Inhibitors of c-jun-n-terminal kinase (jnk)

Abstract

The present invention provides novel compounds according to Formula (I):where Ring A, Ring B, X, L1, L2, RA, RC, RD, RE, m, n, and p are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of human diseases associated with kinase activity, for example, proliferative diseases, neurodegenerative diseases, metabolic disorders, inflammatory diseases, and cardiovascular diseases.

What is claimed is: 
     
         1 - 50 . (canceled) 
     
     
         51 . A method of treating a proliferative disease comprising administering to a subject in need thereof an effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 Ring A is a carbocyclic, heterocyclic, heteroaryl, or aryl ring; 
 each instance of R A  is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A1 ) 2 , and —SR A1 , wherein each occurrence of R A1  is independently selected from the group consisting of hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R A1  groups are joined to form an optionally substituted heterocyclic ring; 
 m is 0, 1, 2, 3, or 4; 
 Ring B is a group of the formula: 
 
       
       
         
           
           
               
               
           
         
         
           R B1  is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B1a , —N(R B1a ) 2 , and —SR B1a , wherein each occurrence of R B1a  is independently selected from the group consisting of hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R B1a  groups are joined to form an optionally substituted heterocyclic ring; 
         
         W B  is N or CR B2 , wherein R B2  is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B2a , —N(R B2a ) 2 , and —SR B2a , wherein each occurrence of R B2a  is independently selected from the group consisting of hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R B2a  groups are joined to form an optionally substituted heterocyclic ring; 
         optionally wherein R B1  and R B2  are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl ring; 
         L 1  is ═C(R L1a )—, —O—, —S—, —NR L1b —, —NR L1b C(═O)—, —C(═O)NR L1b —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L1b C(═S)—, —C(═S)NR L1b —, trans-CH═CH—, cis-CH═CH—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L1b —, —NR L1b S(═O) 2 —, or an optionally substituted C 1-4  hydrocarbon chain, optionally wherein one methylene unit of the hydrocarbon chain is replaced with ═C(R L1a )—, —O—, —S—, —NR L1b —, —NR L1b C(═O)—, —C(═O)NR L1b —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L1b C(═S)—, —C(═S)NR L1b —, trans-CH═CH—, cis-CH═CH—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L1b —, or —NR L1b S(═O) 2 —, wherein R L1a  is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, or —NO 2 , and R L1b  is hydrogen, C 1-6  alkyl, or a nitrogen protecting group; 
            represents a single or double bond; 
         X is an optionally substituted C 1-4  hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, or —NR X —, wherein R X  is hydrogen, C 1-6  alkyl, or a nitrogen protecting group; 
         L 2  is a bond, —O—, —S—, —NR L2a , —NR L2a C(═O)—, —C(═O)NR L2a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L2a C(═S)—, —C(═S)NR L2a —, trans-CR L2b ═CR L2b —, cis-CR L2b ═CR L2b —, —C≡C—, —OC(R L2b ) 2 —, —C(R L2b ) 2 O—, —NR L2a C(R L2b ) 2 —, —C(R L2b ) 2 NR L2a , —SC(R L2b ) 2 , —C(R L2b ) 2 S—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L2a —, —NR L2a S(═O) 2 —, or an optionally substituted C 1-4  hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NR L2a —, —NR L2a C(═O)—, —C(═O)NR L2a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L2a C(═S)—, —C(═S)NR L2a —, trans-CR L2b ═CR L2b —, cis-CR L2b ═CR L2b —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L2a , or —NR L2a S(═O) 2 , wherein R L2a  is hydrogen, C 1-6  alkyl, or a nitrogen protecting group, and wherein each occurrence of R L2b  is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R L2b  groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; 
         each instance of R C  is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR C1 , —N(R C1 ) 2 , and —SR C1 , wherein each occurrence of R C1  is independently selected from the group consisting of hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or two R C1  groups are joined to form an optionally substituted heterocyclic ring; 
         n is 0, 1, 2, 3, or 4; 
         each instance of R D  is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR D1 , —N(R D1 ) 2 , and —SR D1 , wherein each occurrence of R D1  is independently selected from the group consisting of hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R D1  groups are joined to form an optionally substituted heterocyclic ring; 
         p is 0, 1, 2, 3, or 4; 
         R E  is a group of the formula: 
       
       
         
           
           
               
               
           
         
       
       wherein:
 L 3  is a bond, —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —C≡C—, —OC(R L3b ) 2 —, —C(R L3b ) 2 O—, —NR L3a C(R L3b ) 2 —, —C(R L3b ) 2 NR L3a —, —SC(R L3b ) 2 —, —C(R L3b ) 2 S—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, —NR L3a S(═O) 2 —, or an optionally substituted C 1-4  hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein R L3a  is hydrogen, C 1-6  alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b  is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R L3b  groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; 
 L 4  is a bond or an optionally substituted C 1-4  hydrocarbon chain; 
 R E1  is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR E1a , —CH 2 N(R E1a ) 2 , —CH 2 SR E1a , —OR E1a , —N(R E1a ) 2 , and —SR E1a , wherein each occurrence of R E1a  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E1a  groups are joined to form an optionally substituted heterocyclic ring; 
 R E2  is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR E2a , —CH 2 N(R E2a ) 2 , —CH 2 SR E2a , —OR E2a , —N(R E2a ) 2 , —CH 2 N(R E2a ) 2 , and —SR E2a , wherein each occurrence of R E2a  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E2a  groups are joined to form an optionally substituted heterocyclic ring; 
 R E3  is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR E3a , —CH 2 N(R E3a ) 2 , —CH 2 SR E3a , —OR E3a , —N(R E3a ) 2 , and —SR E3a , wherein each occurrence of R E3a  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E3a  groups are joined to form an optionally substituted heterocyclic ring; 
 optionally wherein R E1  and R E3  or R E2  and R E3  or R E1  and R E2  are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; 
 R E4  is a leaving group; 
 Y is O, S, or NR E5 , wherein R E5  is hydrogen, C 1-6  alkyl, or a nitrogen protecting group; 
 a is 1 or 2; and 
 z is 0, 1, 2, 3, 4, 5, or 6. 
 
     
     
         52 - 85 . (canceled) 
     
     
         86 . The method of  claim 51 , wherein L 1  is the group ═C(R L1a )— attached to Ring A by the double bond and attached to Ring B by the single bond. 
     
     
         87 . The method of  claim 51 , wherein 
       
         
           
           
               
               
           
         
       
       is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         88 . The method of  claim 51 , wherein 
       
         
           
           
               
               
           
         
       
       is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         89 . The method of  claim 51 , wherein 
       
         
           
           
               
               
           
         
       
       is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         90 . The method of  claim 51 , wherein 
       
         
           
           
               
               
           
         
       
       is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         91 . The method of  claim 51 , wherein 
       
         
           
           
               
               
           
         
       
       is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         92 . The method of  claim 51 , wherein W B  is CR B2 ; and Ring B is a group of formula: 
       
         
           
           
               
               
           
         
       
     
     
         93 . The method of  claim 51 , wherein X is —NR X —. 
     
     
         94 . The method of  claim 51 , wherein L 2  is —NR L2a C(═O)— or —C(═O)NR L2a —. 
     
     
         95 . The method of  claim 51 , wherein R E  is a group of formula: 
       
         
           
           
               
               
           
         
       
     
     
         96 . The method of  claim 95 , wherein Y is O; L 3  is —NR L3a ; R E1  is hydrogen; R E2  is hydrogen; and R E3  is —CH 2 N(R E3a ) 2 . 
     
     
         97 . The method of  claim 51 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         98 . The method of  claim 51 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         99 . The method of  claim 51 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         100 . The method of  claim 51 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         101 . The method of  claim 51 , wherein the proliferative disease is cancer. 
     
     
         102 . The method of  claim 51 , wherein the proliferative disease is skin cancer, lung cancer, bone cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, kidney cancer, liver cancer, pancreatic cancer, leukemia, lymphoma, or a benign neoplasm. 
     
     
         103 . The method of  claim 51 , wherein the proliferative disease is an inflammatory disease. 
     
     
         104 . The method of  claim 51 , wherein the proliferative disease is rheumatoid arthritis, inflammatory bowel disease, or an autoimmune disease.