BTK inhibitors

Abstract

The invention provides BTK inhibitors, methods for their identification and use, and pharmaceutical compositions comprising BTK inhibitors, including allergy treatments.

1 . A method to alter leukotriene production from mast cells, the method comprising contacting mast cells with an effective leukotriene-altering amount of a LFM analogue of the formula:  
     
       
         
         
             
             
         
       
       where X comprises H, Br, Cl, F, CF 3 , or OCF 3 .  
     
   
   
       2 . The method of  claim 1 , wherein the LFM analogue is selected from the group consisting of LFM-A0, LFM-A1, LFM-A2, LFM-A3, LFM-A4, LFM-A5, LFM-A6, LFM-A7, LFM-A8, LFM-A9, LFM-A10, LFM-A11 and LFM-A12 or a pharmaceutically acceptable salt thereof.  
   
   
       3 . The method of  claim 1  wherein the LFM analogue comprises LFM-A8 or pharmaceutically acceptable salts thereof.  
   
   
       4 . The method of  claim 1  wherein leukotriene production results from IgE/Fc□RI engagement.  
   
   
       5 . The method of  claim 1  wherein the mast cells comprise human mast cells.  
   
   
       6 . The method of  claim 1  wherein the leukotriene comprises leukotriene C 4 , D 4 , E 4 , or B 4 .  
   
   
       7 . The method of  claim 4  wherein the leukotriene comprises leukotriene C 4    
   
   
       8 . A method for treating or preventing asthma in a mammal, the method comprising administering to a mammal a therapeutically effective amount of a LFM analogue of the formula:  
     
       
         
         
             
             
         
       
       where X comprises H, Br, Cl, F, CF 3 , or OCF 3 .  
     
   
   
       9 . The method of  claim 8 , wherein the LFM analogue is selected from the group consisting of LFM-A0, LFM-A1, LFM-A2, LFM-A3, LFM-A4, LFM-A5, LFM-A6, LFM-A7, LFM-A8, LFM-A9, LFM-A10, LFM-A11 and LFM-A12 or a pharmaceutically acceptable salt thereof.  
   
   
       10 . The method of  claim 8  wherein the LFM analogue comprises LFM-A8 or pharmaceutically acceptable salts thereof.  
   
   
       11 . The method of  claim 8  wherein said asthma is associated with an alteration in the number of eosinophils in the bronchioles.  
   
   
       12 . The method of  claim 8  wherein said asthma is associated with airway hyperresponsiveness.  
   
   
       13 . A method of altering the number of eosinophils in the bronchioles, the method comprising administering to a mammal a therapeutically effective amount of a LFM analogue of the formula:  
     
       
         
         
             
             
         
       
       where X comprises H, Br, Cl, F, CF 3 , or OCF 3 .  
     
   
   
       14 . The method of  claim 13 , wherein the LFM analogue is selected from the group consisting of LFM-A0, LFM-A1, LFM-A2, LFM-A3, LFM-A4, LFM-A5, LFM-A6, LFM-A7, LFM-A8, LFM-A9, LFM-A10, LFM-A11 and LFM-A12 or a pharmaceutically acceptable salt thereof.  
   
   
       15 . The method of  claim 13  wherein the LFM analogue comprises LFM-A8 or pharmaceutically acceptable salts thereof.  
   
   
       16 . The method of  claim 15  wherein the eosinophil recruitment to the bronchioles is decreased in mammals pretreated with at least 15 mg/Kg of LFM-A8 by at least 50% as compared to untreated mammals.  
   
   
       17 . A method for reducing bronchial hyperresponsiveness. the method comprising administering to a mammal a therapeutically effective amount of a LFM analogue of the formula:  
     
       
         
         
             
             
         
       
       where X comprises H, Br, Cl, F, CF 3 , or OCF 3 .  
     
   
   
       18 . The method of  claim 17 , wherein the LFM analogue is selected from the group consisting of LFM-A0, LFM-A1, LFM-A2, LFM-A3, LFM-A4, LFM-A5, LFM-A6, LFM-A7, LFM-A8, LFM-A9, LFM-A10, LFM-A11 and LFM-A12 or a pharmaceutically acceptable salt thereof.  
   
   
       19 . The method of  claim 17  wherein the LFM analogue comprises LFM-A8 or pharmaceutically acceptable salts thereof.  
   
   
       20 . The method of  claim 19  wherein the bronchial hyperresponsiveness is decreased in mammals pretreated with at least 15 mg/Kg of LFM-A8 so at least 8.9 times as much sensitizing agent is needed to produce a 100% increase in pulmonary airflow obstruction as compared to untreated mammals.  
   
   
       21 - 32 . (canceled)