Arginine methyltransferase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-2024182426-A1
Application number	US-202318482475-A
Country	US
Kind code	A1
Filing date	Oct 6, 2023
Priority date	Mar 14, 2013
Publication date	Jun 6, 2024
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 . 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 CR 5 ; 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;
L 1 is a bond, —O—, —N(R B )—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(R B )—, —C(O)N(R B )N(R B )—, —OC(O)—, —OC(O)N(R B )—, —NR B C(O)—, —NR B C(O)N(R B )—, —NR B C(O)N(R B )N(R B )—, —NR B C(O)O—, —SC(O)—, —C(═NR B )—, ═NNR B )—, —C(═NOR A )—, —C(═NR B )N(R B )—, —NR B C(═NR B )—, —C(S)—, —C(S)N(R B ), —NR B C(S)—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —SO 2 —, —N(R B )SO 2 —, —SO 2 N(R B )—, or an optionally substituted C 1-6 , saturated or unsaturated hydrocarbon chain, wherein one or more methylene units of the hydrocarbon chain is optionally and independently replaced with —O—, —N(R B )—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(R B )—, —C(O)N(R B )N(R B )—, —OC(O)—, —OC(O)N(R B )—, —NR B C(O)—, —NR B C(O)N(R B )—, —NR B C(O)N(R B )N(R B )—, —NR B C(O)O—, —SC(O)—, —C(═NR B )—, —C(═NNR B )—, —C(═NOR A ), —C(═NR B )N(R B )—, —NR B C(═NR B )—, —C(S)—, —C(S)N(R B —NR B C(S), —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —SO 2 —, —N(R B )SO 2 —, or —SO 2 N(R B )—;
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;
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 an R B and R W on the same nitrogen atom may be taken together with the intervening nitrogen to form an optionally substituted heterocyclic ring;
R W is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; provided that when L 1 is a bond, R W is not hydrogen, optionally substituted aryl, or optionally substituted heteroaryl;
R 3 is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl;
R 4 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl; or optionally substituted C 1-4 alkyl-Cy;
Cy is optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R 5 is hydrogen, halo, —CN, optionally substituted C 1-4 alkyl, or optionally substituted C 3-4 cycloalkyl;

wherein, and unless otherwise specified,
heterocyclyl or heterocyclic refers to a radical of a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur;
carbocyclyl or carbocyclic refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms and zero heteroatoms in the non-aromatic ring system;
aryl refers to a radical of a monocyclic or polycyclic aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system; and
heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.

2 . The compound of claim 1 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 , wherein the compound is of Formula (III):

or a pharmaceutically acceptable salt thereof.

4 - 12 . (canceled)

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

or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

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

or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

15 . The compound of claim 1 , wherein the compound is of Formula (VI-c):

or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

16 . The compound of claim 1 , wherein the compound is of Formula (VI-d):

or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

17 . The compound of claim 1 , wherein the compound is of Formula (VI-e):

or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

18 . The compound of claim 1 , wherein the compound is of Formula (VI-f):

or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted carbocylyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

19 . The compound of claim 1 , wherein the compound is of Formula (VI-g):

or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

20 . The compound of claim 1 , wherein the compound is of Formula (VI-h):

or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted carbocyclyl,

Assignees

• Epizyme Inc

Inventors

• Chesworth Richard
• Mitchell Lorna Helen
• Shapiro Gideon
• Swinger Kerren Kalai

Classifications

• C07D231/12 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• A61K31/415

  1,2-Diazoles · CPC title

• A61K31/4155

  non condensed and containing further heterocyclic rings · CPC title

• C07D401/04

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

• C07D403/04

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