Gcn2 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: 
         Ring A is selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally fused to a 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bridged bicyclic 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, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or
 Het, wherein Het is a 4-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated spirocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         Ring B is 
       
       
         
           
           
               
               
           
         
         Ring C is 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         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; or 
          two R groups are optionally taken together to form a bivalent C 2-4  alkylene chain; 
          two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-7-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; 
         each R′ is independently hydrogen or a C 1-3  aliphatic group optionally substituted with halogen; 
         each of R 1  is independently hydrogen, halogen, —CN, —NO 2 , —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)S(O) 2 R, —C(O)N═S(O)(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —N(R)S(O) 2 R, —N(R)S(O) 2 N(R) 2 , —OR, —ON(R)SO 2 R, —P(O)(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)(NH)R, —S(O) 2 N(R) 2 , —S(NH 2 ) 2 (O)OH, —N═S(O)(R) 2 , —C(R) 2 S(═O)(═NH)R, —C(R) 2 NHSO 2 CH 3 , —CD 3 , —CD 2 N(R)S(O) 2 R, or R; or: 
          two R 1  groups are optionally taken together to form ═O, ═NH or ═NS(O) 2 R; or 
          two R 1  groups are optionally taken together to form a bivalent C 2-4  alkylene chain; 
         each of R 2  is independently hydrogen, halogen, —CN, —C(O)N(R′) 2 , —OR′, —N(R′) 2 , —S(O) 2 R, —S(O) 2 N(R) 2 , —O-phenyl, or an optionally substituted group selected from C 1-3  aliphatic, phenyl, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-8 membered saturated monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 3  is hydrogen, halogen, —CN, —OR′, —N(R′) 2 , or an optionally substituted group selected from C 1-3  aliphatic, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 4  is hydrogen, halogen, —CN, —OR, —N═S(O)(R) 2 , —N(R) 2 , or an optionally substituted group selected from C 1-3  aliphatic, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         m is 0, 1, 2, 3, 4 or 5; 
         n is 0, 1, or 2; 
         p is 0 or 1; and 
         q is 0 or 1. 
       
     
     
         2 . The compound of  claim 1 , wherein Ring A is Het. 
     
     
         3 . The compound of  claim 1 , wherein Ring B is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein Ring C is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein each of R 1  is independently hydrogen, halogen, —CN, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)S(O) 2 R, —C(O)N═S(O)(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —N(R)S(O) 2 R, —N(R)S(O) 2 N(R) 2 , —OR, —ON(R)SO 2 R, —P(O)(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)(NH)R, —S(O) 2 N(R) 2 , —S(NH 2 ) 2 (O)OH, —N═S(O)(R) 2 , —C(R) 2 S(═O)(═NH)R, —C(R) 2 NHSO 2 CH 3 , —CD 3 , —CD 2 N(R)S(O) 2 R, or R. 
     
     
         6 . The compound of  claim 1 , wherein each of R 2  is independently hydrogen, halogen, —CN, —C(O)N(R′) 2 , —OR′, —N(R′) 2 , or an optionally substituted group selected from C 1-3  aliphatic, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         7 . The compound of  claim 1 , wherein R 3  is hydrogen, halogen, —CN, —OR′, —N(R′) 2 , or an optionally substituted group selected from C 1-3  aliphatic, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         8 . The compound of  claim 1 , wherein R 4  is hydrogen, halogen, —CN, —OR, —N(R) 2 , or an optionally substituted group selected from C 1-3  aliphatic, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         9 . The compound of  claim 1 , wherein Ring B is 
       
         
           
           
               
               
           
         
       
       and Ring C is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9 , of one of formula X-a, X-b, or X-c: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The compound of  claim 1 , wherein Ring B is 
       
         
           
           
               
               
           
         
       
       and Ring C is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 11 , of one of formula XVII-a, XVII-b, or XVII-c: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The compound of  claim 11 , of one of formula XXIX-a, XXIX-b, or XXIX-c: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The compound of  claim 1 , wherein m is 1, 2, 3, 4 or 5, in particular 1, 2 or 3. 
     
     
         15 . The compound of  claim 1  wherein the compound is selected from those depicted in Tables 1-4, or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         17 . A method of inhibiting GCN2 in a patient or biological sample comprising administering to said patient, or contacting said biological sample with a compound according to  claim 1 , or a pharmaceutical composition thereof. 
     
     
         18 . A method of treating a GCN2-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound according to  claim 1 , or a pharmaceutical composition thereof. 
     
     
         19 . The method of  claim 18 , wherein the GCN2-mediated disorder, disease or condition is selected from the group consisting of inflammatory conditions, immunological conditions, autoimmune conditions, allergic conditions, rheumatic conditions, thrombotic conditions, cancer, infections, neurodegenerative diseases, degenerative diseases, neuroinflammatory diseases, cardiovascular diseases, and metabolic conditions. 
     
     
         20 . The method of  claim 19 , wherein the cancer is selected the group consisting of a solid tumor, wherein the solid tumor originates from the group of tumors of the epithelium, the bladder, the stomach, the kidneys, of head and neck, the esophagus, the cervix, the thyroid, the intestine, the liver, the brain, the prostate, the uro-genital tract, the lymphatic system, the stomach, the larynx, the bones, including chondrosarcoma and Ewing sarcoma, germ cells, including embryonal tissue tumors, and/or the lung, from the group of monocytic leukemia, lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblastomas, neurofibroma, angiosarcoma, breast carcinoma and/or maligna melanoma, and a tumor of the blood and immune system. 
     
     
         21 - 28 . (canceled)