3-phosphoglycerate dehydrogenase inhibitors and uses thereof

A method for treating a PHGDH-mediated disorder in a patient in need thereof, comprising administering to said patient a compound of formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is methyl;
• R2 is F, Cl, —CF3, —OCF3, —OCHF2, —OCH2Ph, —OCH3, —CN, —CH3,
• R3 is halogen, —OR, —CN, or C1-6 aliphatic optionally substituted with 1, 2, or 3 halogens;
• or R2 and R3 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;
• R4 is hydrogen, halogen, —OR5, —CN, or C1-6 aliphatic optionally substituted with 1, 2, or 3 halogens;
• each R is independently hydrogen or an optionally substituted group selected from C1-6 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;
• R5 is hydrogen, —(CH2)n-phenyl, or C1-6 alkyl optionally substituted with 1, 2, or 3 halogens;
• R6 is hydrogen or C1-4 alkyl;
• R7 is hydrogen or -CO2R;
• L1 is a C1-8 bivalent straight or branched hydrocarbon chain wherein 1-5 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO2—, —SO2N(R)—, —(R)NSO2—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, —(R)NC(S)N(R)—, or -Cy-;
• each -Cy- is independently 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 C1-4 alkyl or —OR;
• and
• n is independently 0, 1, 2, 3, 4, or 5,
• or a pharmaceutical composition thereof, wherein the PHGDH-mediated disorder is melanoma, breast cancer or lung cancer.