PRMT5 inhibitors and uses thereof

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 pharmaceutically acceptable salt thereof.

28. The compound of claim 1 , wherein at least one R y is —N(R B ) 2 .

29. The compound of claim 28 , wherein at least one R y is —NHR B .

30. The compound of claim 29 , wherein R B is optionally substituted heterocyclyl.

31. The compound of claim 1 , wherein Ar is selected from the group consisting of:

32. The compound of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

33. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

34. The compound of claim 1 , wherein Ar is selected from the group consisting of:

35. The compound of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

36. A pharmaceutical composition comprising a compound of claim 32 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

37. A pharmaceutical composition comprising a compound of claim 35 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

38. The compound of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

39. A pharmaceutical composition comprising a compound of claim 38 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.