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;

X is a bond, —O—, —N(R)—, —CR 4 R 5 —, —O—CR 4 R 5 , —N(R)—CR 4 R 5 —, —O—CR 4 R 5 —O—, —N(R)—CR 4 R 5 —O, —N(R)—CR 4 R 5 —N(R)—, —O—CR 4 R 5 —N(R)—, —CR 4 R 5 —O—, —CR 4 R 5 —N(R)—, —O—CR 4 R 5 —CR 6 R 7 —, —N(R)—CR 4 R 5 —CR 6 R 7 —, —CR 6 R 7 —CR 4 R 5 —O—, —CR 6 R 7 —CR 4 R 5 —N(R)—, or —CR 6 R 7 —CR 4 R 5 —;

each R is independently hydrogen or optionally substituted C 1-6 aliphatic;

R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, 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 ; or R 2 and R 3 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;

R 4 and R 5 are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, 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 ; or R 4 and R 5 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;

R 6 and R 7 are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, 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 ; or R 6 and R 7 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;

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 8 , R 9 , R 10 , and R 11 are independently hydrogen, halo, or optionally substituted aliphatic;

Cy is a monocyclic or bicyclic carbocyclic group or a monocyclic or bicyclic aryl group, substituted with 0, 1, 2, 3, or 4 R y groups;

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 ; or an R y group may be optionally taken together with R 2 or R 3 to form an optionally substituted 5- to 6-membered carbocyclic or heterocyclic ring fused to Cy;

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 an optionally substituted heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 (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. The compound of claim 1 , wherein the compound is of Formula (IV):

or a pharmaceutically acceptable salt thereof.

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

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

7. The compound of claim 1 , wherein R 2 is hydrogen.

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

9. The compound of claim 1 , wherein Cy is phenyl substituted with 0, 1, 2, 3, or 4 R y groups.

10. The compound of claim 1 , wherein Cy is a bicyclic carbocyclic group or a bicyclic aryl group, substituted with 0, 1, 2, 3, or 4 R y groups.

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

and pharmaceutically acceptable salts thereof.

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

13. A method of treating a PRMT5-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof;

wherein the PRMT5-mediated disorder is cancer, a metabolic disorder, or a hemoglobinopathy;

wherein the cancer is a hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer; and

wherein the metabolic disorder is diabetes or obesity.

14. The method of claim 13 , wherein the PRMT5-mediated disorder is cancer, and wherein the cancer is a hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer.

15. The method of claim 13 , wherein the PRMT5-mediated disorder is a metabolic disorder, and wherein the metabolic disorder is diabetes or obesity.

16. The method of claim 13 , wherein the PRMT5-mediated disorder is a hemoglobinopathy.

17. The method of claim 16 , wherein the hemoglobinopathy is sickle cell anemia or β-thalessemia.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 , wherein R 2 and R 3 are each hydrogen.

21. The compound of claim 1 , wherein each of R 8 , R 9 , R 10 , and R 11 are hydrogen.

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

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

and pharmaceutically acceptable salts thereof.

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

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

and pharmaceutically acceptable salts thereof.

26. A pharmaceutical composition comprising a compound of claim 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. A pharmaceutical composition comprising a compound of claim 23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

28. A pharmaceutical composition comprising a compound of claim 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.