# US 8,772,276 B2 · Alkyne benzotriazole derivatives

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- Number: US 8,772,276 B2
- Document ID: US8772276B2
- Status: Granted
- Kind: B2
- Application number: 14/115,109
- Filed: 2012-04-30
- Published: 2014-03-27
- Granted: 2014-07-08
- Earliest claimed: 2011-05-03
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Scott D. Kuduk; Jason W. Skudlarek
- Inventors: Scott D. Kuduk; Jason W. Skudlarek
- Web page: https://patentgrep.com/patent/US8772276B2

## CPC

- C07D 249/18: Benzotriazoles
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to alkyne 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;
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;
X is selected from the group consisting of:
(1) H;
(2) C1-8alkyl, C3-8cycloalkyl, C2-8alkenyl or C2-8alkynyl, any of which is optionally substituted with up to 4 substituents selected from R3, said C3-8cycloalkyl further optionally substituted with 1 or 2 oxo groups and said C1-8alkyl further optionally substituted with ═N—OH;
(3) phenyl, benzyl, benzoylmethyl, heteroaryl, heteroaryl-CH2—, heteroaryl-CH2CH2— or heteroaryl-CH2CH2CH2—, any of which is optionally substituted with up to 4 substituents selected from R3;
(4) Het, Het-CH2—, Het-CH2CH2— or Het-CH2CH2CH2—, any of which is optionally substituted with up to 4 substituents selected from R3, the Het portions thereof further optionally substituted with 1 or 2 oxo groups;
each R3 is independently selected from the group consisting of: 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;
or 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 X is Het, optionally substituted with up to 4 substituents selected from R3 and further optionally substituted with 1 or 2 oxo groups.

### Claim 6 (depends on 5)

The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein X is piperidinyl, optionally substituted with up to 4 substituents selected from R3.

### Claim 7 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is heteroaryl optionally substituted with up to 4 substituents selected from R3.

### Claim 8 (depends on 7)

The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein X is pyridinyl, pyrazinyl or pyridazinyl, each optionally substituted with up to 4 substituents selected from R3.

### Claim 9 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is C1-6alkyl or C2-6alkenyl, optionally substituted with hydroxy.

### Claim 10 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is Het, Het-CH2—, Het-CH2CH2— or Het-CH2CH2CH2—, optionally substituted with up to 4 substituents selected from R3, the Het portion thereof further optionally substituted with 1 or 2 oxo groups.

### Claim 11 (depends on 10)

The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein X is imidazolidin-2,4-dione-CH2—, imidazolidin-2,4-dione-CH2CH2— or imidazolidin-2,4-dione-CH2CH2CH2—, each optionally substituted with 1 to 2 substituents selected from R3.

### Claim 12 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is phenyl optionally substituted with up to 4 substituents selected from R3.

### Claim 13 (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;
Y is Cl, Br or CF3;
X is selected from the group consisting of:
(1) piperidinyl, optionally substituted with COR4, up to 4 halogen atoms and C1-4 alkyl, optionally bearing up to 5 halogen atoms;
(2) pyridinyl, pyrazinyl or pyridazinyl, each optionally substituted with up to 4 substituents selected from halogen, methoxy, N(R4)2, COR4, CON(R4)2 and C1-4alkyl, optionally substituted with hydroxy;
(3) C1-6alkyl or C2-6alkenyl, optionally substituted with hydroxy;
(4) imidazolidin-2,4-dione-CH2—, imidazolidin-2,4-dione-CH2CH2— or imidazolidin-2,4-dione-CH2CH2CH2—, wherein the imidazolidin-2,4-dione portion is optionally substituted with methyl; and
(5) phenyl, optionally substituted with up to 4 substituents selected from halogen, methoxy, N(R4)2, COR4, CON(R4)2 and C1-4alkyl, optionally substituted with hydroxy.

### Claim 14 (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 15 (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 16 (depends on 1)

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

### Claim 17 (depends on 16)

The method according to claim 16 wherein the neurological or psychiatric disorder associated with glutamate dysfunction is schizophrenia.