# US 10,308,645 B2 · Piperidine oxadiazole and thiadiazole orexin receptor antagonists

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

- Number: US 10,308,645 B2
- Document ID: US10308645B2
- Status: Granted
- Kind: B2
- Application number: 15/523,251
- Filed: 2015-09-27
- Published: 2017-11-02
- Granted: 2019-06-04
- Earliest claimed: 2014-10-30
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Nigel Liverton; Scott D. Kuduk; Yunfu Luo; Na Meng; Tingting Yu
- Web page: https://patentgrep.com/patent/US10308645B2

## CPC

- C07D 417/14: containing three or more hetero rings
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to piperidine oxadiazole and thiadiazole orexin compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

## Claims

### Claim 1

A compound of the formula Ic:
wherein:
each of R1a and R1b is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C1-6alkyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl, and C3-6cycloalkyl,
(4) —O—C1-6 alkyl, which is unsubstituted or substituted with halogen,
(5) C3-6 cycloalkyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl, and C3-6 cycloalkyl,
(6) —(C═O)—O—C1-6 alkyl, which is unsubstituted or substituted with one to three halogen,
(7) —S(O)2—C1-6 alkyl,
(8) —CN, and
(9) 1,2,3-triazolyl, which is unsubstituted or substituted with halogen, hydroxyl, C1-6 alkyl, —O—C1-6 alkyl or —NO2, wherein only one of R1a and R1b may be 1,2,3-triazolyl;
R2 is selected from the group consisting of:
(1) C 1-6 alkyl,
(2)
wherein each of R6 and R7 is independently selected from the group consisting of hydrogen, —C1-2 alkyl optionally substituted with one to three halogen and —C3-6 cycloalkyl; and R8 is hydrogen or —C1-6 alkyl,
(3) C3-6 cycloalkyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, halogen, hydroxyl, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, —(C═O)O—C 1-6 alkyl, and phenyl, wherein the phenyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1-6 alkyl, halogen and C1-6 alkyl-OH;
R3 is methyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein each of R1a and R1b is independently selected from the group consisting of:
(1) C1-6 alkyl,
(2)
wherein each of R6 and R7 is independently selected from the group consisting of hydrogen, —C1-2 alkyl, —C1-2 alkyl substituted with one to three halogen and —C3-6 cycloalkyl; and R8 is hydrogen or —C1-6 alkyl,
(3) —O—C1-4 alkyl, which is unsubstituted or substituted with one to three halogen,
(4) —(C═O)—O—C1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three halogen,
(5) —S(O)2—C1-6 alkyl,
(6) 1,2,3-triazolyl, and
(7) hydrogen;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of any of claim 1, wherein R2 is selected from the group consisting of:
(1) methyl,
(2) ethyl,
(3) propyl,
(4) butyl,
(5) trifluoromethyl,
or a pharmaceutically acceptable salt thereof.

### Claim 4

A compound which is selected from the group consisting of:
(2R,5R)-5-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-2-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidine,
(2R,5R)-5-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-2-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidine,
(2R,5R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidine,
(2R,5R)-2-methyl-5-[5-(1-methylethyl)-1,2,4-oxadiazol-3-yl]-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidine,
2-{3-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1,2,4-oxadiazol-5-yl}propan-2-ol,
(2S)-1,1,1-trifluoro-2-{3-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl }piperidin-3-yl]-1,2,4-oxadiazol-5-yl}propan-2-ol,
(1S)-2,2,2-trifluoro-1-{3-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl }piperidin-3-yl]-1,2,4-oxadiazol-5-yl}ethanol,
(2R,5R)-5-[5-(1-Methoxyl-1-methylethyl)-1,2,4-oxadiazol-3-yl]-2-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidine,
(1R)-2,2,2-Trifluoro-1-{3-[(3R,6R)-6-methyl-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1,2,4-oxadiazol-5-yl}ethanol,
(2R)-1,1,1-Trifluoro-2-{3-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1,2,4-oxadiazol-5-yl}propan-2-ol,
1-[2-({(2R,5R)-5-[5-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-3-yl]-2-methylpiperidin-1-yl}carbonyl)phenyl]cyclopropanecarbonitrile,
2-{3-[(3R,6R)-6-methyl-1-{[2-(trifluoromethoxy)phenyl]carbonyl}piperidin-3-yl]-1,2,4-oxadiazol-5-yl}propan-2-ol,
2-{3-[(3R,6R)-1-{[2-(difluoromethoxy)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1,2,4-oxadiazol-5-yl}propan-2-ol,
2-(3-{(3R,6R)-1-[(2-ethoxyphenyl)carbonyl]-6-methylpiperidin-3-yl}-1,2,4-oxadiazol-5-yl)propan-2-ol,
methyl2-({(2R,5R)-5-[5-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-3-yl]-2-methylpiperidin-1-yl}carbonyl)benzoate, and
2-{3-[(3R,6R)-1-{[4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1,2,4-oxadiazol-5-yl}propan-2-ol,
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

A composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

A method for treating insomnia in a mammalian subject in need thereof which comprises administering to the subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.