Inhibitors of bruton's tyrosine kinase

Abstract

Described herein are kinase inhibitor compounds, methods for synthesizing such inhibitors, and methods for using such inhibitors in the treatment of diseases. Further described herein are methods, assays and systems for determining an appropriate inhibitor of a protein, including a kinase.

What is claimed is: 
     
         1 . A compound having the structure of Formula (IV) having the structure: 
       
         
           
           
               
               
           
         
         wherein:
 T is a bond, C 1 -C 6 alkylene, or C 3 -C 6 cycloalkylene; 
 Y and Z are each independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 10 cycloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 heteroalkenyl, C 4 -C 10 heterocycloalkenyl and C 2 -C 10 heterocycloalkyl, wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 10 cycloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 heteroalkenyl, C 4 -C 10 heterocycloalkenyl and C 2 -C 10 heterocycloalkyl are optionally substituted with at least one R 1 ; or 
 Y and Z together with the carbon atom to which they are attached form a C 3 -C 10 cycloalkyl, C 2 -C 10 heterocycloalkyl, C 4 -C 10 heterocycloalkenyl, aryl, or heteroaryl, wherein C 3 -C 10 cycloalkyl, C 2 -C 10 heterocycloalkyl, C 4 -C 10 heterocycloalkenyl, aryl, or heteroaryl, are optionally substituted with at least one X; 
 wherein when Y and Z together with the carbon atom to which they are attached form a nitrogen atom-containing C 2 -C 10 heterocycloalkyl or C 4 -C 10 heterocycloalkenyl, the nitrogen atom of the C 2 -C 10 heterocycloalkyl or C 4 -C 10 heterocycloalkenyl is optionally substituted with W and the carbon atoms of the C 2 -C 10 heterocycloalkyl or C 4 -C 10 heterocycloalkenyl are optionally substituted with at least one X; 
 W is selected from J, C(═O)-J, C(═O)O-J, C(═O)NR 2 -J, C(═NR 2 )-J, —C(═NR 2 )NR 2 -J, C(═N—OR 3 )-J, C(═S)-J, S(═O) v -J, S(═O) v O-J; 
 X is F, Cl, Br, I, —CN, —NO 2 , —OR 3 , —N(R 2 ) 2 , —SR 2 , —C 1 -C 6 alkyl, —C(═O)R 2 , —OC(═O)R 2 , —NR 2 C(═O)R 5 , —NR 2 C(═O)N(R 2 ) 2 , —C(═O)N(R 2 ) 2 , —C(═NR 2 )N(R 2 ) 2 , —C(═N—OR 2 )N(R 2 ) 2 , —C(═S)R 2 , —S(═O) v R 2 , —OS(═O) v R 2 , —NR 2 C(═O)OR 2 , —NR 2 S(═O) v R 2 ; 
 J is —C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 2 -C 6 alkene, C 2 -C 6 heterocycloalkyl, aryl, or heteroaryl optionally substituted with at least one R 1 ; 
 v is 1 or 2; 
 R b  is NH 2 , OH, OSO 3 H or NHSO 3 H, halogen, —CN, —NO 2 , —SR 2 , optionally substituted C 1 -C 6 alkyl; N(R 2 ) 2  or NHR 7 ; 
 R 1  is selected from F, Cl, Br, I, —CN, —NO 2 , —SR 2 , —OR 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, heteroaryl, phenyl, —NR 2 S(═O) 2 R 2 , —S(═O) 2 N(R 2 ) 2 , —C(═O)CF 3 , —C(═O)NR 2 S(═O) 2 R 2 , —S(═O) 2 NR 2 C(═O)R 2 , —N(R 2 ) 2 , wherein optionally the two R 2  groups of N(R 2 ) 2  and the nitrogen atom to which they are attached form a C 2 -C 6  heterocycloalkyl ring, —NR 2 C(═O)R 2 , —NR 2 C(═O)R 8 , —NR 2 C(═O)N(R 2 ) 2 , —CO 2 R 2 , —C(═O)R 2 , —OC(═O)R 2 , —C(═O)N(R 2 ) 2 , —OS(═O) 2 R 2 , —OS(═O) 2 OR 2 , —S(═O)R 2 , —S(═O) 2 R 2 , —SO 3 H, and at least one amino acid fragment; 
 R 2  is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 3 -C 6 cycloalkyl; 
 
         R 3  is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, or SO 3 H; 
         R 6  is selected from H, F, Cl, Br, I, —CN, —NO 2 , —SR 2 , —OR 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, phenyl, —NR 2 S(═O) 2 R 2 , —S(═O) 2 N(R 2 ) 2 , —C(═O)CF 3 , —C(═O)NR 2 S(═O) 2 R 2 , —S(═O) 2 NR 2 C(═O)R 2 , —N(R 2 ) 2 , wherein optionally the two R 2  groups of N(R 2 ) 2  and the nitrogen atom to which they are attached form a C 2 -C 6  heterocycloalkyl ring, —NR 2 C(═O)R 2 , —NR 2 C(═O)N(R 2 ) 2 , —CO 2 R 2 , —C(═O)R 2 , —OC(═O)R 2 , —C(═O)N(R 2 ) 2 , —OS(═O) 2 R 2 , —OS(═O) 2 OR 2 , —S(═O)R 2 , —S(═O) 2 R 2 , —SO 3 H, and at least one amino acid fragment; wherein each R 6  cannot all be H; 
         R 7  is an amino protecting group; 
         R 8  is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, or an optionally substituted C 3 -C 6 cycloalkyl; or a pharmaceutically acceptable salt, solvate, or metabolite thereof. 
       
     
     
         2 . The compound of  claim 1  wherein Y and Z together with the carbon atom to which they are attached form a C 3 -C 10 cycloalkyl or C 2 -C 10 heterocycloalkyl. 
     
     
         3 . The compound of  claim 2  wherein Y and Z together with the carbon atom to which they are attached form a C 2 -C 10 heterocycloalkyl. 
     
     
         4 . The compound of  claim 1  wherein W is C(═O)J. 
     
     
         5 . The compound of  claim 4  wherein J is —C 1 -C 6 alkyl or —C 2 -C 6 alkene. 
     
     
         6 . The compound of  claim 5  wherein J is substituted with at least one R 1 . 
     
     
         7 . The compound of  claim 6  wherein R 1  is selected from F, Cl, Br, I, —CN, —NO 2 , —SR 2 , —OR 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, heteroaryl, or phenyl. 
     
     
         8 . The compound of  claim 3  wherein C 2 -C 10 heterocycloalkyl is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 8  wherein C 2 -C 10 heterocycloalkyl is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 5  wherein C 1 -C 6 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. 
     
     
         11 . The compound of  claim 10  wherein C 1 -C 6 alkyl is substituted with one R 1 . 
     
     
         12 . The compound of  claim 10  wherein C 1 -C 6 alkyl is substituted with two R 1 . 
     
     
         13 . The compound of  claim 11  wherein R 1  is selected from F, Cl, Br, I, —CN, NO 2 , —OR 3 , and at least one amino acid fragment. 
     
     
         14 . The compound of  claim 5  wherein J is C 2 -C 6 alkene. 
     
     
         15 . The compound of  claim 14  wherein C 2 -C 6 alkene is C 2 H 3 . 
     
     
         16 . The compound of  claim 15  wherein C 2 -C 6 alkene is substituted with at least one R 1  selected from F, Cl, Br, I, —CN, NO 2 , OH, and —OSO 3 H. 
     
     
         17 . A pharmaceutical formulation comprising a therapeutically effective amount of a compound of  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
         18 . The compound of  claim 1  wherein the compound forms a covalent bond with a Cys 481 residue of Btk or a cysteine residue in the homologous corresponding position of another tyrosine kinase. 
     
     
         19 . A method for treating an autoimmune disease or inflammatory disease or condition comprising administering to a patient in need the compound of  claim 1 . 
     
     
         20 . A method for treating a cancer comprising administering to a patient in need the compound of  claim 1 . 
     
     
         21 . A method for treating an inflammatory disease or condition comprising administering to a patient in need the compound of  claim 1 .