# US 8,772,301 B2 · Compounds for treating disorders mediated by metabotropic glutamate receptor 5, and methods of use thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,772,301 B2
- Document ID: US8772301B2
- Status: Granted
- Kind: B2
- Application number: 12/972,293
- Filed: 2010-12-17
- Published: 2011-12-29
- Granted: 2014-07-08
- Earliest claimed: 2009-12-18
- Assignees: Sunovion Pharmaceuticals Inc.
- Applicants: Larry Wendell Hardy; Michele L. R. Heffernan; Frank Xinhe Wu; Kerry L. Spear; Lakshmi D. Saraswat
- Inventors: Larry Wendell Hardy; Michele L. R. Heffernan; Frank Xinhe Wu; Kerry L. Spear; Lakshmi D. Saraswat
- Web page: https://patentgrep.com/patent/US8772301B2

## CPC

- C07D 239/88: Oxygen atoms
- A61P 25/00: Drugs for disorders of the nervous system
- 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
- C07D 401/14: containing three or more hetero rings
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 471/04: Ortho-condensed systems
- C07D 471/14: Ortho-condensed systems
- C07D 471/20: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 487/08: Bridged systems
- C07D 487/20: Spiro-condensed systems
- C07D 491/20: Spiro-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are compounds and methods of synthesis thereof. The compounds set forth herein are useful for the treatment, prevention, and/or management of various disorders, such as neurological disorders, neurodegenerative disorders, neuropsychiatric disorders, disorders of cognition, learning or memory, gastrointestinal disorders, lower urinary tract disorder, and cancer. Compounds set forth herein modulate the activity of metabotropic glutamate receptor 5 (mGluR5) in the central nervous system or the periphery. Pharmaceutical formulations containing the compounds and their methods of use are also provided herein.

## Claims

### Claim 1

A compound of formula I:
wherein:
R1 is selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted;
R2 and R3, together with the atoms to which they are attached, form a piperidine ring which is optionally substituted;
G is NR2;
Q is N;
X is C;
Z is C═O; b is a single bond; c is a single bond; d is a double bond; e is a single bond; f is a double bond;
Y1, Y2 and Y3 are each independently selected from CH, C-halogen, and C-lower alkyl; and
L1 is selected from —C≡C—, —HC═CH—, -(lower alkyl)C═C(lower alkyl)-, and —CH2—CH2—, or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L1 is —C≡C— or —HC═CH—.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted aryl.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted heteroaryl.

### Claim 6 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted cycloalkyl.

### Claim 8 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are linked to form a group selected from:

### Claim 10 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 11 (depends on 1)

A method of treating or ameliorating a neurological disorder, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the neurological disorder is selected from schizophrenia, psychosis, and a cognitive disorder.

### Claim 12 (depends on 11)

The method of claim 11, wherein the neurological disorder is schizophrenia.

### Claim 13 (depends on 11)

The method of claim 11, wherein the neurological disorder is psychosis.

### Claim 14 (depends on 11)

The method of claim 11, wherein the neurological disorder is a cognitive disorder.

### Claim 15 (depends on 1)

A method of treating or ameliorating a neurological disorder, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the neurological disorder is Alzheimer's disease.

### Claim 16 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L1 is —C≡C—.

### Claim 17 (depends on 16)

The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted aryl.

### Claim 18 (depends on 17)

The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl substituted with 1, 2 or 3 halogens.

### Claim 19 (depends on 18)

The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are linked to form a group selected from:

### Claim 20 (depends on 16)

The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted heteroaryl.

### Claim 21 (depends on 20)

The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted pyridyl.

### Claim 22 (depends on 20)

The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R1 is 2-pyridyl.

### Claim 23 (depends on 22)

The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are linked to form a group selected from:

### Claim 24 (depends on 1)

The compound of claim 1, wherein the compound is of formula (III):
or a pharmaceutically acceptable salt thereof, wherein
R1d is selected from aryl and heteroaryl, each of which is optionally substituted;
R2d and R3d, together with the atoms to which they are attached, form a piperidine ring which is optionally substituted; and
L1d is selected from —C≡C— and —HC═CH—.

### Claim 25 (depends on 24)

The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are linked to form a group selected from:

### Claim 26 (depends on 24)

The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein L1d is —C≡C—.

### Claim 27 (depends on 26)

The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R1d is optionally substituted aryl.

### Claim 28 (depends on 27)

The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein R1d is aryl substituted with 1, 2 or 3 halogens.

### Claim 29 (depends on 26)

The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R1d is optionally substituted heteroaryl.

### Claim 30 (depends on 29)

The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein R1d is optionally substituted pyridyl.

### Claim 31 (depends on 29)

The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein R1d is 2-pyridyl.

### Claim 32 (depends on 1)

The compound of claim 1 having a structure selected from:
or a pharmaceutically acceptable salt thereof.