# US 9,040,707 B2 · Bicyclic thiazoles as allosteric modulators of mGluR5 receptors

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- Number: US 9,040,707 B2
- Document ID: US9040707B2
- Status: Granted
- Kind: B2
- Application number: 13/516,985
- Filed: 2010-12-16
- Published: 2012-10-11
- Granted: 2015-05-26
- Earliest claimed: 2009-12-18
- Assignees: Janssen Pharmaceutica NV
- Applicants: Gregor James MacDonald; Andrés Avelino Trabanco-Suárez; Susana Conde-Ceide; Gary John Tresadern; José Manuel Bartolomé-Nebreda; Joaquin Pastor-Fernández
- Inventors: Gregor James MacDonald; Andrés Avelino Trabanco-Suárez; Susana Conde-Ceide; Gary John Tresadern; José Manuel Bartolomé-Nebreda; Joaquin Pastor-Fernández
- Web page: https://patentgrep.com/patent/US9040707B2

## CPC

- C07D 513/04: Ortho-condensed systems
- A61K 31/4365: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel bicyclic thiazoles which are positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (“mGluR5”) and which are useful for the treatment or prevention of disorders associated with glutamate dysfunction and diseases in which the mGluR5 subtype of receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which mGluR5 is involved.

## Claims

### Claim 1

A compound of formula (I)
or a stereoisomeric form thereof,
wherein
n is 1;
A is selected from the group consisting of —CH2O— and —O—CH2—;
R1 is selected from the group consisting of phenyl and phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of C1-6alkyl, trifluoromethyl, cyano and halo; and
R2 is selected from the group consisting of hydrogen; C1-8alkyl; (C1-6alkyloxy)C1-3alkyl; C3-8cycloalkyl; (C3-8cycloalkyl)C1-3alkyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of C1-6alkyl, C1-3alkyloxy, halo and C1-3alkyl substituted with 1, 2 or 3 independently selected halo substituents; (phenyl)C1-3alkyl; (phenyl)C1-3alkyl wherein the phenyl part is substituted with 1, 2 or 3 independently selected halo substituents; pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from the group consisting of C1-6alkyl, C1-3alkyloxy, halo and C1-3alkyl substituted with 1, 2 or 3 independently selected halo substituents; and (tetrahydro-2H-pyranyl)-methyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound of formula (I) according to claim 1, wherein
A is selected from the group consisting of —CH2O— and —O—CH2—;
R1 is selected from the group consisting of phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of C1-3alkyl and fluoro; and 3-cyanophenyl; and
R2 is selected from the group consisting of hydrogen; C1-6alkyl; (C1-6alkyloxy)C1-3alkyl; C3-8cycloalkyl; (C3-8cycloalkyl)C1-3alkyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of C1-3alkyl, C1-3alkyloxy, halo and C1-3alkyl substituted with 1, 2 or 3 independently selected halo substituents; (phenyl)C1-3alkyl; (phenyl)C1-3alkyl wherein the phenyl part is substituted with 1, 2 or 3 independently selected halo substituents; pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from the group consisting of C1-3alkyl, C1-3alkyloxy, halo and C1-3alkyl substituted with 1, 2 or 3 independently selected halo substituents; and (tetrahydro-2H-pyranyl)-methyl;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein
A is —CH2O—;
R1 is selected from the group consisting of phenyl and phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of C1-3alkyl and fluoro; and 3-cyanophenyl; and
R2 is selected from the group consisting of hydrogen; methyl; ethyl; 1,2,2-trimethyl-propyl; (C1-6alkyloxy)C1-3alkyl; C3-8cycloalkyl; (C3-8cycloalkyl)C1-3alkyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of C1-3alkyl, C1-3alkyloxy, halo and C1-3alkyl substituted with 1, 2 or 3 independently selected halo substituents; (phenyl)C1-3alkyl; (phenyl)C1-3alkyl wherein the phenyl part is substituted with 1, 2 or 3 independently selected halo substituents; pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from the group consisting of C1-3alkyl, C1-3alkyloxy, halo and C1-3alkyl substituted with 1, 2 or 3 independently selected halo substituents; and (tetrahydro-2H-pyranyl)-methyl;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein
A is —CH2O—;
R1 is selected from the group consisting of phenyl and phenyl substituted with 1 or 2 substituents each independently selected from the group consisting of C1-3alkyl and fluoro; and
R2 is selected from the group consisting of hydrogen; methyl; ethyl; 1,2,2-trimethyl-propyl; (C1-6alkyloxy)C1-3alkyl; (C3-8cycloalkyl)C1-3alkyl; phenyl; phenyl substituted with 1 or 2 substituents each independently selected from the group consisting of C1-3alkyl, C1-3alkyloxy, halo and C1-3alkyl substituted with 1, 2 or 3 independently selected halo substituents; (phenyl)C1-3alkyl;
(phenyl)C1-3alkyl wherein the phenyl part is substituted with 1 or 2 independently selected halo substituents; pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from the group consisting of C1-3alkyl, C1-3alkyloxy, halo and C1-3alkyl substituted with 1, 2 or 3 independently selected halo substituents; and (tetrahydro-2H-pyranyl)-methyl;
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein
A is —O—CH2—;
R1 is selected from the group consisting of phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of C1-3alkyl and fluoro; and 3-cyanophenyl; and
R2 is selected from the group consisting of C1-3alkyl;
(C1-6alkyloxy)C1-3alkyl; C3-8cycloalkyl; (C3-8cycloalkyl)C1-3alkyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of C1-3alkyl, C1-3alkyloxy, halo and C1-3alkyl substituted with 1, 2 or 3 fluoro substituents; (phenyl)C1-3alkyl; (phenyl)C1-3alkyl wherein the phenyl part is substituted with 1, 2 or 3 independently selected halo substituents; pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from the group consisting of C1-3alkyl, C1-3alkyloxy, halo and C1-3alkyl substituted with 1, 2 or 3 fluoro substituents; and (tetrahydro-2H-pyranyl)-methyl;
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

A compound according to claim 1, selected from the group consisting of
5-(4-fluorophenyl)-6,7-dihydro-2-(phenylmethoxy)-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-2-(phenoxymethyl)-5-[(tetrahydro-2H-pyran-4-yl)methyl]-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-5-(2-methoxyethyl)-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-5-(5-methyl-2-pyridinyl)-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(4-fluorophenoxy)methyl]-5-(4-fluorophenyl)-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(3-fluorophenoxy)methyl]-6,7-dihydro-5-[(1R)-1,2,2-trimethylpropyl]-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-5-methyl-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(4-fluorophenyl)-6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-6,7-dihydro-2-(phenylmethoxy)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-[(2,4-difluorophenyl)methyl]-6,7-dihydro-2-(phenylmethoxy)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-[(4-fluorophenyl)methyl]-6,7-dihydro-2-(phenylmethoxy)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-[(3-fluorophenyl)methyl]-6,7-dihydro-2-(phenylmethoxy)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-[(2-fluorophenyl)methyl]-6,7-dihydro-2-(phenylmethoxy)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-2-[(3-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-2-[(2-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(4-fluorophenyl)-2-[(3-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
3-[[[5-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-4-oxothiazolo[5,4-c]pyridin-2-yl]oxy]methyl]-benzonitrile,
5-(2,4-difluorophenyl)-6,7-dihydro-2-[(3-methylphenyl)methoxy]-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(4-fluorophenyl)-2-[(2-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-2-[(2,4-difluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-5-methyl-2-(phenylmethoxy)-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(3-fluorophenoxy)methyl]-5-(4-fluorophenyl)-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(3-fluorophenyl)methoxy]-6,7-dihydro-5-[4-(trifluoromethyl)phenyl]-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(3-fluorophenyl)-2-[(3-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-2-[(3-fluorophenoxy)methyl]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(3-fluorophenyl)methoxy]-6,7-dihydro-5-[3-(trifluoromethyl)phenyl]-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(2-fluorophenoxy)methyl]-5-(4-fluorophenyl)-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-2-[(4-fluorophenoxy)methyl]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(2-fluorophenoxy)methyl]-6,7-dihydro-5-[(1R)-1,2,2-trimethylpropyl]-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(4-fluorophenoxy)methyl]-6,7-dihydro-5-[(1R)-1,2,2-trimethylpropyl]-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-2-(phenoxymethyl)-5-[(1R)-1,2,2-trimethylpropyl]-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(2-fluorophenoxy)methyl]-6,7-dihydro-5-(2-methoxyphenyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(3-fluorophenoxy)methyl]-6,7-dihydro-5-(2-methoxyphenyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
5,6,7,8-tetrahydro-5-methyl-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepin-4-one,
5-(cyclopropylmethyl)-6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-cyclopropyl-2-[(3-fluorophenoxy)methyl]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(cyclopropylmethyl)-2-[(3-fluorophenoxy)methyl]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(cyclopropylmethyl)-2-[(2-fluorophenoxy)methyl]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(cyclopropylmethyl)-2-[(4-fluorophenoxy)methyl]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-cyclopropyl-6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-2-(phenoxymethyl)-5-(2-pyridinyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-5-(6-methyl-2-pyridinyl)-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(5-fluoro-2-pyridinyl)-6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-2-(phenoxymethyl)-5-(3-pyridinyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-2-(phenoxymethyl)-5-(4-pyridinyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(3-fluoro-2-pyridinyl)-6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-5-(4-methyl-2-pyridinyl)-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-5-(3-methyl-2-pyridinyl)-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(4-fluorophenoxy)methyl]-5-(5-fluoro-2-pyridinyl)-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(3-fluorophenoxy)methyl]-5-(5-fluoro-2-pyridinyl)-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(2-fluorophenoxy)methyl]-5-(5-fluoro-2-pyridinyl)-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-ethyl-6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(5-fluoro-3-pyridinyl)-6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(3-fluoro-4-pyridinyl)-6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-2-[(2-fluorophenoxy)methyl]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(4-chlorophenoxy)methyl]-5-(4-fluorophenyl)-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-cyclopropyl-2-[(2-fluorophenoxy)methyl]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-cyclopropyl-2-[(4-fluorophenoxy)methyl]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-5-(1-methylethyl)-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(3-fluorophenoxy)methyl]-6,7-dihydro-5-(1-methylethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-2-(phenylmethoxy)-thiazolo[5,4-c]pyridin-4(5H)-one,
2-fluoro-5-[[(4,5,6,7-tetrahydro-4-oxothiazolo[5,4-c]pyridin-2-yl)oxy]methyl]-benzonitrile,
6,7-dihydro-2-[(2-methylphenyl)methoxy]-thiazolo[5,4-c]pyridin-4(5H)-one,
6,7-dihydro-2-[(3-methylphenyl)methoxy]-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(2-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(2-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one trifluoroacetate,
2-[(3-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(3-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one trifluoroacetate,
2-[(4-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
2-[(4-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one trifluoroacetate,
6,7-dihydro-2-[(4-methylphenyl)methoxy]-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-2-[(3,5-difluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-2-[(3,4-difluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,
4-[[[5-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-4-oxothiazolo[5,4-c]pyridin-2-yl]oxy]methyl]-benzonitrile,
2-[[[5-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-4-oxothiazolo[5,4-c]pyridin-2-yl]oxy]methyl]-benzonitrile,
2-[(3-fluorophenyl)methoxy]-6,7-dihydro-5-[(1R)-1,2,2-trimethylpropyl]-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-6,7-dihydro-2-[[4-(trifluoromethyl)phenyl]methoxy]-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-6,7-dihydro-2-[(2-methoxyphenyl)methoxy]-thiazolo[5,4-c]pyridin-4(5H)-one,
5-(2,4-difluorophenyl)-6,7-dihydro-2-[(3-methoxyphenyl)methoxy]-thiazolo[5,4-c]pyridin-4(5H)-one, and
5-(2,4-difluorophenyl)-6,7-dihydro-2-[[2-(trifluoromethyl)phenyl]methoxy]-thiazolo[5,4-c]pyridin-4(5H)-one,
and the stereoisomeric forms, the pharmaceutically acceptable salts thereof.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1 and a pharmaceutically acceptable carrier.