3-(1H-pyrazol-4-yl)pyridine allosteric modulators of the M4 muscarinic acetylcholine receptor

Patent metadata

Field	Value
Publication number	US-11339156-B2
Application number	US-201816621953-A
Country	US
Kind code	B2
Filing date	Jun 22, 2018
Priority date	Jun 27, 2017
Publication date	May 24, 2022
Grant date	May 24, 2022

Abstract

The present invention is directed to pyrazol-4-yl-pyridine 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:
A is selected from: benzofuranone, benzoimidazole, benzoisoxazole, benzothiazole, benzotriazole, benzoxazole, dihydrobenzofuranone, dihydroisoindole, imidazopyridazine, imidazopyridine, indazole, isobenzofuranone, isoindoline, isoindolinone, oxazolopyridine, pyrazolopyridine, pyrrolopyridinone, and triazolopyridine;
R 1 is selected from:
(1) hydrogen,
(2) halogen,
(3) —CN,
(4) —C 1-6 alkyl, which is unsubstituted or substituted with a hydroxy, or 1-3 fluoro,
(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with a hydroxy, or 1-3 fluoro,
(6) —C≡CH,
(7) -pyrazolyl,
(8) —(C═O)—NH 2 , and
(9) —(C═O)—NH(—C 1-6 alkyl);

R 2 is selected from:
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl,
(4) —OC 1-6 alkyl, and
(5) —SC 1-6 alkyl;

R 3 is selected from:
(1) hydrogen,
(2) halogen,
(3) —CN,
(4) —C 1-6 alkyl, and
(5) —NH 2 ;

R 4 is selected from:
(1) hydrogen,
(2) —CN,
(3) chloro, and
(4) fluoro;

R 5 is —C 1-6 alkyl, which is unsubstituted or substituted with:
(1) fluoro,
(2) hydroxy,
(3) —CN,
(4) —OC 1-6 alkyl, which is unsubstituted or substituted with —C 1-6 alkyl, hydroxy, methoxy, fluoro, or —C 1-6 alkyl-fluoro,
(5) —C 3-8 cycloalkyl, which is unsubstituted or substituted with —C 1-6 alkyl, hydroxy, methoxy, fluoro, or —C 1-6 alkyl-fluoro,
(6) furanyl, which is unsubstituted or substituted with —C 1-6 alkyl, hydroxy, methoxy, or 1-3 fluoro, and
(7) phenyl, which is unsubstituted or substituted with —C 1-6 alkyl, hydroxy, methoxy, or 1-3 fluoro;

each of R 8 , R 9 and R 10 is independently selected from:
(1) hydrogen,
(2) halogen,
(3) —OH,
(4) —C 1-6 alkyl, which is unsubstituted or substituted with: hydroxy, —OC 1-6 alkyl, cyclopropyl, cyclobutyl, or 1-3 fluoro; phenyl, which is unsubstituted or substituted with hydroxy, —C 1-6 alkyl or fluoro; or pyridyl, which is unsubstituted or substituted with hydroxy, —C 1-6 alkyl or fluoro,
(5) —OC 1-6 alkyl, which is unsubstituted or substituted with a hydroxy, —OC 1-6 alkyl, cyclopropyl, cyclobutyl, or 1-3 fluoro,
(6) —C 3-6 cyclolkyl, which is unsubstituted or substituted with a hydroxy, methoxy, or 1-3 fluoro,
(7) —NH 2 , —NH(C 1-6 alkyl), or —N(C 1-6 alkyl) 2 , wherein the —C 1-6 alkyl, is unsubstituted or substituted with hydroxy, methoxy, or 1-3 fluoro,
(8) azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, wherein the azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, is unsubstituted or substituted with hydroxy, methoxy, or 1-3 fluoro, and
(9) —CN;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of the formula Ia:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
(1) hydrogen,
(2) fluoro,
(3) chloro,
(4) —CN, and
(5) methyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, R 3 is hydrogen and R 1 is selected from:
(1) hydrogen,
(2) fluoro,
(3) chloro,
(4) —CN, and
(5) methyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —C 1-6 alkyl, which is unsubstituted or substituted with fluoro.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from:
(1) 2,2-dimethylpropyl,
(2) 2,2-difluorobutyl,
(3) 3-methylbutyl,
(4) 3-fluoro-3-methylbutyl,
(5) neopentyl,
(6) 1-(methylcyclopentyl)methyl,
(7) 1-(fluorocyclopentyl)methyl,
(8) cyclopentyl-3,3,3-trifluoro-2,2-dimethylpropyl,
(9) 1-(cyclohexylmethyl), and
(10) (1-(trifluoromethyl)cyclopropyl)methyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 8 , R 9 and R 10 is independently selected from:
(1) hydrogen,
(2) halo,
(3) —OH,
(4) —C 1-6 alkyl, which is unsubstituted or substituted with a hydroxy, or 1-3 fluoro,
(5) —OC 1-6 alkyl, which is unsubstituted or substituted with a hydroxy, or 1-3 fluoro, and
(6) cyclopropyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 8 , R 9 and R 10 is independently selected from:
(1) hydrogen,
(2) fluoro,
(3) —CH 3 ,
(4) —CF 3 , and
(5) —OCH 3 , and
(6) cyclopropyl.

10. A compound which is selected from:
5-(1-(2-cyclopropyl-2,2-difluoroethyl)-1H-pyrazol-4-yl)-6-(imidazo[1,2-a]pyridin-7-yl)picolinonitrile;
2-methyl-6-(6-methyl-3-{1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridin-2-yl)-2H-indazole;
6-(6-methyl-3-{1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridin-2-yl)-1H-indazole;
3-methyl-6-(6-methyl-3-{1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridin-2-yl)-1H-indazole;
3-methyl-6-(6-methyl-3-{1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridin-2-yl)-3H-imidazo[4,5-b]pyridine;
2-cyclopropyl-6-{6-methyl-3-[1-(2-methylpropyl)-1H-pyrazol-4-yl]pyridin-2-yl}-2,3-dihydro-1H-isoindol-1-one;
6-{3-[1-(bicyclo[1.1.1]pent-1-ylmethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}-2-methyl-2,3-dihydro-1H-isoindol-1-one;
6-{3-[1-(bicyclo[1.1.1]pent-1-ylmethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}-2,3-dihydro-1H-isoindol-1-one;
6-{3-[1-(3-fluoro-3-methylbutyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}-2-methyl-2,3-dihydro-1H-isoindol-1-one;
6-{3-[1-(3-fluoro-3-methylbutyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}-2,3-dihydro-1H-isoindol-1-one;
6-[3-(1-benzyl-1H-pyrazol-4-yl)-6-methylpyridin-2-yl]-2-(cyclopropylmethyl)-2, 3-dihydro-1H-isoindol-1-one;
6-{3-[1-(bicyclo[2.2.2]oct-1-ylmethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}-2-(cyclopropylmethyl)-2,3-dihydro-1H-isoindol-1-one;
2-cyclopropyl-6-{3-[1-(2-fluorobenzyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}-2,3-dihydro-1H-isoindol-1-one;
2-(cyclopropylmethyl)-6-(3-{1-[(4,4-difluorocyclohexyl)methyl]-1H-pyrazol-4-yl}-6-methylpyridin-2-yl)-2,3-dihydro-1H-isoindol-1-one;
6-(3-{1-[(4,4-difluoro-1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}-6-methylpyridin-2-yl)-2-methyl-2,3-dihydro-1H-isoindol-1-one;
6-(2-methylimidazo[1,2-a]pyridin-7-yl)-5-[1-(4,4,4-trifluoro-2,2-dimethylbutyl)-1H-pyrazol-4-yl]pyridine-2-carbonitrile;
7-[3-(1-{[1-(2,2-difluoroethyl)cyclopropyl]methyl}-1H-pyrazol-4-yl)pyridin-2-yl]-2-methylimidazo[1,2-a]pyridine;
5-[1-(2,2-difluorobutyl)-1H-pyrazol-4-yl]-6-imidazo[1,2-a]pyridin-7-ylpyridine-2-carbonitrile;
5-(1-{[1-(fluoromethyl)cyclopropyl]methyl}-1H-pyrazol-4-yl)-6-imidazo[1,2-a]pyridin-7-ylpyridine-2-carbonitrile;
5-[1-(2,2-difluoropropyl)-1H-pyrazol-4-yl]-6-(2-methylimidazo[1,2-a]pyridin-7-yl)pyridine-2-carbonitrile;
5-[1-(2,2-difluoro-3-methylbutyl)-1H-pyrazol-4-yl]-6-imidazo[1,2-a]pyridin-7-ylpyridine-2-carbonitrile;
6-(2-methylimidazo[1,2-a]pyridin-7-yl)-5-[1-(2,2,3,3-tetrafluoropropyl)-1H-pyrazol-4-yl]pyridine-2-carbonitrile;
5-[1-(2,2,3,3,4,4-hexafluorobutyl)-1H-pyrazol-4-yl]-6-(2-methylimidazo[1,2-a]pyridin-7-yl)pyridine-2-carbonitrile;
5-[1-(2,2,3,3,4,4,4-heptafluorobutyl)-1H-pyrazol-4-yl]-6-imidazo[1,2-a]pyridin-7-ylpyridine-2-carbonitrile;
6-imidazo[1,2-a]pyridin-7-yl-5-(1-{[(1 S,2S)-2-(trifluoromethyl)cyclopropyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carbonitrile;
7-{6-methyl-3-[1-(3,3,3-trifluoro-2,2-dimethylpropyl)-1H-pyrazol-4-yl]pyridin-2-yl}imidazo[1,2-a]pyridine;
5-[1-(3,3-difluorobutyl)-1H-pyrazol-4-yl]-6-(1,2-dim

Assignees

• Merck Sharp & Dohme
• Msd R&D China Co Ltd

Inventors

• Acton Iii John J
• Bao Jianming
• Deng Qiaolin
• Egbertson Melissa
• Ferguson Ii Ronald
• Gao Xiaolei
• Harrison Scott Timothy
• Henderson Timothy J
• Knowles Sandra L
• Li Chunsing
• Lo Michael Man-Chu
• Mazzola Jr Robert D
• Na Meng
• Rudd Michael T
• Selyutin Oleg B
• Tellers David M
• Tong Ling
• Zhang Fengqi
• Suzuki Takao

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P25/00 Primary

  Drugs for disorders of the nervous system · CPC title