Thienyl-and furanyl-isoquinolinones and methods for using them

1. A compound of Formula I:

wherein:

X is C 1 -C 9 alkylene, C 2 -C 9 alkenylene, or C 2 -C 9 alkynylene;

Y is S or O;

R 1 is halogen, hydroxy, NH 2 , C 1 -C 6 alkoxy, CN, or C 1 -C 6 perfluoroalkyl;

R 2 , R 3 , and R 4 are each, independently, selected from hydrogen, C 1 -C 6 alkyl, halogen, hydroxy, NH 2 , CN, C 1 -C 6 perfluoroalkyl, CO 2 H, OR 8 , COOR 8 , and NHR 8 ;

R 5 and R 6 are each, independently, selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 3 -C 7 cycloalkyl, phenyl, and benzyl, wherein the alkyl, alkenyl and rings of the cycloalkyl, phenyl and benzyl groups are optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4 alkoxy, —CO 2 H, C 1 -C 6 alkoxycarbonyl, NH 2 , C 1 -C 6 mono- or dialkylamino, and halogen; or

R 5 and R 6 together with the nitrogen to which they are attached form a saturated, partially unsaturated, or unsaturated 3 to 12 membered monocyclic or bicyclic heterocyclic ring optionally comprising from one to three additional ring heteroatoms independently selected from N, O, and S, the remaining ring atoms are carbon atoms;

R 7 is hydrogen, halogen, hydroxy, NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy or NO 2 ;

R 8 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 3 -C 7 cycloalkyl wherein the alkyl, alkenyl, and rings of the cycloalkyl are optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4 alkoxy, —CO 2 H, C 1 -C 6 alkoxycarbonyl, NH 2 , C 1 -C 6 mono- or dialkylamino, and halogen;

or a pharmaceutically acceptable salt or zwitterionic form thereof.

2. A compound having Formula I of claim 1 wherein:

X is C 1 -C 9 alkylene, C 2 -C 9 alkenylene, or C 2 -C 9 alkynylene;

Y is S or O;

R 1 is halogen, hydroxy, NH 2 , C 1 -C 6 alkoxy, CN, or C 1 -C 6 perfluoroalkyl;

R 2 , R 3 , and R 4 are each, independently, selected from hydrogen, halogen, hydroxy, NH 2 , C 1 -C 6 alkoxy, CN, and C 1 -C 6 perfluoroalkyl;

R 5 and R 6 are each, independently, selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 3 -C 7 cycloalkyl, phenyl, and benzyl; or

R 5 and R 6 together with the nitrogen to which they are attached form a saturated, partially unsaturated, or unsaturated 3 to 12 membered monocyclic or bicyclic heterocyclic ring optionally comprising from one to three additional ring heteroatoms selected from N, O, and S, the remaining ring atoms are carbon atoms; and

R 7 is hydrogen, halogen, hydroxy, NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy or NO 2 ; or a pharmaceutically acceptable salt or zwitterionic form thereof.

3. A compound of claim 1 having Formula II:

or a pharmaceutically acceptable salt or zwitterionic form thereof.

4. A compound of claim 1 having Formula III:

or a pharmaceutically acceptable salt or zwitterionic form thereof.

5. A compound of claim 1 having Formula IV:

or a pharmaceutically acceptable salt or zwitterionic form thereof.

6. A compound of claim 5 wherein R 3 is halogen or hydrogen.

7. A compound of claim 6 wherein R 3 is hydrogen.

8. A compound of claim 1 wherein Y is S.

9. A compound of claim 1 wherein Y is O.

10. A compound of claim 1 wherein R 5 and R 6 are each, independently, C 1 -C 6 alkyl.

11. A compound of claim 1 wherein R 5 and R 6 together with the nitrogen to which they are attached form a saturated monocyclic heterocyclic ring optionally comprising from one to three additional ring heteroatoms selected from N, O, and S, the remaining ring atoms are carbon atoms.

12. A compound of claim 11 wherein R 5 and R 6 are taken together to form piperidine, morpholine, pyrrolidine, homopiperidine, aziridine, or azetidine.

13. A compound of claim 1 wherein X is C 1 -C 3 alkylene.

14. A compound of claim 1 wherein X is C 1 -C 3 alkylene and R 5 and R 6 are each, independently, C 1 -C 6 alkyl.

15. A compound of claim 1 wherein X is methyl.

16. A compound of claim 1 wherein X is methyl and R 5 and R 6 are each, independently, methyl.

17. A compound of claim 1 wherein:

Y is S;

X is C 1 -C 3 alkylene; and

R 5 and R 6 are each, independently, C 1 -C 6 alkyl.

18. A compound of claim 17 wherein X is methyl.

19. A compound of claim 1 wherein:

Y is O;

X is C 1 -C 3 alkylene; and

R 5 and R 6 are each, independently, C 1 -C 6 alkyl.

20. A compound of claim 19 wherein X is methyl.

21. A compound of claim 1 that is:

2-dimethylaminomethyl-9-methoxythieno[2,3-c]isoquinolin-5(4H)-one;

8-chloro-2-[(dimethylamino)methyl]thieno[2,3-c]isoquinolin-5(4H)-one; or

2-[(dimethylamino)methyl]-8-methoxythieno[2,3-c]isoquinolin-(4H)-one; or

a pharmaceutically salt or zwitterionic form thereof.

22. A compound of claim 1 that is:

2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one or a pharmaceutically acceptable salt or zwitterionic form thereof.

23. A compound of claim 1 that is:

amorphous 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one or a pharmaceutically acceptable salt or zwitterionic form thereof.

24. A compound of claim 1 that is:

2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one hydrate.

25. A compound of claim 1 that is: 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(41-1)-one monohydrate.

26. A compound of claim 1 that is:

2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one monohydrate having an endotherm at about 139° C.

27. A compound of claim 1 that is:

2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one anhydrate.

28. A compound of claim 1 that is:

2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one anhydrate having endotherms at about 210° C. and 270° C.

29. A compound of claim 1 comprising a crystalline anhydrous form of 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one thereof having an X-ray powder diffraction containing at least 3 characteristic 2θ values measured using CuKα radiation selected from 10.4, 10.6, 14.5, 21.3, 26.8 and 32.1.

30. A compound of claim 1 comprising a crystalline monohydrate form of 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one thereof having an X-ray powder diffraction containing at least 3 characteristic 20 values measured using CuKα radiation selected from 8.3, 8.6, 11.7, 18.4, 18.9, 19.4, 25.7 and 28.7.

31. A compound of claim 1 that is:

2-[(dimethylamino)methyl]-7-fluoro-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one; or

a pharmaceutically acceptable salt or zwitterionic form thereof.

32. A compound of claim 1 that is:

2-[(dimethylamino)methyl]-7-fluorothieno[2,3-c]isoquinolin-5(4H)-one;

2-[(dimethylamino)methyl]-9-fluorothieno[2,3-c]isoquinolin-5(4H)-one;

or 2-[(dimethylamino)methyl]furo[2,3-c]isoquinolin-5(4H)-one hydrochloride; or

a pharmaceutically acceptable salt or zwitterionic form thereof.

33. A compound of claim 1 that is:

9-hydroxy-2-(morpholin-4-ylmethyl)thieno[2,3-c]isoquinolin-5(4H)-one;

9-hydroxy-2-(piperidin-1-ylmethyl)thieno[2,3-c]isoquinolin-5(4H)-one;

9-hydroxy-2-(1,3-thiazolidin-3-ylmethyl)thieno[2,3-c]isoquinolin-5(4H)-one;

9-hydroxy-2-{[(1-methylethyl)amino]methyl}thieno[2,3-c]isoquinolin-5(4H)-one;

9-hydroxy-2-(pyrrolidin-1-ylmethyl)thieno[2,3-c]isoquinolin-5(4H)-one;

2-[(4-bromopiperidin-1-yl)methyl]-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one;

2-[(dibenzylamino)methyl]-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one;

2-{[benzyl(methyl)amino]methyl}-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one;

or a pharmaceutically acceptable salt or zwitterionic form thereof.

34. A compound of claim 1 comprising a zwitterion of 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one.

35. A compound of claim 1 comprising a crystalline anhydrous form of 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one with an average particle size of about 5 to 10 μm and more particularly about 7 μm.

36. A compound of claim 1 comprising a crystalline anhydrous form of 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one characterized by orthorhombic agglomerations with an average length of about 5 to 10 μm and more particularly about 6 μm.

37. A compound of claim 1 that is:

2-[(dimethylamino)methyl]thieno[2,3-c]isoquinolin-5(4H)-one or a pharmaceutically acceptable salt or zwitterionic form thereof.

38. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

39. A method for inhibiting poly(ADP-ribose) polymerase in a subject comprising administering to the subject an effective amount of a compound of claim 1 to inhibit poly(ADP-ribose) polymerase in the subject.