US 2019/0315762 A1Published application

6,6-fused heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor

AssigneeMerck Sharp & Dohme Corp.

InventorsXiaolei GAO, Sandra L. KNOWLES, Chunsing LI, Michael Man-Chu LO, Robert D. MAZZOLA, Jr., Ling TONG

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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.

Claims21

Dependent claims

A compound of the formula I:

wherein:
Q is selected from the group consisting of:
(1) —O—,
(2) ═N—,
(3) —NR9—,
(4) —(C═O)—,
(5) —(CHR10)—, and
(6) ═(CR10)—;
X is selected from the group consisting of:
(1) ═N—,
(2) —NR9—,
(3) —(C═O )—,
(4) —(C═NH)—,
(5) —(CHR11)—, and
(6) ═(CR11)—;
Y is selected from the group consisting of:
(1) —O—,
(2) ═N—,
(3) —NR9—,
(4) —(C═O)—,
(5) —(CHR12)—, and
(6) ═(CR12)—;
Z is selected from the group consisting of:
(1) —(C═O)—,
(2) —(CHR10)—, and
(3) ═(CR10)—;
R1 is selected from the group consisting of:
(1) —C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
hydroxy, fluoro, —CN, —O—C1-6alkyl, and C3-6cycloalkyl;
(2) a phenyl, heteroaryl or heterocyclyl ring, wherein the phenyl, heteroaryl or heterocyclyl ring is substituted with one or more R1a, R1b and R1c, wherein R1a, R1b and R1c are independently selected from the group consisting of:
(a) hydrogen,
(b) halogen,
(c) C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
hydroxy and fluoro,
(d) —O—C1-6alkyl,
(e) C3-6cycloalkyl, and
(f) —CN;
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen, and
(2) fluoro;
R7 and R8 are independently selected from the group consisting of:
(1) hydrogen, and
(2) C1-6alkyl;
R9 is selected from the group consisting of:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
hydroxy, methoxy, fluoro, phenyl, or pyridyl;
each of R10, R11 and R12 is independently selected from the group consisting of:
(1) hydrogen,
(2) fluoro,
(3) —OH,
(4) —CH3,
(5) —CF3,
(6) —CH2OH,
(7) —CH2CH2OH,
(8) —CH2OCH3, and
(9) —CH2CH2OCH3;
or a pharmaceutically acceptable salt thereof.

55 more elements

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-y0oxy)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)pipridin-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-b9 pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

54 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/471,675Filed 18 Dec 2017
Priority: CN PCT/CN2016/11152922 Dec 2016
Published: 17 Oct 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

A61P 25/18
Drugs for disorders of the nervous system: antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
C07D 491/052
With only one oxygen atom as ring hetero atom in the oxygen-containing ring: the oxygen-containing ring being six-membered
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…

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US 10,836,775 B2Related patent
US 2019/0315762 A1This patent

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