Chemical compounds

1. A compound of Formula (I):

wherein:

A is selected from C 6 -C 10 aryl, monocyclic heteroaryl and bicyclic heteroaryl;

R 1 is in each instance independently selected from F, Cl, Br, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 3 fluoroalkyl, C 1 -C 3 fluoroalkoxy, acetylenyl, NR 9 R 10 , C(O)NR 11 R 12 , CH 2 R 13 and N═S(O)Me 2 ;

b is 0, 1, 2 or 3;

W is CR 14 or N;

X is CR 15 or N;

Y is CH or N;

Z is O or NR 16 ;

R 2 is H, CN, F, Cl, Br, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 3 fluoroalkyl, C 1 -C 2 fluoroalkoxy or acetylenyl;

R 3a and R 3b are each independently selected from H or Me or, in the case where Z is NR 16 , can also together be ═O;

R 4 , R 5 , R 6 and R 7 are each independently selected from H or Me;

R 8 is H or CH 2 NMe 2 ;

R 9 is H, C 1 -C 4 alkyl, C(O)C 1 -C 3 alkyl or CO 2 C 1 -C 3 alkyl;

R 10 , R 11 and R 12 are each independently selected from H and C 1 -C 4 alkyl; or

R 9 and R 10 together, or R 11 and R 12 together, form a 4-, 5-, 6- or 7-membered saturated heterocycle optionally incorporating O, NH or N(C 1 -C 4 alkyl) group;

R 13 is OH, CN, NR 17 R 18 , C(O)NR 19 R 20 or SO 2 C 1 -C 3 alkyl;

R 14 and R 15 are each independently selected from H, F, Cl, MeO and Me;

R 16 is H, C 1 -C 3 fluoroalkyl or CH 2 R 21 ;

R 17 , R 18 , R 19 and R 20 are each independently selected from H and C 1 -C 4 alkyl or R 17 and R 18 together, or R 19 and R 20 together, form a 4-, 5-, 6- or 7-membered saturated heterocycle optionally incorporating O, NH or N(C 1 -C 4 alkyl) group;

R 21 is selected from the group consisting of:

H;

C 1 -C 3 alkyl optionally substituted with 1 or 2 substituents selected from hydroxy, C 1 -C 3 alkoxy, halo, NR 22 R 23 , C(O)NR 24 R 25 , SO 2 Me, heteroaryl, C 3-7 cycloalkyl or heterocyclyl, wherein said heteroaryl or C 3 -C 7 cycloalkyl is optionally further substituted with C 1 -C 4 alkyl, hydroxy, halo, cyano, or C 1 -C 4 alkoxy and said heterocyclyl is optionally further substituted with C 1 -C 4 alkyl, hydroxy, halo, C(O)Me, C 1 -C 3 alkoxy, C 1 -C 3 fluoroalkyl, C 3 -C 7 cycloalkyl, heterocyclyl or heteroaryl and wherein R 22 , R 23 , R 24 and R 25 are in each instance independently selected from H and C 1 -C 4 alkyl;

C 3 -C 7 cycloalkyl optionally substituted with C 1 -C 4 alkyl, hydroxy or halo;

heterocyclyl optionally substituted with C 1 -C 4 alkyl, hydroxy, halo, C(O)Me, C 1 -C 3 alkoxy, C 1 -C 3 fluoroalkyl, C 3 -C 7 cycloalkyl, CH 2 cyclopropyl, heterocyclyl or heteroaryl; and

heteroaryl optionally substituted with C 1 -C 4 alkyl, hydroxy, halo, cyano or C 1 -C 4 alkoxy;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 15 .

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CR 14 .

4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CH.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is N.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl or 1H-pyridin-2-one.

7. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from:

and the corresponding compounds in which the NH group is replaced by a N(C 1 -C 4 )alkyl group.

8. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is O.

9. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is NR 16 .

10. A compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b are independently selected from H and Me.

11. A compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b together are ═O.

12. A compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 21 is selected from H and C 1 -C 3 alkyl optionally substituted with 1 or 2 substituents selected from hydroxy, C 1 -C 3 alkoxy, halo, NR 22 R 23 , C(O)NR 24 R 25 , SO 2 Me and C 1 -C 4 alkoxy.

13. A compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 16 is Me.

14. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, having the Formula (In)

wherein:

A is selected from phenyl and bicyclic heteroaryl;

R 1 is in each instance independently selected from F, Cl, Br, OH, CN, C 1 -C 4 alkyl, C 1 -C 2 alkoxy or C 1 -C 2 fluoroalkyl;

b is 0, 1, 2 or 3;

R 2 is CN, F, Cl, Me, Et, CF 3 , MeO or acetylenyl;

R 7 is H or Me;

R 8 is H or CH 2 NMe 2 ; and

R 14 is F, Cl, MeO and Me; or

Formula (Io)

wherein:

A is selected from phenyl and bicyclic heteroaryl;

R 1 is in each instance independently selected from F, Cl, Br, OH, CN, C 1 -C 4 alkyl, C 1 -C 2 alkoxy or C 1 -C 2 fluoroalkyl;

b is 0, 1, 2 or 3;

R 2 is CN, F, Cl, Me, Et, CF 3 , MeO or acetylenyl;

R 3a and R 3b are each independently selected from H or Me or together are ═O;

R 7 is H or Me;

R 8 is H or CH 2 NMe 2 ;

R 14 is F, Cl, MeO and Me; and

R 16 is H or Me; or

Formula (Ip)

wherein:

A is selected from phenyl and bicyclic heteroaryl;

R 1 is in each instance independently selected from F, Cl, Br, OH, CN, C 1 -C 4 alkyl, C 1 -C 2 alkoxy or C 1 -C 2 fluoroalkyl;

b is 0, 1, 2 or 3;

R 2 is CN, F, Cl, Me, Et, MeO or acetylenyl;

R 7 is H or Me;

R 8 is H or CH 2 NMe 2 ;

R 14 is F, Cl, MeO and Me; and

R 16 is H or Me.

15. A compound according to claim 14 wherein A is phenyl.

16. A compound according to claim 14 wherein A is selected from:

17. A compound according to claim 1 , or pharmaceutically acceptable salt thereof, selected from:

1-((4aR)-11-Chloro-10-(2-fluoro-6-hydroxyphenyl)-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl)prop-2-en-1-one;

1-((4aR)-11-Chloro-10-(5-methyl-1H-indazol-4-yl)-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl)prop-2-en-1-one;

1-((4aS)-11-Chloro-10-(5-methyl-1H-indazol-4-yl)-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl)prop-2-en-1-one;

1-((4aR)-11-Chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl)prop-2-en-1-one;

(2E)-1-[(4aR)-11-Chloro-10-(2-fluoro-6-hydroxyphenyl)-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl]-4-(dimethylamino)but-2-en-1-one;

1-((4aR)-11-Chloro-10-(2-fluoro-6-hydroxyphenyl)-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]cinnolin-3(4H)-yl)prop-2-en-1-one;

1-((4aS)-11-Chloro-6-(2-(dimethylamino)ethyl)-10-(2-fluoro-6-hydroxyphenyl)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-3-yl)prop-2-en-1-one;

1-[(2R,4aR)-11-Chloro-10-(2-fluoro-6-hydroxyphenyl)-2-methyl-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl]prop-2-en-1-one;

1-((4aS)-11-Chloro-10-(2-fluoro-6-hydroxyphenyl)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-3-yl)prop-2-en-1-one;

1-((4aS)-11-Chloro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-3-yl)prop-2-en-1-one;

(4aR)-3-Acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(4aS)-3-Acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(4aR)-11-chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(2R,4aR)-11-Chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-2,6-dimethyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

1-[(4aR)-11-Chloro-10-(2-fluoro-6-hydroxyphenyl)-9-methoxy-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl]prop-2-en-1-one;

(4aR)-11-Chloro-9-fluoro-6-methyl-10-(5-methyl-1H-benzimidazol-4-yl)-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(2R,4aR)-11-Chloro-9-fluoro-2,6-dimethyl-10-(5-methyl-1H-benzimidazol-4-yl)-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(2R,4aR)-11-Chloro-3-[(2E)-4-(dimethylamino)but-2-enoyl]-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(2R,4aR)-11-Chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-2-methyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

11-Chloro-10-(2-fluoro-6-hydroxyphenyl)-4a,6-dimethyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(4aR)-11-Chloro-9-fluoro-10-[2-fluoro-6-(hydroxymethyl)phenyl]-6-methyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(2E)-1-[(2R,4aR)-11-Chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-2-methyl-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl]-4-(dimethylamino)but-2-en-1-one;

1-[(4aR)-11-Chloro-10-(2-fluoro-6-hydroxyphenyl)-9-methyl-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl]prop-2-en-1-one;

1-[(2R,4aR)-11-Chloro-10-(2-fluoro-6-hydroxyphenyl)-2,9-dimethyl-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl]prop-2-en-1-one;

(4aR)-3-Acryloyl-9,11-difluoro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(4aR)-3-Acryloyl-10-(2-fluoro-6-hydroxyphenyl)-6,9,11-trimethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

8-[(4aR)-11-Chloro-3-(prop-2-enoyl)-1,2,3,4,4a,5-hexahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-10-yl]-7-fluoroisoquinolin-1(2H)-one;

7-[(4aR)-11-Chloro-9-fluoro-3-(prop-2-enoyl)-1,2,3,4,4a,5-hexahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-10-yl]-6-methyl-1,3-benzoxazol-2(3H)-one;

(4aR)-11-Chloro-9-fluoro-6-methyl-10-(5-methyl-1H-indazol-4-yl)-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(4aR)-11-Chloro-10-(2-chloro-6-hydroxyphenyl)-9-fluoro-6-methyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(4aR)-11-Chloro-9-fluoro-10-(2-hydroxy-6-methylphenyl)-6-methyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(4aR)-11-Chloro-9-fluoro-10-(2-hydroxynaphthalen-1-yl)-6-methyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(4aR)-11-Chloro-10-(2,3-difluoro-6-hydroxyphenyl)-9-fluoro-6-methyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(4aR)-11-Chloro-12-fluoro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(4aR)-11,12-Dichloro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(4aR)-11-Chloro-10-[2-(difluoromethyl)-6-hydroxyphenyl]-9-fluoro-6-methyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

1-[(2R,4aR)-9,11-Difluoro-10-(2-fluoro-6-hydroxyphenyl)-2-methyl-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl]prop-2-en-1-one;

11-[(4aR)-11-Chloro-10-(5-methyl-1H-benzimidazol-4-yl)-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl]prop-2-en-1-one;

7-[(4aR)-11-Chloro-3-(prop-2-enoyl)-1,2,3,4,4a,5-hexahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-10-yl]-1,6-dimethyl-1,3-dihydro-2H-benzimidazol-2-one;

8-[(4aR)-11-Chloro-3-(prop-2-enoyl)-1,2,3,4,4a,5-hexahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-10-yl]-7-methylisoquinolin-1(2H)-one;

4-[(4aR)-11-Chloro-3-(prop-2-enoyl)-1,2,3,4,4a,5-hexahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-10-yl]-5-methyl-1,3-dihydro-2H-benzimidazol-2-one;

1-[(4aS)-11-Chloro-6-[2-(dimethylamino)ethyl]-10-(5-methyl-1H-indazol-4-yl)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-3-yl]prop-2-en-1-one;

1-[(4aR)-11-Ethynyl-10-(5-methyl-1H-indazol-4-yl)-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl]prop-2-en-1-one;

1-[(4aR)-11-Chloro-9-fluoro-10-(5-methyl-1H-benzimidazol-4-yl)-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl]prop-2-en-1-one;

(4aR)-9-Chloro-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

1-[(2R,4aS)-11-Chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-2-methyl-1,2,4,4a,5,6-hexahydro-3H-benzo[h]pyrazino[1,2-a][1,6]naphthyridin-3-yl]prop-2-en-1-one;

1-[(4aR)-11-Chloro-10-(2-fluoro-6-hydroxyphenyl)-12-methoxy-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl]prop-2-en-1-one;

7-[(4aR)-11-Chloro-9-fluoro-3-(prop-2-enoyl)-1,2,3,4,4a,5-hexahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-10-yl]-1,6-dimethyl-1,3-dihydro-2H-benzimidazol-2-one;

7-[(4aR)-11-Chloro-9-fluoro-3-(prop-2-enoyl)-1,2,3,4,4a,5-hexahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c]quinolin-10-yl]-6-methyl-2,3-dihydro-1H-isoindol-1-one;

(4aR)-11-Chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one;

(4aR)-11-Chloro-6-ethyl-10-(2-fluoro-6-hydroxyphenyl)-3-(prop-2-enoyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinolin-5(6H)-one; and

(8aR)-3-(2-Fluoro-6-hydroxyphenyl)-2,4,7-trimethyl-10-(prop-2-enoyl)-9,10,11,12-tetrahydro-7H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridin-8(8aH)-one;

and each individual stereoisomer, for example atropisomer, thereof.

18. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.