Tyrosine kinase inhibitors

Abstract

The present disclosure provides compounds of formula (I) that are tyrosine kinase inhibitors, in particular Bruton tyrosine kinase (“BTK”) inhibitors, and are therefore useful for the treatment of diseases treatable by inhibition of BTK such as cancer, autoimmune, inflammatory, and thromboembolic diseases. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       and/or a pharmaceutically acceptable salt thereof, wherein:
 R 1  and R 2  are independently hydrogen, alkyl, alkoxy, haloalkyl, or halo; 
 X is —O—, —CONR—, NRCO—, or —NR—CO—NR′, where R and R′ are independently hydrogen or alkyl; 
 Ar is heteroaryl or phenyl, each ring optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy, and hydroxy; 
 
       
         
           
           
               
               
           
         
          is a group of formula (i)-(x) 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 R 3  is hydrogen, alkyl, cyclopropyl, halo, haloalkyl, haloalkoxy, alkoxy, or cyano; and 
 R 4  is hydrogen, alkyl, or halo; 
 
         Y is a bond or alkylene; 
         ring Z is heterocycloamino optionally substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, and fluoro; and 
         R c  is alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 6 R 7 , heterocyclylalkyl, or heterocyclyl, wherein:
 R 6  and R 7  are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, or heterocyclyl, wherein the heterocyclyl ring is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, acyl, and alkoxycarbonyl; or 
 R 6  and R 7  together with the nitrogen atom to which they are attached form 
 
       
       
         
           
           
               
               
           
         
         
            where:
 one or two of X 1 , X 2 , and X 3  are nitrogen and the rest are carbon, and 
 the ring is optionally substituted with one or two substituents independently selected from alkyl, haloalkyl, and halo; 
 
           the heterocyclyl and heterocyclyl in heterocyclylalkyl is independently substituted with one, two, or three substituents, where:
 two of the substituents are independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, amino, and oxo; and 
 one of the substituents is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, acyl, alkoxycarbonyl, or heterocyclyl, wherein the heterocyclyl ring is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, and alkoxy; provided that if: 
 
         
       
       
         
           
           
               
               
           
         
         
           
              is a group of formula (i) or (iii) 
           
           X is —O—; and 
           Ar is phenyl optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy, and hydroxy, then: 
           R c  is heterocyclylalkyl, wherein the heterocyclyl ring in heterocyclylalkyl is substituted with one, two, or three substituents, where:
 two substituents are independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, amino, and oxo; and 
 one of the substituents is a heterocyclyl that is substituted with alkyl or fluoro on the carbon atom of heterocyclyl that is attached to the heterocyclyl of heterocyclylalkyl. 
 
         
       
     
     
         2 . The compound of  claim 1  and/or a pharmaceutically acceptable salt thereof, wherein:
 X is —O—; and 
 —X—Ar is attached at the 4-position of the phenyl ring substituted with R 1  and R 2 , the carbon atom of the same phenyl ring attached to G being position 1. 
 
     
     
         3 . The compound of  claim 1  and/or a pharmaceutically acceptable salt thereof wherein X is —CONR— or —NRCO—. 
     
     
         4 . The compound of  claim 1  and/or a pharmaceutically acceptable salt thereof, wherein X is —NR—CO—NR′. 
     
     
         5 . The compound of  claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy, and hydroxy. 
     
     
         6 . The compound of  claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl optionally substituted with one, two, or three halo. 
     
     
         7 . The compound of  claim 1  and/or a pharmaceutically acceptable salt thereat wherein Ar is phenyl or 2,6-difluorophenyl. 
     
     
         8 . The compound of  claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein Ar is heteroaryl optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy, and hydroxy. 
     
     
         9 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein:
 —X—Ar is attached at the 4 position of the phenyl ring substituted with R 1  and R 2 ; and 
 (1) both R 1  and R 2  are H; or (2) one of R 1  and R 2  is H and the other is fluoro attached at the 2-position the phenyl ring, the carbon atom of the same phenyl ring attached to G being position 1. 
 
     
     
         10 . The compound of  claim 1  and/or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1  and/or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
         is a group of formula (vi)-(x) above. 
       
     
     
         16 . The compound of  claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
       
       where the stereochemistry at *C is R or S. 
     
     
         17 . The compound of  claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
       
       where the stereochemistry at *C is R or S. 
     
     
         18 . The compound of  claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R c  is cycloalkyl. 
     
     
         19 . The compound of  claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R c  is alkyl. 
     
     
         20 . The compound of  claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R c  is -(alkylene)-NR 6 R 1 , where R 6  and R 7  are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, or heterocyclyl. 
     
     
         21 . The compound of  claim 1  and/or a pharmaceutically acceptable salt thereof, wherein:
 R c  is heterocyclyl optionally substituted with one, two, or three substituents where:
 two of the optional substituents are independently selected from alkyl, alkoxy, hydroxy, halo, amino, and oxo; and 
 one of the optional substituent is alkyl, hydroxyalkyl, alkoxyalkyl, acyl, or heterocyclyl. 
 
 
     
     
         22 . The compound of  claim 1  and/or a pharmaceutically acceptable salt thereof, wherein:
 R c  is heterocyclylalkyl, wherein the heterocyclyl in heterocyclylalkyl is optionally substituted with one, two, or three substituents, where:
 two of the optional substituents are independently selected from alkyl, alkoxy, hydroxy, halo, amino, and oxo; and 
 one of the optional substituent is alkyl, hydroxyalkyl, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, and alkoxy. 
 
 
     
     
         23 . The compound of  claim 1  and/or a pharmaceutically acceptable salt thereof, wherein the compound is chosen from:
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-5-(2-fluoro-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (S)-2-(3-(4-amino-5-(2-fluoro-4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(7-amino-1-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile; 
 (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile; 
 (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(methyl(oxetan-3-0amino)pent-2-enenitrile; 
 (S)-4-(4-amino-1-((1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (S)-2-(24 (8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; 
 (S)-2-(2-((8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile; 
 (S)-2-(2-((8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(methyl(oxetan-3-yl)amino)pent-2-enenitrile; 
 (S)-2-(2-((8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (S)-4-(4-amino-1-((1-(2-cyano-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (S)-4-(4-amino-1-((1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(1-(oxetan-3-yl)piperidin-4-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(3-oxopiperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-methyl-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(3-methyl-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-4-(4-amino-1-(1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)piperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(4-ethyl-3-oxopiperazin-1-yl)-4-methylpent-2-enenitrile; 
 (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methyl-1-(oxetan-3-yl)piperidin-4-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyrindin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-5-(4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (S)-2-(3-(4-amino-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(7-amino-1-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyrimidin-3-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-ethyl-3-oxopiperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-(4-ethyl-3-oxopiperazin-1-yl)-4-methylpent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(4-methyl-1-(oxetan-3-yl)piperidin-4-yl)acrylonitrile; 
 (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)acrylonitrile; 
 (R)-2-(3-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-4-(4-amino-1-(1-(2-cyano-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enoyl)piperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (R)-4-(4-amino-1-(1-(2-cyano-4-methyl-4-(methyl(oxetan-3-yl)amino)pent-2-enoyl)piperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (R)-4-(4-amino-1-(1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)piperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)acrylonitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(4-methyl-1-(oxetan-3-yl)piperidin-4-yl)acrylonitrile; 
 (R)-4-(4-amino-1-(1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)piperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(4-fluoropyridin-2-yl)benzamide; 
 (R)-2-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)acrylonitrile; 
 (R)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)acrylonitrile; 
 (R)-2-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-methyl 4-(5-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate; 
 (R)-4-(4-acetylpiperazin-1-yl)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile; 
 (R)-methyl 4-(5-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate; 
 (R)-4-(4-acetylpiperazin-1-yl)-2-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; 
 2-((R)-3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-((S)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pent-2-enenitrile; 
 2-((R)-3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-((R)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pent-2-enenitrile; 
 2-((R)-3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-yl)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pent-2-enenitrile; 
 2-((R)-3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-((R)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)-4-methylpiperazine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)-4-methylpiperazine-1-carbonyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)acrylonitrile; 
 2-((R)-3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-((R)-3-oxotetrahydro-1H-oxazolo[3,4-a]pyrazin-7(3H)-yl)pent-2-enenitrile; 
 2-((R)-3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-yl)-3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)pent-2-enenitrile; 
 2-((R)-3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-((R)-3-oxotetrahydro-1H-oxazolo[3,4-a]pyrazin-7(3H)-yl)pent-2-enenitrile; 
 2-((R)-3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-((S)-3-oxotetrahydro-1H-oxazolo[3,4-a]pyrazin-7(3H)-yl)pent-2-enenitrile; and 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile,
 or a stereoisomer of any of the above compounds, 
 or an E or Z isomer thereof, 
 and/or a pharmaceutically acceptable salt of any of the above compounds. 
 
 
     
     
         24 . The compound of  claim 23  and/or a pharmaceutically acceptable salt thereof, wherein the compound is chosen from:
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4-c]pyridin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile; 
 (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile; 
 (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (S)-4-(4-amino-1-((1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (S)-2-(2-((8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; 
 (S)-2-(2-((8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile; 
 (S)-2-(2-((8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(methyl(oxetan-3-yl)amino)pent-2-enenitrile; 
 (S)-2-(2-((8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (S)-4-(4-amino-1-((1-(2-cyano-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (S)-4-(4-amino-1-((1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(1-(oxetan-3-yl)piperidin-4-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(3-oxopiperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-methyl-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(3-methyl-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-4-(4-amino-1-(1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)piperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(4-ethyl-3-oxopiperazin-1-yl)-4-methylpent-2-enenitrile; 
 (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methyl-1-(oxetan-3-yl)piperidin-4-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-ethyl-3-oxopiperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-(4-ethyl-3-oxopiperazin-1-yl)-4-methylpent-2-enenitrile; 
 (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(4-methyl-1-(oxetan-3-yl)piperidin-4-yl)acrylonitrile; 
 (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(4-m ethyltetrahydro-2H-pyran-4-yl)acrylonitrile; 
 (R)-2-(3-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-4-(4-amino-1-(1-(2-cyano-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enoyl)piperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (R)-4-(4-amino-1-(1-(2-cyano-4-methyl-4-(methyl(oxetan-3-yl)amino)pent-2-enoyl)piperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (R)-4-(4-amino-1-(1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)piperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2-yl)benzamide; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)acrylonitrile; 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-yl)piperidine-1-carbonyl)-3-(4-methyl-1-(oxetan-3-yl)piperidin-4-yl)acrylonitrile; 
 (R)-4-(4-amino-1-(1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)piperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(4-fluoropyridin-2-yl)benzamide; 
 (R)-2-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)acrylonitrile; 
 (R)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)acrylonitrile; 
 (R)-2-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; 
 (R)-methyl 4-(5-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate; 
 (R)-4-(4-acetylpiperazin-1-yl)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile; 
 (R)-methyl 4-(5-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate; 
 (R)-4-(4-acetylpiperazin-1-yl)-2-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-ethylpent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; 
 2-((R)-3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-((S)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pent-2-enenitrile; 
 2-((R)-3-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-((R)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pent-2-enenitrile; 
 2-((R)-3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl piperidine-1-carbonyl)-4-methyl-4-((S)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pent-2-enenitrile; 
 2-((R)-3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carbonyl)-4-methyl-4-((R)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)-4-methylpiperazine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; 
 (R)-2-(3-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)-4-methylpiperazine-1-carbonyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)acrylonitrile; and 
 (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile;
 or a stereoisomer of any of the above compounds, 
 or an E or Z isomer thereof, 
 and/or a pharmaceutically acceptable salt of any of the above compounds. 
 
 
     
     
         25 . A pharmaceutical composition comprising:
 a compound of  claim 1  and/or a pharmaceutically acceptable salt; and   a pharmaceutically acceptable excipient.   
     
     
         26 . A method of treating a disease treatable by inhibition of BTK in a mammal in recognized need thereof of such treatment, wherein said method comprises administering to the mammal a pharmaceutical composition comprising:
 a therapeutically effective amount of a compound of,  claim 1  and/or pharmaceutically acceptable salt; and   a pharmaceutically acceptable excipient.   
     
     
         27 . The method of  claim 26 , wherein the disease is chosen from autoimmune diseases, inflammatory diseases, and cancers. 
     
     
         28 . The method of  claim 27 , wherein the disease is chosen from rheumatoid arthritis, psoriatic arthritis, lupus, uveitis, myasthenia gravis, warm autoimmune hemolytic anemia, urtarica, Wegener's granulomatosis, Sjogren's disease, Sjogren's dry eye, non-Sjogren's dry eye disease, psoriasis, and asthma. 
     
     
         29 . The method of  claim 27 , wherein the disease is chosen from B-cell proliferative disorders. 
     
     
         30 . The method of  claim 29 , wherein the disease is chosen from diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, small lymphocytic lymphoma (SLL), multiple myeloma, B-cell non-Hodgkin lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.