Arginine methyltransferase inhibitors and uses thereof

• US 9,630,961 B2
• Filed: 07/24/2015
• Issued: 04/25/2017
• Est. Priority Date: 03/14/2013
• Status: Active Grant

• Current Assignee: Magseis FF, LLC
• Original Assignee: Epizyme, Inc. (Ipsen Sa)
• Inventors: Chesworth, Richard, Mitchell, Lorna Helen, Shapiro, Gideon, Moradei, Oscar Miguel
• Primary Examiner(s): SHTERENGARTS, SAMANTHA L
• Application Number:
  US14/808,270
• Publication Number:
  US 20160185772A1
• Time in Patent Office: 641 Days
• Field of Search: None
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• 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 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 407/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 411/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

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 (III):

4. The compound of claim 1, wherein the compound is of Formula (IV):

5. The compound of claim 1, wherein the compound is of Formula (V):

6. The compound of claim 1, wherein Q is an optionally substituted 8- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

7. The compound of claim 6, wherein Q is an optionally substituted 9-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

8. The compound of claim 1, wherein Q is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

9. The compound of claim 8, wherein Q is an optionally substituted 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

10. The compound of claim 1, wherein Q is an unsubstituted, monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

11. The compound of claim 1, wherein Q is substituted, monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

12. The compound of claim 1, wherein Q is substituted or unsubstituted pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted indolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted isobenzothiophenyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzoisofuranyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzoxadiazolyl, substituted or unsubstituted benzisoxazolyl, substituted or unsubstituted benzthiazolyl, substituted or unsubstituted benzisothiazolyl, substituted or unsubstituted benzthiadiazolyl, substituted or unsubstituted indolizinyl, substituted or unsubstituted purinyl, substituted or unsubstituted pyrrolopyridinyl, substituted or unsubstituted triazolopyridinyl, substituted or unsubstituted naphthyridinyl, substituted or unsubstituted pteridinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted quinazolinyl, or substituted or unsubstituted phthalazinyl.

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

14. The compound of claim 1, wherein R³ is hydrogen or methyl.

15. The compound of claim 1, wherein R⁵ is hydrogen.

16. The compound of claim 1, wherein R^x is methyl.

17. The compound of claim 1, wherein R^x is ethyl.

18. The compound of claim 1, wherein R^x is hydroxyethyl or methoxyethyl.

19. The compound of claim 1, wherein R^x is cyclopropyl or isopropyl.

20. The compound of claim 1, wherein R⁴ is hydrogen.

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

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

24. 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.

22. A pharmaceutical composition comprising a compound selected from the group consisting of: