IP Library › Patent Application 15738051

Patent Application

App. No. 15/738,051

TYROSINE KINASE INHIBITORS

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Patent No.: US None
App. No.: 15/738,051

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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.

Claims (210)

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: