Tyrosine kinase inhibitors

Abstract

The present disclosure provides compounds 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): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are independently hydrogen, alkyl, alkoxy, haloalkyl, or halo; 
 X is —O—; 
 Ar is heteroaryl or phenyl where heteroaryl and phenyl are optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy, and hydroxy; 
 A is —N— or —CR 3 — wherein R 3  is hydrogen, alkyl, cyclopropyl, halo, haloalkyl, haloalkoxy, alkoxy, or cyano; 
 Y is bond or alkylene; 
 ring Z is heterocycloamino optionally substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, and fluoro; 
 R 5  is a group of formula (i) or (iv): 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R a  is hydrogen, fluoro, or cyano; provided that when R a  is cyano then R b  is hydrogen and R c  is not hydrogen; 
 R b  is hydrogen or alkyl; and 
 R c  is hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl (optionally substituted with one or two substituents independently selected from hydroxy, hydoxyalkyl, heteroaryl (optionally substituted with one or two substituents independently selected from alkyl and heterocyclyl wherein heterocyclyl is optionally substituted with one or two substituents independently selected from halo and alkyl), and —CONR 9 R 10  (where R 9  and R 10  are independently hydrogen or alkyl, or R 9  and R 10  together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted with one or two substituents selected from alkyl and heterocyclyl)), cycloalkyl (optionally substituted with one or two substituents independently selected from halo, alkyl, alkoxyalkyl and aryl; or wherein two adjacent substituents of the cycloalkyl together with the carbon atoms to which they are attached form a heterocyclyl group), heterocyclylalkyl, heterocyclyl (wherein heterocyclyl and heterocyclyl in heterocyclylalkyl are 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, alkoxy, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, or heterocyclyl wherein the heterocyclyl is substituted with one or two substitutents independently selected from hydrogen, alkyl, halo, hydroxy, and alkoxy), or -(alkylene)-NR 6 R 7  (where R 6  and R 7  are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, or heterocyclyl wherein the heterocyclyl 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); or a pharmaceutically acceptable salt thereof provided that:
 when A is —N—, then R a  is cyano and R c  is heterocycloaminolalkyl wherein the heterocycloamino in heterocycloaminoalkyl is optionally substituted with one or two substituents independently selected from alkyl, alkoxy, hydroxy, halo, amino, and oxo, and the nitrogen atom of heterocycloamino is substituted with heterocyclyl wherein the heterocyclyl is substituted with one or two substituents independently selected from hydrogen, alkyl, halo, hydroxy, and alkoxy. 
 
     
     
         2 - 51 . (canceled) 
     
     
         52 . A compound of the following Formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are independently hydrogen, alkyl, alkoxy, haloalkyl, or halo; 
 X is —O—; 
 Ar is phenyl optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy, and hydroxy; 
 R 3  is hydrogen, alkyl, cyclopropyl, halo, haloalkyl, haloalkoxy, alkoxy, or cyano; 
 Y is alkylene; 
 ring Z is a 5-membered heterocycloamino optionally substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, and fluoro; 
 R 5  is 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R a  is cyano, provided that R b  is hydrogen and R c  is not hydrogen; and 
 R c  is alkyl (optionally substituted with one or two substituents independently selected from hydroxy, hydroxyalkyl, heteroaryl (optionally substituted with one or two substituents independently selected from alkyl and heterocyclyl wherein heterocyclyl is optionally substituted with one or two substituents independently selected from halo and alkyl), and —CONR 9 R 10  (where R 9  and R 10  are independently hydrogen or alkyl, or R 9  and R 10  together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted with one or two substituents selected from alkyl and heterocyclyl)), cycloalkyl (optionally substituted with one or two substituents independently selected from halo, alkyl, alkoxyalkyl and aryl; or wherein two adjacent substituents of the cycloalkyl together with the carbon atoms to which they are attached form a heterocyclyl group), heterocyclylalkyl, heterocyclyl (wherein heterocyclyl and heterocyclyl in heterocyclylalkyl are 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, alkoxy, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, or heterocyclyl wherein the heterocyclyl is substituted with one or two substituents independently selected from hydrogen, alkyl, halo, hydroxy, and alkoxy), or -(alkylene)-NR 6 R 7  (where R 6  and R 7  are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, or heterocyclyl wherein the heterocyclyl 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); or a pharmaceutically acceptable salt thereof. 
     
     
         53 . A compound of  claim 52 , selected from the group consisting of
 (S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile   (S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile   (S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile   (S)-methyl 4-(5-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-Imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate   (S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile   (S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile   (S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(methyl(oxetan-3-yl)amino)pent-2-enenitrile   or a pharmaceutically acceptable salt thereof.   
     
     
         54 . A compound of the following Formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are independently hydrogen, alkyl, alkoxy, haloalkyl, or halo; 
 X is —O—; 
 Ar is phenyl optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy, and hydroxy; 
 R 3  is hydrogen, alkyl, cyclopropyl, halo, haloalkyl, haloalkoxy, alkoxy, or cyano; 
 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; 
 R 5  is 
 
       
         
           
           
               
               
           
         
       
       wherein:
 each R b  is independently hydrogen or alkyl; or 
 a pharmaceutically acceptable salt thereof. 
 
     
     
         55 . A compound of  claim 54 , selected from the group consisting of
 (R)-4-amino-1-(1-(but-2-ynoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one   (S)-4-amino-1-((1-(but-2-ynoyl)pyrrolidin-2-yl)methyl)-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one   or a pharmaceutically acceptable salt thereof.   
     
     
         56 . A compound of the following Formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are independently hydrogen, alkyl, alkoxy, haloalkyl, or halo; 
 X is —O—; 
 Ar is phenyl optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy, and hydroxy; 
 R 3  is hydrogen, alkyl, cyclopropyl, halo, haloalkyl, haloalkoxy, alkoxy, or cyano; 
 Y is a bond or alkylene; 
 ring Z is 6-membered heterocycloamino optionally substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, and fluoro; 
 R 5  is 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R a  is hydrogen, fluoro, or cyano; provided that when R a  is cyano then R b  is hydrogen and R c  is not hydrogen; 
 each R b  is independently hydrogen or alkyl; and 
 R c  is alkyl (optionally substituted with one or two substituents independently selected from hydroxy, hydroxyalkyl, heteroaryl (optionally substituted with one or two substituents independently selected from alkyl and heterocyclyl wherein heterocyclyl is optionally substituted with one or two substituents independently selected from halo and alkyl), and —CONR 9 R 10  (where R 9  and R 10  are independently hydrogen or alkyl, or R 9  and R 10  together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted with one or two substituents selected from alkyl and heterocyclyl)), cycloalkyl (optionally substituted with one or two substituents independently selected from halo, alkyl, alkoxyalkyl and aryl; or wherein two adjacent substituents of the cycloalkyl together with the carbon atoms to which they are attached form a heterocyclyl group), heterocyclylalkyl, heterocyclyl (wherein heterocyclyl and heterocyclyl in heterocyclylalkyl are 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, alkoxy, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, or heterocyclyl wherein the heterocyclyl is substituted with one or two substituents independently selected from hydrogen, alkyl, halo, hydroxy, and alkoxy), or -(alkylene)-NR 6 R 7  (where R 6  and R 7  are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, or heterocyclyl wherein the heterocyclyl 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); or 
       a pharmaceutically acceptable salt thereof. 
     
     
         57 . A compound of  claim 56 , selected from the group consisting of
 (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)acrylonitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-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-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(1-methylpiperidin-4-yl)pent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)-4-methylpent-2-enenitrile.   (R)-methyl 4-(5-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile   2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-methylpent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(tetrahydro-2H-thiopyran-4-yl)acrylonitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(3-oxopiperazin-1-yl)pent-2-enenitrile   (R)-2-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-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)-2-oxo-2,3-dihydro-1H-imidazo[4,5-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)-2-oxo-2,3-dihydro-1H-imidazo[4,5-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-(2-fluoro-4-phenoxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-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)-2-oxo-2,3-dihydro-1H-imidazo[4,5-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-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-methylpent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-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-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-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)-2-oxo-2,3-dihydro-1H-imidazo[4,5-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-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(1-oxidotetrahydro-2H-thiopyran-4-yl)acrylonitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-(4-ethyl-3-oxopiperazin-1-yl)-4-methylpent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(4-methyl-1-(oxetan-3-yl)piperidin-4-yl)acrylonitrile   (R)-tert-butyl 4-(5-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-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-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile   2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-methylpent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(piperazin-1-yl)pent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4,4-dimethyl-5-(4-(oxetan-3-yl)piperazin-1-yl)-5-oxopent-2-enenitrile   2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-((1R,5S)-3-oxabicyclo[3.1.0]hexan-6-yl)acrylonitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)pent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(pyridin-2-yl)pent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(4-methylpiperazin-1-yl)pyrimidin-2-yl)pent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enenitrile   2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-((S)-3-methoxypyrrolidin-1-yl)-4-methylpent-2-enenitrile   2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-((R)-3-methoxypyrrolidin-1-yl)-4-methylpent-2-enenitrile   2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-((R)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pent-2-enenitrile   2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-((R)-2-(methoxymethyl)pyrrolidin-1-yl)-4-methylpent-2-enenitrile   2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-4-methylpent-2-enenitrile   2-((R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-((S)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pent-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(4-ethyltetrahydro-2H-pyran-4-yl)acrylonitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(4-(methoxymethyl)tetrahydro-2H-pyran-4-yl)acrylonitrile   
       or a pharmaceutically acceptable salt thereof. 
     
     
         58 . A compound of the following Formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are independently hydrogen, alkyl, alkoxy, haloalkyl, or halo; 
 X is —O—; 
 Ar is phenyl optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy, and hydroxy; 
 R 3  is hydrogen, alkyl, cyclopropyl, halo, haloalkyl, haloalkoxy, alkoxy, or cyano; 
 Y is a bond or alkylene; 
 ring Z is heterocyclohexylamino optionally substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, and fluoro; 
 R 5  is 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R a  is hydrogen, fluoro, or cyano; provided that when R a  is cyano then R b  is hydrogen and R c  is not hydrogen; 
 each R b  is independently hydrogen or alkyl; and 
 R c  is alkyl (optionally substituted with one or two substituents independently selected from hydroxy, hydroxyalkyl, heteroaryl (optionally substituted with one or two substituents independently selected from alkyl and heterocyclyl wherein heterocyclyl is optionally substituted with one or two substituents independently selected from halo and alkyl), and —CONR 9 R 10  (where R 9  and R 10  are independently hydrogen or alkyl, or R 9  and R 10  together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted with one or two substituents selected from alkyl and heterocyclyl)), cycloalkyl (optionally substituted with one or two substituents independently selected from halo, alkyl, alkoxyalkyl and aryl; or wherein two adjacent substituents of the cycloalkyl together with the carbon atoms to which they are attached form a heterocyclyl group), heterocyclylalkyl, heterocyclyl (wherein heterocyclyl and heterocyclyl in heterocyclylalkyl are 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, alkoxy, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, or heterocyclyl wherein the heterocyclyl is substituted with one or two substituents independently selected from hydrogen, alkyl, halo, hydroxy, and alkoxy), or -(alkylene)-NR 6 R 7  (where R 6  and R 7  are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, or heterocyclyl wherein the heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, acyl, and alkoxycarbonyl; or 
 a pharmaceutically acceptable salt thereof. 
 
     
     
         59 . A compound of  claim 58 , selected from the group consisting of
 (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(1-methylcyclobutyl)acrylonitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-cyclobutylacrylonitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-6-hydroxy-4-(2-hydroxyethyl)hex-2-enenitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(1-phenylcyclopropyl)acrylonitrile   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(1-methylcyclopropyl)acrylonitrile   (R)-5-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)-4-cyano-N,N,2,2-tetramethyl-5-oxopent-3-enamide   (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-3-(2,2-difluorocyclopropyl)acrylonitrile   (R)-4-amino-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile   or a pharmaceutically acceptable salt thereof.   
     
     
         60 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         61 . A pharmaceutical composition comprising a compound of  claim 52  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         62 . A pharmaceutical composition comprising a compound of  claim 54  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         63 . A pharmaceutical composition comprising a compound of  claim 56  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         64 . A pharmaceutical composition comprising a compound of  claim 58  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.