US2017362246A1PendingUtilityA1

Inhibitors of bruton's tyrosine kinase

Assignee: PHARMACYCLICS LLCPriority: Mar 28, 2007Filed: Aug 31, 2017Published: Dec 21, 2017
Est. expiryMar 28, 2027(~0.7 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 37/00A61P 37/06A61P 35/02A61P 35/04A61P 29/00A61P 19/08A61P 19/10A61P 19/04A61P 19/02A61K 31/519A61K 31/4985C07D 487/04A61K 45/06
69
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Claims

Abstract

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

Claims

exact text as granted — not AI-modified
1 - 100 . (canceled) 
     
     
         101 . A compound of Formula (B5) having the structure: 
       
         
           
           
               
               
           
         
         wherein:
 Y and R 12  taken together form a 4-, 5-, or 6-membered heterocyclic ring; 
 each R a  is independently H, halogen, CF 3 , CN, NO 2 , OH, NH 2 , -L a -(substituted or unsubstituted alkyl), -L a -(substituted or unsubstituted alkenyl), -L a -(substituted or unsubstituted heteroaryl), or -L a -(substituted or unsubstituted aryl), wherein L a  is a bond, O, S, S(═O), S(═O) 2 , NH, C(O), CH 2 , NHC(O)O, NHC(O), or C(O)NH; 
 G is 
 
       
       
         
           
           
               
               
           
         
         
           wherein R 6  is selected from H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl; 
           or a pharmaceutically acceptable salt thereof. 
         
       
     
     
         102 . The compound of  claim 101 , wherein R 6  is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl. 
     
     
         103 . The compound of  claim 102 , wherein R 6  is lower alkyl. 
     
     
         104 . The compound of  claim 103 , wherein R 6  is methyl. 
     
     
         105 . The compound of  claim 101 , wherein Y and R 12  taken together form a 5-membered heterocyclic ring. 
     
     
         106 . The compound of  claim 105 , wherein R 6  is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl. 
     
     
         107 . The compound of  claim 106 , wherein R 6  is lower alkyl. 
     
     
         108 . The compound of  claim 107 , wherein R 6  is methyl. 
     
     
         109 . A compound of Formula (B5) having the structure: 
       
         
           
           
               
               
           
         
         wherein:
 Y and R 12  taken together form a 4-, 5-, or 6-membered heterocyclic ring; 
 R a  at positions 2, 3, 5, and 6 are each H; 
 R a  at position 4 is H, halogen, CF 3 , CN, NO 2 , OH, NH 2 , -L a -(substituted or unsubstituted alkyl), -L a -(substituted or unsubstituted alkenyl), -L a -(substituted or unsubstituted heteroaryl), or -L a -(substituted or unsubstituted aryl), wherein L a  is a bond, O, S, S(═O), S(═O) 2 , NH, C(O), CH 2 , NHC(O)O, NHC(O), or C(O)NH; 
 G is 
 
       
       
         
           
           
               
               
           
         
         
           wherein R 6  is selected from H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl; 
           or a pharmaceutically acceptable salt thereof. 
         
       
     
     
         110 . The compound of  claim 109 , wherein R a  at position 4 is -L a -(substituted or unsubstituted heteroaryl). 
     
     
         111 . The compound of  claim 110 , wherein L a  is C(O)NH. 
     
     
         112 . The compound of  claim 111 , wherein Y and R 12  taken together form a 5-membered heterocyclic ring. 
     
     
         113 . The compound of  claim 112 , wherein R 6  is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl. 
     
     
         114 . The compound of  claim 113 , wherein R 6  is lower alkyl. 
     
     
         115 . The compound of  claim 114 , wherein R 6  is methyl. 
     
     
         116 . The compound of  claim 109 , wherein Y and R 12  taken together form a 5-membered heterocyclic ring. 
     
     
         117 . The compound of  claim 116 , wherein R 6  is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl. 
     
     
         118 . The compound of  claim 117 , wherein R 6  is lower alkyl. 
     
     
         119 . The compound of  claim 118 , wherein R 6  is methyl. 
     
     
         120 . A compound of Formula (B5) having the structure: 
       
         
           
           
               
               
           
         
         wherein:
 Y and R 12  taken together form a 4-, 5-, or 6-membered heterocyclic ring; 
 each R a  is independently H, halogen, CF 3 , CN, NO 2 , OH, NH 2 , -L a -(substituted or unsubstituted alkyl), -L a -(substituted or unsubstituted alkenyl), -L a -(substituted or unsubstituted heteroaryl), or -L a -(substituted or unsubstituted aryl), wherein L a  is a bond, O, S, S(═O), S(═O) 2 , NH, C(O), CH 2 , NHC(O)O, NHC(O), or C(O)NH; 
 G is 
 
       
       
         
           
           
               
               
           
         
         
           wherein R 6  is selected from H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl. 
         
       
     
     
         121 . The compound of  claim 120 , wherein R 6  is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl. 
     
     
         122 . The compound of  claim 121 , wherein R 6  is lower alkyl. 
     
     
         123 . The compound of  claim 122 , wherein R 6  is methyl. 
     
     
         124 . The compound of  claim 120 , wherein Y and R 12  taken together form a 5-membered heterocyclic ring. 
     
     
         125 . The compound of  claim 124 , wherein R 6  is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl. 
     
     
         126 . The compound of  claim 125 , wherein R 6  is lower alkyl. 
     
     
         127 . The compound of  claim 126 , wherein R 6  is methyl.

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