PRMT5 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9365519-B2
Application number	US-201514619371-A
Country	US
Kind code	B2
Filing date	Feb 11, 2015
Priority date	Dec 21, 2012
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

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.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
represents a single or double bond;
R 1 is hydrogen, R z , or —C(O)R z , wherein R z is optionally substituted C 1-6 alkyl;
L is —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, or —OC(O)N(R)—;
each R is independently hydrogen or optionally substituted C 1-6 aliphatic;
Ar is a monocyclic or bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with 0, 1, 2, 3, 4, or 5 R y groups, as valency permits;
each R y is independently selected from the group consisting of halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —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(═NNR 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 A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —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 aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R B is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
R 5 , R 6 , R 7 , and R 8 are independently hydrogen, halo, or optionally substituted aliphatic;
each R x is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, —OR′, and —N(R″) 2 ;
R′ is hydrogen or optionally substituted aliphatic;
each R″ is independently hydrogen or optionally substituted aliphatic, or two R″ are taken together with their intervening atoms to form a heterocyclic ring; and
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits;
wherein each instance of aliphatic is independently an alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl group.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , wherein the compound is of Formula (I′-a):

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 4 , wherein the compound is of Formula (I′-b):

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein L is —C(O)N(R)—, or —OC(O)NH—.

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

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein the compound is of Formula (II-a):

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 8 , wherein the compound is of Formula (II-b):

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein R 1 is hydrogen.

12. The compound of claim 1 , wherein n is 0, 1, or 2.

13. The compound of claim 1 , wherein Ar is heteroaryl.

14. The compound of claim 13 , wherein Ar is a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

15. The compound of claim 14 , wherein Ar is pyridyl.

16. The compound of claim 1 , wherein Ar is substituted with 1 or 2 R y groups.

17. The compound of claim 16 , wherein Ar is substituted with one R y group.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 , wherein the compound is of Formula (IX):

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 , wherein the compound is of Formula (XV):

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 , wherein the compound is of Formula (XVII):

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutica

Assignees

• Epizyme Inc

Inventors

• Duncan Kenneth W
• Chesworth Richard
• Boriack-Sjodin Paula Ann
• Munchhof Michael John
• Jin Lei

Classifications

• C12N9/1007

  Methyltransferases (general) (2.1.1.) · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D217/12 Primary

  with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring · CPC title

• A61K31/506 Primary

  not condensed and containing further heterocyclic rings · CPC title