Inhibitors of Burton's tyrosine kinase

1. A compound of Formula I,

wherein:

R is H, —R 1 , —R 1 —R 2 —R 3 , —R 1 —R 3 , or —R 2 —R 3 ;

R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with one or more R 1′ ;

each R 1′ is independently lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, nitro, or lower haloalkyl;

R 2 is —C(═O), —C(═O)O, —C(═O)N(R 2′ ), —(CH 2 ) q , —O(CH 2 ) q , —(CH 2 ) q C(═O)O, —O(CH 2 ) q C(═O)N(R 2′ ), —CH 2 C(═O)N(R 2′ ), or —S(═O) 2 ;

R 2′ is H or lower alkyl;

q is 1, 2, or 3;

R 3 is H or R 4 ;

R 4 is lower alkyl, lower alkoxy, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl;

Q is CH or N;

Y 1 is H or lower alkyl;

Y 2 is Y 2a or Y 2b ;

Y 2a is H or halogen;

Y 2b is lower alkyl, optionally substituted with one or more Y 2b′ ;

Y 2b′ is hydroxy, lower alkoxy, or halogen;

each Y 2 ′ is independently Y 2′a or Y 2′b ;

y 2 ′a is halogen;

Y 2′b is lower alkyl, optionally substituted with one or more Y 2′b′ ;

Y 2b′ is hydroxy, lower alkoxy, or halogen;

n is 0, 1, 2, or 3;

Y 3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen;

m is 0 or 1;

Y 4 is Y 4a , Y 4b , Y 4c , or Y 4d ;

Y 4a is H or halogen;

Y 4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, cyano and lower alkoxy;

Y 4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and

Y 4d is amino, optionally susbstituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Y 1 is methyl.

3. The compound of claim 2 , wherein n is 0, and m is 0.

4. The compound of claim 3 , wherein Y 2 is hydroxymethyl.

5. The compound of claim 4 , wherein Q is N.

6. The compound of claim 4 , wherein Q is CH.

7. The compound of claim 6 , wherein Y 4 is

wherein, Y 5 is H, halogen, lower alkyl, or lower haloalkyl.

8. The compound of claim 7 , wherein

R is —R 1 —R 2 —R 3 ;

R 1 is phenyl or pyridyl;

R 2 is —C(—O);

R 3 is R 4 ; and

R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.

9. The compound of claim 7 , wherein

R is —R 1 —R 2 —R 3 ; and

R 1 is heteroaryl.

10. The compound of claim 7 , wherein

R is —R 1 —R 2 ; and

R 1 is heteroaryl.

11. The compound of claim 7 , wherein

R is —R 1 ; and

R 1 is heteroaryl.

12. The compound of claim 6 , wherein Y 4 is

wherein, Y 5 and Y 6 are independently H or lower alkyl.

13. The compound of claim 12 , wherein

R is —R 1 —R 2 —R 3 ;

R 1 is phenyl or pyridyl;

R 2 is —C(—O);

R 3 is R 4 ; and

R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.

14. A compound of Formula II,

wherein:

R is H, —R 1 , —R 1 —R 2 —R 3 , —R 1 —R 3 , or —R 2 —R 3 ;

R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with one or more R 1′ ;

each R 1′ is independently lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, cycloalkyl lower alkyl, heterocycloalkyl, cyano, nitro, or lower haloalkyl;

R 2 is —C(—O), —C(—O)O, —C(—O)N(R 2′ ) 2 , —(CH 2 ) q , —O(CH 2 ) q , —CH 2 C(—O), —CH 2 C(—O)N(R 2′ ) 2 , or —S(—O) 2 ;

each R 2′ is independently H, lower alkyl, lower alkoxy, lower haloalkyl, or lower hydroxyalkyl;

q is 1, 2, or 3;

R 3 is H or R 4 ;

R 4 is lower alkyl, lower alkoxy, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl;

Q is CH 2 , CH(Y′) or NH;

Y′ is halogen, hydroxy, or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen;

Y 1 is H or lower alkyl;

Y 2 is Y 2a or Y 2b ;

Y 2a H or halogen;

Y 2b is lower alkyl, optionally substituted with one or more Y 2b′ ;

Y 2b′ is hydroxy, lower alkoxy, or halogen;

each Y 2′ is independently Y 2′a or Y 2b′ ;

Y 2′a halogen;

Y 2′b is lower alkyl, optionally substituted with one or more Y 2′b′ ;

Y 2′b′ is hydroxy, lower alkoxy, or halogen;

n is 0, 1, 2, or 3;

Y 3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen;

m is 0 or 1;

Y 4 is Y 4a , Y 4b , Y 4c , or Y 4d ;

Y 4a is H or halogen;

Y 4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, cyano and lower alkoxy;

Y 4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and

Y 4d is amino, optionally susbstituted with one or more lower alkyl;

or a pharmaceutically acceptable salt thereof

15. The compound of claim 14 , wherein Y 1 is methyl.

16. The compound of claim 15 , wherein n is 0, and m is 0.

17. The compound of claim 16 , wherein Y 2 is hydroxymethyl.

18. The compound of claim 17 , wherein Q is NH.

19. The compound of claim 17 , wherein Q is CH 2 .

20. The compound of claim 19 , wherein Y 4 is

wherein, Y 5 is H, halogen, lower alkyl, or lower haloalkyl.

21. The compound of claim 20 , wherein

R is —R 1 —R 2 —R 3 ;

R 1 is phenyl or pyridyl;

R 2 is —C(—O);

R 3 is R 4 ; and

R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.

22. The compound of claim 20 , wherein

R is R 1 ; and

R 1 is pyrazolyl, optionally substituted with R 1′ .

23. The compound of claim 14 , wherein Y 4 is

wherein, Y 5 and Y 6 are independently H or lower alkyl.

24. The compound of claim 20 , wherein

R is —R 1 —R 2 —R 3 ;

R 1 is phenyl or pyridyl;

R 2 is —C(—O);

R 3 is R 4 ; and

R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.

25. The compound of claim 20 , wherein

R is R 1 ; and

R 1 is pyrazolyl, optionally substituted with R 1′ .

26. A compound selected from the group consisting of:

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-2H-isoquinolin-1-one;

2-{3-[6-(2,2-Difluoro-benzo[1,3]dioxo1-5-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-hydroxymethyl-phenyl}-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-{3-[6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-hydroxymethyl-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-{2-hydroxymethyl-3-[4-methyl-6-(1-methyl-1H-pyrazol-4-ylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N,N-dimethyl-benzamide;

4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N,N-diethyl-benzamide;

6-Dimethylamino-2-(2-hydroxymethyl-3-{4-methyl-6[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-{2-hydroxymethyl-3-methyl-6-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-5-oxo-6-[4-(pyrrolidine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-(1-Fluoro-cyclopropyl)-2-(2-hydroxymethyl-3-{4-methyl-6[ 4 -(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{6-[4-(4hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{6-[4-(4-methoxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-(2-hydroxy-ethyl)-N-methyl-benzamide;

6-Cyclopropyl-2-[3-(6-{4-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-hydroxymethyl-phenyl]-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(3-{6-[4-(2,6-dimethyl-morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(3-{6-[4-(1,1-dioxo-1λ 6 -thiomorpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(3-{6-[4-(4-ethoxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(3-{6-[4-(4-ethyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-6-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-(3-{6-[4-(1,1-dioxo-1λ 6 -thiomorpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

2-(3-{6-[4-(4-Acetyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-6-cyclopropyl-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-5-oxo-6-[4-(3-oxo-piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(3-{6-[4-(4,4-difluoro-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

2-(3-{6-[4-(4-Amino-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-6-cyclopropyl-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{6-[4-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-(2-methoxy-ethyl)-N-methyl-benzamide;

4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino }-N-ethyl-N-methyl-benzamide;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-{3-[6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-hydroxymethyl-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-(3-{6-[4-(4-ethyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N,N-bis-(2-methoxy-ethyl)-benzamide;

4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino }-N-(2-methoxy-ethyl)-benzamide;

4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N,N-bis-(2-hydroxy-ethyl)-benzamide;

6-tert-Butyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(4-methyl-[1,4]diazepane-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3 -oxo-3 ,4-dihydro-pyrazin-2-ylamino }-N-ethyl-benzamide;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{6-[4-(4-isopropyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-(3-{6-[4-(4-ethoxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-(2-hydroxymethyl-3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{6-(4-methoxymethyl-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{6-[1-(2-methoxy-ethyl)-1H-pyrazol-4-ylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-5-oxo-6-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-ylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

2-(4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino }-pyrazol-1-yl)-N,N-dimethyl-acetamide;

6-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-5-oxo-6-(1H-pyrazol-3-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-5-oxo-6-[4-(piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{6-[3-methoxy-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-y}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

7-{6-[3-(6-tert-Butyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-3,4-dihydro-1H-quinolin-2-one;

2-{3-[6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-hydroxymethyl-phenyl}-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;

7-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-3,4-dihydro-1H-quinolin-2-one;

7-{6-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-3,4-dihydro-1H-quinolin-2-one;

6-tent-Butyl-2-{3-[6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-hydroxymethyl-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(3-{6-[4-((S)-3-ethoxy-pyrrolidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(3-{6-[4-((R)-3-ethoxy-pyrrolidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-(2-hydroxymethyl-3-{4-methyl-5-oxo-6-[4-(piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-{2-hydroxymethyl-3-[6-(1-isopropyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-3-nitro-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

2-(4-{6-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-pyrazol-1-yl)-N,N-dimethyl-acetamide;

6-Cyclopropyl-2-(3-{6-[3-fluoro-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-{3-[6-(3-fluoro-4-morpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro -pyrazin-2-yl]-2-hydroxymethyl-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

2-[3-(6-{4-[Bis-(2-hydroxy-ethyl)-amino]-phenylamino }-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-hydroxymethyl-phenyl]-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-5-oxo-6-(4-piperidin-1-ylmethyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrazol-4-ylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3 ,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-{3-[6-(1-cyclopropylmethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-hydroxymethyl-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-(3-{6-[4-(2-hydroxy-ethoxy)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-(Ethyl-methyl-amino)-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl) -phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(3-{6-[1-(2,2-difluoro-ethyl)-1H-pyrazol-4-ylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

2-(4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-pyrazol-1-yl)-N-methyl-acetamide;

6-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-5-oxo-6-(1-propyl-1H-pyrazol-4-ylamino)-4,5 -dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

2-{3-[6-(1-Cyclobutylmethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-hydroxymethyl-phenyl}-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-{2-hydroxymethyl-3-[4-methyl-5-oxo-6-(1-propyl-1H-pyrazol-4-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-6-(4-morpholin-4-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

2-{3-[6-(3,4-Dihydro-2H-benzo [1,4]oxazin-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-hydroxymethyl-phenyl}-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;

6-Cyclopropyl-2-(3-{6-[1-(2-hydroxy-ethyl)-1H-pyrazol-4-ylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-6-(2-morpholin-4-yl-pyridin-4-ylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

6-tent-Butyl-2-{2-hydroxymethyl-3-[4-methyl-6-(2-morpholin-4-yl-pyridin-4-ylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

2-{3-[6-(1-Ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-hydroxymethyl-phenyl}-6-(1-hydroxy-1-methyl-ethyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-(2-hydroxymethyl-3-{4-methyl-6-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-5-oxo-6-(1,2,3,4-tetrahydro-isoquinolin-7-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;

2-(3-{6-[1-(2,2-Difluoro-ethyl)-1H-pyrazo1-4-ylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-6-(1-hydroxy-1-methyl-ethyl)-3,4-dihydro-2H-isoquinolin-1-one;

2-(3-{6-[1-(2,2-Difluoro-ethyl)-1H-pyrazo1-4-ylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-(3-{6-[4-(2-dimethylamino-ethoxy)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

2-[2-(3-{6-[1-(2,2-Difluoro-ethyl)-1H-pyrazol-4-ylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrile;

6-Dimethylamino-2-(2-hydroxymethyl-3-{6-[1-(2-hydroxy-propyl)-1H-pyrazol-4-ylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-(3-{6-[4-(1,4-dimethyl-3-oxo-piperazin-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;

2-(3-{6-[1-(2,3-Dihydroxy-propyl)-1H-pyrazol-4-ylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;

6-Dimethylamino-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-2H-isoquinolin-1-one;

6-Cyclopropyl-2-{3-[6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-hydroxymethyl-phenyl}-2H-isoquinolin-1-one;

2-(4-{6-[3-(6-Dimethylamino-1-oxo-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenoxy)-N-methyl-acetamide;

(4-{6-[3-(6-Cyclopropyl-1-oxo-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-pyrazol-1-yl)-acetic acid; and

6-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[1-(1-methyl-1H-imidazol-2-ylmethyl)-1H-pyrazol-4-ylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-2H-isoquinolin-1-one.

27. A pharmaceutical composition comprising the Btk inhibitor compound of claim 14 , admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.