Heterocyclic tyrosine kinase inhibitors

Abstract

The present invention provides compounds useful as inhibitors of Tec family kinases, compositions thereof, and methods of using the same.

1 - 41 . (canceled) 
     
     
         42 . A method of treating a disorder responsive to inhibition of a Tec kinase comprising administering to a subject an effective amount of a compound of formula IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein: 
 each of m and q is independently 0-5; 
 Ring A is 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; 
 R 2  is halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , or an optionally substituted group selected from C 1-12  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 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; 
 each R is independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
 two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
 each R 3  and R 4  is independently halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , or an optionally substituted group selected from C 1-12  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 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. 
 
     
     
         43 . The method of  claim 42 , wherein Ring A is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         44 . The method of  claim 42 , wherein Ring A is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         45 . The method of  claim 44  wherein Ring A selected from: 
       
         
           
           
               
               
           
         
         wherein each Ring D is a 5 membered saturated, partially unsaturated, or aryl fused ring having 1-2 heteroatoms in addition to the nitrogen atom independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         46 . The method of  claim 42 , wherein Ring A is selected from: 
       
         
           
           
               
               
           
         
       
       wherein X is halogen. 
     
     
         47 . The method of  claim 42 , wherein the compound is listed in Table 4 and selected from any one of the compounds 4, 5, 7, 11, 12, 17-34, 41, 51, 52, 58, 60-73, 75, 79-81, 89-92, 105, 226-228, or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The method of  claim 42 , wherein the Tec kinase is tyrosine kinase expressed in hepatocellular carcinoma, Bruton's tyrosine kinase, interleukin-2 (IL-2)-inducible T-cell kinase, resting lymphocyte kinase, or bone-marrow tyrosine kinase gene on chromosome X. 
     
     
         49 . The method of  claim 48 , wherein Tec kinase is Bruton's tyrosine kinase. 
     
     
         50 . The method of  claim 42 , wherein the disorder is selected from the group consisting of autoimmune disorders, inflammatory disorders, and cancers. 
     
     
         51 . The method of  claim 50 , wherein the disorder is an autoimmune disorder. 
     
     
         52 . The method of  claim 50 , wherein the disorder is an inflammatory disorder. 
     
     
         53 . The method of  claim 50 , wherein the disorder is cancer. 
     
     
         54 . A method of treating a disorder selected from the group consisting of autoimmune disorders, inflammatory disorders, and cancers comprising administering to a subject an effective amount of a compound of formula IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein: 
 each of m and q is independently 0-5; 
 Ring A is 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; 
 R 2  is halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , or an optionally substituted group selected from C 1-12  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 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; 
 each R is independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
 two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
 each R 3  and R 4  is independently halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , or an optionally substituted group selected from C 1-12  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 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. 
 
     
     
         55 . The method of  claim 54 , wherein Ring A is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         56 . The method of  claim 54 , wherein Ring A is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         57 . The method of  claim 54 , wherein Ring A selected from: 
       
         
           
           
               
               
           
         
         wherein each Ring D is a 5 membered saturated, partially unsaturated, or aryl fused ring having 1-2 heteroatoms in addition to the nitrogen atom independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         58 . The method of  claim 54 , wherein Ring A is selected from: 
       
         
           
           
               
               
           
         
       
       wherein X is halogen. 
     
     
         59 . The method of  claim 54 , wherein the compound is listed in Table 4 and selected from any one of the compounds 4, 5, 7, 11, 12, 17-34, 41, 51, 52, 58, 60-73, 75, 79-81, 89-92, 1052, 226-228, or a pharmaceutically acceptable salt thereof. 
     
     
         60 . The method of  claim 54 , wherein the disorder is an autoimmune disorder. 
     
     
         61 . The method of  claim 54 , wherein the disorder is an inflammatory disorder. 
     
     
         62 . The method of  claim 54 , wherein the disorder is cancer. 
     
     
         63 . The method of  claim 54 , wherein the disorder is rheumatoid arthritis. 
     
     
         64 . The method of  claim 54 , wherein the disorder is lupus. 
     
     
         65 . The method of  claim 62 , wherein the disorder is leukemia or lymphoma.