Substituted dihydroquinazolines as platelet ADP receptor inhibitors

1. A compound having the formula (I):

wherein

Y 1 is NH;

Y 2 is CO,

each R 1 , R 2 and R 3 is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —N(R 7 ) 2 , C 1-6 alkoxy, halogen, C 1-6 haloalkyl, hydroxyC 1-6 alkyl, cyano, —C(O)R 6 , C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, aryl and arylC 1-6 alkyl, wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and aryl portions is optionally substituted with from 1 to 3 substituents, each independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, amino, C 1-6 alkoxy, halogen, hydroxyl, cyano, oxo, thio, C 3-6 cycloalkyl, aryl and heteroaryl;

R 4 is H or —(CH 2 ) m CO 2 H;

R 6 is selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkoxy, heterocyclylC 1-6 alkoxy and —N(R 7 ) 2 ;

each R 7 is independently selected from the group consisting of H, C 1-6 alkyl and arylC 1-6 alkyl or optionally, two R 7 groups attached to nitrogen are combined with the nitrogen atom to form an azetidine, pyrrolidine, piperidine or morpholine ring; wherein each of said C 1-6 alkyl and arylC 1-6 alkyl is optionally substituted with from 1 to 3 substituents, each independently selected from the group consisting of halogen, amino, hydroxyl, C 1-6 alkoxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, and heteroaryl;

Ar 1 is an aromatic ring selected from the group consisting of benzene and thiophene, each of which is optionally substituted with from 1-2 R 8 substituents,

Ar 2 is an aromatic ring selected from the group consisting of benzene, tetrazole and thiophene, each of which is optionally substituted with from 1-2 R 8 substituents,

each R 8 is independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 3-5 cycloalkyl-C 1-6 alkoxy, —NR 7 , —C(═NR 8a )—N(R 8b ) 2 , —C(O)R 8a , —O(CH 2 ) m OR 8b , —(CH 2 ) m OR 8b , —O(CH 2 ) m N(R 8b ) 2 and —(CH 2 ) m N(R 8b ) 2 ,

each R 8a is a member independently selected from the group consisting of H, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and —NR 7 ;

each R 8b is a member independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl, and optionally, two R 8b groups attached to nitrogen are combined with the nitrogen atom to form an azetidine, pyrrolidine, piperidine or morpholine ring; wherein each of said C 1-4 alkyl and C 1-4 alkanoyl is optionally substituted with from 1 to 3 substituents, each independently selected from the group consisting of halogen, amino, hydroxyl, C 1-6 alkoxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, and heteroaryl;

L 1 is a linking group selected from the group consisting of —CO— and —CH 2 —,

L 2 is a linking group selected from the group consisting of a —C(R 9 ) 2 —, —C(R 9 ) 2 CH 2 — and —CO—;

each R 9 is independently selected from the group consisting of H, C 1-6 alkyl, —(CH 2 ) m C(O)R 6 , —C(O)R 6 and heterocyclyl substituted with from 0 to 2 substituents selected from the group halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkyl, oxo and thio;

each subscript m is independently 1, 2 or 3,

or pharmaceutically acceptable salts thereof.

2. A compound of claim 1 , wherein Ar 1 is benzene, which is optionally substituted with from 1-2 R 8 substituents.

3. A compound of claim 1 , wherein Ar 1 is thiophene, which is optionally substituted with from 1-2 R 8 substituents.

4. A compound of claim 1 , wherein Ar 2 is tetrazole, which is optionally substituted with from 1-2 R 8 substituents.

5. A compound of claim 1 , wherein Ar 2 is benzene, which is optionally substituted with from 1-2 R 8 substituents.

6. A compound of claim 1 , wherein Ar 2 is thiophene, which is optionally substituted with from 1-2 R 8 substituents.

7. A compound of claim 1 , wherein at least one R 9 is —C(O)R 6 .

8. A compound of claim 1 , wherein at least one R 9 is —(CH 2 ) m C(O)R 6 .

9. A compound of claim 1 , wherein at least one R 9 is heterocyclyl.

10. A compound of claim 9 , wherein at least one R 9 is independently selected from the group consisting of:

each of which is substituted with from 0 to 2 substituents selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkyl, oxo and thio; and wherein the wavy line indicates the point of attachment to the rest of the molecule.

11. A compound of claim 9 , wherein at least one R 9 is independently selected from the group consisting of:

and wherein the wavy line indicates the point of attachment to the rest of the molecule.

12. A compound of claim 1 , having the formula:

wherein the subscript n is an integer of from 0 to 2.

13. A compound of claim 12 , wherein R 1 is H, NHR 7 or halogen; R 2 is H, C 1-6 alkyl, NHR 7 or halogen; R 3 is H; R 7 is C 1-6 alkyl or arylC 1-6 alkyl; R 8 is halogen, or C 1-6 alkoxy; Ar 2 is thiophene or benzene, each of which is optionally substituted with from 1-2 R 8 substituents; and n is 1.

14. A compound of claim 13 , wherein R 1 is F, R 2 is NH R 7 , and R 7 is CH 3 or 4-fluorobenzyl.

15. A compound of claim 1 , selected from the group consisting of:

2-(5-chlorothiophen-2-yl)-2-(5-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)thiophene-2-carboxamido)acetic acid; and

2-(5-chlorothiophen-2-yl)-2-(5-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)thiophene-3-carboxamido)acetic acid.

16. A compound of claim 1 , having the formula:

wherein the subscript n is an integer of from 0 to 2.

17. A compound of claim 16 , wherein R 1 is H, NHR 7 or halogen; R 2 is H, C 1-6 alkyl, NHR 7 or halogen; R 3 is H; R 7 is C 1-6 alkyl or arylC 1-6 alkyl; R 8 is halogen, or C 1-6 alkoxy; Ar 2 is thiophene or benzene, each of which is optionally substituted with from 1-2 R 8 substituents; and n is 1.

18. A compound of claim 16 , wherein R 1 is F, R 2 is NHR 7 , and R 7 is CH 3 or 4-fluorobenzyl.

19. A compound selected from the group consisting of:

2-(4-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)-3-(thiophen-2-yl)propanoic acid;

2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)-3-(thiophen-2-yl)propanoic acid;

N-((1H-tetrazol-5-yl)methyl)-4-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

N-((3-chlorophenyl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

N-((4-chlorophenyl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

2-(4-chlorophenyl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;

2-(3-chlorophenyl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;

N-((1H-tetrazol-5-yl)(m-tolyl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-((3-methoxyphenyl) (1H-tetrazol-5-yl)methyl)benzamide;

4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-((3-fluorophenyl) (1H-tetrazol-5-yl)methyl)benzamide;

N-((2-chlorophenyl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

N-((3,4-dichlorophenyl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

N-((3,5-dichlorophenyl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

N-((1H-tetrazol-5-yl)(3-(trifluoromethoxy)phenyl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

N-((1H-tetrazol-5-yl)(3-(trifluoromethyl)phenyl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

2-(5-chloro-N-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) benzyl)thiophene-2-carboxamido)acetic acid; and

3-(5-chlorothiophen-2-yl)-3-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzylamino)propanoic acid.

20. A compound of claim 1 , having the formula:

wherein the subscript n is an integer of from 0 to 2.

21. A compound of claim 20 , wherein R 1 is F, R 2 is NHR 7 , and R 7 is CH 3 or 4-fluorobenzyl.

22. A compound selected from the group consisting of:

N-((5-chlorothiophen-2-yl)methyl)-4-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

2-(4-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)-2-(thiophen-2-yl)acetic acid;

N-((5-chlorothiophen-2-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;

2-(N-((5-chlorothiophen-2-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;

N((5-chlorothiophen-2-yl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)-2-(thiophen-2-yl)acetic acid;

2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;

2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) benzamido)-2-(5-methylthiophen-2-yl)acetic acid;

2-(5-chlorothiophen-2-yl)-2-(4-(7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;

N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

ethyl 2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetate;

3-(5-chlorothiophen-2-yl)-3-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)propanoic acid;

N-((5-chlorothiophen-2-yl)(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

2-(5-chlorothiophen-2-yl)-2-(4-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) benzamido)acetic acid;

N-((1H-tetrazol-5-yl)(3-(trifluoromethyl)phenyl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

2-morpholinoethyl 2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetate;

N-(1-(5-chlorothiophen-2-yl)-2-hydroxyethyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

2-(5-chlorothiophen-2-yl)-2-(4-(6-iodo-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) benzamido)acetic acid;

2-(5-chlorothiophen-2-yl)-2-(4-(6-isopropoxy-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) benzamido)acetic acid;

2-(5-chlorothiophen-2-yl)-2-(4-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) benzamido)acetic acid;

3-(N-((5-chlorothiophen-2-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)propanoic acid;

2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methoxybenzamido)acetic acid;

2-(2-chloro-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) benzamido)-2-(5-chlorothiophen-2-yl)acetic acid;

2-(5-chlorothiophen-2-yl)-2-(2-fluoro-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;

N-(2-amino-1-(5-chlorothiophen-2-yl)-2-oxoethyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

2-(5-chlorothiophen-2-yl)-2-(4-(7-fluoro-6-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;

N-((5-chlorothiophen-2-yl)(1H-tetrazol-5-yl)methyl)-4-(7-fluoro-6-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(7-fluoro-6-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;

2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-methoxybenzamido)acetic acid;

N-((5-chlorothiophen-2-yl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-methoxybenzamide;

N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-methoxybenzamide;

2-(5-chlorothiophen-2-yl)-2-(4-(6-ethyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl) benzamido)acetic acid;

2-(1-((5-chlorothiophen-2-yl)methyl)-3-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-1H-1,2,4-triazol-5-ylthio)acetic acid; and

2-(5-chlorothiophen-2-yl)-2-(3-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid.

23. The compound of claim 1 :

N-(( 5 -chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide.

24. The compound of claim 1 :

(S)-N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide.

25. The compound of claim 1 :

(R)-N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide.

26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .