Bruton's Tyrosine Kinase Inhibitors

Abstract

Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (BTK). Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the BTK inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions. (Formula I)

1 . A compound having Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         A is arylene, 5-membered heteroarylene or 6-membered heteroarylene, optionally substituted with one, two, three or four R 6  independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxy and (C 1 -C 4 )alkoxy; 
         X is O, S, C(═O), C(OR 4 ) or C(R 6a )(R 6b ); 
         W is aryl, 5-membered heteroaryl or 6-membered heteroaryl, optionally substituted with one, two, three, four or five R 7  independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, 4-6 membered saturated heterocycle, halo, hydroxy, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, and halo(C 1 -C 4 )alkoxy; 
         R 1  is a 4-8 membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally further substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy; 
         R is cyano, cyano(C 1 -C 3 )alkyl, 
       
       
         
           
           
               
               
           
         
         R 2a , R 2b , R 3a , R 3b  and R 4  are independently selected from the group consisting of hydrogen or (C 1 -C 3 )alkyl; 
         R 5a  and R 5b  are independently selected from the group consisting of hydrogen, halo and (C 1 -C 3 )alkyl; 
         R a  is hydrogen, halo, cyano, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkylsulfonyl, or (C 1 -C 6 )alkyl optionally substituted by halo, hydroxyl, (C 1 -C 6 )alkoxy or halo(C 1 -C 6 )alkoxy; 
         R b  and R c  are independently selected from the group consisting of hydrogen, halo, cyano, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, C(═O)R d  and (C 1 -C 6 )alkyl optionally substituted with one, two or three R f  independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy and aryl; or R b  and R c  taken together with the carbon to which they are bound form a 4-7 membered carbocycyl or heterocycyl optionally substituted with one, two or three R f  independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy; halo(C 1 -C 6 )alkoxy and aryl; 
         R d  is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, N(R e ) 2  or aryl; 
         R e  is independently selected for each occurence from the group consisting of hydrogen and (C 1 -C 4 ) alkyl, or both R e  taken together with the nitrogen atom to which they are bound form a 4-7 membered heterocycyl; and 
         G is a 5-7 membered carbocycyl or heterocycyl optionally substituted with one, two or three R f  independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy; halo(C 1 -C 6 )alkoxy and aryl. 
       
     
     
         2 . The compound of  claim 1 , wherein R is cyano or cyano(C 1 -C 3 )alkyl. 
     
     
         3 . The compound of  claim 1 , wherein R is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
       and R 6  is independently selected for each occurrence from the group consisting of hydrogen, (C 1 -C 4 )alkyl, halo(C 1 -C 3 )alkyl and halo. 
     
     
         5 . The compound of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
       and R 6  is independently selected for each occurrence from the group consisting of hydrogen, (C 1 -C 4 )alkyl, halo(C 1 -C 3 )alkyl and halo. 
     
     
         6 . The compound of  claim 4 , wherein R 6  is hydrogen. 
     
     
         7 . The compound of  claim 1 , wherein X is O, CH 2  or C(═O). 
     
     
         8 . The compound of  claim 1 , wherein X is O. 
     
     
         9 . The compound of  claim 1 , wherein X is CH 2 . 
     
     
         10 . The compound of  claim 1 , wherein W is phenyl optionally substituted with one, two, three, four or five R 7  independently selected for each occurrence from the group consisting of (C 1 -C 4 )alkyl, halo(C1-C3)alkyl, (C 1 -C 4 )alkoxy, and halo. 
     
     
         11 . The compound of  claim 10 , wherein W is 
       
         
           
           
               
               
           
         
       
       and R 7  is independently selected from the group consisting of F, Cl, methoxy and methyl. 
     
     
         12 . The compound of  claim 1 , wherein W is pyridyl optionally substituted with one, two, three, or four R 7  independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxy, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and (C 1 -C 4 )haloalkoxy. 
     
     
         13 . The compound of  claim 12 , wherein W is 
       
         
           
           
               
               
           
         
       
       and R 7  is independently selected for each occurrence from the group consisting F, Cl and CF 3 . 
     
     
         14 . The compound of  claim 1 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy. 
     
     
         15 . A compound having Formula (II) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is 
       
       
         
           
           
               
               
           
         
       
       and
 W is phenyl or pyridyl, optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 3 )haloalkyl and halo. 
 
     
     
         16 . The compound of  claim 15 , wherein W is 
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound of structure 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salts thereof. 
     
     
         18 . A compound having formula (II) 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein 
         R 1  is 
       
       
         
           
           
               
               
           
         
         R a  is hydrogen, halo, cyano, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkylsulfonyl, or (C 1 -C 6 )alkyl optionally substituted by halo, hydroxyl, (C 1 -C 6 )alkoxy or halo(C 1 -C 6 )alkoxy; 
         R b  and R c  are independently selected from the group consisting of hydrogen, halo, cyano, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, C(═O)R d  and (C 1 -C 6 )alkyl optionally substituted with one, two or three R f  independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy and halo(C 1 -C 6 )alkoxy; 
         R d  is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, N(R e ) 2  or aryl; 
         R e  is independently selected for each occurence from the group consisting of hydrogen and (C 1 -C 4 ) alkyl, or both R e  taken together with the nitrogen atom to which they are bound form a 4-7 membered heterocycyl; and 
         W is phenyl or pyridyl, optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 3 )haloalkyl and halo. 
       
     
     
         19 . The compound of  claim 18 , wherein W is 
       
         
           
           
               
               
           
         
       
     
     
         20 . A compound of structure 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salts thereof. 
     
     
         21 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient or dilutent. 
     
     
         22 - 25 . (canceled) 
     
     
         26 . A method for treating a cancer in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to  claim 21 . 
     
     
         27 . The method of  claim 26 , wherein the cancer is a B-cell proliferative disorder. 
     
     
         28 . The method of  claim 27 , wherein the B-cell proliferative disorder is chronic lymphocytic lymphoma, diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia.