PRMT5 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 PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.
1. A compound of Formula (III):
or a pharmaceutically acceptable salt thereof,
wherein:
R 2 is selected from the group consisting of optionally substituted C 1-4 alkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, —C(O)R A , and —SO 2 R A ;
R A is C 1-4 alkyl;
n is 0; and
m is 0;
wherein:
each instance of optionally substituted when on a carbon is independently halogen, —CN, —N 3 , —OH, —OR aa , —N(R bb ) 2 , —SH, —SR aa , —C(═O)R aa , —CO 2 H, —CHO, —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , —NR bb C(═O)R aa , —NR bb CO 2 R aa , —NR bb C(═O)N(R bb ) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl wherein C 1-4 alkyl is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —OR ee , and —N(R ff ) 2 ;
and, when on a nitrogen is independently C 1-4 alkyl;
each instance of R aa and R ee is independently C 1-4 alkyl; and
each instance of R bb and R ff is independently selected from the group consisting of hydrogen and C 1-4 alkyl.
2. The compound of claim 1 , wherein R 2 is optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl.
3. The compound of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
4. The compound of claim 1 , wherein the compound is of Formula (III-a):
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein the compound is of Formula (III-b):
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein R 2 is optionally substituted phenyl.
7. The compound of claim 6 , wherein R 2 is halophenyl.
8. The compound of claim 7 , wherein R 2 is fluorophenyl or chlorophenyl.
9. The compound of claim 6 , wherein R 2 is phenyl substituted with a 5-6 membered heterocyclic ring.
10. The compound of claim 9 , wherein R 2 is phenyl substituted with morpholinyl.
11. The compound of claim 1 , wherein R 2 is optionally substituted 5-10 membered heteroaryl.
12. The compound of claim 11 , wherein R 2 is optionally substituted quinolinyl.
13. The compound of claim 1 , wherein R 2 is selected from the group consisting of:
14. The compound of claim 11 , wherein R 2 is optionally substituted pyridinyl.
15. The compound of claim 14 , wherein R 2 is pyridinyl substituted with a 5-6 membered heterocyclic ring.
16. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
17. A kit or packaged pharmaceutical comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and instructions for use thereof.
18. A pharmaceutical composition comprising a compound of claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.