Shmt inhibitors and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

1 - 15 . (canceled) 
     
     
         16 . A method for treating a SHMT1 and/or SHMT2-mediated disorder in a patient in need thereof, comprising administering to said patient a compound of Formula II-a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         each R 1  is independently halogen, —CN, —NO 2 , —OR, -Cy, or an optionally substituted C 1-6  aliphatic group; or
 two R 1  groups can be taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; 
 
         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 partially unsaturated or 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 partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         each -Cy is independently an optionally substituted group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic partially unsaturated or 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 partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R x  and R y  are independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic or phenyl; 
         R x′  and R y′  are independently hydrogen or C 1-4  alkyl; or
 R y  and R y′  can be taken together with their intervening atoms to form a 3-6 membered saturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; and 
 
         m is 1, 2, 3, or 4, 
         or a pharmaceutical composition thereof. 
       
     
     
         17 . The method of  claim 16 , wherein each of R 1  is independently halogen, —CN, —OR, -Cy, or an optionally substituted C 1-6  aliphatic group. 
     
     
         18 . The method of  claim 16 , wherein two R 1  groups are taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. 
     
     
         19 . The method of  claim 16 , wherein R x  and R y  are independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic. 
     
     
         20 . The method of  claim 16 , wherein R x′  and R y′  are independently hydrogen or C 1-2  alkyl. 
     
     
         21 . The method of  claim 16 , wherein m is 1, 2, or 3. 
     
     
         22 . The method of  claim 16 , wherein R y  and R y′  are taken together with their intervening atoms to form a 3-6 membered saturated carbocyclic ring. 
     
     
         23 . The method of  claim 16 , wherein each of R 1  is independently chloro or -Cy. 
     
     
         24 . The method of  claim 16 , wherein m is 1 or 2. 
     
     
         25 . The method of  claim 16 , wherein said compound is selected from one of the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         26 . The method of  claim 16 , wherein the pharmaceutically acceptable composition thereof comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         27 . The method of  claim 16 , wherein the SHMT1 and/or SHMT2-mediated disorder is a cellular proliferative disorder, inflammatory disorder or disease, or metabolic disease. 
     
     
         28 . The method of  claim 27 , wherein the cellular proliferative disorder is a cancer selected from lymphoma, lung cancer, acute lymphocytic leukemia, acute myelocytic leukemia, multiple myeloma, and chronic lymphocytic leukemia. 
     
     
         29 . The method of  claim 27 , wherein the inflammatory disorder or disease is selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, gout, pulmonary disease, interstitial lung disease, and scleroderma. 
     
     
         30 . The method of  claim 27 , wherein the metabolic disease is selected from Type 1 diabetes, Type 2 diabetes, metabolic syndrome, and obesity.