Arginine methyltransferase inhibitors and uses thereof

• US 9,365,527 B2
• Filed: 03/14/2014
• Issued: 06/14/2016
• 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
• Primary Examiner(s): Barker, Michael
• Assistant Examiner(s): Cheng, Karen
• Application Number:
  US14/213,272
• Publication Number:
  US 20140315961A1
• Time in Patent Office: 823 Days
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/54 having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 249/06 with aryl radicals directly attached to ring atoms
• CPC Class Codes: C07D 261/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 263/32 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 285/06 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 285/10 1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
• 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 compound of Formula (II):

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

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

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

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

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

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

8. The method of claim 7, wherein the arginine methyl transferase is PRMT1, PRMT3, PRMT6, PRMT8, or CARM1.

9. The method of claim 8, wherein the arginine methyl transferase is PRMT1.

10. 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.

11. 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.

12. 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.

13. The method of claim 12, wherein the RMT-mediated disorder is a PRMT1-mediated disorder, a PRMT3-mediated disorder, a PRMT6-mediated disorder, a PRMT8-mediated disorder, or a CARM1-mediated disorder.

14. The method of claim 13, wherein the RMT-mediated disorder is a PRMT1-mediated disorder.

15. The method of claim 12, wherein the disorder is a proliferative disorder, a neurological disorder, a muscular dystrophy, an autoimmune disorder, a vascular disorder, or a metabolic disorder.

16. The method of claim 15, wherein the proliferative disorder is cancer.

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

18. The compound of claim 1, wherein R^x is CH₃.

19. The compound of claim 1, wherein R³ is hydrogen.

20. The compound of claim 1, wherein R^N is optionally substituted aryl.

21. The compound of claim 1, wherein R^N is independently of Formula (i):

22. The compound of claim 21, wherein q is 1.

23. The compound of claim 21, wherein Formula (i) is of formula:

24. The compound of claim 21, wherein R^N is selected from the group consisting of:

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

26. The compound of claim 25, wherein R^x is methyl, ethyl, isopropyl, propyl, butyl, hydroxyethyl, methoxyethyl, cyclopropyl, or cyclobutyl.

27. The compound of claim 25, wherein R³ is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, or cyclobutyl.

28. The compound of claim 25, wherein R^N is optionally substituted aryl.

29. The compound of claim 28, wherein R^N is independently of Formula (i):

30. The compound of claim 1, wherein:

each instance of R^C is independently selected from the group consisting of hydrogen, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-6 carbocyclyl, 4- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, C_1-4 alkyl-Cy, —

OR^A, —

N(R^B)₂, and —

C(═

O)R^A;

each instance of R^A is independently selected from the group consisting of hydrogen and C_1-4 alkyl;

each instance of R^B is independently selected from the group consisting of hydrogen and C_1-4 alkyl, or two R^B groups are taken together with their intervening atoms to form a 4- to 6-membered heterocyclic ring; and

each instance of Cy is independently C_3-6 cycalkyl, 4- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl.

31. A pharmaceutical composition comprising a compound of claim 4, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

32. The method of claim 16, wherein the cancer is breast cancer, prostate cancer, lung cancer, colon cancer, bladder cancer, or leukemia.

33. The method of claim 15, wherein the disorder is an autoimmune disorder, and the autoimmune disorder is rheumatoid arthritis.