)R^A, —

S(O)R^A, —

OS(O)₂R^A, —

SO₂R^A, —

NR^BSO₂R^A, or —

SO₂N(R^B)₂.

6. The compound of claim 5, wherein R¹ is —

OR^A.

7. The compound of claim 6, wherein R¹ is —

OR^A, wherein R^A is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclic.

8. The compound of claim 7, wherein R¹ is —

OR^A, wherein R^A is optionally substituted C_1-6alkyl.

9. The compound of claim 8, wherein R¹ is —

O-propyl, —

O-isopropyl, —

O-isobutyl, or —

O-isoamyl.

10. The compound of claim 8, wherein R¹ is —

OR^A, wherein R^A is substituted C_1-6alkyl.

11. The compound of claim 10, wherein R¹ is —

O—

C_1-6alkyl-carbocyclyl or —

O—

C_1-6alkyl-heterocyclyl.

12. The compound of claim 1, wherein R⁶ is hydrogen, —

OR^A, halo, —

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

13. The compound of claim 12, wherein R⁶ is halo.

14. The compound of claim 13, wherein R⁶ is fluoro or chloro.

15. The compound of claim 1, wherein R² is hydrogen.

16. The compound of claim 1, wherein R⁷ and R⁸ are hydrogen.

17. The compound of claim 1, wherein R³ is C_1-4alkyl.

18. The compound of claim 17, wherein R³ is methyl.

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

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

21. The compound of claim 1, wherein R⁵ is hydrogen or optionally substituted C₁₄alkyl.

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

23. The compound of claim 22, wherein R^x is methyl.

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

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

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

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

28. The method of claim 27, wherein the arginine methyl transferase is PRMT1, PRMT3, PRMT6, PRMT8, or CARM1.

29. The method of claim 28, wherein the arginine methyl transferase is PRMT1.

30. 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.

31. 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.

32. A method of treating an 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;

wherein;

the RMT-mediated disorder is a cancer, a neurological disorder, or an autoimmune disease;

and wherein;

the cancer is breast cancer, prostate cancer, lung cancer, colon cancer, bladder cancer, or leukemia;

the neurological disorder is amyotrophic lateral sclerosis; and

the autoimmune disease is rheumatoid arthritis.

33. The method of claim 32 wherein the RMT-mediated disorder is amyotrophic lateral sclerosis.

34. A pharmaceutical composition comprising a compound of claim 24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

35. A compound selected from the group consisting of:

36. A pharmaceutical composition comprising a compound of claim 35, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.