3-phosphoglycerate dehydrogenase inhibitors and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or C 1-4 alkyl;
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 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;
R 5 is hydrogen, —(CH 2 ) n -phenyl, or C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens;
each L is independently a C1-6 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 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 6 is hydrogen or C 1-4 alkyl;
R 7 is a bivalent 3-7 membered heterocyclic ring;
L′ of —CONH-L 1 - is
L 1 of -L 1 R 7 is a covalent bond;
n is independently 0, 1, 2, 3, 4, or 5.
2. The compound according to claim 1 , wherein R 1 is hydrogen or methyl.
3. The compound according to claim 2 , wherein R 2 is halogen, —OR, —CN, or -L-R′.
4. The compound according to claim 2 , wherein R 2 is F, Cl, —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 Ph, —OCH 3 , —CN, —CH 3 ,
5. The compound according to claim 2 , wherein R 3 is halogen or —OR.
6. The compound according to claim 2 , wherein both of R 2 and R 3 are halogen.
7. The compound according to claim 6 , wherein R 4 is hydrogen.
8. The compound according to claim 2 , wherein R 5 is hydrogen, —(CH 2 ) n -phenyl, or C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens.
9. The compound according to claim 2 , wherein L 1 of —CONH-L 1 - is
10. The compound according to claim 9 , wherein L 1 of —CONH-L 1 - is
11. The compound according to claim 1 , wherein said compound is of Formulae II-a, II-b, II-c, II-d, II-e, II-f, or II-g:
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
13. A method for treating a PHGDH-mediated disorder in a patient in need thereof, comprising administering to said patient the compound of claim 1 or a pharmaceutical composition thereof.
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, breast, or lung 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 melanoma, breast, or lung cancer.
16. The method of claim 15 , wherein the lung cancer comprises a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC).