GCN2 inhibitors and uses thereof

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is selected from a 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally fused to a 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or

Het, wherein Het is a 5-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated spirocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Ring B is

each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

two R groups are optionally taken together to form a bivalent C 2-4 alkylene chain;

two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R′ is independently hydrogen or a C 1-3 aliphatic group optionally substituted with halogen;

each of R 1 is independently hydrogen, halogen, —NO 2 , —C(O)R, —C(O)NRS(O) 2 R, —C(O)N═S(O)R 2 , —NR 2 , —NRC(O)R, —NRC(O)NR 2 , —NRC(O)OR, —NRS(O) 2 R, —NRS(O) 2 NR 2 , —OR, —ON(R)SO 2 R, —P(O)R 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)(NH)R, —S(O) 2 N(R) 2 , —S(NH 2 ) 2 (O)OH,—N═S(O)R 2 , —CH 3 , —CH 2 OH, —CH 2 NHSO 2 CH 3 , —CD 3 , or —CD 2 NRS(O) 2 R, or

each R 1 is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

two R 1 groups are optionally taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

two R 1 groups are optionally taken together to form —O or ═NH; or

two R 1 groups are optionally taken together to form a bivalent C 2-4 alkylene chain;

each of R 2 is independently hydrogen, halogen, —C(O)N(R′) 2 , —OR′, —N(R′) 2 , —S(O) 2 R, —S(O) 2 N(R) 2 , —O— phenyl, or an optionally substituted group selected from C 1-3 aliphatic, phenyl, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-8 membered saturated monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 3 is hydrogen, halogen, —CN, —OR′, —N(R′) 2 , or an optionally substituted group selected from C 1-3 aliphatic, or a 5 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 4 is hydrogen, halogen, —CN, —OR, or an optionally substituted group selected from C 1-3 aliphatic, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, or 2;

p is 0 or 1; and

q is 0 or 1.

2. The compound of claim 1 , wherein Ring A is Het.

3. The compound of claim 2 , wherein Het is a 5-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated spirocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

4. The compound of claim 1 , wherein each of R 1 is independently hydrogen, halogen, —C(O)R, —C(O)NRS(O) 2 R, —C(O)N═S(O)R 2 , —NR 2 , —NRC(O)R, —NRC(O)NR 2 , —NRC(O)OR, —NRS(O) 2 R, —NRS(O) 2 NR 2 , —OR, —ON(R)SO 2 R, —P(O)R 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)(NH)R, —S(O) 2 N(R) 2 , —S(NH 2 ) 2 (O)OH, —N═S(O)R 2 , —CH 3 , —CH 2 OH, —CH 2 NHSO 2 CH 3 , —CD 3 , or —CD 2 NRS(O) 2 R, or each R 1 is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

two R 1 groups are optionally taken together to form a bivalent C 2-4 alkylene chain; or

two R 1 groups are optionally taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

5. The compound of claim 1 , wherein each of R 2 is independently hydrogen, halogen, —C(O)N(R′) 2 , —OR′, —N(R′) 2 , or an optionally substituted group selected from C 1-3 aliphatic, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

6. The compound of claim 1 , wherein R 3 is hydrogen, halogen, —CN, —OR′, —N(R′) 2 , or an optionally substituted group selected from C 1-3 aliphatic, or a 5 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

7. The compound of claim 1 , wherein R 4 is hydrogen, halogen, —CN, —OR, or an optionally substituted group selected from C 1-3 aliphatic, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

8. The compound of claim 1 , which is a compound of one of formulae IV-a, IV-b, or IV-c:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , which is a compound of one of formulae XIII-a, XIII-b, or XIII-c:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , which is a compound of one of formulae XIV-a, XIV-b, or XIV-c:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , which is a compound of one of formulae XV-a, XV-b, or XV-c:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein m is 1, 2, 3, 4 or 5.

13. A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

14. The compound of claim 1 , wherein Ring A is

15. The compound of claim 1 , wherein Ring A is

16. The compound of claim 1 , wherein Ring A is

17. The compound of claim 1 , wherein R 1 is

18. The compound of claim 1 , wherein R 1 is

19. The compound of claim 1 , wherein R 1 is

20. The compound of claim 1 , wherein R 1 is

21. The compound of claim 1 , wherein R 2 is fluoro, chloro, bromo, methyl, ethyl, —CF 3 ,

22. The compound of claim 1 , wherein R 4 is fluoro, chloro, methyl, —CF 3 , —OH,

23. The compound of claim 1 , wherein n is 1.

24. The compound of claim 1 , wherein p is 0.

25. The compound of claim 1 , wherein q is 0.