Quinolinone PDE2 inhibitors

1. A compound of the formula I:

wherein:

R 1 is selected from the group consisting of:

(1) —C 5-6 heterocycle selected from the group consisting of thiophenyl and pyridyl, which is unsubstituted or substituted with R 14 , provided that when R 1 is thiophenyl and R 2 is —O(CH 2 ) n C 5-10 heterocycle then n is 0-1; and when R 1 is thiophenyl and R 2 is —OCH 3 then R 3 and R 4 are not both hydrogen;

(2) phenyl, which is unsubstituted;

(3) —C 1-6 alkyl, which is unsubstituted or substituted with R 14 ;

R 2 is selected from the group consisting of:

(1) —O(C 1-6 alkyl), unsubstituted or substituted with R 14 ;

(2) —O(CH 2 ) n C 6-10 aryl, which is unsubstituted or substituted with R 14 ;

(3) —O(CH 2 ) n C 3-10 cycloakyl;

(4) —O(CH 2 ) n C 5-10 heterocycle, which is unsubstituted or substituted with R 14 ,

(5) phenyl, substituted with R 14 ;

(6) —(CH 2 ) n C 5-10 heterocycle, which is unsubstituted or substituted with R 14 , provided said heterocycle is not thiophenyl;

(7) —(CH 2 ) n C 5-10 aryl, which is unsubstituted or substituted with R 14 ;

(8) —(CH 2 ) n C 3-10 cycloakyl;

(9) —(C 2-6 alkenyl)C 5-10 heterocycle, which is unsubstituted or substituted with R 14 ;

(10) —(C 2-6 alkenyl)C 6-10 aryl, which is unsubstituted or substituted with R 14 ;

(11) —(C 2-6 alkenyl)C 3-10 cycloalkyl, which is unsubstituted or substituted with R 14 ;

R 3 is selected from the group consisting of:

(1) Hydrogen

(2) Halogen

(3) —C 6-10 aryl, which is unsubstituted or substituted with R 14 ;

(4) —C 5-10 heteroaryl, which is unsubstituted or substituted with R 14 ;

(5) -(Q)C 6-10 aryl, which is unsubstituted or substituted with R 14 ;

(6) -(Q)C 5-10 heteroaryl, which is unsubstituted or substituted with R 14 ;

(7) -(Q)-C(R 5 ,R 6 )—OH;

(8) —CN;

(9) —C 2-4 alkenyl;

(10) —OC 1-6 alkyl;

Q is selected independently from:

a. —C 1-6 alkyl;

b. —C 2-4 alkynyl;

c. —C 2-4 alkenyl;

R 4 , is selected independently from

(1) Hydrogen;

(2) —(CH 2 ) n CH 3 ;

(3) —OC 1-6 alkyl;

(4) Halogen

R 5 and R 6 are selected independently from

(1) Hydrogen;

(2) —(CH 2 ) n CH 3 ;

(3) —OC 1-6 alkyl;

R 14 is selected from the group consisting of:

(1) Hydroxyl;

(2) Halogen;

(3) C 1-6 alkyl;

(4) —CN;

(5) —CO 2 H;

(6) —C(O)NH 2 ;

(7) —(CH 2 ) n C 6-10 aryl;

(8) —(CH 2 ) n C 5-10 heterocycle;

(9) —NO 2 ;

(10) -(Q)-C(R 5 ,R 6 )—OH;

(11) -Q(CH 2 ) n C 6-10 heteroaryl, which is unsubstituted or substituted with R 15 ;

(12) —(CH 2 ) n C 3-10 cycloakyl;

(13) -Q(CH 2 ) n C 6-10 aryl, which is unsubstituted or substituted with R 15 ;

R 15 is selected from the group consisting of:

(1) Hydroxyl;

(2) Halogen;

(3) C 1-6 alkyl;

(4) —CN; and

n is 0-3;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 1 is thiophenyl, which is unsubstituted or substituted with R 14 , provided that when R 1 is thiophenyl and R 2 is —O(CH 2 ) n C 5-10 heterocycle then n is 0-1 and when R 1 is thiophenyl and R 2 is —OCH 3 then R3 and R4 are not both hydrogen.

3. The compound of claim 2 wherein n is 1.

4. The compound of claim 1 wherein R 1 is pyridyl.

5. The compound of claim 1 wherein R 1 is unsubstituted phenyl.

6. The compound of claim 1 wherein R 2 is selected from the group consisting of —O(CH2) n C 6-10 aryl, —O(CH2) n C 3-10 cycloalkyl, —O(CH2) n C 5-10 heterocycle, substituted phenyl and —(C 2-6 alkenyl)C 5-10 heterocycle, said aryl, cycloalkyl, and heterocycle unsubstituted or substituted with R 14 .

7. The compound according to claim 6 wherein the cycloalkyl, and heterocycle is optionally substituted pyranyl, pyridyl, piperidinyl, or cyclohexyl, said alkenyl is ethylenyl, and n is 0-1.

8. The compound according to claim 1 wherein R 3 is selected from the group consisting of hydrogen, halogen, —C 6-10 aryl, —C 5-10 heteroaryl, and -(Q)-C(R 5 ,R 6 )—OH, said aryl and heteroaryl unsubstituted or substituted with R 14 .

9. The compound according to claim 8 wherein R 3 is hydrogen, bromine, iodine, phenyl, pyridyl, pyrazolyl, pyrimidinyl, and -(Q)-C(R 5 ,R 6 )—OH, wherein R 5 and R 6 are C 1-6 alky, and Q is C 2 alkynyl, and wherein said phenyl, pyridyl, pyrazolyl and pyrimidinyl are optionally substituted with 1 to 3 groups of R 14 .

10. The compound according to claim 1 wherein R 1 is thiophenyl, R 2 is optionally substituted O(CH2) n pyranyl, O(CH2) n pyridyl, O(CH2) n piperidinyl, O(CH2) n phenyl, O(CH2) n cyclohexyl, and —(C 2-6 alkenyl)C 5-10 heterocycle, wherein said alkenyl is ethylenyl, and n is 0-1.

11. A compound which is selected from the group consisting of:

6-phenyl-4-(pyridin-2-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-iodo-4-(pyridin-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[(3-methylbenzyl)oxy]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(cyclohexylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(pyridin-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(pyridin-3-yl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(piperidin-4-ylmethoxy)-3-(pyridin-3-yl)quinolin-2(1H)-one;

4-(benzyloxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

3-(6-bromo-7-methoxy-2-oxo-3-phenyl-1,2-dihydroquinolin-4-yl)benzonitrile;

3-[6-bromo-7-methoxy-2-oxo-3-(thiophen-2-yl)-1,2-dihydroquinolin-4-yl]benzonitrile;

6-phenyl-4-(piperidin-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

3-(6-bromo-7-methoxy-2-oxo-3-phenyl-1,2-dihydroquinolin-4-yl)benzamide;

6-bromo-4-[(1-methylpiperidin-4-yl)methoxy]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(piperidin-4-ylmethoxy)-6-(pyridin-3-yl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(piperidin-4-ylmethoxy)-6-(pyridin-3-ylethynyl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-(phenylethynyl)-4-(piperidin-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

2-[2-oxo-4-(piperidin-4-ylmethoxy)-3-(thiophen-2-yl)-1,2-dihydroquinolin-6-yl]benzonitrile;

3-[7-methoxy-2-oxo-6-phenyl-3-(thiophen-2-yl)-1,2-dihydroquinolin-4-yl]benzonitrile;

4-(piperidin-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(piperidin-4-ylmethoxy)-3-(pyridin-4-yl)quinolin-2(1H)-one;

3-methyl-4-(piperidin-4-ylmethoxy)quinolin-2(1H)-one;

4-(piperidin-4-ylmethoxy)-6-(pyridin-3-yl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[(1-methylpiperidin-4-yl)methoxy]-6-(pyridin-3-ylethynyl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-(4-methylphenyl)-4-(piperidin-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(piperidin-4-ylmethoxy)-6-(pyridin-4-yl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(piperidin-4-ylmethoxy)-6-(pyrimidin-5-yl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-(2-methylphenyl)-4-(piperidin-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-(3-methylphenyl)-4-(piperidin-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

2-oxo-4-(piperidin-4-ylmethoxy)-3-(thiophen-2-yl)-1,2-dihydroquinoline-6-carbonitrile;

4-(piperidin-4-ylmethoxy)-3-(propan-2-yl)quinolin-2(1H)-one;

6-bromo-4-(pyridin-2-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

2-[2-oxo-4-(pyridin-2-ylmethoxy)-3-(thiophen-2-yl)-1,2-dihydroquinolin-6-yl]benzonitrile;

4-(piperidin-4-ylmethoxy)-6-(pyridin-2-yl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(pyridin-2-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

3-ethyl-4-(piperidin-4-ylmethoxy)quinolin-2(1H)-one;

6-(pyridin-3-yl)-4-(pyridin-2-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-(1-benzyl-1H-pyrazol-4-yl)-4-(pyridin-2-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-bromo-4-(cyclohexylmethoxy)-3-phenylquinolin-2(1H)-one;

4-[(4-methylbenzyl)oxy]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(piperidin-3-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(2,2-dimethylpropoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-bromo-3-phenyl-4-(pyridin-2-ylmethoxy)quinolin-2(1H)-one;

3-phenyl-4-[(E)-2-(pyridin-2-yl)ethenyl]quinolin-2(1H)-one;

4-(benzyloxy)-6-bromo-3-phenylquinolin-2(1H)-one;

6-(3-nitrophenyl)-4-(pyridin-2-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(pyridin-2-ylmethoxy)-6-(pyrimidin-5-yl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[2-oxo-4-(pyridin-2-ylmethoxy)-3-(thiophen-2-yl)-1,2-dihydroquinolin-6-yl]benzonitrile;

6-(pyridin-4-yl)-4-(pyridin-2-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-ethenyl-4-(pyridin-2-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-(1H-pyrazol-4-yl)-4-(pyridin-2-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-bromo-4-[(E)-2-(pyridin-2-yl)ethenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-bromo-4-(cyclohexylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-bromo-4-(tetrahydro-2H-pyran-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(cyclohexylmethoxy)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[(E)-2-(pyridin-2-yl)ethenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[2-(pyridin-2-yl)ethyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one; 4-(3-ethylphenyl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[3-(pyridin-3-yl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[3-(pyridin-2-yl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[3-(3,3-dimethylbut-1-yn-1-yl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

6,7-dimethoxy-4-[3-(pyridin-2-yl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

6,7-dimethoxy-4-[3-(phenylethynyl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

6,7-dimethoxy-4-[3-(pyridin-2-ylethynyl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[3-(3,3-dimethylbut-1-yn-1-yl)phenyl]-6,7-dimethoxy-3-(thiophen-2-yl)quinolin-2(1H)-one;

6,7-dimethoxy-4-[3-(pyridin-4-yl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one; 4-(biphenyl-3-yl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(3-cyclopropylphenyl)-6,7-dimethoxy-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[3-(phenylethynyl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

6,7-dimethoxy-4-[3-(pyridin-3-yl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

6,7-dimethoxy-4-{3-[(E)-2-(pyridin-2-yl)ethenyl]phenyl}-3-(thiophen-2-yl)quinolin-2(1H)-one; 4-(3-ethylphenyl)-6,7-dimethoxy-3-(thiophen-2-yl)quinolin-2(1H)-one;

6,7-dimethoxy-4-[3-(propan-2-yl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

6,7-dimethoxy-4-[3-(2-methylpropyl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[3-(pyridin-3-ylethynyl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

6,7-dimethoxy-4-[3-(pyridin-4-ylethynyl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl]-6,7-dimethoxy-3-(thiophen-2-yl)quinolin-2(1H)-one;

6,7-dimethoxy-4-{3-[(E)-2-phenylethenyl]phenyl}-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(biphenyl-3-yl)-6,7-dimethoxy-3-(thiophen-2-yl)quinolin-2(1H)-one;

6,7-dimethoxy-4-{3-[(E)-2-(pyridin-3-yl)ethenyl]phenyl}-3-(thiophen-2-yl)quinolin-2(1H)-one;

6,7-dimethoxy-4-{3-[(E)-2-(pyridin-4-yl)ethenyl]phenyl}-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(3-cyclopentylphenyl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[3-(propan-2-yl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(3-cyclopentylphenyl)-6,7-dimethoxy-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[3-(pyridin-2-ylethynyl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[3-(pyridin-3-yl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-[3-(pyridin-4-yl)phenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-(3-cyclopropylphenyl)-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-{3-[(E)-2-phenylethenyl]phenyl}-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-{3-[(E)-2-(pyridin-2-yl)ethenyl]phenyl}-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-{3-[(E)-2-(pyridin-3-yl)ethenyl]phenyl}-3-(thiophen-2-yl)quinolin-2(1H)-one;

4-{3-[(E)-2-(pyridin-4-yl)ethenyl]phenyl}-3-(thiophen-2-yl)quinolin-2(1H)-one

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

13. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use in medicine.

14. A method for treating a neurological or psychiatric disorder associated with PDE2 dysfunction in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

15. A method for treating a neurological or psychiatric disorder associated with striatal hypofunction or basal ganglia dysfunction in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

16. A method for treating schizophrenia in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

17. A method for treating bipolar disorder in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

18. A method for treating Huntington's disease in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. A method for enhancing cognition in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

20. A method for treating anxiety in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.