Tyrosine kinase inhibitors

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salts thereof that are tyrosine kinase inhibitors, in particular BLK, BMX, EGFR, HER2, HER4, ITK, TEC, BTK, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts thereof and processes for preparing such compounds and pharmaceutically acceptable salts thereof.

1 - 47 . (canceled) 
     
     
         48 . A compound of Formula (Id) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 Z 2  is —N— or CR 2  where R 2  is hydrogen or alkyl; 
 R 3  is methyl, chloro, fluoro, cyclopropyl, hydroxy, methoxy, cyano, trifluoromethyl or trifluoromethoxy; 
 R 4  is hydrogen, methyl, chloro, fluoro, cyclopropyl, hydroxy, methoxy, cyano, trifluoromethyl or trifluoromethoxy; 
 R 6  and R 7  are independently hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, or cyano; 
 —Z-EWG- is -(alkylene)-NR′CO—, -(alkylene)-NR′SO 2 —, 
 
       
         
           
           
               
               
           
         
       
       each ring optionally substituted with one or two substituents independently selected from alkyl, hydroxy, and halo and the carbonyl and sulfonyl group in -(alkylene)-NR′CO—, -(alkylene)-NR′SO 2 —, 
       
         
           
           
               
               
           
         
       
       is attached to —C(CN)═CHR c ; and each R′ is independently hydrogen or alkyl; and
 R c  is a cycloalkyl or 3 to 6 membered saturated monocyclic heterocyclyl containing one or two heteroatoms selected from N, O, and S and optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro, 
 or a mixture of R and S isomers thereof; 
 or an individual (E) or (Z) isomer of any of the foregoing compounds; 
 or a pharmaceutically acceptable salt of any of the foregoing compounds. 
 
     
     
         49 . The compound or a pharmaceutically acceptable salt thereof of  claim 48  wherein:
 R c  is a 3 to 6 membered saturated monocyclic heterocyclyl containing one or two heteroatoms selected from N, O, and S and optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro; and 
 
       
         
           
           
               
               
           
         
       
       is: 
       
         
           
           
               
               
           
         
       
     
     
         50 . The compound or a pharmaceutically acceptable salt thereof of  claim 48  wherein R c  is a 3 to 6 membered saturated monocyclic heterocyclyl containing one or two heteroatoms selected from N, O, and S and optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro; and 
       
         
           
           
               
               
           
         
       
     
     
         51 . The compound or a pharmaceutically acceptable salt thereof of  claim 49  wherein: 
       
         
           
           
               
               
           
         
       
       is a ring of formula 
       
         
           
           
               
               
           
         
       
     
     
         52 . The compound or a pharmaceutically acceptable salt thereof of  claim 49  wherein: 
       
         
           
           
               
               
           
         
       
       is a ring of formula: 
       
         
           
           
               
               
           
         
       
     
     
         53 . The compound or a pharmaceutically acceptable salt thereof of  claim 49  wherein: 
       
         
           
           
               
               
           
         
       
       is a ring of formula 
       
         
           
           
               
               
           
         
       
       is a ring of formula: 
       
         
           
           
               
               
           
         
       
     
     
         54 . The compound or a pharmaceutically acceptable salt thereof of  claim 53  wherein 
       
         
           
           
               
               
           
         
       
       is a ring of formula 
       
         
           
           
               
               
           
         
       
     
     
         55 . The compound or a pharmaceutically acceptable salt thereof of  claim 49  wherein:
 —Z-EWG- is 
 
       
         
           
           
               
               
           
         
       
       optionally substituted with one or two substituents independently selected from alkyl, hydroxy, and halo. 
     
     
         56 . The compound or a pharmaceutically acceptable salt thereof of  claim 55  wherein R c  is 
       
         
           
           
               
               
           
         
       
       X is O, S, SO 2 , NH, or N-alkyl, and each of the ring is optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro. 
     
     
         57 . The compound or a pharmaceutically acceptable salt thereof of  claim 55  wherein:
 R c  is 2-pyrrolidinyl, 3- or 4-piperidinyl, 1-methylpiperidin-4-yl, 1-methylpiperidin-3-yl, or 4-tetrahydropyranyl, and each of the heterocyclic ring is optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro. 
 
     
     
         58 . The compound or a pharmaceutically acceptable salt thereof of  claim 57  wherein R c  is 4-tetrahydropyranyl optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro. 
     
     
         59 . The compound or a pharmaceutically acceptable salt thereof of  claim 49  wherein:
 —Z-EWG- is 
 
       
         
           
           
               
               
           
         
       
       optionally substituted with one or two substituents independently selected from alkyl, hydroxy, and halo. 
     
     
         60 . The compound or a pharmaceutically acceptable salt thereof of  claim 59  wherein R c  is 
       
         
           
           
               
               
           
         
       
       X is O, S, SO 2 , NH, or N-alkyl, and each of the ring is optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro. 
     
     
         61 . The compound or a pharmaceutically acceptable salt thereof of  claim 60  wherein:
 R c  is 2-pyrrolidinyl, 3- or 4-piperidinyl, 1-methylpiperidin-4-yl, 1-methylpiperidin-3-yl, or 4-tetrahydropyranyl, and each of the heterocyclic ring is optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro. 
 
     
     
         62 . The compound or a pharmaceutically acceptable salt thereof of  claim 61  wherein R c  is 4-tetrahydropyranyl optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro. 
     
     
         63 . The compound or a pharmaceutically acceptable salt thereof of  claim 49  wherein:
 —Z-EWG- is 
 
       
         
           
           
               
               
           
         
       
       which is optionally substituted with one or two substituents independently selected from alkyl, hydroxy, and halo. 
     
     
         64 . The compound or a pharmaceutically acceptable salt thereof of  claim 63  wherein R c  is 
       
         
           
           
               
               
           
         
       
       X is O, S, SO 2 , NH, or N-alkyl, and each of the ring is optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro. 
     
     
         65 . The compound or a pharmaceutically acceptable salt thereof of  claim 64  wherein R c  is 2-pyrrolidinyl, 3- or 4-piperidinyl, 1-methylpiperidin-4-yl, 1-methylpiperidin-3-yl, or 4-tetrahydropyranyl, and each of the heterocyclic ring is optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro. 
     
     
         66 . The compound or a pharmaceutically acceptable salt thereof of  claim 65  wherein R c  is 4-tetrahydropyranyl optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro. 
     
     
         67 . A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of  claim 48 , and a pharmaceutically acceptable excipient.