# US 10,246,432 B2 · 4-(3-cyanophenyl)-6-pyridinylpyrimidine mGlu5 modulators

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- Number: US 10,246,432 B2
- Document ID: US10246432B2
- Status: Granted
- Kind: B2
- Application number: 15/618,504
- Filed: 2017-06-09
- Published: 2017-09-28
- Granted: 2019-04-02
- Earliest claimed: 2013-07-17
- Assignees: Heptares Therapeutics Limited
- Applicants: Heptares Therapeutics Limited
- Inventors: John Andrew Christopher; Miles Stuart Congreve; Sarah Joanne Aves; Benjamin Gerald Tehan
- Web page: https://patentgrep.com/patent/US10246432B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/06: Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 1/10: Laxatives
- A61P 1/12: Antidiarrhoeals
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/04: Anorexiants; Antiobesity agents
- 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 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/04: Antipruritics
- 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 25/16: 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 25/32: Alcohol-abuse
- A61P 25/36: Opioid-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The disclosures herein relate to novel compounds of formula wherein R1, R2, R3 and R4 and n are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of inflammation, neurological or psychiatric disorders associated with modulating mGlu5 receptor function.

## Claims

### Claim 1

A method for the treatment of a disorder, comprising administering an effective amount of a compound to a subject in need thereof, wherein the compound is selected from the group consisting of the compounds represented by the following formulae:
or a pharmaceutically acceptable salt thereof, wherein
R1 is halogen, optionally substituted C1-C3 alkyl, cyclopropyl, optionally substituted C1-C3 alkoxy, cyano, hydroxyl, nitro or NH2;
R2 is H or F;
R3 is H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy or cyano;
R4 is H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or cyano; and
n is 0-3,
wherein the disorder is migraine, dystonia, depression, anxiety or amyotrophic lateral sclerosis (ALS).

### Claim 2 (depends on 1)

The method of claim 1, wherein the disorder is migraine.

### Claim 3 (depends on 1)

The method of claim 1, wherein the disorder is dystonia.

### Claim 4 (depends on 1)

The method of claim 1, wherein the disorder is depression.

### Claim 5 (depends on 1)

The method of claim 1, wherein the disorder is anxiety.

### Claim 6 (depends on 1)

The method of claim 1, wherein the disorder is amyotrophic lateral sclerosis (ALS).

### Claim 7 (depends on 1)

The method according to claim 1 wherein R1 is F, Cl, OMe, CH2OMe, Me, fluoromethyl or cyano.

### Claim 8 (depends on 1)

The method according to claim 1 wherein R1 is F, Cl or cyano.

### Claim 9 (depends on 1)

The method according to claim 1 wherein R3 is H, Me, F, Cl or cyano.

### Claim 10 (depends on 1)

The method according to claim 1 wherein R3 is H or F.

### Claim 11 (depends on 1)

The method according to claim 1 wherein n is 0 or 1.

### Claim 12 (depends on 1)

The method according to claim 1 wherein the compound is selected from the group consisting of:
3-chloro-4-fluoro-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile,
3-chloro-5- [6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile,
6-[6-(3-chloro-5-cyanophenyl)pyrimidin-4-yl]pyridine-3-carbonitrile,
3-methyl-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile,
3-chloro-5-[6-(pyridazin-3-yl)pyrimidin-4-yl]benzonitrile,
3-(4,4′-bipyrimidin-6-yl)-5-chlorobenzonitrile,
3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile,
5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzene-1,3-dicarbonitrile,
3-chloro-5-[6-(5-methylpyridin-2-yl)pyrimidin-4-yl]benzonitrile,
3-chloro-5-[6-(5-chloropyridin-2-yl)pyrimidin-4-yl]benzonitrile,
5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzene-1,3-dicarbonitrile,
3-chloro-4-fluoro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile,
3-methyl-5-[6-(5-methylpyridin-2-yl)pyrimidin-4-yl]benzonitrile,
3-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]-5-methoxymethyl)benzonitrile, and
3-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]-5-methoxybenzonitrile,
or a pharmaceutically acceptable salt thereof.