Pyrimidinyl tyrosine kinase inhibitors

Abstract

The present invention provides compounds and compositions thereof which are useful as inhibitors of Bruton's tyrosine kinase and which exhibit desirable characteristics for the same.

1 . A pharmaceutical salt of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 each R 1  is independently hydrogen, an optionally substituted C 1-6  aliphatic group, an optionally substituted 3-7 membered monocyclic heterocyclic group, or an optionally substituted heterocyclylalkyl group having 3-7 carbon atoms and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
 or two R 1  groups are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 
 wherein optionally substituted groups may be substituted with halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —N(R)C(O)OR, —C(O)N(R) 2 , —OC(O)R, —N(R)C(O)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ; 
 each R is independently hydrogen or C 1-6  aliphatic;
 or two R groups attached to the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms, in which any second heteroatom is independently selected from nitrogen, oxygen, and sulfur; 
 
 Ring A is 
 
       
         
           
           
               
               
           
         
         R 2  is —Cl or —F; and 
         R 3  is —CF 3 , —OCF 3 , or —F. 
       
     
     
         2 . The pharmaceutical salt of  claim 1 , wherein the compound is of formula II-a: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The pharmaceutical salt of  claim 1 , wherein the compound is of formula II-b: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The pharmaceutical salt of  claim 1 , wherein the compound is of formula III: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The pharmaceutical salt of  claim 1 , wherein the compound is formula IV: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The pharmaceutical salt of  claim 5 , wherein R 3  is —CF 3  or —F. 
     
     
         7 . (canceled) 
     
     
         8 . The pharmaceutical salt of  claim 5 , wherein both R 1  are hydrogen. 
     
     
         9 . The pharmaceutical salt of  claim 5 , wherein one R 1  is hydrogen and the other R is an optionally substituted C 1-6  aliphatic. 
     
     
         10 . The pharmaceutical salt of  claim 9 , wherein one R 1  is hydrogen and the other R 1  is methyl. 
     
     
         11 . The pharmaceutical salt of  claim 5 , wherein both R 1  are optionally substituted C 1-6  aliphatic groups. 
     
     
         12 . The pharmaceutical salt of  claim 1 , wherein one R 1  is hydrogen and the other an is optionally substituted C 1-6  aliphatic. 
     
     
         13 . The pharmaceutical salt of  claim 1 , wherein both R 1  are optionally substituted C 1-6  aliphatic groups. 
     
     
         14 . The pharmaceutical salt of  claim 1 , wherein both R 1  are hydrogen. 
     
     
         15 .- 19 . (canceled) 
     
     
         20 . A pharmaceutical salt selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . A method of decreasing the enzymatic activity of Bruton's tyrosine kinase comprising contacting Bruton's tyrosine kinase with an effective amount of a pharmaceutical salt of  claim 1  or a composition thereof. 
     
     
         22 . A method of treating a disorder responsive to inhibition of Bruton's tyrosine kinase comprising administering to a subject an effective amount of a pharmaceutical salt of  claim 1  or a composition thereof. 
     
     
         23 . 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 pharmaceutical salt of  claim 1  or a composition thereof. 
     
     
         24 . The method of  claim 23 , wherein the disorder is rheumatoid arthritis, systemic lupus erythematosus, or atopic dermatitis. 
     
     
         25 .- 26 . (canceled) 
     
     
         27 . The method of  claim 23 , wherein the disorder is leukemia or lymphoma. 
     
     
         28 . A pharmaceutical composition comprising a pharmaceutical salt of  claim 1  and one or more pharmaceutically acceptable excipients.