3-phosphoglycerate dehydrogenase inhibitors and uses thereof

Abstract

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 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 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 a covalent bond or 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; 
         -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 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 1  is 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 , 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 2 , wherein R 3  is halogen or —OR. 
     
     
         6 . The compound according to  claim 3 , 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 L 1  is SO 2 NH—, 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to  claim 8 , wherein L 1  is 
       
         
           
           
               
               
           
         
       
     
     
         10 - 16 . (canceled) 
     
     
         17 . The compound according to  claim 1 , wherein said compound is any of Formulae 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. 
       
     
     
         18 . The compound according to  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         19 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle. 
     
     
         20 . (canceled) 
     
     
         21 . 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. 
     
     
         22 . (canceled) 
     
     
         23 . 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 a melanoma, breast, or lung cancer. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 23 , wherein the tumor comprises a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC). 
     
     
         26 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 . A pharmaceutical composition comprising a compound according to any one of  claim 26  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle. 
     
     
         28 . A method for treating cancer in a patient in need thereof, comprising administering to said patient the compound of  claim 26 , wherein the cancer is melanoma or breast cancer. 
     
     
         29 . A method for treating a tumor in a patient in need thereof, comprising administering to said patient the compound of  claim 26 , wherein the tumor comprises a melanoma, breast, or lung cancer. 
     
     
         30 . The method of  claim 29 , wherein the tumor comprises a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC).