# US 8,785,486 B2 · Imidazo[1,2-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors

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- Number: US 8,785,486 B2
- Document ID: US8785486B2
- Status: Granted
- Kind: B2
- Application number: 12/742,638
- Filed: 2008-11-12
- Published: 2011-01-13
- Granted: 2014-07-22
- Earliest claimed: 2007-11-14
- Assignees: Janssen Pharmaceuticals, Inc.; Addex Pharma SA
- Applicants: Andres Avelino Trabanco-Suarez; Gary John Tresadern; Juan Antonio Vega Ramiro; Jose Maria Cid-Nunez
- Inventors: Andres Avelino Trabanco-Suarez; Gary John Tresadern; Juan Antonio Vega Ramiro; Jose Maria Cid-Nunez
- Web page: https://patentgrep.com/patent/US8785486B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/10: for petit-mal
- 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 25/22: 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 25/32: Alcohol-abuse
- A61P 25/34: Tobacco-abuse
- A61P 25/36: Opioid-abuse
- A61P 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 519/00: 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel compounds, in particular novel imidazo[1,2-a]piridine derivatives according to Formula (I). The compounds according to the invention are positive allosteric modulators of metabotropic receptors-sub-type 2 (‘mGluR2’) which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

## Claims

### Claim 1

A compound having the formula (I)
or a stereochemically isomeric form thereof, wherein
R1 is C1-6 alkyl; C3-6 cycloalkyl; trifluoromethyl; C1-3 alkyl substituted with trifluoromethyl, C3-7 cycloalkyl, phenyl, or phenyl substituted with C1-3 alkyl, C1-3alkyloxy, cyano, halo, trifluoromethyl; phenyl; phenyl substituted with 1 or 2 substituents selected from the group consisting of C1-3 alkyl, cyano, halo, trifluoromethyl; or 4-tetrahydropyranyl;
R2 is cyano, halo, trifluoromethyl, C1-3 alkyl or cyclopropyl;
R3 is a radical of formula (a) or (b) or (d)
R4 is hydroxyC3-6 cycloalkyl; pyridinyl; pyridinyl substituted with one or two C1-3 alkyl groups; pyrimidinyl; pyrimidinyl substituted with one or two C1-3 alkyl groups; phenyl; phenyl substituted with 1 or 2 substituents selected from the group consisting of halo, C1-3 alkyl, hydroxyC1-3 alkyl, mono- or polyhaloC1-3 alkyl, cyano, hydroxyl, carboxyl, C1-3 alkyloxyC1-3 alkyl, C1-3 alkyloxy, mono- or polyhalo-C1-3 alkyloxy, and morpholinyl;
R5 is hydrogen, fluoro, hydroxyl, hydroxyC1-3 alkyl, fluoroC1-3 alkyl, morpholinyl or cyano;
X is C or N in which case R5 represent the electron pair on N; or
R4—X—R5 represents a radical of formula (h) or (i) or (j)
n is 0 or 1;
q is 1 or 2;
R6 is C1-3 alkyl; C3-6cycloalkyl; hydroxyC2-4alkyl; (C3-6cycloalkyl)C1-3alkyl; phenyl; pyridinyl; or phenyl or pyridinyl substituted with one or two substituents selected from the group consisting of halo, C1-3alkyl, C1-3alkoxy, hydroxyC1-3alkyl, trifluoromethyl and (CH2)m—CO2H, wherein m=0, 1, or 2; or
R6 is a cyclic radical of formula (k)
wherein R8 is hydrogen, C1-3alkyl, hydroxyC1-3alkyl;
p is 1 or 2;
Z is O, CH2 or CR9(OH) wherein R9 is hydrogen or C1-3alkyl;
R7 is hydrogen, halo or trifluoromethyl;
Y is a covalent bond, O, NH, S, C(OH)(CH3), —CH2—O—, —O—CH2—, CHF or CF2; or
R6—Y is morpholinyl, pyrrolidinyl, or piperidinyl optionally substituted with hydroxyl or hydroxyC1-3alkyl; and
A is O or NH;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 having the formula (I)
or a stereochemically isomeric form thereof, wherein
R1 is C1-6 alkyl; trifluoromethyl; C1-3 alkyl substituted with trifluoromethyl, C3-7 cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl; phenyl; phenyl substituted with halo, trifluoromethyl; or 4-tetrahydropyranyl;
R2 is cyano, halo, trifluoromethyl, C1-3 alkyl or cyclopropyl;
R3 is a radical of formula (a) or (b)
R4 is pyridinyl; pyrimidinyl; pyrimidinyl substituted with one or two C1-3 alkyl groups; phenyl; phenyl substituted with 1 or 2 substituents selected from the group consisting of halo, C1-3 alkyl, hydroxyC1-3 alkyl, polyhaloC1-3 alkyl, cyano, hydroxyl, carboxyl, C1-3 alkyloxyC1-3 alkyl, C1-3 alkyloxy, polyhaloC1-3 alkyloxy, and morpholinyl;
R5 is hydrogen, fluoro, hydroxyl, hydroxyC1-3 alkyl, fluoroC1-3 alkyl, or cyano;
X is C or N in which case R5 represent the electron pair on N;
n is 0 or 1;
R6 is phenyl; pyridinyl; or phenyl or pyridinyl substituted with one or two substituents selected from the group consisting of halo, C1-3alkyl, C1-3alkoxy, trifluoromethyl and (CH2)m—CO2H, wherein m=0, 1, or 2; or
R6 is a cyclic radical of formula (k)
wherein R8 is hydrogen, C1-3alkyl, hydroxyC1-3alkyl;
p is 1 or 2;
Z is O or CR9(OH) wherein R9 is hydrogen or C1-3alkyl;
R7 is hydrogen, halo or trifluoromethyl;
Y is a covalent bond, O, NH, S, or CF2; or
a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1 or a stereochemically isomeric form thereof, wherein
R1 is C1-6 alkyl; trifluoromethyl; C1-3 alkyl substituted with trifluoromethyl, or phenyl; or phenyl;
R2 is cyano or halo;
R3 is a radical of formula (a) or (b)
R4 is pyrimidinyl; pyrimidinyl substituted with one or two C1-3 alkyl groups; phenyl; phenyl substituted with 1 or 2 substituents selected from the group consisting of halo, polyhalo C1-3 alkyl,
R5 is hydrogen or hydroxyl;
X is C or N in which case R5 represent the electron pair on N;
n is 0 or 1;
R6 is pyridinyl substituted with one or two substituents selected from the group consisting of C1-3 alkyl;
R7 is hydrogen or halo;
Y is O; or
a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound according to claim 1 wherein
R1 is methyl; ethyl, 1-propyl, trifluoromethyl; 2,2,2-trifluoroethyl, 4,4,4-trifluorobutyl, phenylmethyl or phenyl;
R2 is cyano;
R3 is a radical of formula (a) or (b)
R4 is pyrimidinyl; pyrimidinyl substituted with one or two C1-3 alkyl groups; phenyl;
phenyl substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro and trifluoromethyl;
R5 is hydrogen or hydroxyl;
X is C or N in which case R5 represent the electron pair on N;
n is 0 or 1;
R6 is pyridinyl substituted with one or two substituents selected from the group consisting of methyl;
R7 is hydrogen, fluoro or chloro;
Y is O; or
a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein said compound has the formula