# US 2024/0199640 A1 · Negative allosteric modulators of metabotropic glutamate receptor 2

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- Number: US 2024/0199640 A1
- Document ID: US20240199640A1
- Status: Published application
- Kind: A1
- Application number: 18/550,996
- Filed: 2022-03-18
- Published: 2024-06-20
- Earliest claimed: 2021-03-19
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: Craig W. Lindsley; P. Jeffrey Conn; Andrew S. Felts; Rory A. Capstick; David L. Whomble; Jeremy Coleman; Upendra Rathnayake; Daren Engers
- Web page: https://patentgrep.com/patent/US20240199640A1

## CPC

- C07D 498/04: Ortho-condensed systems
- A61K 31/4035: Isoindoles, e.g. phthalimide
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5365: ortho- or peri-condensed with heterocyclic ring systems
- C07D 209/46: with an oxygen atom in position 1
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- 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 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- 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)

## Abstract

Described are 6-aryl isoindolin-1-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—, —C(O)—, 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 a 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, at each occurrence, is independently hydrogen, fluorine, or C1-4alkyl;
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, —OC1-2haloalkyl, and G;
G3 is a 5-membered heteroaryl containing 1-3 heteroatoms that are independently S, O, or N or a 4- to 6-membered heterocyclyl containing 1-2 heteroatoms that are independently S, O, or N;
R1 is a 6- to 12-membered aryl or 5- to 12-membered heteroaryl, wherein R 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 C1-6alkylene 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.

### Claim 3 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein L1 is
wherein X is selected from the group consisting of —O—, —S—, —SO—, —SO2—, and —N(R)—.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L1 is a C2-4alkylene or C2-4fluoroalkylene, wherein 1 or 2 methylene groups in the alkylene or fluoroalkylene of L1 are independently replaced with —O—, —S—, —SO—, —SO2—, —C(O)—, or —N(R)—, and 1 methylene group in the alkylene or fluoroalkylene of L1 is replaced with -Cy-.

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

The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R1 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 R2 is hydrogen.

### 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 R4 is the unsubstituted or substituted 5- to 12-membered heteroaryl.

### 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 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 9 (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 the ring system of the unsubstituted or substituted 5- to 12-membered heteroaryl at R4 is a 9- to 10-membered fully aromatic bicyclic heteroaryl.

### Claim 10 (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 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 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

### Claim 12 (depends on 1, 2, 3, 4, 5, 6)

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

### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 12)

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

### Claim 14 (depends on 13)

The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R4 is

### 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 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 fused to a 5- to 6-membered heterocycle containing 1-2 heteroatoms, wherein the heteroatoms are oxygen.

### Claim 18 (depends on 15)

The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R3 is

### Claim 19 (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 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 19)

The compound of any one of claims 1-14 or 19, 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- to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 19)

The compound of any one of claims 1-14 or 19, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 5- to 12-membered heteroaryl at R3 is a 9- to 10-membered bicyclic heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 19)

The compound of any one of claims 1-14 or 19, or a pharmaceutically acceptable salt thereof, wherein R3 is

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

The compound of any one of claims 1-22, 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 24 (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)

The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each hydrogen.

### 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 the compound is a compound of formula (Ia):

### 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 the compound is a compound of formula (Tb):

### Claim 27 (depends on 1)

The compound of claim 1, selected from the group consisting of:
6-(4-fluorophenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((2-methylthiazol-5-yl)methoxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((4-methylthiazol-2-yl)methoxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-isopropyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((6-methylpyridin-3-yl)methoxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-(pyridin-4-ylmethoxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((3-methoxybenzyl)oxy)isoindolin-1-one;
5-((2-fluorobenzyl)oxy)-6-(4-fluorophenyl)isoindolin-1-one;
6-(4-fluorophenyl)-5-((5-methyloxazol-4-yl)methoxy)isoindolin-1-one;
5-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)methoxy)-6-(4-fluorophenyl)isoindolin-1-one;
6-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
6-(4-methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
6-(2-fluorophenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
4-(6-((1-methyl-1H-pyrazol-3-yl)methoxy)-3-oxoisoindolin-5-yl)benzonitrile;
6-(2-fluoro-4-methoxyphenyl)-5-((2-methylthiazol-4-yl)methoxy)isoindolin-1-one;
6-(2-fluorophenyl)-5-((2-methylthiazol-4-yl)methoxy)isoindolin-1-one;
5-((1-(difluoromethyl)-1H-pyrazol-3-yl)methoxy)-6-(4-fluorophenyl)isoindolin-1-one;
6-(4-fluorophenyl)-5-((2-methylthiazol-4-yl)methoxy)isoindolin-1-one;
6-(4-methoxyphenyl)-5-((2-methylthiazol-4-yl)methoxy)isoindolin-1-one;
2-(6-((2-methylthiazol-4-yl)methoxy)-3-oxoisoindolin-5-yl)benzonitrile;
6-(2-(methoxy-d3)phenyl)-5-((2-methylthiazol-4-yl)methoxy)isoindolin-1-one
6-(4-(methoxy-d3)phenyl)-5-((2-methylthiazol-4-yl)methoxy)isoindolin-1-one
6-(2-(methoxy-d3)phenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one
6-(4-(methoxy-d3)phenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one
5-((1-(difluoromethyl)-1H-pyrazol-3-yl)methoxy)-6-(2-fluoro-4-methoxyphenyl)isoindolin-1-one;
6-(4-fluorophenyl)-5-((2-methylthiazol-5-yl)methoxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-(1-(pyridin-4-yl)ethoxy)isoindolin-1-one;
6-(2,4-difluorophenyl)-5-(1-(pyridin-4-yl)ethoxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-(1-(4-methylthiazol-2-yl)ethoxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-methyl-1H-pyrazol-4-yl)methoxy-d2)isoindolin-1-one;
6-(4-fluorophenyl)-5-(pyridin-4-yloxy)isoindolin-1-one;
6-(2,4-difluorophenyl)-5-(pyridin-4-yloxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-(pyridin-4-yl)azetidin-3-yl)oxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-methyl-1H-pyrazol-4-yl)methoxy-d2)isoindolin-1-one-3,3-d2;
6-(4-fluorophenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one-3,3-d2;
5-(1-(pyridin-4-yl)ethoxy)-6-(4-(thiophen-2-yl)phenyl)isoindolin-1-one;
6-(4-(difluoromethoxy)-2-fluorophenyl)-5-(1-(pyridin-4-yl)ethoxy)isoindolin-1-one;
6-(4-morpholinophenyl)-5-(1-(pyridin-4-yl)ethoxy)isoindolin-1-one;
5-(1-(pyridin-4-yl)ethoxy)-6-(4-(trifluoromethoxy)phenyl)isoindolin-1-one;
6-(6-fluoropyridin-3-yl)-5-(1-(pyridin-4-yl)ethoxy)isoindolin-1-one;
6-(2,6-difluoropyridin-4-yl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
6-(4-(difluoromethoxy)-2-fluorophenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
5-((1-methyl-1H-pyrazol-3-yl)methoxy)-6-(4-(trifluoromethoxy)phenyl)isoindolin-1-one;
6-(6-fluoropyridin-3-yl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
6-(1,3-dimethyl-1H-pyrazol-4-yl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
5-((1-methyl-1H-pyrazol-3-yl)methoxy)-6-(1-methyl-1H-pyrazol-4-yl)isoindolin-1-one;
5-((1-methyl-1H-pyrazol-3-yl)methoxy)-6-(1-methyl-1H-pyrrol-3-yl)isoindolin-1-one;
6-(1,3-dimethyl-1H-pyrazol-5-yl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
1,5-dimethyl-4-(6-((1-methyl-1H-pyrazol-3-yl)methoxy)-3-oxoisoindolin-5-yl)-1H-pyrrole-2-carbonitrile;
6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
6-(2,3-dihydrobenzofuran-5-yl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
6-(benzo[d]thiazol-6-yl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
6-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
5-((1-methyl-1H-pyrazol-3-yl)methoxy)-6-(2-methyl-2H-indazol-5-yl)isoindolin-1-one;
6-(benzo[d][1,3]dioxol-5-yl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
6-(1-methyl-1H-indazol-5-yl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((6-methylpyridin-3-yl)methoxy-d2)isoindolin-1-one;
3-fluoro-5-(6-((6-methylpyridin-3-yl)methoxy-d2)-3-oxoisoindolin-5-yl)benzonitrile;
6-(6-fluoropyridin-3-yl)-5-((6-methylpyridin-3-yl)methoxy-d2)isoindolin-1-one;
5-((6-methylpyridin-3-yl)methoxy-d2)-6-(p-tolyl)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy-d2)isoindolin-1-one;
6-(4-fluorophenyl)-5-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)isoindolin-1-one;
6-(4-fluorophenyl)-5-(((1-methyl-1H-pyrazol-3-yl)oxy)methyl)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-(6-methylpyrazolo[1,5-a]pyrimidine-2-carbonyl)azetidin-3-yl)oxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-(3-(trifluoromethyl)benzoyl)azetidin-3-yl)oxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-(thiophene-2-carbonyl)azetidin-3-yl)oxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-isonicotinoylazetidin-3-yl)oxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-(isoxazole-5-carbonyl)azetidin-3-yl)oxy)isoindolin-1-one;
3-(3-((6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)oxy)azetidine-1-carbonyl)benzonitrile;
6-(4-fluorophenyl)-5-((1-(1-methyl-1H-pyrazol-3-yl)azetidin-3-yl)oxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-((2-methylthiazol-5-yl)sulfonyl)azetidin-3-yl)oxy)isoindolin-1-one;
5-((1-((1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)oxy)-6-(4-fluorophenyl)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-((3-methylisoxazol-4-yl)sulfonyl)azetidin-3-yl)oxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-(isoquinolin-6-ylsulfonyl)azetidin-3-yl)oxy)isoindolin-1-one;
5-((1-((2,4-dimethylthiophen-3-yl)sulfonyl)azetidin-3-yl)oxy)-6-(4-fluorophenyl)isoindolin-1-one;
5-((1-((1,5-dimethyl-1H-pyrazol-3-yl)sulfonyl)azetidin-3-yl)oxy)-6-(4-fluorophenyl)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-((1-methyl-1H-pyrazol-4-yl)methyl)azetidin-3-yl)oxy)isoindolin-1-one 6-(4-fluorophenyl)-5-((1-((2-methylthiazol-4-yl)methyl)azetidin-3-yl)oxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-((5-methylisoxazol-3-yl)methyl)azetidin-3-yl)oxy)isoindolin-1-one;
6-(4-fluorophenyl)-5-((1-((5-(trifluoromethyl)furan-2-yl)methyl)azetidin-3-yl)oxy)isoindolin-1-one;
5-((1-((2-chloropyridin-3-yl)methyl)azetidin-3-yl)oxy)-6-(4-fluorophenyl)isoindolin-1-one; and
6-(4-fluorophenyl)-5-((1-(quinolin-6-ylmethyl)azetidin-3-yl)oxy)isoindolin-1-one;
or a pharmaceutically acceptable salt thereof.

### 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)

A pharmaceutical composition comprising the compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 29 (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)

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 1-27, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 28.

### Claim 30 (depends on 29)

The method of claim 29, 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 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)

A compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 28, 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 32 (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)

Use of a compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 28, 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.