# US 8,785,482 B2 · Cyclohexene benzotriazole derivatives

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- Number: US 8,785,482 B2
- Document ID: US8785482B2
- Status: Granted
- Kind: B2
- Application number: 14/115,121
- Filed: 2012-04-30
- Published: 2014-03-27
- Granted: 2014-07-22
- Earliest claimed: 2011-05-03
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Douglas C. Beshore; Scott D. Kuduk
- Inventors: Douglas C. Beshore; Scott D. Kuduk
- Web page: https://patentgrep.com/patent/US8785482B2

## CPC

- C07D 249/04: 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- A61K 31/4192: 1,2,3-Triazoles
- C07D 249/18: Benzotriazoles
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/08: linked by a carbon chain containing alicyclic rings
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/08: linked by a carbon chain containing alicyclic rings
- 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

The present invention is directed to cyclohexene benzotriazole derivatives which are potentiators of metabotropic glutamate receptors, particularly the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.

## Claims

### Claim 1

A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group consisting of:
(1) C2-8alkyl,
(2) C2-8alkenyl,
(3) C2-8alkynyl,
(4) C3-6cycloalkyl-(CH2)p—, wherein p is 1, 2, 3 or 4, and
(5) benzyl, wherein groups (1) to (5) above are optionally substituted with 1 to 3 Ra groups;
each Ra and R2 is independently selected from the group consisting of: halo, OH, C1-4alkyl, C1-4alkoxy, CF3, —OCF3 and —CN;
X is CH2 or N(R), wherein R is H or C1-4alkyl;
Y is selected from the group consisting of: halo, CN, C1-4alkyl, C2-4alkenyl and CH3—S(O)k—, wherein said C1-4alkyl and C2-4alkenyl are optionally substituted with hydroxy, oxo and one or more fluoro groups as allowed by valence, and k is 0, 1 or 2;
R3 is selected from the group consisting of: H, halogen, OH, CN, CF3, R5, OR5, SR5, SOR5, SO2R5, SO2N(R4)2, COR4, CO2R4, CON(R4)2, CON(R4)OR5, N(R4)2, NO2, NR4COR5, NR4CO2R5, NR4—C1-4alkyl-CO2R5, —C1-4alkyl-N(R4)2, —C1-4alkyl-NR4COR5 and —C1-4alkyl-NR4CO2R5;
each R4 independently represents: (1) H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C3-10cycloalkylC1-4alkyl, C3-10cycloalkenyl or C3-10cycloalkenylC1-4alkyl, any of which except H optionally bear up to 5 halogen atoms or OH, CN, CF3 and C1-4alkoxy; (2) phenyl, benzyl or heteroaryl, optionally bridged with a methylene, any of which optionally bear up to 3 substituents independently selected from halogen, OH, oxo, CN, CF3, C1-4alkyl, C1-4hydroxyalkyl, C3-6cycloalkyl, phenyl, heteroaryl, C1-4alkoxy, acetyl, amino, carbamoyl, CO2—C1-4alkyl, C1-4alkylamino and di(C1-4alkyl)amino; and (3) Het, optionally bridged with a methylene and said Het optionally bearing up to 3 substituents independently selected from halogen, OH, oxo, CN, CF3, C1-4alkyl, C1-4hydroxyalkyl, C3-6cycloalkyl, phenyl, heteroaryl, C1-4alkoxy, acetyl, amino, carbamoyl, CO2—C1-4alkyl, C1-4alkylamino and di(C1-4alkyl)amino;
and when two R4 group are attached to the same nitrogen atom, they may be joined together with said nitrogen atom to form a non-aromatic monocyclic, a non-aromatic or partially aromatic bicyclic or a non-aromatic spiro-linked heterocyclic system of up to 12 ring atoms which optionally bears up to 4 substitutents independently selected from halogen, OH, oxo, CN, CF3, C1-4alkyl, C3-6cycloalkyl, phenyl, heteroaryl, C1-4alkoxy, acetyl, amino, C1-4alkylamino and di(C1-4alkyl)amino;
R5 has the same definition as R4 except that R5 is not H;
each “heteroaryl” independently refers to 5- or 6-membered aromatic monocyclic or 9- or 10-membered aromatic bicyclic ring systems, in which at least one ring atom is selected from N or N-oxide, O and S; and
each “Het” independently refers to nonaromatic or partially aromatic mono- or bicyclic heterocyclic systems of up to 10 ring atoms, in which at least one ring atom is selected from N, O and S, where the sulfur atom may be in the form of the S-oxide or S,S-dioxide.

### Claim 2 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is not present.

### Claim 3 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from 2,2-dimethylpropyl, 1,2,2-trimethylpropyl, 4,4,4-trifluorobutyl, cyclopropylmethyl and cyclobutylmethyl.

### Claim 4 (depends on 3)

The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from 2,2-dimethylpropyl and cyclopropylmethyl.

### Claim 5 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is CO2R4.

### Claim 6 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is C1-6alkyl substituted with hydroxyl.

### Claim 7 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from H, hydroxy or CN.

### Claim 8 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is 3-methylimidazolidine-2,4-dione-CH2—.

### Claim 9 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from 2,2-dimethylpropyl and cyclopropylmethyl;
R2 is not present; and
Y is Cl, Br or CF3;
R3 is selected from the group consisting of: H, hydroxy, CN, CO2R4, C1-6alkyl substituted with hydroxy, and 3-methylimidazolidine-2,4-dione-CH2—.

### Claim 10 (depends on 1)

A compound according to claim 1 selected from the following group:
or a pharmaceutically acceptable salt of any of the foregoing compounds.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 12 (depends on 1)

A method for treating a neurological or psychiatric disorder associated with glutamate dysfunction in a patient having said disorder comprising administering to the patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 12)

The method according to claim 12 wherein the neurological or psychiatric disorder associated with glutamate dysfunction is schizophrenia.