6,5-fused heteroaryl piperidine ether allosteric modulators of the M4 muscarinic acetylcholine receptor

1. A compound of the formula I:

wherein:

K is N or C—R 8 ;

Q is N or C;

X is selected from the group consisting of:

(1) ═N—,

(2) —(NR 9 )—,

(3) —C═O—,

(4) ═(CR 10 )—, and

(5) —(CHR 10 —;

Y is selected from the group consisting of:

(1) —O—,

(2) ═N—,

(3) —(NR 9 )—,

(4) —C═O—, and

(5) —(CR 11 R 12 )—;

Z is selected from the group consisting of:

(1) —(NR 9 )—,

(2) —C═O—,

(3) ═(CR 12 )—,

(4) —(CHR 12 )—, and

(5) —(SO 2 )—;

with the proviso that if X is —(CHR 10 )—, Y is —(NR 9 )—, and Z is —(C═O)—, then Q is —N—;

R 1 is selected from the group consisting of:

benzodioxolyl, benzoimidazolyl, benzoxazolyl, 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 group 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) hydroxy,

(c) halogen,

(d) C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of: hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, fluoro, and —OCH 3 ,

(e) —O—C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of: hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, fluoro, and —OCH 3 ,

(f) C 3-6 cycloalkyl, which is unsubstituted or substituted with substituents selected from the group consisting of: hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, fluoro, and —OCH 3 , and

(p) —CN;

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

(1) hydrogen,

(2) fluoro,

(3) hydroxy, and

(4) —CH 3 ;

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

(1) hydrogen,

(2) C 1-6 alkyl,

(5) -fluoro, and

(6) -chloro;

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, —C(C═O)O—C 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C(C═O)NH 2 , —C(C═O)OH, oxetanyl, or pyridyl,

(3) —C 3-6 cycloalkyl, which is unsubstituted or substituted with fluoro,

(4) —C═O—C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of: hydroxy, methoxy, ethoxy, fluoro, azetidinyl, oxetanyl, or —C 3-6 cycloalkyl which is unsubstituted or substituted with fluoro, pyrrolyl, imidazolyl, —NH 2 , —NH(C 1-6 alkyl), or —N(C 1-6 alkyl) 2 ,

(4) —(C═O)O—C 1-6 alkyl,

(5) —(SO 2 )—C 1-6 alkyl, and

(6) —(SO 2 )—C 3-6 cycloalkyl,

and when Y is —(NR 9 )—and X is —(CHR 10 )—, X and Y may be joined together with —CH 2 OCH 2 CH 2 —to form a morpholinyl ring, or with —CH 2 NHCH 2 CH 2 —to form a piperazinyl ring;

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

(1) hydrogen,

(2) fluoro,

(3) —OH,

(3) —CH 3 ,

(4) —CF 3 ,

(5) —CH 2 OH,

(6) —CH 2 CH 2 OH, and

(7) —C(CH 3 ) 2 OH;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the group:

is selected from the group consisting of:

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) hydroxyl,

(c) halogen,

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

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

(g) —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, 1-3 fluoro.

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

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

7-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidin-3(2H)-one;

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

7-((3 S,4R)-3-fluoro-4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidin-3(2H)-one;

7-(4-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)piperidin-1-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidin-3(2H)-one;

7-((3R,4R)-3-fluoro-4-(1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidin-3 (2H)-one;

2,6-dimethyl-7-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrimidin-3(2H)-one;

7-((3S,4R)-3-fluoro-4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3 (2H)-one;

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

7-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-2-(2-hydroxyethyl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidin-3 (2H)-one;

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

6-methyl-7-(4-phenoxypiperidine-1-yl)-[1,2,4]triazolo[4,3-a]pyrimidin-3 (2H)-one;

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

3 ((1-(2,6-dimethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-7-yl)piperidin-4-yl)oxy)benzonitrile;

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

2,6-dimethyl-7-(4-phenoxypiperidine-1-yl)-[1,2,4]triazolo[4,3-a]pyrimidin-3 (2H)-one;

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

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

3-((1-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)piperidin-4-yl)oxy)benzonitrile;

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

6-(4-((1H-indazol-6-yl)oxy)piperidin-1-yl)-5-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one;

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

3-((1-(1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)piperidin-4-yl)oxy)benzonitrile;

6-(4-((1H-indazol-6-yl)oxy)piperidin-1-yl)-1,5-dimethyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one;

5-chloro-7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methylimidazo[1,2-a]pyrimidine;

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

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

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

3-methyl-2-(4-phenoxypiperidine-1-yl)furo[3,4-b]pyridin-5(7H)-one;

3-((1-(3-methyl-5-oxo-5,7-dihydrofuro[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)benzonitrile;

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

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine;

3-methyl-2-(4-phenoxypiperidine-1-yl)-6,7dihydro-5H-pyrrolo[3,4-b]pyridine;

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-(pyridin-4-ylmethyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one;

2-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-1-ol;

6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-1,5-dimethyl-1H-pyrazolo[3,4-b]pyridine;

3-Hydroxy-1-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)propan-1-one;

1-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-1-one;

cyclopropyl(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone;

(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(3-methyloxetan-3-yl)methanone;

ethyl 2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate;

(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(1-methylcyclopentyl)methanone;

1-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2,2-dimethylpropan-1-one;

cyclopentyl(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone;

cyclopropyl(3-methyl-2-(4-phenoxypiperidine-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone;

(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(oxetan-2-yl)methanone;

(3,3-difluorocyclobutyl)(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone;

(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(1H-pyrrol-2-yl)methanone;

(S)-2-hydroxy-1-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)propan-1-one;

(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(1-methylazetidin-3-yl)methanone;

3-(dimethylamino)-1-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)propan-1-one;

2-(dimethylamino)-1-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-1-one;

(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(oxetan-3-yl)methanone;

3-methoxy-1-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)propan-1-one;

(2,2-difluorocyclopropyl)(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone;

6-(cyclopropyl sulfonyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine;

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-(methyl sulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine;

3-methyl-6-(methylsulfonyl)-2-(4-phenoxypiperidine-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine;

methyl 2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate;

methyl 3-methyl-2-(4-phenoxypiperidine-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate;

6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-1H-pyrazolo[3,4-b]pyridine;

5-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,6-dimethyl-2H-pyrazolo[4,3-b]pyridine;

5-(4((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethyl-1H-pyrazolo[4,3-b]pyridine;

5-(4((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-1,6-dimethyl-1H-pyrazolo[4,3-b]pyridine;

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-yl)-6-methylimidazo[1,2-a]pyrimidine;

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one;

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

6,6-difluoro-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one;

(R)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-ol;

(S)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-ol;

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine; 2-(4-(6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6,6-trimethyl-6,7-dihydro-5H-cyclopenta[b]pyri din-5-one;

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

5-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methyl-2,3-dihydroisothiazolo[4,5-b]pyridine 1,1-dioxide;

3-((1-(6-methyl-1,1-dioxido-2,3-dihydroisothiazolo[4,5-b]pyridin-5-yl)piperidin-4-yl)oxy)benzonitrile;

6-methyl-5-(4-phenoxypiperidine-1-yl)-2,3-dihydroisothiazolo[4,5-b]pyridine 1,1-dioxide 2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-(trifluoromethyl)imidazo[1,5-a]pyrimidine;

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

7-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrimidine;

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.