# US 2013/0158042 A1 · Novel compounds

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- Number: US 2013/0158042 A1
- Document ID: US20130158042A1
- Status: Published application
- Kind: A1
- Application number: 13/709,312
- Filed: 2012-12-10
- Published: 2013-06-20
- Earliest claimed: 2011-12-14
- Assignees: Boehringer Ingelheim International GmbH
- Inventors: Annekatrin HEIMANN; Georg DAHMANN; Marc GRUNDL; Stephan Georg MUELLER; Bernd WELLENZOHN
- Web page: https://patentgrep.com/patent/US20130158042A1

## CPC

- C07D 513/04: Ortho-condensed systems
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/14: containing three or more hetero rings
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention relates to compounds of formula I their use as positive allosteric modulators of mGlu5 receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of neurological and psychiatric disorders associated with glutamate dysfunction such as schizophrenia or cognitive decline such as dementia or cognitive impairment. R1, R2, R3, R4, Q have meanings given in the description.

## Claims

### Claim 1

A compound of formula I
in which
R1 represents phenyl or pyridyl which latter two groups are optionally substituted with one to three groups selected independently of one another from halogen, cyano, nitro, amino, C1-5alkyl, C3-6cycloalkyl, —O—C1-5alkyl, —N(R5)(R6) and —C(O)N(R5)(R6) which latter five groups are optionally substituted with one or more fluorine atoms;
R2 represents a 5-14-membered aryl or 5-14-membered heteroaryl which latter two groups are optionally substituted with 1 to 4 groups selected from —OH, halogen, cyano, 4-9-membered heterocyclyl, C6-10 aryl, 5-9 membered heteroaryl, C1-5alkyl, —C1-5alkyl-OH, —O—C1-5-alkyl, —O—C1-5alkyl-O—C1-5-alkyl, —O—C3-5 alkynyl, —C1-5alkyl-O—C1-5-alkyl, C3-7cycloalkyl, —O—C3-7cycloalkyl, —O—CH2—C3-7cycloalkyl, C1-5alkyl-CO—, —C1-5alkyl-N(R5)(R6), —N(R5)(R6) and —S(O)2—C1-5alkyl which latter sixteen groups are optionally substituted with one or more fluorine atoms;
R3 and R4 independently represent hydrogen, C1-3alkyl and —C1-3alkyl-O—C1-3alkyl which latter three groups are optionally substituted with one or more fluorine atoms, with the proviso that R3 and R4 both are not hydrogen;
or
R3 and R4 if both are attached to the same carbon atom, they may together with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl which latter seven groups are optionally substituted with one or more fluorine atoms;
R5 and R6 independently represent hydrogen, C1-5alkyl, benzyl, —C(O)—C1-5alkyl, —C(S)—C1-5alkyl and —S(O)2—C1-5alkyl which latter five groups are optionally substituted with one or more fluorine atoms,
or
R5 and R6 together with the nitrogen atom to which they are attached form a 4-6-membered heterocyclyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl ring which latter four groups are optionally substituted with one or more fluorine atoms;
Q represents CH or N;
or a physiologically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, namely a compound of formula Ia
in which
R1, R2, R3, R4, Q have the same meaning as defined in claim 1;
or a salt thereof, particularly a physiologically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein
R1 represents phenyl,

### Claim 4 (depends on 3)

The compound according to claim 3, wherein
R3 and R4 independently represent hydrogen, methyl, ethyl, propyl or —CH2—O—CH3 which latter four groups are optionally substituted with one or more fluorine atoms with the proviso that R3 and R4 both are not hydrogen;
or
R3 and R4 if both are attached to the same carbon atom, they may together with the carbon atom to which they are attached form a ring selected from cyclopropyl, cyclobutyl and cyclopentyl which latter three groups are optionally substituted with one or more fluorine atoms.

### Claim 5 (depends on 4)

The compound according to claim 4, wherein
R3 and R4 represent methyl.

### Claim 6 (depends on 1)

The compound according to claim 1, namely a compound of formula Ib
in which
R7 represents hydrogen, halogen, cyano, nitro, amino, C1-5alkyl, C3-6cycloalkyl, —O—C1-5alkyl, —N(R5)(R6) or —C(O)N(R5)(R6) which latter five groups are optionally substituted with one or more fluorine atoms;
R5 and R6 independently represent hydrogen, C1-3alkyl, benzyl or —C(O)—C1-3alkyl, which latter three groups are optionally substituted with one or more fluorine atoms,
or
R5 and R6 together with the nitrogen atom to which they are attached form a group selected from azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl which latter four groups are optionally substituted with one or more fluorine atoms.
or a physiologically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound according to claim 1, namely a compound of formula Ic
in which
R7 represents hydrogen, halogen, cyano, nitro, amino, C1-5alkyl, C3-6cycloalkyl, —O—C1-5alkyl, —N(R5)(R6) or —C(O)N(R5)(R6) which latter five groups are optionally substituted with one or more fluorine atoms;
R5 and R6 independently represent hydrogen, C1-3alkyl, benzyl or —C(O)—C1-3alkyl, which latter three groups are optionally substituted with one or more fluorine atoms,
or
R5 and R6 together with the nitrogen atom to which they are attached form a group selected from azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl which latter four groups are optionally substituted with one or more fluorine atoms.
or a physiologically acceptable salt thereof.

### Claim 8 (depends on 2, 6, 7)

The compound according to claim 2, 6 or 7, wherein
R2 represents phenyl, naphthyl, 3-isochinolyl,
R9 represents fluoro, chloro, bromo, cyano, C1-4-alkyl, C3-6-cycloalkyl, —O—C3-6cycloalkyl, —O—CH2—C3-6cycloalkyl, 4-6-membered heterocyclyl, —O—C1-4-alkyl, —O—CH2-ethynyl, —O—C1-2alkyl-OC1-2alkyl, CF3, —O—CF3, CF2H, —NMe2, phenyl,
R10, R11 independently represents hydrogen, chloro, fluoro, methyl, ethyl, propyl, iso-propyl, CF3, —CF2H, —OCH3, —OCF3 or —NH—COCH3.

### Claim 9

A compound of formula II
in which
R2 represents phenyl, naphthyl, 3-isochinolyl,
R7 represents hydrogen, fluoro, bromo, chloro, cyano or methyl;
R9 represents fluoro, chloro, bromo, cyano, C1-4-alkyl, C3-6-cycloalkyl, —O—C3-6cycloalkyl, —O—CH2—C3-6cycloalkyl, 4-6-membered heterocyclyl, —O—C1-4-alkyl, —O—CH2-ethynyl, —O—C1-2alkyl-OC1-2alkyl, CF3, —O—CF3, CF2H, —NMe2, phenyl,
R10, R11 independently represents hydrogen, chloro, fluoro, methyl, ethyl, propyl, iso-propyl, CF3, —CF2H, —OCH3, —OCF3 or —NH—COCH3;
or a physiologically acceptable salt thereof.

### Claim 10

A compound according to formula III
in which
R2 represents phenyl, naphthyl, 3-isochinolyl,
R7 represents hydrogen, fluoro, bromo, chloro, cyano or methyl;
R9 represents fluoro, chloro, bromo, cyano, C1-4-alkyl, C3-6-cycloalkyl, —O—C3-6cycloalkyl, —O—CH2—C3-6cycloalkyl, 4-6-membered heterocyclyl, —O—C1-4-alkyl, —O—CH2-ethynyl, —O—C1-2alkyl-OC1-2alkyl, CF3, —O—CF3, CF2H, —NMe2, phenyl,
R10, R11 independently represents hydrogen, chloro, fluoro, methyl, ethyl, propyl, iso-propyl, CF3, —CF2H, —OCH3, —OCF3 or —NH—COCH3;
or a physiologically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound according to any one of claim 1, wherein
R1 represents phenyl,
R2 represents
R3 and R4 independently represent hydrogen, methyl, ethyl, propyl or —CH2—O—CH3 which latter four groups are optionally substituted with one or more fluorine atoms with the proviso that R3 and R4 both are not hydrogen;
or
R3 and R4 if both are attached to the same carbon atom, they may together with the carbon atom to which they are attached form a ring selected from cyclopropyl, cyclobutyl and cyclopentyl which latter three groups are optionally substituted with one or more fluorine atoms;
or a physiologically acceptable salt thereof.

### Claim 12

A compound selected from the group consisting of
or a physiologically acceptable salt thereof.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.

### Claim 14 (depends on 1)

A method of treating schizophrenia, schizoaffective disorder and substance induced psychotic disorder; cognitive disorders and dementias including age-associated learning and memory impairments or losses, post stroke dementia, deficits in concentration, mild cognitive impairment, the cognitive dysfunction in Alzheimers disease or the cognitive dysfunction of schizophrenia comprising administering to a patient a therapeutically effective amount of a compound according to claim 1.