Phenyl amino piperidine mTORC inhibitors and uses thereof

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 is N or CH;

A 2 is N(Ring A);

A 3 is C(R′) or N;

A 4 is CH or N;

R′ is H, C 1-6 aliphatic, or halogen;

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;

each of m, n, p, q, and x is independently 0, 1, or 2;

each of y and z is independently 0, 1, 2, 3 or 4;

each of R 1 and R 2 is independently R, or:

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

two R 2 groups are optionally taken together to form ═O;

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

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

an R 1 group and Ring A are optionally taken together with their intervening atoms to form a 5-8 membered fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

an R 2 group and Ring B are optionally taken together with their intervening atoms to form a 5-8 membered fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R 3 is independently R, halogen, —OR, —CN, or two R 3 groups are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 4 is hydrogen or an optionally substituted C 1-6 aliphatic group;

Ring A is an optionally substituted ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring B is an optionally substituted ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; and

L 1 is a covalent bond or a C 1 -3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, —C(R) 2 —, —CH(R)—, —C(F) 2 —, —N(R)—, or —S(O) 2 —.

2. The compound according to claim 1 , wherein A 1 is N.

3. The compound according to claim 2 , wherein m is 1 and n is 1.

4. The compound according to claim 2 , wherein A 3 is C(R′).

5. The compound according to claim 2 , wherein A 4 is CH.

6. The compound according to claim 2 , wherein p is 1 and q is independently 0, 1, or 2.

7. The compound according to claim 2 , wherein each of R 1 and R 2 is independently R, or: two R 1 groups are optionally taken together to form ═O; two R 2 groups are optionally taken together to form ═O; two R 1 groups are optionally taken together to form a covalent bond or a bivalent C 1-4 alkylene chain; or two R 2 groups are optionally taken together to form a covalent bond or a bivalent C 1-4 alkylene chain.

8. The compound according to claim 7 , wherein R 1 is

9. The compound according to claim 7 , wherein R 2 is hydrogen or methyl.

10. The compound according to claim 2 , wherein, each of R 3 is independently R, halogen, —OR, or —CN.

11. The compound according to claim 2 , wherein Ring A is 1

12. The compound according to claim 2 , wherein Ring B is an optionally substituted ring selected from 6-membered aryl containing 0-2 nitrogen atoms.

13. The compound according to claim 12 , wherein Ring B is

14. The compound according to claim 2 , wherein L 1 is a covalent bond or a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —C(O)—, —C(S)—, —C(R) 2 —, —CH(R)—, —C(F) 2 —, —N(R)—, or —S(O) 2 —.

15. The compound according to claim 1 , wherein said compound is of Formula II:

or a pharmaceutically acceptable salt thereof,

wherein each Rº is a monovalent substituent independently selected from: halogen, —(CH 2 ) 0-2 R ● , -(haloR ● ), —(CH 2 ) 0-2 OH, —(CH 2 ) 0-2 OR ● , —(CH 2 ) 0-2 CH(OR ● ) 2 ; —O(haloR ● ), —CN, —N 3 , —(CH 2 ) 0-2 C(O)R ● , —(CH 2 ) 0-2 C(O)OH, —(CH 2 ) 0-2 C(O)OR ● , —(CH 2 ) 0-2 SR ● , —(CH 2 ) 0-2 SH, —(CH 2 ) 0-2 NH 2 , —(CH 2 ) 0-2 NHR ● , —(CH 2 ) 0-2 NR ● 2 , —NO 2 , —SiR ● 3 , —OSiR ● 3 , —C(O)SR ● , —(C 1- 4 straight or branched alkylene)C(O)OR ● , or —SSR ● ,

wherein each R ● is unsubstituted or, where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

16. The compound according to claim 1 , wherein the compound is selected from:

or pharmaceutically acceptable salts thereof.

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