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

Patent metadata

Field	Value
Publication number	US-10836775-B2
Application number	US-201716471675-A
Country	US
Kind code	B2
Filing date	Dec 18, 2017
Priority date	Dec 22, 2016
Publication date	Nov 17, 2020
Grant date	Nov 17, 2020

Abstract

The present invention is directed to 6,6-fused heteroarylpiperidine ether compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which M4 muscarinic acetylcholine receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which M4 muscarinic acetylcholine receptors are involved.

First claim

What is claimed is:

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)pyr

Assignees

• Merck Sharp & Dohme
• Gao Xiaolei
• Knowles Sandra L
• Li Chunsing
• Lo Michael Man Chu
• Mazzola Jr Robert D
• Tong Ling

Inventors

• Gao Xiaolei
• Knowles Sandra L
• Li Chunsing
• Lo Michael Man-Chu
• Mazzola Jr Robert D
• Tong Ling

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D491/052 Primary

  the oxygen-containing ring being six-membered · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title