# US 2024/0199641 A1 · Quinazoline-4(3h)-one derivatives as negative allosteric modulators of metabotropic glutamate receptor 2

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

- Number: US 2024/0199641 A1
- Document ID: US20240199641A1
- Status: Published application
- Kind: A1
- Application number: 18/553,406
- Filed: 2022-04-01
- Published: 2024-06-20
- Earliest claimed: 2021-04-02
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: Elizabeth S. Childress; Craig W. Lindsley
- Web page: https://patentgrep.com/patent/US20240199641A1

## CPC

- C07D 498/04: Ortho-condensed systems
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- 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
- C07D 239/88: Oxygen atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- 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

Described are 6-aryl quinazolin-4(3H)-ones as negative allosteric modulators of metabotropic glutamate receptor 2 (mGlu2), pharmaceutical compositions including the compounds, and methods of using the compounds and compositions for treating depression, anxiety, obsessive-compulsive disorder, cognitive disorders, Alzheimer's disease, or autism spectrum disorders in a subject.

## Claims

### Claim 1

A compound of formula (I), or a pharmaceutically acceptable salt thereof,
wherein:
L1 is a C1-6alkylene or C1-6fluoroalkylene, wherein optionally 1 or 2 methylene groups in the alkylene or fluoroalkylene of L1 are independently replaced with —O—, —S—, —SO—, —SO2—, or —N(R)—, wherein 2 methylene groups replaced with —O—, —S—, —SO—, —SO2—, or —N(R)— are separated by two or more carbon atoms in the alkylene or fluoroalkylene; and/or optionally 1 methylene group in the alkylene or fluoroalkylene of L1 is replaced with -Cy-;
Cy is C3-6cycloalkylene or a 4- to 6-membered heterocyclylene, wherein Cy is optionally substituted with 1-6 substituents independently selected from the group consisting of C1-C4alkyl, C1-2fluoroalkyl, and halogen;
R, at each occurrence, is independently hydrogen or C1-4alkyl;
R1 is hydrogen or C1-6alkyl;
R2 is hydrogen or C1-6alkyl;
R3 is a 6- to 12-membered aryl or 5- to 12-membered heteroaryl, wherein R3 is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-4alkyl, halogen, cyano, C1-2haloalkyl, —OC1-4alkyl, and —OC1-2haloalkyl;
R4 is a 6- to 12-membered aryl or 5- to 12-membered heteroaryl, wherein R4 is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-4alkyl, halogen, cyano, C1-2haloalkyl, —OC1-4alkyl, and —OC1-2haloalkyl; and
R5 and R6 are each independently hydrogen, C1-4alkyl, halogen, cyano, C1-2haloalkyl, —OC1-4alkyl, or —OC1-2haloalkyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L1 is a C1-4alkylene, wherein 1 or 2 methylene groups in the alkylene of L1 are replaced with —O—, wherein 2 methylene groups replaced with —O— are separated by two or more carbon atoms in the alkylene.

### Claim 3 (depends on 1, 2)

The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L1 is a C2-3alkylene, wherein 1 methylene group in the alkylene of L1 is replaced with —O—.

### Claim 4 (depends on 1, 2, 3)

The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein L1 is

### Claim 5 (depends on 1, 2, 3, 4)

The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

### Claim 6 (depends on 1, 2, 3, 4, 5)

The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R4 is the unsubstituted or substituted 5- to 12-membered heteroaryl.

### Claim 7 (depends on 1, 2, 3, 4, 5, 6)

The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 5- to 12-membered heteroaryl at R4 is an 8- to 10-membered fused bicyclic heteroaryl having 2-4 double bonds and 1-4 heteroatoms independently selected from the group consisting of N, O, and S.

### Claim 8 (depends on 1, 2, 3, 4, 5, 6, 7)

The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R4 is an unsubstituted 9-membered fused bicyclic heteroaryl having 2 double bonds and 1-3 heteroatoms independently selected from the group consisting of N and O.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7, 8)

The compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein R4 is

### Claim 10 (depends on 1, 2, 3, 4, 5, 6)

The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 5- to 12-membered heteroaryl at R4 is a 5- or 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S.

### Claim 11 (depends on 10)

The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 5- or 6-membered monocyclic heteroaryl is pyridinyl, imidazolyl, thiazolyl, pyrazolyl, or oxazolyl.

### Claim 12 (depends on 11)

The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R4 is

### Claim 13 (depends on 12)

The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R4 is

### Claim 14 (depends on 1, 2, 3, 4, 5)

The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R4 is the unsubstituted or substituted 6- to 12-membered aryl.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R3 is the unsubstituted or substituted 6- to 12-membered aryl.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)

The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 6- to 12-membered aryl at R3 is phenyl.

### Claim 17 (depends on 16)

The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R3 is

### Claim 18 (depends on 17)

The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R3 is

### Claim 19 (depends on 18)

The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R3 is

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R3 is the unsubstituted or substituted 5- to 12-membered heteroaryl.

### Claim 21 (depends on 20)

The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 5- to 12-membered heteroaryl at R3 is a 5- or 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S.

### Claim 22 (depends on 21)

The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 5- or 6-membered monocyclic heteroaryl is pyrrolyl.

### Claim 23 (depends on 22)

The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R3 is

### Claim 24 (depends on 23)

The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R3 is

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)

The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently selected from the group consisting of hydrogen, C1-4alkyl, and halogen.

### Claim 26 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)

The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each hydrogen.

### Claim 27 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)

The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

### Claim 28 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27)

The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Ia):

### Claim 29 (depends on 1)

The compound of claim 1, selected from the group consisting of:
6-(4-fluorophenyl)-7-((1-methyl-1H-pyrazol-3-yl)methoxy)quinazolin-4(3H)-one;
6-(4-fluorophenyl)-7-((1-methyl-1H-pyrazol-5-yl)methoxy)quinazolin-4(3H)-one;
7-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methoxy)-6-(4-fluorophenyl)quinazolin-4(3H)-one;
6-(2-fluoro-4-methoxyphenyl)-7-((1-methyl-1H-pyrazol-3-yl)methoxy)quinazolin-4(3H)-one;
6-(2,4-difluorophenyl)-7-((1-methyl-1H-pyrazol-3-yl)methoxy)quinazolin-4(3H)-one;
7-((1-methyl-1H-pyrazol-3-yl)methoxy)-6-(1-methyl-1H-pyrrol-3-yl)quinazolin-4(3H)-one;
6-(4-methoxyphenyl)-7-((1-methyl-1H-pyrazol-3-yl)methoxy)quinazolin-4(3H)-one; and
7-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methoxy)-6-(4-methoxyphenyl)quinazolin-4(3H)-one;
or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)

A pharmaceutical composition comprising the compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)

A method for treating a disease or disorder associated with dysfunction of metabotropic glutamate receptor 2 (mGlu2) comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30.

### Claim 32 (depends on 31)

The method of claim 31, wherein the disease or disorder is selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive disorders, Alzheimer's disease, and autism spectrum disorders.

### Claim 33 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)

A compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, for use in the treatment of a disease or disorder selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive disorders, Alzheimer's disease, and autism spectrum disorders.

### Claim 34 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)

Use of a compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, in the manufacture of a medicament for the treatment of a disease or disorder selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive disorders, Alzheimer's disease, and autism spectrum disorders.