3-phosphoglycerate dehydrogenase inhibitors and uses thereof

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is methyl;

each of R 2 and R 3 is independently halogen, —OR, —CN, C 1-6 aliphatic optionally substituted with 1, 2, or 3 halogens, or -L-R′; or R 2 and R 3 are optionally taken together with the carbon atoms to which they are attached and any intervening atoms to form a 5-8 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 4 is hydrogen, halogen, —OR 5 , —CN, C 1-6 aliphatic optionally substituted with 1, 2, or 3 halogens, or -L-R′;

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;

R 5 is hydrogen, —(CH 2 ) n -phenyl, —(CH 2 ) n -Cy′, or C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens;

each L is independently a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —C(O)N(R)—, —(R)NC(O)—, —N(R)—, —N(R)C(O)N(R)—, —S—, —SO—, or —SO 2 —;

each R′ is independently hydrogen, C 1-6 aliphatic, or an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 6 is hydrogen or C 1-4 alkyl;

R 7 is hydrogen, —CO 2 R, optionally substituted C 1-6 aliphatic, -Cy-, or a bivalent 3-7 membered ring;

L 1 is —SO 2 NH—,

-Cy- is a bivalent 6-membered arylene ring containing 0-2 nitrogen atoms, or a bivalent 5-membered heteroarylene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a bivalent partially unsaturated 8-10 membered bicyclic heterocyclene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein -Cy- is optionally substituted with 1 or 2 substituents independently selected from C 1-4 alkyl or —OR;

-Cy′ is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 10 is C 1-6 aliphatic optionally substituted with 1, 2, or 3 halogens, —C(O)CH 3 , or —SO 2 —N(R 1 )(R 11 );

R 11 is —C(O)CH 3 , —C(O)NHR 1 , or pyrazinyl;

n is independently 0, 1, 2, 3, 4, or 5;

m is independently 0, 1, or 2;

X is O, S, or —N(R 10 )—; and

each of Y 1 and Y 2 is independently ═N— or ═C(R 4 )—.

2. The compound according to claim 1 , wherein R 2 is halogen, —OR, —CN, or -L-R′.

3. The compound according to claim 1 , wherein R 2 is F, Cl, —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 Ph, —OCH 3 , —CN, —CH 3 ,

4. The compound according to claim 1 , wherein R 3 is halogen or —OR.

5. The compound according to claim 1 , wherein both of R 2 and R 3 are halogen.

6. The compound according to claim 1 , wherein R 4 is hydrogen.

7. The compound according to claim 1 , wherein L 1 is

8. The compound according to claim 1 , wherein R 7 is hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, tetrazolyl, or —CO 2 H.

9. The compound according to claim 1 , wherein X is O.

10. The compound according to claim 1 , wherein X is —N(R 10 )—.

11. The compound according to claim 1 , wherein said compound is selected from Formulae II-a, II-b, II-c, II-d, II-e, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, or III-i:

or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 , wherein the compound is selected from one of the following:

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

14. A method for treating cancer in a patient in need thereof, comprising administering to said patient the compound of claim 1 , wherein the cancer is melanoma or breast cancer.

15. A method for treating a tumor in a patient in need thereof, comprising administering to said patient the compound of claim 1 , wherein the tumor comprises lung cancer.

16. The method of claim 15 , wherein the tumor comprises a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC).