Arginine methyltransferase inhibitors and uses thereof
View Patent ↗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.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
X is NR 2 and Y is N; or
X is N and Y is NR 2 ;
each instance of R 1 is independently selected from the group consisting of halogen, —N 3 , —CN, —NO 2 , —OH, optionally substituted C 1-6 alkyl, and —OR A , wherein at least one instance of R 1 is —OR A ;
m is 1 or 2;
R 2 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted to 4- to 6-membered heterocyclyl;
R 3 is hydrogen, C 1-4 alkyl, or C 3-4 carbocyclyl;
R x is optionally substituted C 1-4 alkyl or optionally substituted C 3-4 carbocyclyl;
each instance of R A is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 3-6 carbocyclyl, optionally substituted phenyl, optionally substituted 5- to 6-membered heterocyclyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted C 1-6 alkyl-Cy;
each instance of Cy is independently optionally substituted C 3-6 cycloalkyl, optionally substituted 5- to 6-membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5- to 6-membered heteroaryl; and
each instance of substituted independently refers to substitution with 1, 2, or 3 groups independently selected from the group consisting of —N 3 , halogen, —NO 2 , —CN, C 1-4 alkyl, and —OR aa , wherein each instance of R aa is independently C 1-4 alkyl.
2. The compound of claim 1 , wherein the compound is of Formula (II-a):
or a pharmaceutically acceptable salt thereof,
wherein:
R 4 is optionally substituted C 1-6 alkyl, optionally substituted C 3-6 carbocyclyl, optionally substituted phenyl, optionally substituted 5- to 6-membered heterocyclyl, optionally substituted 5- to 6-membered heteroaryl, or optionally substituted C 1-6 alkyl-Cy.
3. The compound of claim 2 , wherein R 4 is optionally substituted C 1-3 alkyl, optionally substituted C 5 carbocyclyl, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl or optionally substituted C 1-3 alkyl-Cy, wherein Cy is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl.
4. The compound of claim 2 , wherein the compound is of Formula (II-a1):
or a pharmaceutically acceptable salt thereof,
wherein:
n is 1, 2, 3, 4, 5, or 6;
R 4 is selected from the group consisting of:
each instance of R 6 is independently halogen, —N 3 , —CN, —NO 2 , or C 1-4 alkyl; and
p is 0, 1, 2, or 3.
5. The compound of claim 2 , wherein the compound is of Formula (II-a2):
or a pharmaceutically acceptable salt thereof,
wherein:
each instance of R 6 is independently halogen, —N 3 , —CN, —NO 2 , or C 1-4 alkyl; R B is hydrogen or C 1-4 alkyl;
n is 1, 2, 3, 4, 5, 6; and
q is 0, 1, or 2.
6. The compound of claim 1 , wherein X is NR 2 and Y is N.
7. The compound of claim 1 , wherein X is N and Y is NR 2 .
8. The compound of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
10. A kit or packaged pharmaceutical comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and instructions for use thereof.
11. The compound of claim 1 , wherein R x is methyl, ethyl, isopropyl, propyl, butyl, hydroxyethyl, methoxyethyl, cyclopropyl, or cyclobutyl.
12. The compound of claim 1 , wherein R 3 is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, or cyclobutyl.
13. A pharmaceutical composition comprising a compound of claim 8 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.