US 2017/0320856 A1Published application

Amidoethyl azole orexin receptor antagonists

AssigneeMerck Sharp & Dohme Corp.

InventorsScott D. Kuduk, Nigel Liverton, Yunfu Luo

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Abstract

The present invention is directed to amidoethyl azole 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 potential prevention or treatment of such diseases in which orexin receptors are involved.

Claims16

Dependent claims

A compound of the formula I:

wherein:
A is selected from the group consisting of phenyl, naphthyl and heteroaryl;
X is N or CH;
each of R1a, R1b and R1c is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —(C═O)m—On—C1-6alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one to three substituents independently selected from R4,
(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from R4,
(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one to three substituents independently selected from R4,
(7) —(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one to three substituents independently selected from R4,
(8) —(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one to three substituents independently selected from R4,
(9) —(C═O)m—On-heterocycle, where the heterocycle is unsubstituted or substituted with one to three substituents independently selected from R4,
(10) —(C═O)m—NR10R11, wherein R10 and R11 are independently selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl, which is unsubstituted or substituted with R4,
(c) C3-6alkenyl, which is unsubstituted or substituted with R4,
(d) C3-6alkynyl, which is unsubstituted or substituted with R4,
(e) C3-6cycloalkyl which is unsubstituted or substituted with R4,
(f) phenyl, which is unsubstituted or substituted with R4, and
(g) heterocycle, which is unsubstituted or substituted with R4,
(11) —S(O)2—NR10R11,
(12) —S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of R10 and R11,
(13) —CO2H,
(14) —CN, and
(15) —NO2;
R3 is selected from hydrogen and C1-6alkyl;
R4 is selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C1-6alkyl,
(4) —C3-6cycloalkyl,
(5) —O—C1-6alkyl,
(6) —O(C═O)—C1-6alkyl,
(7) —NH2,
(8) —NH—C1-6alkyl,
(9) —NO2,
(10) phenyl,
(11) heterocycle,
(12) —CO2H, and
(13) —CN;
R5 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C1-6alkyl, which is unsubstituted or substituted with halogen or hydroxyl,
(4) —O—C1-6alkyl, which is unsubstituted or substituted with halogen, and
(5) —(C═O)—O—C1-6alkyl;
R6 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C1-6alkyl, which is unsubstituted or substituted with halogen or hydroxyl,
(4) —O—C1-6alkyl, which is unsubstituted or substituted with halogen, and
(5) —(C═O)—O—C1-6alkyl;
or a pharmaceutically acceptable salt thereof.

51 more elements

A compound which is selected from the group consisting of:

N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-ethyl-N-(2-(4-(2-hydroxybutan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-ethyl-N-(2-(4-(1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;
2-cyclopropyl-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(pyrrolidin-1-yl)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-((trifluoromethyl)thio)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(trifluoromethoxy)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-isopropoxybenzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2,2,2-trifluoroethoxy)nicotinamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-isopropoxynicotinamide;
2-ethoxy-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)nicotinamide
2-(2,2-difluoroethoxy)-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)nicotinamide;
2-(difluoromethoxy)-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(trifluoromethoxy)benzamide;
2-ethoxy-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;
2-cyclopropyl-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(1H-pyrazol-1-yl)benzamide;
N-ethyl-4-fluoro-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-phenylnicotinamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-propylbenzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2,2,2-trifluoroethoxy)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2,2,2-trifluoroethyl)benzamide;
2-(2,2-difluoroethoxy)-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2,2,2-trifluoroethyl)nicotinamide;
2-(2,2-difluoroethyl)-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;
2-(2,2-difluorocyclopropyl)-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;
2-cyclopropyl-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-6-methoxynicotinamide;
2-cyclobutyl-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(pyrrolidin-1-yl)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-tetrazol-2-yl)benzamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-3-(2H-1,2,3-triazol-2-yl)picolinamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-3-phenylpicolinamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-3-(pyridin-2-yl)pyrazine-2-carboxamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-3-(1H-pyrazol-1-yl)pyrazine-2-carboxamide;
N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(1H-pyrazol-1-yl)nicotinamide;
N-ethyl-N-{2-[4-(1-hydroxy-1-methylethyl)-1H-pyrazol-1-yl]ethyl}-2-(2H-1,2,3-triazol-2-yl)benzamide;
and
N-ethyl-N-{2-[3-(1-hydroxy-1-methylethyl)-1H-pyrazol-1-yl]ethyl}-2-(2H-1,2,3-triazol-2-yl)benzamide;
or a pharmaceutically acceptable salt thereof.

37 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/535,271Filed 18 Dec 2015
Priority: CN PCT/CN2014/09459023 Dec 2014
Published: 9 Nov 2017
Term ends: Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…
A61K 31/4192
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,3-Triazoles
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents

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US 10,155,750 B2Related patent
US 2017/0320856 A1This patent

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Abstract

A compound of the formula I:

wherein:
A is selected from the group consisting of phenyl, naphthyl and heteroaryl;
X is N or CH;
each of R1a, R1b and R1c is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —(C═O)m—On—C1-6alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one to three substituents independently selected from R4,
(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from R4,
(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one to three substituents independently selected from R4,
(7) —(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one to three substituents independently selected from R4,
(8) —(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one to three substituents independently selected from R4,
(9) —(C═O)m—On-heterocycle, where the heterocycle is unsubstituted or substituted with one to three substituents independently selected from R4,
(10) —(C═O)m—NR10R11, wherein R10 and R11 are independently selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl, which is unsubstituted or substituted with R4,
(c) C3-6alkenyl, which is unsubstituted or substituted with R4,
(d) C3-6alkynyl, which is unsubstituted or substituted with R4,
(e) C3-6cycloalkyl which is unsubstituted or substituted with R4,
(f) phenyl, which is unsubstituted or substituted with R4, and
(g) heterocycle, which is unsubstituted or substituted with R4,
(11) —S(O)2—NR10R11,
(12) —S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of R10 and R11,
(13) —CO2H,
(14) —CN, and
(15) —NO2;
R3 is selected from hydrogen and C1-6alkyl;
R4 is selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C1-6alkyl,
(4) —C3-6cycloalkyl,
(5) —O—C1-6alkyl,
(6) —O(C═O)—C1-6alkyl,
(7) —NH2,
(8) —NH—C1-6alkyl,
(9) —NO2,
(10) phenyl,
(11) heterocycle,
(12) —CO2H, and
(13) —CN;
R5 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C1-6alkyl, which is unsubstituted or substituted with halogen or hydroxyl,
(4) —O—C1-6alkyl, which is unsubstituted or substituted with halogen, and
(5) —(C═O)—O—C1-6alkyl;
R6 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C1-6alkyl, which is unsubstituted or substituted with halogen or hydroxyl,
(4) —O—C1-6alkyl, which is unsubstituted or substituted with halogen, and
(5) —(C═O)—O—C1-6alkyl;
or a pharmaceutically acceptable salt thereof.

51 more elements

Facts

Application

15/535,271Filed 18 Dec 2015

Priority

CN PCT/CN2014/09459023 Dec 2014

Published

9 Nov 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…
A61K 31/4192
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,3-Triazoles
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents