Ethynyl derivatives

Patent metadata

Field	Value
Publication number	US-9725416-B2
Application number	US-201615245955-A
Country	US
Kind code	B2
Filing date	Aug 24, 2016
Priority date	Feb 25, 2014
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

The present invention relates to compounds that may be used in the treatment or prevention of disorders relating to allosteric modulation of the mGluR4 receptor. Such compounds may be used for the treatment of Parkinson's disease, anxiety, emesis, obsessive compulsive disorder, autism, neuroprotection, cancer, depression and diabetes type 2.

First claim

The invention claimed is:

1. A compound of formula I

wherein
Y is N or C—R 1′ ;
R 1′ is hydrogen or F;
R 1 is hydrogen, halogen or lower alkyl substituted by halogen;
R 2 is hydrogen or lower alkyl;
or R 2 forms together with R 4 a 6 membered heterocyclic ring containing —CH 2 —CH 2 —O—CH 2 — or —CH 2 —CH 2 —NR—C(O)—;
R is hydrogen, lower alkyl, phenyl or benzyl;

R 3 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
R 4′ is hydrogen, lower alkyl or lower alkoxyalkyl;
R 4 is hydrogen, lower alkyl, phenyl optionally substituted by halogen or lower alkoxy, or is cycloalkyl, or is pyridinyl optionally substituted by halogen, lower alkyl, lower alkoxy or ═O, or is pyrimidinyl optionally substituted by lower alkyl, lower alkoxy or ═O, or is 1-lower alkyl-pyridinyl, or is pyrazinyl, or is pyridazinyl optionally substituted by lower alkyl, lower alkoxy or ═O, or is 1-methylpyrrolo[2,3-b]pyridine-5-yl, or is 6-imidazo[1,2-b]pyridazin-6-yl;
or R 4 forms together with R 4′ a 4, 5 or 6 membered heterocyclic ring containing —(CH 2 ) 5 —, —CH 2 —CH 2 —O—CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —O—CH 2 —CH 2 — or CH 2 —CH 2 —CH 2 —O—CH 2 ; and

R 5 and R 5′ are hydrogen or lower alkyl;
or R 4 forms together with R 5 a saturated 5-membered ring containing —CH 2 —CH 2 —CH 2 —;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

2. A compound of formula IA according to claim 1 ,

wherein
Y is N or C—R 1′ ;
R 1′ is hydrogen or F;
R 1 is hydrogen, halogen or lower alkyl substituted by halogen;
R 2 is hydrogen or lower alkyl;
R 3 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
R 4′ is hydrogen, lower alkyl or lower alkoxyalkyl;
R 4 is hydrogen, lower alkyl, phenyl optionally substituted by halogen or lower alkoxy, or is cycloalkyl, or is pyridinyl optionally substituted by halogen, lower alkyl, lower alkoxy or ═O, or is pyrimidinyl optionally substituted by lower alkyl, lower alkoxy or ═O, or is 1-lower alkyl-pyridinyl, or is pyrazinyl, or is pyridazinyl optionally substituted by lower alkyl, lower alkoxy or ═O, or is 1-methylpyrrolo[2,3-b]pyridine-5-yl, or is 6-imidazo[1,2-b]pyridazin-6-yl; and
R 5 and R 5′ are hydrogen or lower alkyl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

3. A compound of formula IA according to claim 2 , wherein the compound is selected from the group consisting of
3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,6,6-trimethyl-hexahydropyrimidine-2,4-dione
3-[2-chloro-4-(2-phenylethynyl)phenyl]-1,6,6-trimethyl-hexahydropyrimidine-2,4-dione
(5RS)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,5,6,6-tetramethyl-hexahydropyrimidine-2,4-dione
3-[2-chloro-6-fluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1,6,6-trimethyl-hexahydropyrimidine-2,4-dione
3-[2-chloro-6-fluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1-ethyl-6,6-dimethyl-hexahydropyrimidine-2,4-dione
(6RS)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-phenyl-hexahydropyrimidine-2,4-dione
(6RS)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-phenyl-hexahydropyrimidine-2,4-dione
(6RS)-3-[2,6-difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1-ethyl-6-methyl-6-phenyl-hexahydropyrimidine-2,4-dione
(6RS)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6-ethyl-1,6-dimethyl-hexahydropyrimidine-2,4-dione
(6S)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-phenyl-hexahydropyrimidine-2,4-dione
(6R)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-phenyl-hexahydropyrimidine-2,4-dione
3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6,6-diethyl-hexahydropyrimidine-2,4-dione
3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6,6-diethyl-1-methyl-hexahydropyrimidine-2,4-dione
(6RS)-1,6-dimethyl-6-phenyl-3-[5-(2-phenylethynyl)-2-pyridyl]hexahydropyrimidine-2,4-dione
(6RS)-1,6-dimethyl-6-phenyl-3-[4-(2-phenylethynyl)phenyl]hexahydropyrimidine-2,4-dione
(6RS)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6-isopropyl-1,6-dimethyl-hexahydropyrimidine-2,4-dione
(6RS)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-(2-pyridyl)hexahydropyrimidine-2,4-dione
(6RS)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-(4-pyridyl)hexahydropyrimidine-2,4-dione
(6RS)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-(3-pyridyl)hexahydropyrimidine-2,4-dione
(6RS)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6-(methoxymethyl)-1,6-dimethyl-hexahydropyrimidine-2,4-dione
(6RS)-6-cyclohexyl-3-[2,6-difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1,6-dimethyl-hexahydropyrimidine-2,4-dione
(6RS)-3-[3-chloro-5-(2-phenylethynyl)-2-pyridyl]-1,6-dimethyl-6-phenyl-hexahydropyrimidine-2,4-dione
(6RS)-3-[2-chloro-6-fluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1,6-dimethyl-6-(3-pyridyl)hexahydropyrimidine-2,4-dione
(6RS)-3-[2-chloro-6-fluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1,6-dimethyl-6-phenyl-hexahydropyrimidine-2,4-dione
(6RS)-6-(3-chlorophenyl)-3-[2,6-difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1,6-dimethyl-hexahydropyrimidine-2,4-dione
(6RS)-6-(2-chlorophenyl)-3-[2,6-difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1,6-dimethyl-hexahydropyrimidine-2,4-dione
(6RS)-6-(4-chlorophenyl)-3-[2,6-difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1,6-dimethyl-hexahydropyrimidine-2,4-dione
(6RS)-3-[2,6-difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-6-(3-methoxyphenyl)-1,6-dimethyl-hexahydropyrimidine-2,4-dione
(6RS)-6-tert-butyl-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6-methyl-hexahydropyrimidine-2,4-dione
(6RS)-6-tert-butyl-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-hexahydropyrimidine-2,4-dione
(6RS)-3-[3-fluoro-5-(2-phenylethynyl)-2-pyridyl]-1,6-dimethyl-6-phenyl-hexahydropyrimidine-2,4-dione
(6RS)-1,6-dimethyl-6-phenyl-3-[5-(2-phenylethynyl)-3-(trifluoromethyl)-2-pyridyl]hexahydropyrimidine-2,4-dione
(6RS)-3-[2-Chloro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-(3-pyridyl)hexahydropyrimidine-2,4-dione
(6RS)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-6-ethyl-1-methyl-6-phenyl-hexahydropyrimidine-2,4-dione
(6S)-3-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-(3-pyridyl)hexahydropyrimidine-2,4-dione
(6S)-3-[3-Fluoro-5-(2-phenylethynyl)-2-pyridyl]-1,6-dimethyl-6-(3-pyridyl)hexahydropyrimidine-2,4-dione
(6RS)-6-(6-Chloro-3-pyridyl)-3-[2,6-difluoro-4- (2-phenylethynyl)phenyl]-1,6-dimethyl-hexahydropyrimidine-2,4-dione
(6S)-3-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1-ethyl-6-methyl-6-(3-pyridyl)hexahydropyrimidine-2,4-dione
(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1,6-dimethyl-6-(3-pyridyl)hexahydropyrimidine-2,4-dione
(6S)-3-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-(6-methyl-3-pyridyl)hexahydropyrimidine-2,4-dione
(6S)-3-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-pyrimidin-4-yl-hexahydropyrimidine-2,4-dione
(6S)-3-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-pyrimidin-5-yl-hexahydropyrimidine-2,4-dione
(6S)-3-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-pyrazin-2-yl-hexahydropyrimidine-2,4-dione
(6S)-3-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-pyridazin-3-yl-hexahydropyrimidine-2,4-dione
(6S)-3-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-6-(5-fluoro-3-pyridyl)-1,6-dimethyl-hexahydropyrimidine-2,4-dione
(6S)-6-(2-Chloro-4-pyridyl)-3-[2,6-difluoro-4-(2-phen

Assignees

• Hoffmann La Roche

Inventors

• Vieira Eric
• Jaeschke Georg
• Guba Wolfgang
• Ricci Antonio
• Rueher Daniel
• Biemans Barbara
• Plancher Jean-Marc
• O'Hara Fionn

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/48

  of the pancreatic hormones · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/22

  Anxiolytics · CPC title