Pyrazole acc inhibitors and uses thereof

Abstract

The present invention provides pyrazole 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 or agriculturally acceptable salt thereof, wherein: 
         X is —O—, —S—, or —NR—; 
         R 1  is hydrogen or C 1-4  aliphatic optionally substituted with 1-4 groups independently selected from 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)S(O) 2 R, —S(O) 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —S(O) 2 R; 
         each R 2 , R 6 , R 7 , and R 8  is independently oxo, halogen, —CN, —R a , —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)S(O) 2 R, —S(O) 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —S(O) 2 R; 
         each R is independently hydrogen, or R a ; 
         each R a  is independently 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; 
         L 1  is a covalent bond, a 1-6 membered straight or branched bivalent hydrocarbon chain, cyclopropylenyl, cyclobutylenyl, or oxetanylenyl; 
         L 2  is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain, wherein L 2  is substituted by n instances of R 9 ; 
         R 3  is —OR, —C(O)OR, —N(R)C(O)OR, —OC(O)N(R) 2 , —C(O)N(R)OR, —C(O)NH 2 , —C(O)NHR a , —C(O)N(R a ) 2 , or —C(O)Hy; 
         Hy is a 3-8 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, wherein Hy is substituted by p instances of R 6 ; 
         R 4  is 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, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R 4  is substituted by q instances of R 7 ; 
         each R 5  is independently selected from hydrogen, C 1-4  aliphatic, 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, wherein each R 5  is substituted with r instances of R 8 ; 
         each R 9  is independently oxo or —OR 5 ; 
         m is 0, 1, 2, or 3; 
         n is 0, 1, or 2; 
         p is 0, 1, 2, 3, or 4; 
         q is 0, 1, 2, 3, 4, or 5; and 
         r is 0, 1, 2, 3, or 4. 
       
     
     
         2 . The compound of  claim 1 , wherein X is —S—. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is methyl. 
     
     
         4 . The compound of  claim 1 , wherein m is 0. 
     
     
         5 . The compound of  claim 1 , wherein L 1  is —CH 2 —, —C(CH 3 ) 2 —, or —CH(CH 3 )—. 
     
     
         6 . The compound of  claim 1 , wherein L 2  is —CH 2 C(O)—, or —CH 2 CH(OR 5 )—. 
     
     
         7 . The compound of  claim 1 , wherein L 2 (R 9 ) n , taken together is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein # is the point of attachment to R 4 . 
       
     
     
         8 . The compound of  claim 1 , wherein R 3  is —C(O)NHR a  or —C(O)N(R a ) 2 . 
     
     
         9 . The compound of  claim 1 , wherein R 3  is —C(O)Hy. 
     
     
         10 . The compound of  claim 1 , wherein R 3  is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , wherein -L 1 -R 3 , taken together, is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1 , L 1 -R 3 , taken together, is: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1 , wherein R 4 (R 7 ) q , taken together, is: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , wherein R 4 (R 7 ) q , taken together, is: 
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound of formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or agriculturally acceptable salt thereof. 
       
     
     
         16 . The compound of  claim 1 , wherein the compound is provided as a pharmaceutically acceptable salt. 
     
     
         17 . The compound of  claim 1 , wherein the compound is provided as an agriculturally acceptable salt. 
     
     
         18 . A composition comprising the compound according to  claim 1  and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         19 . A method of inhibiting ACC in a patient in need thereof, comprising administering to said patient the composition according to  claim 18 . 
     
     
         20 . A method of inhibiting ACC in a biological sample, comprising contacting the biological sample with the compound according to  claim 1 . 
     
     
         21 . 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 18 . 
     
     
         22 . The method of  claim 21 , wherein the infection is a fungal infection. 
     
     
         23 . The method of  claim 22 , wherein the fungal infection is an infection by one or more of  Candida albicans, Candida krusei , or  Candida parapsilosis.    
     
     
         24 . A composition for agriculture use comprising a compound according to  claim 1  and an agriculturally acceptable carrier, optionally comprising an adjuvant, optionally comprising one or more additional pesticides, and optionally comprising one or more biological control agents, microbial extracts, natural products, plant growth activators or plant defense agents or mixtures thereof. 
     
     
         25 . A method of controlling agricultural fungal pathogens, the method comprising administering the composition of  claim 24  to a plant, a seed or soil. 
     
     
         26 . A method of inhibiting ACC in a plant, comprising contacting the plant with the compound according to  claim 1 .