# US 2018/0022712 A1 · Negative allosteric modulators of metabotropic glutamate receptor 3

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- Number: US 2018/0022712 A1
- Document ID: US20180022712A1
- Status: Published application
- Kind: A1
- Application number: 15/549,944
- Filed: 2016-02-10
- Published: 2018-01-25
- Earliest claimed: 2015-02-10
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: P. Jeffrey Conn; Craig W. Lindsley; Kyle A. Emmitte; Julie L. Engers; Katrina A. Bollinger; Megan M. Breiner
- Web page: https://patentgrep.com/patent/US20180022712A1

## CPC

- C07D 239/60: Three or more oxygen or sulfur atoms
- C07D 213/04: having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D 213/69: Two or more oxygen atoms
- C07D 237/16: Two oxygen atoms
- C07D 239/52: Two oxygen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Described are negative allosteric modulators of metabotropic glutamate receptor 3 (mGlu3), pharmaceutical compositions including the compounds, and methods of using the compounds and compositions for treating depression, cognitive disorders, schizophrenia, Alzheimer's disease, or cancer in a subject.

## Claims

### Claim 1

A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein
A is aryl, heteroaryl, heterocycle, or cycloalkyl;
Z is a bond, O, S, NR2, or CR1gR1h;
X is —(CR1eR1f)m, O, S, NR2, —C(O)—, —O—C(O)—, —C(O)—O—, —O—C(O)—NR2—, —C(O)—NR2—, —NR2—C(O)—, —NR2—C(O)—O—, —NR2—C(O)—NR2—, —NR2—SO2—, —SO—, or —SO2—;
R1e, R1f, R1g and R1h are each independently hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy;
m is 1-3;
R2 is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl;
R1a, R1b, R1c, and R1d are each independently hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy;
Q is N or CR3a;
V is N or CR3b;
W is N or CR3c; wherein no more than one of Q, V and W is N;
R3a, R3b, and Rc are hydrogen, cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy; and
Y is aryl, heteroaryl, cycloalkyl, or heterocycle;
wherein said aryl, heteroaryl, cycloalkyl, and heterocycle, at each occurrence, are independently substituted or unsubstituted.

### Claim 2

(canceled)

### Claim 3 (depends on 1)

The compound of claim 1, wherein A is aryl or heteroaryl with 0-3 substituents independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy(C1-C6)alkyl, C1-C6 hydroxyalkyl, C1-C6 hydroxy(C1-C6)fluoroalkyl, C1-C6 alkoxy(C1-C6)fluoroalkyl, C1-C6 cyanoalkyl, C1-C6 cyanofluoroalkyl, C3-C8 cycloalkyl, C3-C8 fluorocycloalkyl, OR4, and NR5aR5b; wherein
R4 is hydrogen, C1-C6 alkyl or C1-C6 fluoroalkyl; and
R5a and R5b are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 heteroalkyl; or R5a and R5b together with the nitrogen atom to which they are attached form a heterocycle; wherein each R5a and R5b are substituted with 0-3 fluorine atoms.

### Claim 4 (depends on 3)

The compound of claim 3, wherein A is aryl substituted with 0-3 substituents independently selected from fluoro, chloro, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy(C1-C3)alkyl, and OR4; wherein R4 is hydrogen, C1-C3 alkyl, or C1-C3 fluoroalkyl.

### Claim 5 (depends on 3)

The compound of claim 3, wherein A is heteroaryl substituted with 0-3 substituents independently selected from fluoro, chloro, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy(C1-C3)alkyl, and OR4; wherein R4 is hydrogen, C1-C3 alkyl, or C1-C3 fluoroalkyl.

### Claim 6 (depends on 1)

The compound of claim 1, wherein Z is a bond.

### Claim 7 (depends on 1)

The compound of claim 1, wherein X is —(CR1eR1f)m, O, S, NR2, —SO—, or —SO2—; wherein R1e and R1f are independently hydrogen, fluoro, or C1-C3 alkyl; and R2 is hydrogen, C1-C3 alkyl or C1-C3 fluoroalkyl.

### Claim 8 (depends on 6)

The compound of claim 6, wherein X is O, S, or NR2; wherein R2 is hydrogen, C1-C3 alkyl or C1-C3 fluoroalkyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R1a, R1b, R1c, and R1d are each independently hydrogen, fluoro, C1-C3 alkyl, or C1-C3 fluoroalkyl.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R1a, R1b, R1c, and R1d are each independently hydrogen or C1-C3 alkyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein Q is CR3a; V is CR3b; and W is CR3c.

### Claim 12

(canceled)

### Claim 13 (depends on 1)

The compound of claim 1, wherein Q is N; V is CR3b; and W is CR3c.

### Claim 14

(canceled)

### Claim 15 (depends on 1)

The compound of claim 1, wherein Q is CR3a; V is CR3b; and W is N.

### Claim 16

(canceled)

### Claim 17

(canceled)

### Claim 18 (depends on 1)

The compound claim 1, wherein Y is aryl or heteroaryl, with 0-3 substituents independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy(C1-C6)alkyl, C1-C6 hydroxy(C1-C6)alkyl, C1-C6 hydroxy(C1-C6)fluoroalkyl, C1-C6 alkoxy(C1-C6)fluoroalkyl, C1-C6 cyanoalkyl, C1-C6 cyanofluoroalkyl, C3-C5 cycloalkyl, C3-C8 fluorocycloalkyl, OR4, and NR5aR5b; wherein
R4 is hydrogen, C1-C6 alkyl or C1-C6 fluoroalkyl; and
R5a and R5b are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 heteroalkyl; or R5a and R5b together with the nitrogen atom to which they are attach form a heterocycle; wherein each R5a and R5b are substituted with 0-3 fluorine atoms.

### Claim 19 (depends on 18)

The compound of claim 18, wherein Y is aryl substituted with 0-3 substituents independently selected from fluoro, chloro, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy(C1-C3)alkyl, and OR4; wherein R4 is hydrogen, C1-C3 alkyl, or C1-C3 fluoroalkyl.

### Claim 20 (depends on 18)

The compound of claim 18, wherein Y is heteroaryl substituted with 0-3 substituents independently selected from fluoro, chloro, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy(C1-C3)alkyl, and OR4; wherein R4 is hydrogen, C1-C3 alkyl, or C1-C3 fluoroalkyl.

### Claim 21 (depends on 1)

The compound of claim 1, wherein
A is aryl substituted with 0-3 substituents independently selected from fluoro, chloro, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy(C1-C3)alkyl, and OR4; wherein R4 is hydrogen, C1-C3 alkyl, or C1-C3 fluoroalkyl;
Z is a bond;
X is O;
R1a, R1b, R1c, and R1d are each independently hydrogen or C1-C3 alkyl;
Q is N or CR3a;
V is CR3b;
W is CR3c;
R3a, R3b and R3c are hydrogen, fluoro, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 fluoroalkyl; and
Y is aryl substituted with 0-3 substituents independently selected from fluoro, chloro, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy(C1-C3)alkyl, and OR4; wherein R4 is hydrogen, C1-C3 alkyl, or C1-C3 fluoroalkyl.

### Claim 22 (depends on 1)

The compound of claim 1, selected from the group consisting of:
1-(4-fluorophenyl)-4-(3-phenylpropoxy)pyridin-2(1H)-one;
1-(4-fluorophenyl)-4-(2-phenoxyethoxy)pyridin-2(1H)-one;
1-(4-fluorophenyl)-4-(2-(phenylthio)ethoxy)pyridin-2(1H)-one;
1-(4-fluorophenyl)-4-(2-(methyl(phenyl)amino)ethoxy)pyridin-2(1H)-one;
1-(3-fluorophenyl)-4-(2-phenoxyethoxy)pyridin-2(1H)-one;
1-(2-fluorophenyl)-4-(2-phenoxyethoxy)pyridin-2(1H)-one;
1-(3,4-difluorophenyl)-4-(2-phenoxyethoxy)pyridin-2(1H)-one;
1-(3,5-difluorophenyl)-4-(2-phenoxyethoxy)pyridin-2(1H)-one;
3-(2-oxo-4-(2-phenoxyethoxy)pyridin-1(2H)-yl)benzonitrile;
3-fluoro-5-(2-oxo-4-(2-phenoxyethoxy)pyridin-1(2H)-yl)benzonitrile;
4-(2-oxo-4-(2-phenoxyethoxy)pyridin-1(2H)-yl)benzonitrile;
4-(2-phenoxyethoxy)-2H-[1,2′-bipyridin]-2-one;
6′-fluoro-4-(2-phenoxyethoxy)-2H-[1,2′-bipyridin]-2-one;
6′-fluoro-4-(2-phenoxyethoxy)-2H-[1,3′-bipyridin]-2-one;
4-(2-phenoxyethoxy)-2H-[1,4′-bipyridin]-2-one;
4-(2-(2-fluorophenoxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-(3-fluorophenoxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-(4-fluorophenoxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-(2,3-difluorophenoxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-(2,4-difluorophenoxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-(2,5-difluorophenoxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-(2,6-difluorophenoxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-(2-chlorophenoxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-(3-chlorophenoxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-(4-chlorophenoxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
1-(4-fluorophenyl)-4-(2-((2-fluoropyridin-3-yl)oxy)ethoxy)pyridin-2(1H)-one;
3-(2-((1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)ethoxy)benzonitrile;
4-(2-((1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)ethoxy)benzonitrile;
1-(4-fluorophenyl)-4-(2-(4-(methoxymethyl)phenoxy)ethoxy)pyridin-2(1H)-one;
1-(4-fluorophenyl)-4-(2-(pyridin-3-yloxy)ethoxy)pyridin-2(1H)-one;
1-(4-fluorophenyl)-4-(2-((6-fluoropyridin-3-yl)oxy)ethoxy)pyridin-2(1H)-one;
4-(2-((5-chloropyridin-3-yl)oxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-((4-chloropyridin-3-yl)oxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-((2-chloropyridin-3-yl)oxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
1-(4-fluorophenyl)-4-(2-(pyridin-2-yloxy)ethoxy)pyridin-2(1H)-one;
1-(4-fluorophenyl)-4-(2-((3-fluoropyridin-2-yl)oxy)ethoxy)pyridin-2(1H)-one;
1-(4-fluorophenyl)-4-(2-((5-fluoropyridin-2-yl)oxy)ethoxy)pyridin-2(1H)-one;
4-(2-((6-chloropyridin-2-yl)oxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-((3-chloropyridin-2-yl)oxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-((4-chloropyridin-2-yl)oxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-((5-chloropyridin-2-yl)oxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
2-(2-((1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)ethoxy)nicotinonitrile;
2-(2-((1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)ethoxy)isonicotinonitrile;
6-(2-((1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)ethoxy)nicotinonitrile;
6-(2-((1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)ethoxy)picolinonitrile;
1-(4-fluorophenyl)-4-(2-phenoxyethoxy)pyrimidin-2(1H)-one;
1-(3-fluorophenyl)-4-(2-phenoxyethoxy)pyrimidin-2(1H)-one;
1-(3,4-difluorophenyl)-4-(2-phenoxyethoxy)pyrimidin-2(1H)-one;
1-(5-fluoropyridin-2-yl)-4-(2-phenoxyethoxy)pyrimidin-2(1H)-one;
3-(4-fluorophenyl)-6-(2-phenoxyethoxy)pyrimidin-4(3H)-one;
2-(4-fluorophenyl)-5-(2-phenoxyethoxy)pyridazin-3 (2H)-one;
2-oxo-4-(2-phenoxyethoxy)-2H-[1,3′-bipyridine]-5′-carbonitrile;
5′-fluoro-4-(2-phenoxyethoxy)-2H-[1,3′-bipyridin]-2-one;
1-(4-fluorophenyl)-4-(2-phenoxypropoxy)pyridin-2(1H)-one;
1-(4-fluorophenyl)-4-((1-phenoxypropan-2-yl)oxy)pyridin-2(1H)-one;
4-(2-(Benzyloxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-(cyclopentyloxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
4-(2-(cyclohexyloxy)ethoxy)-1-(4-fluorophenyl)pyridin-2(1H)-one;
1-(4-fluorophenyl)-4-(2-(phenylsulfinyl)ethoxy)pyridin-2(1H)-one; and
1-(4-fluorophenyl)-4-(2-(phenylsulfonyl)ethoxy)pyridin-2(1H)-one;
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

A method for treating a disease or disorder associated with dysfunction of metabotropic glutamate receptor 3 (mGlu3), comprising administration of a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

### Claim at position 24

-25. (canceled)

### Claim 26 (depends on 23)

The method of claim 23, wherein the disease or disorder is selected from at least one of schizophrenia, autism, Alzheimer's disease, post-traumatic stress disorder, anxiety, and depression.

### Claim 27

(canceled)

### Claim 28 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers.