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 —O—, —N(R)—, —C(R 2 )(R 3 )—, —O—CR 2 R 3 , —N(R)—CR 2 R 3 —, —O—CR 2 R 3 —O—, —N(R)—CR 2 R 3 —O, —N(R)—CR 2 R 3 —N(R)—, —O—CR 2 R 3 —N(R)—, —CR 2 R 3 —O—, —CR 2 R 3 —N(R)—, —O—CR 2 R 3 —CR 9 R 10 —, —N(R)—CR 2 R 3 —CR 9 R 10 —, —CR 2 R 3 —CR 9 R 10 —O—, —CR 2 R 3 —CR 9 R 10 —N(R)—, or —CR 2 R 3 —CR 9 R 10 —;

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;

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;

Ring A is phenyl;

R 4 is -L 1 -Cy;

L 1 is a bond;

Cy is an optionally substituted, monocyclic, aromatic ring selected from the group consisting of optionally substituted phenyl and optionally substituted 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R 5 , R 6 , R 7 , and R 8 are independently hydrogen, halo, or optionally substituted aliphatic;

R 9 and R 10 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 9 and R 10 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;

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 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;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits;

m is 0, 1, 2, 3, or 4, as valency permits; and

p is 1;

wherein each instance of aliphatic is independently an alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl group.

2. The compound of claim 1 , wherein L is —O—.

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

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

5. The compound of claim 1 , wherein L is —N(R)— or —C(R 2 )(R 3 )—.

6. The compound of claim 1 , wherein the compound is of formula V:

or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , and X 4 are independently selected from the group consisting of CH and CR y .

7. The compound of claim 1 , wherein Cy is optionally substituted phenyl.

8. The compound of claim 1 , wherein Cy is optionally substituted 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

10. The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

11. A pharmaceutical composition comprising a compound of claim 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. The compound of claim 1 , wherein the compound is of formula (I′):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is hydrogen or C 1-4 alkyl;

L is —O—, —N(R)—, —C(R 2 )(R 3 )—, —CR 2 R 3 —O—, or —CR 2 R 3 —N(R)—;

each R is independently hydrogen or C 1-4 alkyl;

R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl;

Ring A is phenyl;

R 4 is -L 1 -Cy;

L 1 is a bond;

Cy is an optionally substituted, monocyclic, aromatic ring selected from the group consisting of optionally substituted phenyl and optionally substituted 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R 5 , R 6 , R 7 , and R 8 are independently hydrogen, halo, or C 1-4 alkyl;

each R y is independently selected from the group consisting of halo and C 1-4 alkyl;

each R x is independently selected from the group consisting of halo, —CN, C 1-4 alkyl, —OR′, and —N(R″) 2 ;

R′ is hydrogen or C 1-4 alkyl;

each R″ is independently hydrogen or C 1-4 alkyl, or two R″ are taken together with their intervening atoms to form a heterocyclic ring;

n is 0, 1, 2, or 3, as valency permits;

m is 0, 1, 2, or 3 as valency permits; and

p is 1.

13. The compound of claim 12 , wherein L is —O— or —N(R)—.

14. The compound of claim 12 , wherein R 1 is hydrogen.

15. The compound of claim 1 , wherein n is 0.

16. The compound of claim 12 , wherein R 5 , R 6 , R 7 , and R 8 are hydrogen.

17. The compound of claim 12 , wherein the compound is of formula V:

or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , and X 4 are independently selected from the group consisting of CH and CR Y .

18. The compound of claim 12 , wherein Cy is optionally substituted phenyl.

19. The compound of claim 12 , wherein Cy is optionally substituted 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

20. A compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

21. A pharmaceutical composition comprising a compound of claim 20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

22. The compound of claim 8 , wherein Cy is optionally substituted pyridyl or optionally substituted pyrimidyl.

23. The compound of claim 19 , wherein Cy is optionally substituted pyridyl or optionally substituted pyrimidyl.