Thiazolyl- and oxazolyl-isoquinolinones and methods for using them

1. A method for inhibiting poly(ADP-ribose) polymerase thereby treating and/or reducing tissue damage due to ischemia with 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 hydrogen;

R 5 and R 6 are C 1 -C 6 alkyl, optionally substituted with one or more groups 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, and the remainder of the ring atoms are carbon atoms;

R 7 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 3 -C 7 cycloalkyl, wherein the alkyl, alkenyl, and 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.

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 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 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 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;

and a pharmaceutically acceptable salt form thereof.

14. The method of claim 1 , wherein the compound is:

2-Dimethylaminomethyl-9-hydroxy-4H-1,3-thiazolo[5,4-c]isoquinolin-5-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; or

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

15. The method of claim 1 , wherein the tissue damage due to ischemia is associated with stroke, cerebral or spinal trauma, epileptic events, cerebral damage due to cardiac arrest, prolonged hypotension, cardiopathies, damage to kidney, damage to liver, damage to intestine, or damage to skeletal musculature.