6,7-dihydro-5H-pyrrolo[3,4-B]pyridin-5-one allosteric modulators of the M4 muscarinic acetylcholine receptor

Patent metadata

Field	Value
Publication number	US-10329289-B2
Application number	US-201615386009-A
Country	US
Kind code	B2
Filing date	Dec 21, 2016
Priority date	Dec 23, 2015
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

Abstract

The present invention is directed to 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one 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:
R 1 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, fluoro, —CN, —O—C 1-6 alkyl, C 3-6 cycloalkyl, bicycle[1.1.1]pentane, tetrahydrofuranyl, phenyl, pyridyl, oxazolyl, —NH 2 , —NH(—C 1-6 alkyl), —N(—C 1-6 alkyl) 2 , and —N(C═O)—C 1-6 alkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is unsubstituted or substituted with substituents selected from the group consisting of: fluoro, cyano, CF 3 , C 1-6 alkyl or —O—C 1-6 alkyl;
(3) 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) 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, azetidinyl, fluoro, —OCH 3 , —OCH 2 CH 2 OCH 3 , —(C═O)—C 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ,
(e) —O—C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of: hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, fluoro, —OCH 3 , —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , and —NH(C═O)(C 1-6 alkyl),
(f) C 3-6 cycloalkyl, which is unsubstituted or substituted with substituents selected from the group consisting of: C 1-6 alkyl, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, fluoro, —OCH 3 , —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ,
(g) —NH 2 ,
(h) —NH(C 1-6 alkyl),
(i) —NH(C 2-6 alkyl)-OH,
(j) —N(C 1-6 alkyl) 2 ,
(k) —SO 2 —C 1-6 alkyl,
(l) —(C═O)H,
(m) —(C═O)—C 1-6 alkyl,
(n) —(C═O)O—C 1-6 alkyl, and
(o) —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 4 is hydrogen or methyl, and R 6 is hydrogen or methyl, or R 4 and R 6 are joined together with a —(CH 2 ) 2 — to form a bridged ring with the piperidine ring to which they are attached;
R 5 is hydrogen, or where R 2 is hydrogen, R 3 and R 5 may be joined together with a —(CH 2 )— to form a bridged ring with the piperidine ring to which they are attached;
R 7 and R 8 are independently 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, fluoro, and —OCH 3 ,
(3) —CH═CH 2 ,
(4) cyclopropyl,
(5) -fluoro,
(6) -chloro,
(7) -bromo,
(8) —CN,
(9) —(C═O)H, and
(10) —(C═O)O—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, —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,
(4) —C(C═O)O—C 1-6 alkyl, and
(5) —P(O)(OH) 2 ;

each of R 10 and R 11 is independently selected from the group consisting of:
(1) hydrogen,
(2) —OH,
(3) —CH 3 ,
(4) —CH 2 OH,
(5) —CH 2 CH 2 OH, and
(6) —C(CH 3 ) 2 OH,
or R 10 and R 11 taken together form a cyclopropyl group, a ═CH 2 group or a keto group;
or a pharmaceutically acceptable salt thereof; with the proviso that the compound is other than:

2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro,5H-pyrrolo[3,4-b]pyridin-5-one;
3-((1-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)benzonitrile;
3-methyl-2-(4-4((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-methyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-methyl-2-(4-((5-methylpyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
2-(4-(isochroman-7-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-methyl-2-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]poyridin-5-one;
2-[4-(1,3-dihydro-2-benzofuran-5-yloxy)piperidin-1-yl]-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-methyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
2-(4-((2,3-dihydrobenzofuran-6-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
2-(4-(isochroman-6-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3,4-dimethyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
6-(2-hydroxyethyl)-3,4-dimethyl-2-(4-phenoxylpiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
6-(2-hydroxyethyl)-3,4-dimethyl-2-(4-((1-methycyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or
2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: benzodioxolyl, benzoimidazolyl, benzoxazolyl, benzoxazinone, benzoxazolone, 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 one or more 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 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) 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 , R 3 , R 4 , R 5 and R 6 are each hydrogen.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from the group consisting of:
(1) hydrogen,
(2) methyl,
(3) ethyl,
(4) —CH 2 OH,
(5) —CH 2 F,
(6) —CHF 2 ,
(7) —CF 3 ,
(8) —CH═CH 2 ,
(9) cyclopropyl,
(10) -fluoro,
(11) -chloro,
(12) -bromo,
(13) —CN,
(14) —(C═O)H, and
(15) —(C═O)O—C 1-6 alkyl

Assignees

• Bao Jianming
• Gao Xiaolei
• Knowles Sandra L
• Li Chunsing
• Lo Michael Man Chu
• Mazzola Jr Robert D
• Ondeyka Debra L
• Stamford Andrew W
• Zhang Fengqi
• Merck Sharp & Dohme

Inventors

• Bao Jianming
• Gao Xiaolei
• Knowles Sandra L
• Li Chunsing
• Lo Michael Man-Chu
• Mazzola Jr Robert D
• Ondeyka Debra L
• Stamford Andrew W
• Zhang Fengqi

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D491/048

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