Thiazolyl- and oxazolyl-isoquinolinones and methods for using them

1. A method of treating a cancer in a subject by inhibiting poly(ADP-ribose) polymerase (PARP), wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, multiple myeloma, leukemia and colon cancer, the method comprising administering to the subject an effective amount of 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 O or S;

R 1 is hydrogen, hydroxy, or OR 7 ;

R 2 , R 3 , and R 4 are independently hydrogen;

R 5 and R 6 are each, independently, C 1 -C 6 alkyl, wherein the alkyl is 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 remainder of the ring atoms are carbon atoms; and

R 7 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 form thereof.

2. The method of claim 1 , wherein R 1 is hydrogen or hydroxy, or a pharmaceutically acceptable salt form thereof.

3. The method of claim 1 , wherein the compound is according to Formula III:

or a pharmaceutically acceptable salt form thereof.

4. The method of claim 1 , wherein X is C 1 -C 3 alkylene, C 2 -C 3 alkenylene, or C 2 -C 3 alkynylene.

5. The method of claim 1 , wherein Y is O.

6. The method of claim 1 , wherein Y is S.

7. The method of claim 1 , wherein R 5 and R 6 are each, independently, C 1 -C 6 alkyl.

8. The method 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, and the remainder of the ring atoms are carbon atoms.

9. The method of claim 1 , wherein R 5 and R 6 together with the nitrogen to which they are attached form piperidine, morpholine, pyrrolidine, homopiperidine, aziridine, or azetidine.

10. The method of claim 1 , wherein X is C 2 -C 3 alkynylene.

11. The method 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.

12. The method 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.

13. The method of claim 1 , wherein the compound is selected from:

2-[(Dimethylamino)methyl[1,3]thiazolo[5,4-c]isoquinolin-5(4H)-one;

2-[3-(Dimethylamino)prop-1-yn-1-yl][1,3]thiazolo[5,4-c]isoquinolin-5(4H)-one;

2-(2-(Dimethylamino)ethyl)thiazolo[5,4-c]isoquinolin-5(4H)-one;

2-((Dimethylamino)methyl)-9-hydroxythiazolo[5,4-c]isoquinolin-5(4H)-one;

9-Hydroxy-2-(morpholin-4-ylmethyl)[1,3]thiazolo[5,4-c]isoquinolin-5(4H)-one;

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

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

2-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-9-hydroxy[1,3]thiazolo[5,4-c]isoquinolin-5(4H)-one;

9-Hydroxy-2-(octahydroquinolin-1(2H)-ylmethyl)[1,3]thiazolo[5,4-c]isoquinolin-5(4H)-one;

2-{[(2R,6S)-2,6-Dimethylmorpholin-4-yl]methyl}-9-hydroxy[1,3]thiazolo[5,4-c]isoquinolin-5(4H)-one;

9-Hydroxy-2-[(2-methylpyrrolidin-1-yl)methyl][1,3]thiazolo[5,4-c]isoquinolin-5(4H)-one;

9-Hydroxy-2-{[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]methyl}[1,3]thiazolo[5,4-c]isoquinolin-5(4H)-one; and

2-{[(2R,6S)-2,6-Dimethylpiperidin-1-yl]methyl}-9-hydroxy[1,3]thiazolo[5,4-c]isoquinolin-5(4H)-one; or

a pharmaceutically acceptable salt form thereof.