Intracellular kinase inhibitors

Abstract

Intracellular kinase inhibitors and their therapeutic uses for patients with T cell malignancies, B cell malignancies, autoimmune disorders, and transplanted organs.

1 . A protein kinase inhibitor which has a structural formula selected from the group consisting of:
 (a)   
       
         
           
           
               
               
           
         
          wherein R 3 , R 4 , R 5 , and R 6  are independently hydrogen or optionally substituted C 1 -C 6  alkyl, wherein R 22  is selected from hydrogen, C 1 -C 4  alkyl, —NR′R″, —COH, —COOH, —CNR′R″, and —CONHR′, and wherein R′ and R″ are independently selected from hydrogen and C 1 -C 4  alkyl; 
         (b) 
       
       
         
           
           
               
               
           
         
          wherein R 3 , R 4 , R 5 , and R 6  are as defined above and wherein R 24  is 
       
       
         
           
           
               
               
           
         
         (c) 
       
       
         
           
           
               
               
           
         
          wherein L is 
       
       
         
           
           
               
               
           
         
          and wherein R 3 , R 4 , R 5 , and R 6  are as defined above; 
         (d) 
       
       
         
           
           
               
               
           
         
          wherein T, U, V, and W independently are selected from hydrogen; halogen; —O; C 1 -C 3  alkyl; and C 1 -C 3  alkyloxy; and wherein R 25  is hydrogen or C 1 -C 3  alkyl; 
         (e) 
       
       
         
           
           
               
               
           
         
          wherein T, U, V, and W independently are selected from hydrogen; halogen; —O; C 1 -C 3  alkyl; and C 1 -C 3  alkyloxy; and wherein R 8  is hydrogen or C 1 -C 3  alkyl; 
         (f) 
       
       
         
           
           
               
               
           
         
          wherein T, U, V, and W independently are selected from hydrogen; halogen; —O; C 1 -C 3  alkyl; and C 1 -C 3  alkyloxy; and wherein R 8  is hydrogen or C 1 -C 3  alkyl; 
         (g) 
       
       
         
           
           
               
               
           
         
          wherein D is S, O, or NH; 
         (h) 
       
       
         
           
           
               
               
           
         
          wherein D is as defined above; and 
         (i) 
       
       
         
           
           
               
               
           
         
          wherein G′ is NH or CH, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The protein kinase inhibitor of  claim 1 , which is a compound of formula (X). 
     
     
         3 . The protein kinase inhibitor of  claim 1 , which is a compound of formula (XII). 
     
     
         4 . The protein kinase inhibitor of  claim 1 , which is a compound of formula (XIII). 
     
     
         5 . The protein kinase inhibitor of  claim 1 , which is a compound of formula (XIV). 
     
     
         6 . The protein kinase inhibitor of  claim 1 , which is a compound of formula (XV). 
     
     
         7 . The protein kinase inhibitor of  claim 1 , which is a compound of formula (XVI). 
     
     
         8 . The protein kinase inhibitor of  claim 1 , which is a compound of formula (XVII). 
     
     
         9 . The protein kinase inhibitor of  claim 1 , which is a compound of formula (XVIII). 
     
     
         10 . The protein kinase inhibitor of  claim 1 , which is a compound of formula (XIX). 
     
     
         11 . A composition, comprising:
 (a) a pharmaceutically acceptable vehicle; and   (b) the protein kinase inhibitor of  claim 1 .   
     
     
         12 . An adduct formed between (a) the protein kinase inhibitor of  claim 1 ; and (b) a DKC triad kinase domain. 
     
     
         13 . The adduct of  claim 12 , wherein the DKC triad kinase comprises ITK. 
     
     
         14 . A complex, comprising the protein kinase inhibitor of  claim 1  which is bound to a DKC triad kinase. 
     
     
         15 . The complex of  claim 14 , wherein the DKC triad kinase comprises ITK. 
     
     
         16 . A method of inhibiting kinase activity, comprising contacting a DKC triad kinase with the protein kinase inhibitor of  claim 1  or a pharmaceutically acceptable salt thereof, whereby kinase activity of the DKC triad kinase is inhibited. 
     
     
         17 . The method of  claim 16 , wherein the DKC triad kinase comprises ITK. 
     
     
         18 . The method of  claim 16 , wherein the contacting occurs in a cell-free system. 
     
     
         19 . The method of  claim 16 , wherein the contacting occurs in a cell. 
     
     
         20 . The method of  claim 19 , wherein the cell is in vitro. 
     
     
         21 . The method of  claim 19 , wherein the cell is in a patient. 
     
     
         22 . The method of  claim 21 , wherein patient has an organ transplant, an autoimmune disease, or a blood cell malignancy. 
     
     
         23 . The method of  claim 22 , wherein the patient has a blood cell malignancy and the blood cell malignancy is selected from the group consisting of a B cell malignancy and a T cell malignancy. 
     
     
         24 . The method of  claim 16 , wherein the DKC triad kinase comprises ITK.