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

Patent metadata

Field	Value
Publication number	US-11230556-B2
Application number	US-201716471672-A
Country	US
Kind code	B2
Filing date	Dec 18, 2017
Priority date	Dec 22, 2016
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

Abstract

The present invention is directed to 6,5-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:
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,

Assignees

• Merck Sharp & Dohme

Inventors

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

Classifications

• C07D491/048

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

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title