Poly-ADP ribose polymerase (PARP) inhibitors

1. A method of treating cell death in a subject after surgery, comprising administering to the subject an effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and wherein said compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or two substituents selected from the group consisting of -halogen, —CN, —NO 2 , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , —C(═O)R b , halo(C 1 -C 5 )alkyl and (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl is optionally substituted one or two groups selected from —CN, —NO 2 , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , and —C(═O)R a ;

each R a and each R b are independently selected from —H and (C 1 -C 5 )alkyl optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

R c is —H, halo(C 1 -C 5 )alkyl or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

i is 0, 1, or 2;

Ring B is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, each optionally substituted with one or two substituents represented by R 3 ;

is absent or a bond;

E is N or CH when is absent or E is C when is a bond;

 is optionally substituted with (C 1 -C 5 )alkyl or hydroxy (C 1 -C 5 )alkyl;

each R 3 is independently selected from the group consisting of -halogen, —CN, —NO 2 , —OR d , —S(O) i R e , —C(═NR e )NR e R f , —NR e S(O) i R f , —S(O) i NR e R f , —C(═O)OR e , —OC(═O)OR e , —C(═S)OR e , —O(C═S)R e , —C(═O)NR e R f , —NR e C(═O)R f , —C(═S)NR e R f , —NR e C(═S)R f , —NR e (C═O)OR f , —O(C═O)NR e R f , —NR e (C═S)OR f , —O(C═S)NR e R f , —NR e (C═O)NR e R f , —NR e (C═S)NR e R f , —C(═S)R e , —C(═O)R e , halo(C 1 -C 5 )alkyl, and (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl represented by R 3 is optionally substituted with —CN, —NO 2 , —OR e , —NR e R f , —S(O) i R e , —NR e S(O) i R f , —S(O) i NR e R f , —C(═O)OR e , —OC(═O)OR e , —C(═S)OR e , —O(C═S)R e , —C(═O)NR e R f , —NR e C(═O)R f , —C(═S)NR e R f , —NR e C(═S)R f , —NR e (C═O)OR f , —O(C═O)NR e R f , —NR e (C═S)OR f , —O(C═S)NR e R f , —NR e (C═O)NR e R f , —NR e (C═S)NR e R f , —C(═S)R e , or —C(═O)R e ;

R d is —H, halo(C 1 -C 5 )alkyl or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

each R e is independently selected from the group consisting of —H and (C 1 -C 5 )alkyl optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

each R f is independently selected from the group consisting of —H, (C 1 -C 5 )alkyl optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy, (C 3 -C 6 )cycloalkyl optionally substituted with (C 1 -C 2 ) alkyl, and 4-6 membered oxygen-containing heterocyclyl optionally substituted with (C 1 -C 2 ) alkyl; or

—NR e R f taken together is a 4-6 membered heterocyclyl optionally substituted with (C 1 -C 2 ) alkyl; or

—C(═NR e )NR e R f taken together is a 4-6 membered heterocyclyl optionally substituted with R e ;

R 5 is —H or (C 1 -C 5 )alkyl; and

i is 0, 1, or 2,

wherein 5-6 membered heteroaryl refers to a monocyclic aromatic ring group having five or six ring atoms selected from carbon and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur; and

5-6 membered heterocyclyl refers to a monocyclic non-aromatic ring radical containing 5-6 ring atoms selected from carbon atom and 1 or 2 heteroatoms, each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (NO), oxygen, sulfur, sulfoxide and sulfone.

2. The method of claim 1 , wherein said compound, said pharmaceutically acceptable salt thereof, or said pharmaceutical composition is administered orally.

3. The method of claim 1 , wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or two substituents selected from the group consisting of -halogen, —CN, —NO 2 , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , —C(═O)R b , halo(C 1 -C 5 )alkyl and (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl is optionally substituted one or two groups selected from —CN, —NO 2 , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , and —C(═O)R a ;

each R a and each R b are independently selected from —H and (C 1 -C 5 )alkyl optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

R e is —H, halo(C 1 -C 5 )alkyl or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

i is 0, 1, or 2;

Ring B is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, each optionally substituted with one or two substituents represented by R 3 ;

is absent or a bond;

E is N or CH when is absent or E is C when is a bond;

 is optionally substituted with (C 1 -C 5 )alkyl or hydroxy (C 1 -C 5 )alkyl;

each R 3 is independently selected from the group consisting of -halogen, —CN, —NO 2 , —OR d , —S(O) i R e , —C(═NR e )NR e R f , —NR e S(O) i R f , —S(O) i NR e R f , —C(═O)OR e , —OC(═O)OR e , —C(═S)OR e , —O(C═S)R e , —C(═O)NR e R f , —NR e C(═O)R f , —C(═S)NR e R f , —NR e C(═S)R f , —NR e (C═O)OR f , —O(C═O)NR e R f , —NR e (C═S)OR f , —O(C═S)NR e R f , —NR e (C═O)NR e R f , —NR e (C═S)NR e R f , —C(═S)R e , —C(═O)R e , halo(C 1 -C 5 )alkyl and (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl represented by R 3 is optionally substituted with —CN, —NO 2 , —OR e , —NR e R f , —S(O) i R e , —NR e S(O) i R f , —S(O) i NR e R f , —C(═O)OR e , —OC(═O)OR e , —C(═S)OR e , —O(C═S)R e , —C(═O)NR e R f , —NR e C(═O)R f , —C(═S)NR e R f , —NR e C(═S)R f , —NR e (C═O)OR f , —O(C═O)NR e R f , —NR e (C═S)OR f , —O(C═S)NR e R f , —NR e (C═O)NR e R f , —NR e (C═S)NR e R f , —C(═S)R e , or —C(═O)R e ;

R d is —H, halo(C 1 -C 5 )alkyl or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

each R e is independently selected from the group consisting of —H and (C 1 -C 5 )alkyl optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

each R f is independently selected from the group consisting of —H, (C 1 -C 5 )alkyl optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy, (C 3 -C 6 )cycloalkyl optionally substituted with (C 1 -C 2 ) alkyl, and 4-6 membered oxygen-containing heterocyclyl optionally substituted with (C 1 -C 2 ) alkyl; or

—NR e R f taken together is a 4-6 membered heterocyclyl optionally substituted with (C 1 -C 2 ) alkyl; or

C(═NR e )NR e R f taken together is a 4-6 membered heterocyclyl optionally substituted with R e ; and

i is 0, 1, or 2.

4. The method of claim 3 , wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or two substituents selected from the group consisting of -halogen, —CN, —NO 2 , —OR e , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , —C(═O)R b , halo(C 1 -C 5 )alkyl and (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl is optionally substituted one or two groups selected from —CN, —NO 2 , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , and —C(═O)R a ;

each R a and each R b are independently selected from —H and (C 1 -C 5 )alkyl optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

R c is —H, halo(C 1 -C 5 )alkyl or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

i is 0, 1, or 2;

Ring B is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, each optionally substituted with one or two substituents represented by R 3 ; and

 is optionally substituted with (C 1 -C 5 )alkyl or hydroxy(C 1 -C 5 )alkyl.

5. The method of claim 1 , wherein the compound is represented by a structural formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of N and CH, provided no more than two of X 1 , X 2 , X 3 and X 4 is N;

X 5 is NR 2 , O, or S;

Ring B is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, each optionally substituted with one or two substituents represented by R 3 ;

 is optionally substituted with (C 1 -C 5 )alkyl or hydroxy(C 1 -C 5 )alkyl;

each R 1 is independently selected from the group consisting of -halogen, —CN, —NO 2 , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , —C(═O)R b , halo(C 1 -C 5 )alkyl and (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl represented by R 1 is optionally substituted with —CN, —NO 2 , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R a ;

R 2 is —H, C 1 -5 alkyl, phenyl, —C(O)(C 1 -C 5 alkyl), —C(O)(phenyl), —C(O)O(C 1 -5 alkyl), —C(O)O(phenyl), —S(O) 2 (C 1 -C 5 alkyl) or —S(O) 2 (phenyl), wherein each alkyl in the groups represented by R 2 independently is optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, cyano, phenyl, 5-6 membered heteroaryl, (C 1 -C 5 ) alkoxy, and halo(C 1 -C 5 )alkoxy, and wherein each phenyl in the groups represented by R 2 independently is optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy and halo(C 1 -C 5 )alkoxy;

each R a and each R b are independently selected from —H and (C 1 -C 5 )alkyl optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

R c is —H, halo(C 1 -C 5 )alkyl or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

i is 0, 1, or 2; and

n is 0, 1 or 2.

6. The method of claim 1 , wherein the compound is represented by a structural formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, wherein:

Ring B is aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, each optionally substituted with one or more substituents represented by R 3 ; and

 is optionally substituted with (C 1 -C 5 )alkyl or hydroxy(C 1 -C 5 )alkyl.

7. The method of claim 5 , wherein:

each R 1 is independently halogen, (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, halo(C 1 -C 5 )alkoxy or cyano;

each R 3 is independently selected from the group consisting of -halogen, —CN, —C(═NR e )NHR f , —S(O) i NR e R f , —C(═O)NR e R f , —C(═S)NR e R f , —O(C═O)NR e R f , —O(C═S)NR e R f , —NR e (C═O)NR e R f , —NR e (C═S)NR e R f , and (C 1 -C 5 )alkyl.

8. The method of claim 7 , wherein:

each R 1 is independently halogen or (C 1 -C 5 )alkyl;

each R 3 is independently selected from the group consisting of -halogen, —CN, —C(═O)NR e R f , —C(═NR e )NHR f and (C 1 -C 5 )alkyl.

9. The method of claim 8 , wherein:

each R 1 is independently chloro, fluoro or methyl;

each R 3 is independently selected from the group consisting of chloro, fluoro, —CN, —C(═NR e )NHR f , —C(═O)NR e R f and methyl;

the

 group is optionally substituted with methyl or hydroxymethyl.

10. The method of claim 1 , wherein Ring B is selected from the group consisting of:

each R 4 is —H, (C 1 -C 5 )alkyl, or hydroxy (C 1 -C 5 )alkyl;

each p is independently 0 or 1; and

each m is 0 or 1, or 2.

11. The method of claim 10 , wherein Ring B is selected from the group consisting of

12. The method of claim 7 , wherein each R e and each R f are independently selected from the group consisting of —H and methyl; or R e is —H and R f is —(C 3 -C 6 )cycloalkyl or 4-6 membered oxygen-containing heterocyclyl each optionally substituted with (C 1 -C 2 ) alkyl.

13. The method of claim 12 , wherein each R e and each R f are independently selected from the group consisting of —H and methyl; or R e is —H and R f is cyclopropyl, cyclobutyl or oxetanyl each optionally substituted with methyl.

14. The method of claim 7 , wherein ach R 3 is independently selected from the group consisting of chloro, fluoro, —CN, —C(O)NH(cyclopropyl), —C(O)NH 2 , —C(O)NH(CH 3 ), —C(O)N(CH 3 ) 2 ,

—C(O)NH(cyclobutyl),

—C(═NH)NHCH 3 , and methyl.

15. The method of claim 5 , wherein R 2 is —H or (C 1 -C 5 )alkyl.

16. The method of claim 15 , wherein R 2 is —H or methyl.

17. The method of claim 1 , wherein the compound is of the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is F or methyl; and

R 3 is —CN, —C(═NH)NHCH 3 ,

 or methyl.

18. The method of claim 17 , wherein:

R 1 is F; and

R 3 is —CN.

19. The method of claim 1 , wherein the compound is 6-[(3S)-4-[3-(6-fluoro-4-oxo-3H-quinazolin-2-yl)propanoyl]-3-methyl-piperazin-1-yl]pyridine-3-carbonitrile.

20. The compound of claim 1 , wherein the compound is 6-[(3S)-4-[3-(5-fluoro-4-oxo-3H-quinazolin-2-yl)propanoyl]-3-methyl-piperazin-1-yl]pyridine-3-carbonitrile.