3-phosphoglycerate dehydrogenase inhibitors and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same.
1. 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:
R 1 is methyl;
R 2 is F, Cl, —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 Ph, —OCH 3 , —CN, —CH 3 ,
R 3 is halogen, —OR, —CN, or C 1-6 aliphatic optionally substituted with 1, 2, or 3 halogens; 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, or C 1-6 aliphatic optionally substituted with 1, 2, or 3 halogens;
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, or C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens;
R 6 is hydrogen or C 1-4 alkyl;
R 7 is hydrogen or -CO 2 R;
L 1 is a C 1-8 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—, —SO 2 —, —SO 2 N(R)—, —(R)NSO 2 —, —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 C 1-4 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.
2. The method of claim 1 , wherein the PHGDH-mediated disorder is melanoma.
3. The method of claim 1 , wherein the cancer PHGDH-mediated disorder is melanoma or breast cancer.
4. The method of claim 1 , wherein the PHGDH-mediated disorder is lung cancer.
5. The method of claim 4 , wherein the lung cancer is a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC).
6. The method of claim 1 , wherein R 2 is F, Cl, —CF 3 , —OCHF 2 , —OCH 2 Ph, —OCH 3 , —CN.
7. The method of claim 1 , wherein R 3 is halogen or —OR.
8. The method of claim 1 , wherein both of R 2 is F or Cl and R 3 is halogen.
9. The method of claim 1 , wherein R 4 is hydrogen.
10. The method of claim 1 , wherein R 5 is hydrogen, —(CH 2 ) n -phenyl, or C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens.
11. The method of claim 1 , wherein L 1 is
12. The method of claim 1 , wherein L 1 is
13. The method of 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.
14. A method for treating a PHGDH-mediated disorder in a patient in need thereof, comprising administering to said patient a compound selected from:
or a pharmaceutical salt thereof, wherein the PHGDH-mediated disorder is melanoma, breast cancer or lung cancer.
15. The method of claim 14 , wherein the PHGDH-mediated disorder is melanoma.
16. The method of claim 15 , wherein the PHGDH-mediated disorder is breast cancer.
17. The method of claim 15 , wherein the PHGDH-mediated disorder is lung cancer.
18. The method of claim 17 , wherein the lung cancer is a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC).