Arginine methyltransferase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-2016185772-A1
Application number	US-201514808270-A
Country	US
Kind code	A1
Filing date	Jul 24, 2015
Priority date	Mar 14, 2013
Publication date	Jun 30, 2016
Grant date	—

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.

First claim

1 - 47 . (canceled)

48 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
X is N, Z is NR 4 , and Y is CR 5 ; or
X is NR 4 . Z is N, and Y is CR5; or
X is CR 5 , Z is NR 4 , and Y is N; or
X is CR 5 , Z is N. and Y is NR 4 ;
R x : is optionally substituted C 1-4 alkyl or optionally substituted C 3-4 cycloalkyl;

Q is an optionally substituted, monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Q is not pyridine;
R: hydrogen, C alkyl, or C 3-4 cycloalkyl;
R 4 is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl; and
R 5 is hydrogen, halo, —CN, optionally substituted C 1-4 alkyl, or optionally substituted C 3-4 cycloalkyl.

or a pharmaceutically acceptable salt thereof.

50 . The compound of claim 48 , wherein the compound is of Formula (III):

or a pharmaceutically acceptable salt thereof.

51 . The compound of claim 48 , wherein the compound is of For V

or a pharmaceutically acceptable salt thereof.

52 . The compound of claim 48 , wherein the compound is of Formula (V):

or a phainiaceutically acceptable salt thereof

53 . The compound of claim 48 , wherein Q is an optionally substituted 8- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

54 . The compound of claim 53 , wherein Q is an optionally substituted 9-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

55 . The compound of claim 48 , wherein Q is an optionally substituted 5- to 6-membered. heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

56 . The compound of claim 55 , wherein Q is an optionally substituted 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

57 . The compound of claim 48 , wherein Q is an unsubstituted, monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

58 . The compound of claim 48 , wherein Q is substituted, monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

59 . The compound of claim 48 , 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 triazolyi, 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 isoindotyl, 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 henzimidazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzoxadia,zolyl, 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.

60 . The compound of claim 48 , wherein Q is selected from the group consisting of:

wherein:
each R q is independently selected from the group consisting of halo, —CN, —NO 2 , 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 , —SRA, —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 B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R″, —C(═S)N(R B ) 2 , -NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 RA, —NR B SO 2 R A , and —SO 2 N(R B ) 2 ;
each R A is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom; and
each R B is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring.

61 . The compound of claim 48 , wherein R 3 is hydrogen or methyl.

62 . The compound of claim 48 , wherein R 5 is hydrogen.

63 . The compound of claim 48 , wherein Rx − is methyl.

64 . The compound of claim 48 , wherein R x is ethyl.

65 . The compound of claim 48 , wherein Rx is hydroxyethyl or methoxyethyl.

66 . The compound of claim 48 , wherein R x is cyclopropyl or isopropyl.

67 . The compound of claim 48 , wherein R 4 is hydrogen.

68 . A pharmaceutical composition comprising a compound of claim 48 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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

Assignees

• Epizyme Inc

Inventors

• Chesworth Richard
• Mitchell Lorna Helen
• Shapiro Gideon
• Moradei Oscar Miguel

Classifications

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/4155

  non condensed and containing further heterocyclic rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title