Pyrazole derivatives as arginine methyltransferase inhibitors and uses thereof

• US 9,776,972 B2
• Filed: 03/14/2014
• Issued: 10/03/2017
• 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:
  US14/775,232
• Publication Number:
  US 20160137609A1
• Time in Patent Office: 1,299 Days
• Field of Search: None
• 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 not hydrogen.

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_1-6 alkyl.

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_1-6 alkyl.

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_1-4 alkyl.

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_1-6 alkyl.

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

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

28. The compound of claim 27, wherein R¹ is —

OR^A, —

N(R^B)₂, or optionally substituted alkoxyalkyl.

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

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

31. A pharmaceutical composition comprising a compound of claim 29 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.