6,6-fused heteroaryl piperidine ether allosteric modulators of the M4 muscarinic acetylcholine receptor

1. A compound of the formula I:

wherein:

the group:

is selected from:

R 1 is selected from the group consisting of:

(1) —C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of: hydroxy, fluoro, —CN, —O—C 1-6 alkyl, and C 3-6 cycloalkyl;

(2) a phenyl, heteroaryl or heterocyclyl ring, wherein the phenyl, heteroaryl or heterocyclyl ring is substituted with one or more R 1a , R 1b and R 1c , wherein R 1a , R 1b and R 1c are independently selected from the group consisting of:

(a) hydrogen,

(b) halogen,

(c) C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of: hydroxy and fluoro,

(d) —O—C 1-6 alkyl,

(e) C 3-6 cycloalkyl, and

(f) —CN;

R 2 and R 3 are independently selected from the group consisting of:

(1) hydrogen, and

(2) fluoro;

R 7 and R 8 are independently selected from the group consisting of:

(1) hydrogen, and

(2) C 1-6 alkyl;

R 9 is selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of: hydroxy, methoxy, fluoro, phenyl, or pyridyl;

each of R 10 , R 11 and R 12 is independently selected from the group consisting of:

(1) hydrogen,

(2) fluoro,

(3) —OH,

(4) —CH 3 ,

(5) —CF 3 ,

(6) —CH 2 OH,

(7) —CH 2 CH 2 OH,

(8) —CH 2 OCH 3 , and

(9) —CH 2 CH 2 OCH 3 ;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: benzodioxolyl, benzoimidazolyl, benzoxazoly, benzooxazinone, benzooxazolone, benzothiazolyl, chromanyl, cyclopentapyridinyl, dihydrobenzo[1,4]dioxinyl, dihydrobenzofuranyl, dihydrobenzo[1,4]oxazinyl, dihydrofuropyridinyl, dihydroisobenzofuranyl, dihydroisoquinolinone, dihydropyranopyridinyl, dihydroimidazopyridine, dihydropyrido[1,4]oxazinyl, dihydroquinolinone, indazolyl, indanyl, indolyl, isochromanone, isobenzofuranone, isochromanyl, isoindolinyl, isoxazolyl, oxoisoindolinyl, phenyl, pyrazolopyridinyl, pyrazolyl, pyridyl, pyrrolopyridinyl, pyrimidinyl, quinolinone, quinolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and tetrahydropyranyl, which is substituted with R 1a , R 1b and R 1c .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl or pyridyl, which is substituted with R 1a , R 1b and R 1c , wherein R 1a , R 1b and R 1c are independently selected from the group consisting of

(a) hydrogen,

(b) halogen,

(c) C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of: hydroxy and fluoro,

(d) —O—C 1-6 alkyl,

(e) C 3-6 cycloalkyl, and

(f) —CN.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, which is unsubstituted or substituted with —CN.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is pyridyl, which is unsubstituted or substituted with —OCH 3 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen and R 3 is hydrogen.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —CH 3 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-6 alkyl, which is unsubstituted or substituted with hydroxy, methoxy, or 1-3 fluoro.

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

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one;

6-(4-methoxybenzyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one;

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-(pyridin-4-ylmethyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one;

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-1,6-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione;

3-((1-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)piperidin-4-yl)oxy)benzonitrile;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione;

2-(hydroxymethyl)-7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methylpyrido[2,3-d]pyrimidin-4(3H)-one;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methylpyrido[2,3-d]pyrimidin-4(3H)-one;

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methylpyrido[2,3-d]pyridazin-5(6H)-one;

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-1,6-naphthyridin-5(6H)-one;

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethylpyrido[2,3-d]pyridazin-5(6H)-one;

6-methyl-7-(4-phenoxypiperidin-1-yl)pyrido[2,3-d]pyrimidin-4(3H)-one;

3-((1-(6-methyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yl)piperidin-4-yl)oxy)benzonitrile;

6-methyl-7-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrido[2,3-d]pyrimidin-4(3H)-one;

7-(4-(cyclopropylmethoxy)piperidin-1-yl)-6-methylpyrido[2,3-d]pyrimidin-4(3H)-one;

2-(4-(cyclopentylmethoxy)piperidin-1-yl)-3-methylpyrido[2,3-d]pyridazin-5 (6H)-one;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,6-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one;

2,6-dimethyl-7-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)pyrido[2,3-d]pyrimidin-4(3H)-one;

3-((1-(3-methyl-5-oxo-5,6-dihydropyrido[2,3-d]pyridazin-2-yl)piperidin-4-yl)oxy)benzonitrile;

7-(4-((5,7-dihydrofuro[3,4-b]pyridin-3-yl)oxy)piperidin-1-yl)-2,6-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one;

3-methyl-2-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrido[2,3-d]pyridazin-5 (6H)-one;

3-methyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)pyrido[2,3-d]pyridazin-5 (6H)-one;

6-methyl-7-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione;

6-methyl-7-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione;

2,6-dimethyl-7-(4-(1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrido[2,3-d]pyrimidin-4(3H)-one;

2-(methoxymethyl)-7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methylpyrido[2,3-d]pyrimidin-4(3H)-one;

2-(4-((5,7-dihydrofuro[3,4-b]pyridin-3-yl)oxy)piperidin-1-yl)-3-methylpyrido[2,3-d]pyridazin-5 (6H)-one;

2-(2-methoxyethyl)-7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methylpyrido[2,3-d]pyrimidin-4(3H)-one;

6-ethyl-7-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione;

7-(4-(cyclobutylmethoxy)piperidin-1-yl)-6-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione;

7-(4-(cyclopropylmethoxy)piperidin-1-yl)-6-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione;

7-(4-(cyclohexylmethoxy)piperidin-1-yl)-6-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methyl-4H-pyrano[2,3-b]pyridin-4-one;

7-(4-isobutoxypiperidin-1-yl)-6-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione;

3-ethyl-2-(4((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyrido[2,3-d]pyridazin-5 (6H)-one;

7-(4-(cyclopentylmethoxy)piperidin-1-yl)-6-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione;

3-((1-(2-(methoxymethyl)-6-methyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yl)piperidin-4-yl)oxy)benzonitrile;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,3,6-trimethylpyrido[2,3-d]pyrimidin-4(3H)-one;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,6-dimethyl-4H-pyrano[2,3-b]pyridin-4-one;

6-(2-hydroxyethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methylpyrido[2,3-d]pyridazin-5(6H)-one;

6-(2-hydroxyethyl)-3-methyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)pyrido[2,3-d]pyridazin-5(6H)-one;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one;

7-(4-((5,7-dihydrofuro[3,4-b]pyridin-3-yl)oxy)piperidin-1-yl)-2,3,6-trimethylpyrido[2,3-d]pyrimidin-4(3H)-one;

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-1,7-naphthyridin-8 (5H)-one;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methyl-2H-pyrido[2,3-d][1,3]oxazine-2,4(1H)-dione;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methyl-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-1,6-dimethylpyrido[2,3-d]pyrimidin-2(1H)-one;

2-imino-7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methyl-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one;

6-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methylpyrido[2,3-d]pyridazin-5(6H)-one;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methyl-2H-pyrido[3,2-e][1,3]oxazine-2,4(3H)-dione;

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione;

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5H-pyrano[4,3-b]pyridin-5-one; and

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,7-dimethyl-5H-pyrano[4,3-b]pyridin-5-one;

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

12. A method for the treatment of schizophrenia in a mammal comprising the step of administering at least one compound of claim 1 , or a pharmaceutically acceptable salt of said compound, to a patient in need thereof in an amount effective to treat said disorder.

13. The method of claim 12 , wherein the mammal has been diagnosed with a need for treatment of schizophrenia prior to the administering step.