Acc inhibitors and uses thereof

Abstract

The present invention provides compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is —O—, —S—, or —NR—; 
         R 1  is hydrogen or C 1-4  aliphatic, optionally substituted with one or more halogen, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R; 
         R 2  is halogen, —R, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R, or Hy, where Hy is selected from 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 R 1  and R 2  are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, or heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring; 
         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; 
         each of L 1  and L 2  is independently a covalent bond or an optionally substituted 1-6 membered straight or branched bivalent hydrocarbon chain; or a cyclopropylenyl, cyclobutylenyl, or oxetanyl group; 
         R 3  is hydrogen, halogen, —CN, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —C(O)N(R)S(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, —SO 2 R, —B(OH) 2 , or an optionally substituted ring selected from phenyl or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
         R 4  is hydrogen or an optionally substituted ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
         wherein if L 2  is a covalent bond, then R 4  is not hydrogen; and 
         wherein the group -L 2 -R 4  is not alkyl when R 2  is unsubstituted alkyl; and 
         wherein the group -L 1 -R 3  taken together is not unsubstituted alkyl. 
       
     
     
         2 . The compound according to  claim 1 , wherein X is —S—. 
     
     
         3 . The compound according to  claim 2 , wherein R 1  is methyl or trifluoromethyl. 
     
     
         4 . The compound according to  claim 3 , wherein R 2  is halogen, —C(O)OR, —C(O)N(R) 2 , or oxazolyl. 
     
     
         5 . The compound according to  claim 3 , wherein R 1  and R 2  are taken together to form a 5-6 membered partially unsaturated carbocyclic ring. 
     
     
         6 . The compound according to  claim 3 , wherein R 3  is tetrazolyl, —C(O)OR, —C(O)N(R) 2 , or —OR. 
     
     
         7 . A compound of formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is hydrogen or C 1-4  aliphatic, optionally substituted with one or more halogen, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R; 
         R 2  is halogen, —R, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R, or Hy, where Hy is selected from 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 R 1  and R 2  are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, or heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring; 
         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 3  is hydrogen, halogen, —CN, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, —SO 2 R, —B(OH) 2 , or an optionally substituted ring selected from phenyl or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 4  is an optionally substituted phenyl or naphthyl ring; 
         each of R 5  and R 5 ′ is independently —R, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R; or R 5  and R 5 ′ are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group; and 
         each of R 7  and R 7 ′ is independently hydrogen, —R, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R; or R 7  and R 7 ′ are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         8 . A compound of formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is hydrogen or C 1-4  aliphatic, optionally substituted with one or more halogen, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R; 
         R 2  is halogen, —R, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R, or Hy, where Hy is selected from 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 R 1  and R 2  are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, or heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring; 
         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 3  is hydrogen, halogen, —CN, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, —SO 2 R, —B(OH) 2 , or an optionally substituted ring selected from phenyl or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         each of R 5  and R 5 ′ is independently —R, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R; or R 5  and R 5 ′ are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group; 
         R 6  is —R, —C(O)N(R) 2 , or —C(O)R; 
         each R 8  is independently selected from halogen, —R, —OR, —SR, —N(R) 2  or deuterium; and 
         n is 0-5. 
       
     
     
         9 . A compound of formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is hydrogen or C 1-4  aliphatic, optionally substituted with one or more halogen, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R; 
         R 2  is halogen, —R, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R, or Hy, where Hy is selected from 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 R 1  and R 2  are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, or heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring; 
         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 3  is hydrogen, halogen, —CN, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, —SO 2 R, —B(OH) 2 , or an optionally substituted ring selected from phenyl or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         each of R 5  and R 5 ′ is independently —R, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R; or R 5  and R 5 ′ are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group; 
         R 6  is —R, —C(O)N(R) 2 , or —C(O)R; 
         each R 8  is independently selected from halogen, —R, —OR, —SR, —N(R) 2  or deuterium; and 
         n is 0-5. 
       
     
     
         10 . A composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         11 . A method of inhibiting Acetyl CoA Carboxylase (ACC) in a patient in need thereof, comprising administering to said patient the composition according to  claim 10 . 
     
     
         12 . A method of inhibiting Acetyl CoA Carboxylase (ACC) in a biological sample, comprising contacting the biological sample with the compound according to  claim 1 . 
     
     
         13 . A method for treating a metabolic disorder in a patient in need thereof, comprising administering to said patient the composition according to  claim 10 . 
     
     
         14 . The method according to  claim 13 , wherein the metabolic disorder is obesity. 
     
     
         15 . The method according to  claim 13 , wherein the metabolic disorder is dyslipidemia or hyperlipidemia. 
     
     
         16 . The method according to  claim 14 , wherein the obesity is a symptom of Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome or MOMO syndrome. 
     
     
         17 . The method according to  claim 14 , wherein the obesity is a side effect of the administration of another medication selected from a sulfonylurea, thiazolidinedione, an antipsychotic, an antidepressant, a steroid, an anticonvulsant, pizotifen, or a hormonal contraceptive. 
     
     
         18 . A method of treating a cancer or other proliferative disorder in a patient in need thereof, comprising administering to said patient the composition according to  claim 10 . 
     
     
         19 . A method of treating a fungal, parasitic, or bacterial infection in a patient in need thereof, comprising administering to said patient the composition according to  claim 10 . 
     
     
         20 . A method of inhibiting Acetyl CoA Carboxylase (ACC) in a plant, comprising contacting the plant with the compound according to  claim 1 . 
     
     
         21 . A method of treating a liver disease in a patient in need thereof, comprising administering to said patient the composition according to  claim 10 . 
     
     
         22 . The method of  claim 21 , wherein the liver disease is selected from hepatitis C, hepatocellular carcinoma, familial combined hyperlipidemia, non-alcoholic steatohepatitis (NASH), liver cancer, cholangiocarcinoma, angiosarcoma, hemangiosarcoma, and progressive familial intrahepatic cholestasis. 
     
     
         23 . A method of treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to said patient the composition according to  claim 10 . 
     
     
         24 . A compound selected from Table 1 or a pharmaceutically acceptable salt thereof.