US 10,766,880 B2Granted

Substituted 1,2,3-triazoles as NR2B-selective NMDA modulators

AssigneeJanssen Pharmaceutica NV

InventorsGang Chen, Christa C. Chrovian, Heather R. Coate, Curt A. Dvorak, Christine F. Gelin, Afton Hiscox, Michael A. Letavic, Jason C. Rech, Akinola Soyode-Johnson, Brice Stenne, Jessica L. Wall, Wei Zhang

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Abstract

Substituted 1,2,3-triazoles as NR2B receptor ligands. Such compounds may be used in NR2B receptor modulation and in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by NR2B receptor activity.

Claims27

Dependent claims

A compound, and pharmaceutically acceptable salts thereof, having the structure of Formula (I):

wherein:
Ar1 is selected from the group consisting of:
(a) phenyl substituted with one substituent selected from the group consisting of:
F, Br, I, C1-6alkyl, C1-6perhaloalkyl, and OC1-6perhaloalkyl;
phenyl substituted with two or three substituents each independently selected from the group consisting of:
halo, C1-6alkyl, C1-6perhaloalkyl, OC1-6alkyl, OC1-6perhaloalkyl, C3-6cycloalkyl, and azetidinyl;
(b) pyridinyl;
pyridinyl substituted with one or two members each independently selected from the group consisting of:
halo, CH3, CF3, and CF2H;
and
(c) thienyl substituted with CF3;
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl;
or 2,3-dihydro-1H-inden-5-yl;
R1 is H, halo, or CH3;
R2 is H or CH3;
and
Ar3 is selected from the group consisting of:
(a) pyridinyl;
pyridinyl substituted with one or two substituents each independently selected from the group consisting of:
Cl, F, CH3, OCH3, CF3, C(CH3)2OH;
azetidin-1-yl;
3-fluoroazetidin-1-yl;
and 3,3-difluoroazetidin-1-yl;
(b) pyridazinyl;
pyridazinyl substituted with one or two substituents each independently selected from the group consisting of:
CH3, OCH3, and CF3;
(c) pyrimidin-4-yl;
pyrimidin-4-yl substituted with one or two substituents each independently selected from the group consisting of:
Cl, CH3, CF3, and OCH3;
pyrimidin-2-yl;
pyrimidin-2-yl substituted one or two members each independently selected from the group consisting of:
halo, C1-6alkyl, C1-6alkyl substituted with OH or OCH3, C(OH)(CH3)(CF3), CH2OCHF2, CH2OCF3, CH2OCH2CH3, CH(NH2)CH3, CH2NH(CH3), C1-6perhaloalkyl, OC1-6alkyl, OC1-6perhaloalkyl, C(═N-OH)(CH3), NH2, NH(CH3), N(CH3)2, NH(CH2CH3), NH(CH2CHF2), NH(cyclopropyl), NH(difluorocyclobutyl), NH-oxetanyl, CN, C(═O)CH3, C(═O)NH(CH3), C(═O)N(CH3)2, SO2CH3, CO2CH3, C(CH3)(═N-OH), cyclopropyl, azetidin-1-yl, 3-fluoroazetidin-1-yl, 3,3-difluoroazetidin-1-yl, 3-(difluoromethyl)azetidin-1-yl, 3-methoxyazetidin-1-yl, 3-fluoro-3-methyl-azetidin-1-yl, pyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, piperidin-1-yl, morpholinyl, 1H-pyrrol-2-yl, 2-furyl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-pyrazol-1-yl, 2-methyl-1H-imidazol-1-yl, 1-methylpyrazol-3-yl, and phenyl;
(d) 5-fluoro-pyrazin-2-yl;
5-methylpyrazin-2-yl;
6-methylpyrazin-2-yl;
pyrazin-2-yl;
(2-thienyl)pyrazin-2-yl, and 2,3-dimethyl pyrazin-5-yl;
and
(e) 5-methyl-1H-imidazol-2-yl;
5-methylthiazol-2-yl.

37 more elements

A compound selected from the group consisting of:

2-[[1-[3-(Difluoromethoxy)-4-fluoro-phenyl]triazol-4-yl]methoxy]pyridine;
3-[[1-[4-Chloro-3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]pyridine;
2-[[1-[3-(Difluoromethoxy)-4-fluoro-phenyl]triazol-4-yl]methoxy]-6-methyl-pyridine;
2-[[1-[4-Chloro-3-(difluoromethyl)phenyl]triazol-4-yl]methoxy]pyridine;
3-[[1-[4-Chloro-3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]pyridazine;
2-[[1-[4-Chloro-3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrazine;
2-[[1-[4-Chloro-3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]-5-methyl-pyrazine;
5-Chloro-2-[[1-(2,4-difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(2,4-Difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]-5-methyl-pyrimidine;
2-[[1-(2,4-Difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]-5-ethyl-pyrimidine;
2-[[1-[3-(Difluoromethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]-5-(trifluoromethyl)pyridine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-5-methyl-pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-5-methoxy-pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-5-ethyl-pyrimidine;
5-Chloro-2-[[1-[3-(difluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-(5-Bromo-6-methyl-2-pyridyl)triazol-4-yl]methoxy]-5-methyl-pyrimidine;
3-[[1-[4-Chloro-3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]-2-methoxy-pyridine;
5-[[1-[4-Chloro-3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]-2-methyl-pyridine;
3-Chloro-2-[[1-[4-chloro-3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]pyridine;
5-Chloro-2-[[1-[4-chloro-3-(difluoromethoxy) phenyl]triazol-4-yl]methoxy]-3-methoxy-pyridine;
2-[[1-[4-Chloro-3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]-3-fluoro-pyridine;
2-[[1-[4-Chloro-3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]-3-methoxy-pyridine;
2-[[1-[3-(Difluoromethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]pyridine;
5-Chloro-2-[[1-[3-(difluoromethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]pyridine;
2-[[1-[3-(Difluoromethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]-6-methyl-pyridine;
2-[[1-[3-(Difluoromethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]-5-methyl-pyridine;
2-[[1-[3-(Difluoromethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]-4-methyl-pyridine;
2-[[1-[3-(Difluoromethoxy)-4-fluoro-phenyl]triazol-4-yl]methoxy]-4-methyl-pyridine;
5-Chloro-2-[[1-[3-(difluoromethoxy)-4-fluoro-phenyl]triazol-4-yl]methoxy]pyridine;
2-[[1-[3-(Difluoromethoxy)-4-fluoro-phenyl]triazol-4-yl]methoxy]-5-methyl-pyridine;
2-[[1-[3-(Difluoromethoxy)-4-fluoro-phenyl]triazol-4-yl]methoxy]-5-(trifluoromethyl)pyridine;
5-Methyl-2-((1-(5-(trifluoromethyl)thiophen-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)pyrimidine;
5-Methyl-2-((1-(4-(trifluoromethyl)thiophen-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)pyrimidine;
2-((1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-methylpyrimidine;
2-((1-(4-Chloro-3-(difluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-methylthiazole;
1-(4-Chloro-3-(difluoromethyl)phenyl)-4-(((5-methyl-1H-imidazol-2-yl)oxy)methyl)-1H-1,2,3-triazole;
2-((1-(4-Chloro-3-(difluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-methyl pyridine;
2-((1-(4-Chloro-3-(difluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-methyl pyridine;
6-((1-(4-Chloro-3-(difluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,3-dimethyl pyridine;
2-((1-(4-Chloro-3-(difluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-methylpyrazine;
5-((1-(4-Chloro-3-(difluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,3-dimethylpyrazine;
6-((1-(4-Chloro-3-(difluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dimethylpyridazine;
3-((1-(4-Chloro-3-(difluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-(trifluoromethyl)pyridazine;
3-((1-(4-Chloro-3-(difluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-methoxypyridazine;
2-((1-(5-Chloro-6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)-5-methylpyrimidine;
2-((1-(2-(Difluoromethyl)pyridin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)-5-methylpyrimidine;
3-((1-(4-Chloro-3-(difluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-methoxypyridine;
4-Chloro-3-((1-(4-chloro-3-(difluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)pyridine;
4-((1-(3-(Difluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-methoxypyrimidine;
2-((1-(3-(Difluoromethyl)phenyl)-5-methyl-1H-1,2,3-triazol-4-yl)methoxy)-5-methylpyrimidine;
5-Methyl-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)pyrimidine;
2-((1-(5-Bromo-6-fluoropyridin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)-5-methylpyrimidine;
5-Methyl-2-((1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-4,5-dimethyl-pyrimidine;
2-[[1-[4-Fluoro-3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]pyridine;
[2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidin-4-yl]methanol;
[2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidin-5-yl]methanol;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-5-methyl-pyrimidin-4-amine;
5-Chloro-2-[[1-(4-fluorophenyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]-5-methyl-triazol-4-yl]methoxy]-5-methoxy-pyrimidine;
5-Methyl-2-[[1-(6-methyl-2-pyridyl)triazol-4-yl]methoxy]pyrimidine;
5-Methyl-2-[[1-(2-methyl-4-pyridyl)triazol-4-yl]methoxy]pyrimidine;
5-Methyl-2-[[1-(5-methyl-3-pyridyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(2-Bromo-4-pyridyl)triazol-4-yl]methoxy]-5-methyl-pyrimidine;
2-[[1-[4-Chloro-3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]-5-fluoro-pyrazine;
5-Chloro-2-[[1-(4-chlorophenyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(4-Chlorophenyl)triazol-4-yl]methoxy]-5-(trifluoromethyl)pyrimidine;
2-[[1-(4-Chlorophenyl)triazol-4-yl]methoxy]-5-(difluoromethoxy)pyrimidine;
2-[[1-(3-Fluorophenyl)triazol-4-yl]methoxy]pyrimidine;
5-Fluoro-2-[[1-(3-fluorophenyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(3-Fluorophenyl)triazol-4-yl]methoxy]-5-methoxy-pyrimidine;
5-Chloro-2-[[1-(3-fluorophenyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(3-Fluorophenyl)triazol-4-yl]methoxy]-5-methyl-pyrimidine;
5-Ethyl-2-[[1-(3-fluorophenyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(3-Bromophenyl)triazol-4-yl]methoxy]-5-methyl-pyrimidine;
2-[[1-(3-Bromophenyl)triazol-4-yl]methoxy]-4-methyl-pyrimidine;
2-[[1-(o-Tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Fluoro-2-[[1-(o-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Methoxy-2-[[1-(o-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Chloro-2-[[1-(o-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Methyl-2-[[1-(o-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Ethyl-2-[[1-(o-tolyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(m-Tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Methyl-2-[[1-(m-tolyl)triazol-4-yl]methoxy]pyrimidine;
4-Methyl-2-[[1-(m-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Ethyl-2-[[1-(m-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Chloro-2-[[1-(m-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Fluoro-2-[[1-(m-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Methoxy-2-[[1-(m-tolyl)triazol-4-yl]methoxy]pyrimidine;
2-[2-[[1-(m-Tolyl)triazol-4-yl]methoxy]pyrimidin-5-yl]propan-2-ol;
4-(Methoxymethyl)-2-[[1-(m-tolyl)triazol-4-yl]methoxy]pyrimidine;
4,5-Dimethyl-2-[[1-(m-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Fluoro-4-methyl-2-[[1-(m-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Chloro-4-methyl-2-[[1-(m-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Methyl-2-[[1-(m-tolyl)triazol-4-yl]methoxy]pyrimidin-4-amine;
1-[2-[[1-(m-Tolyl)triazol-4-yl]methoxy]pyrimidin-5-yl]ethanone;
2-[[1-(p-Tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Fluoro-2-[[1-(p-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Methoxy-2-[[1-(p-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Chloro-2-[[1-(p-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Methyl-2-[[1-(p-tolyl)triazol-4-yl]methoxy]pyrimidine;
5-Ethyl-2-[[1-(p-tolyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(3-Isopropylphenyl)triazol-4-yl]methoxy]pyrimidine;
5-Fluoro-2-[[1-(3-isopropylphenyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(3-Isopropylphenyl)triazol-4-yl]methoxy]-5-methoxy-pyrimidine;
5-Chloro-2-[[1-(3-isopropylphenyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(3-Isopropylphenyl)triazol-4-yl]methoxy]-5-methyl-pyrimidine;
5-Ethyl-2-[[1-(3-isopropylphenyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-4-methyl-pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-5-fluoro-pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-4-isopropyl-pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-4-(methoxymethyl)pyrimidine;
2-[2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidin-5-yl]propan-2-ol;
5-(Difluoromethyl)-2-[[1-[3-(difluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
4-(Difluoromethyl)-2-[[1-[3-(difluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-5-(trifluoromethyl)pyrimidine;
5-(Difluoromethoxy)-2-[[1-[3-(difluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-N,N-dimethyl-pyrimidin-4-amine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-5-fluoro-4-methyl-pyrimidine;
5-Chloro-2-[[1-[3-(difluoromethyl)phenyl]triazol-4-yl]methoxy]-4-methyl-pyrimidine;
2-Chloro-4-[[1-[3-(difluoromethyl)phenyl]triazol-4-yl]methoxy]-5-methyl-pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-N,N,5-trimethyl-pyrimidin-4-amine;
5-Cyclopropyl-2-[[1-[3-(difluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
4-Cyclopropyl-2-[[1-[3-(difluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-4-pyrrolidin-1-yl-pyrimidine;
2-[[1-[3-(Difluoromethyl)phenyl]triazol-4-yl]methoxy]-4-(1-piperidyl)pyrimidine;
5-Methyl-2-[[1-[3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Ethyl-2-[[1-[3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Isopropyl-2-[[1-[3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-(Difluoromethyl)-2-[[1-[3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
4,5-Dimethyl-2-[[1-[3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Chloro-4-methyl-2-[[1-[3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Bromo-2-[[1-[3-(1,1-difluoroethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Chloro-2-[[1-[3-(1,1-difluoroethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-5-fluoro-pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-4-methyl-pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-5-methyl-pyrimidine;
[2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]pyrimidin-5-yl]methanol;
[2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]pyrimidin-4-yl]methanol;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-4-(methoxymethyl)pyrimidine;
2-[2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]pyrimidin-5-yl]propan-2-ol;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-5-(difluoromethyl)pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-4-(difluoromethyl)pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-4-(trifluoromethyl)pyrimidine;
(R/S)-2-[2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]pyrimidin-5-yl]-1,1,1-trifluoro-propan-2-ol;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-5-methoxy-pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-4-methoxy-pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-5-(difluoromethoxy)pyrimidine;
1-[2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]pyrimidin-5-yl]ethanone;
(R/S)-1-[2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]pyrimidin-5-yl]ethanol;
(R/S)-2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-5-(1-methoxyethyl)pyrimidine;
5-Chloro-2-[[1-[3-(1,1-difluoroethyl)phenyl]triazol-4-yl]methoxy]-4-methyl-pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-5-fluoro-4-methyl-pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-5-methyl-pyrimidin-4-amine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-5-fluoro-N-methyl-pyrimidin-4-amine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]pyrimidin-4-amine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-N-methyl-pyrimidin-4-amine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-N,N-dimethyl-pyrimidin-4-amine;
5-Cyclopropyl-2-[[1-[3-(1,1-difluoroethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-(Azetidin-1-yl)-2-[[1-[3-(1,1-difluoroethyl)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-5-(3-fluoroazetidin-1-yl)pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)phenyl]triazol-4-yl]methoxy]-4-pyrrolidin-1-yl-pyrimidine;
2-[[1-[3-(Difluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(Difluoromethoxy)phenyl]triazol-4-yl]methoxy]-5-fluoro-pyrimidine;
2-[[1-[3-(Difluoromethoxy)phenyl]triazol-4-yl]methoxy]-5-methoxy-pyrimidine;
5-Chloro-2-[[1-[3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(Difluoromethoxy)phenyl]triazol-4-yl]methoxy]-5-methyl-pyrimidine;
2-[[1-[3-(Difluoromethoxy)phenyl]triazol-4-yl]methoxy]-5-ethyl-pyrimidine;
2-[[1-[4-(Difluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-[4-(Difluoromethoxy)phenyl]triazol-4-yl]methoxy]-5-fluoro-pyrimidine;
2-[[1-[4-(Difluoromethoxy)phenyl]triazol-4-yl]methoxy]-5-methoxy-pyrimidine;
5-Chloro-2-[[1-[4-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-[4-(Difluoromethoxy)phenyl]triazol-4-yl]methoxy]-5-methyl-pyrimidine;
2-[[1-[4-(Difluoromethoxy)phenyl]triazol-4-yl]methoxy]-5-ethyl-pyrimidine;
2-[[1-[4-(Trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Fluoro-2-[[1-[4-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Methoxy-2-[[1-[4-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Chloro-2-[[1-[4-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Methyl-2-[[1-[4-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Ethyl-2-[[1-[4-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(Trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Methyl-2-[[1-[3-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Methyl-2-[[1-[3-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidin-4-amine;
1-[2-[[1-[3-(Trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidin-5-yl]ethanone;
2-[2-[[1-[3-(Trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidin-5-yl]propan-2-ol;
4-(Methoxymethyl)-2-[[1-[3-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
4-Methyl-2-[[1-[3-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Fluoro-2-[[1-[3-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Methoxy-2-[[1-[3-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Chloro-2-[[1-[3-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
5-Ethyl-2-[[1-[3-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidine;
N-Methyl-2-[[1-[3-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidin-4-amine;
2-[[1-[3-(Trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyrimidin-4-amine;
2-[[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)triazol-4-yl]methoxy]-5-methyl-pyrimidine;
2-[[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)triazol-4-yl]methoxy]pyrimidine;
5-Chloro-2-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)triazol-4-yl]methoxy]-5-fluoro-4-methyl-pyrimidine;
2-[[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)triazol-4-yl]methoxy]-5-fluoro-pyrimidine;
2-[[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)triazol-4-yl]methoxy]-4,5-dimethyl-pyrimidine;
2-[(1-Indan-5-yltriazol-4-yl)methoxy]-5-methyl-pyrimidine;
5-Chloro-2-[(1-indan-5-yltriazol-4-yl)methoxy]pyrimidine;
2-[(1-Indan-5-yltriazol-4-yl)methoxy]-4-(methoxymethyl)pyrimidine;
2-[2-[(1-Indan-5-yltriazol-4-yl)methoxy]pyrimidin-5-yl]propan-2-ol;
4-(Difluoromethyl)-2-[(1-indan-5-yltriazol-4-yl)methoxy]pyrimidine;
5-Chloro-2-[(1-indan-5-yltriazol-4-yl)methoxy]-4-methyl-pyrimidine;
2-[[1-[4-Chloro-3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]-6-fluoro-pyridine;
2-[[1-[3-(Difluoromethoxy)-4-fluoro-phenyl]triazol-4-yl]methoxy]-6-(trifluoromethyl)pyridine;
2-[[1-[3-(Difluoromethoxy)-4-fluoro-phenyl]triazol-4-yl]methoxy]-5-methyl-pyrazine;
2-[[1-[3-(Difluoromethoxy)-4-fluoro-phenyl]triazol-4-yl]methoxy]-5-(2-thienyl)pyrazine;
3-Fluoro-2-[[1-[4-fluoro-3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]pyridine;
5-Chloro-2-[[1-[4-fluoro-3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]pyridine;
2-[[1-[4-Fluoro-3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]-4-methyl-pyridine;
2-[[1-[4-Fluoro-3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]-6-methyl-pyridine;
2-[[1-[4-Fluoro-3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]-5-methyl-pyridine;
2-[[1-[4-Fluoro-3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]-5-(trifluoromethyl)pyridine;
2-[6-[[1-[4-Fluoro-3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]-3-pyridyl]propan-2-ol;
2-[[1-[4-Fluoro-3-(trifluoromethyl)phenyl]triazol-4-yl]methoxy]pyrazine;
2-[[1-[3-(Difluoromethyl)phenyl]-5-methyl-triazol-4-yl]methoxy]-4,5-dimethyl-pyrimidine;
5-Chloro-2-[[1-[3-(difluoromethyl)phenyl]-5-methyl-triazol-4-yl]methoxy]pyrimidine;
2-[[1-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]pyridine;
2-[[1-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]-3-fluoro-pyridine;
2-[[1-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]-6-methyl-pyridine;
2-[[1-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]-4-methyl-pyridine;
2-[[1-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]-5-methyl-pyridine;
2-[[1-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]-5-(trifluoromethyl)pyridine;
6-[[1-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]-2,3-dimethyl-pyridine;
3-[[1-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]triazol-4-yl]methoxy]-2-methoxy-pyridine;
2-[[1-(2,4-Difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]-5-isopropyl-pyrimidine;
2-[[1-(2,4-Difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]-4-isopropyl-pyrimidine;
5-(Difluoromethyl)-2-[[1-(2,4-difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]pyrimidine;
4-(Difluoromethyl)-2-[[1-(2,4-difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(2,4-Difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]-5-(trifluoromethyl)pyrimidine;
2-[2-[[1-(2,4-Difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]pyrimidin-5-yl]propan-2-ol;
2-[[1-(2,4-Difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]-4-(methoxymethyl)pyrimidine;
5-(Difluoromethoxy)-2-[[1-(2,4-difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]pyrimidine;
5-Cyclopropyl-2-[[1-(2,4-difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]pyrimidine;
4-Cyclopropyl-2-[[1-(2,4-difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(2,4-Difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]-5-fluoro-4-methyl-pyrimidine;
5-Chloro-2-[[1-(2,4-difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]-4-methyl-pyrimidine;
2-[[1-(2,4-Difluoro-3-methyl-phenyl)triazol-4-yl]methoxy]-5-methyl-pyrimidin-4-amine;
2-[[1-[3-(Difluoromethyl)-2,4-difluoro-phenyl]triazol-4-yl]methoxy]-5-(trifluoromethyl)pyrimidine;
5-Chloro-2-[[1-(2,4-difluoro-5-methyl-phenyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(2,4-Difluoro-5-methyl-phenyl)triazol-4-yl]methoxy]-5-methyl-pyrimidine;
2-[[1-(2,4-Difluoro-5-methyl-phenyl)triazol-4-yl]methoxy]-5-ethyl-pyrimidine;
5-(Difluoromethyl)-2-[[1-(2,4-difluoro-5-methyl-phenyl)triazol-4-yl]methoxy]pyrimidine;
5-Chloro-2-[[1-(2,4-difluoro-5-methyl-phenyl)triazol-4-yl]methoxy]-4-methyl-pyrimidine;
5-Cyclopropyl-2-[[1-(2,4-difluoro-5-methyl-phenyl)triazol-4-yl]methoxy]pyrimidine;
5-Chloro-2-[[1-(6-methyl-2-pyridyl)triazol-4-yl]methoxy]pyrimidine;
5-Ethyl-2-[[1-(6-methyl-2-pyridyl)triazol-4-yl]methoxy]pyrimidine;
5-Chloro-4-methyl-2-[[1-(6-methyl-2-pyridyl)triazol-4-yl]methoxy]pyrimidine;
5-Methyl-2-[[1-(4-methyl-2-pyridyl)triazol-4-yl]methoxy]pyrimidine;
5-Ethyl-2-[[1-(4-methyl-2-pyridyl)triazol-4-yl]methoxy]pyrimidine;
5-Ethyl-2-[[1-(2-methyl-4-pyridyl)triazol-4-yl]methoxy]pyrimidine;
2-[[1-(2-Bromo-4-pyridyl)triazol-4-yl]methoxy]-5-ethyl-pyrimidine;
5-Methyl-2-[[1-[2-(trifluoromethyl)-4-pyridyl]triazol-4-yl]methoxy]pyrimidine;
5-Ethyl-2-[[1-[2-(trifluoromethyl)-4-pyridyl]triazol-4-yl]methoxy]pyrimidine;
5-Fluoro-4-methyl-2-((1-(5-(trifluoromethyl)thiophen-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)pyrimidine;
5-Methoxy-2-((1-(5-(trifluoromethyl)thiophen-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)pyrimidine;
5-(Trifluoromethyl)-2-((1-(5-(trifluoromethyl)thiophen-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)pyrimidine;
5-(Azetidin-1-yl)-2-((1-(3-(difluoromethoxy)-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)pyridine;
2-((1-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-(3-fluoroazetidin-1-yl)pyridine;
5-(3,3-Difluoroazetidin-1-yl)-2-((1-(3-(difluoromethoxy)-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)pyridine;
2-(Azetidin-1-yl)-6-((1-(3-(difluoromethoxy)-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)pyridine;
2-((1-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-(3-fluoroazetidin-1-yl)pyridine;
2-(3,3-Difluoroazetidin-1-yl)-6-((1-(3-(difluoromethoxy)-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)pyridine;
4-(Azetidin-1-yl)-2-((1-(3-(difluoromethoxy)-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)pyridine;
2-((1-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-(3-fluoroazetidin-1-yl)pyridine;
4-(3,3-Difluoroazetidin-1-yl)-2-((1-(3-(difluoromethoxy)-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)pyridine;
and pharmaceutically acceptable salts thereof.

268 more elements

A pharmaceutical composition comprising:

(A) an effective amount of at least one compound selected from compounds of Formula (I):
wherein:
Ar1 is selected from the group consisting of:
(a) phenyl substituted with one substituent selected from the group consisting of:
F, Br, I, C1-6alkyl, C1-6perhaloalkyl, and OC1-6perhaloalkyl;
phenyl substituted with two or three substituents each independently selected from the group consisting of:
halo, C1-6alkyl, C1-6perhaloalkyl, OC1-6alkyl, OC1-6perhaloalkyl, C3-6cycloalkyl, and azetidinyl;
(b) pyridinyl;
pyridinyl substituted with one or two members each independently selected from the group consisting of:
halo, CH3, CF3, and CF2H;
and
(c) thienyl substituted with CF3;
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl;
or 2,3-dihydro-1H-inden-5-yl;
R1 is H, halo, or CH3;
R2 is H or CH3;
and
Ar3 is selected from the group consisting of:
(a) pyridinyl;
pyridinyl substituted with one or two substituents each independently selected from the group consisting of:
Cl, F, CH3, OCH3, CF3, C(CH3)2OH;
azetidin-1-yl;
3-fluoroazetidin-1-yl;
and 3,3-difluoroazetidin-1-yl;
(b) pyridazinyl;
pyridazinyl substituted with one or two substituents each independently selected from the group consisting of:
CH3, OCH3, and CF3;
(c) pyrimidin-4-yl;
pyrimidin-4-yl substituted with one or two substituents each independently selected from the group consisting of:
Cl, CH3, CF3, and OCH3;
pyrimidin-2-yl;
pyrimidin-2-yl substituted one or two members each independently selected from the group consisting of:
halo, C1-6alkyl, C1-6alkyl substituted with OH or OCH3, C(OH)(CH3)(CF3), CH2OCHF2, CH2OCF3, CH2OCH2CH3, CH(NH2)CH3, CH2NH(CH3), C1-6perhaloalkyl, OC1-6alkyl, OC1-6perhaloalkyl, C(═N-OH)(CH3), NH2, NH(CH3), N(CH3)2, NH(CH2CH3), NH(CH2CHF2), NH(cyclopropyl), NH(difluorocyclobutyl), NH-oxetanyl, CN, C(═O)CH3, C(═O)NH(CH3), C(═O)N(CH3)2, SO2CH3, CO2CH3, C(CH3)(═N-OH), cyclopropyl, azetidin-1-yl, 3-fluoroazetidin-1-yl, 3,3-difluoroazetidin-1-yl, 3-(difluoromethyl)azetidin-1-yl, 3-methoxyazetidin-1-yl, 3-fluoro-3-methyl-azetidin-1-yl, pyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, piperidin-1-yl, morpholinyl, 1H-pyrrol-2-yl, 2-furyl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-pyrazol-1-yl, 2-methyl-1H-imidazol-1-yl, 1-methylpyrazol-3-yl, and phenyl;
(d) 5-fluoro-pyrazin-2-yl;
5-methylpyrazin-2-yl;
6-methylpyrazin-2-yl;
pyrazin-2-yl;
(2-thienyl)pyrazin-2-yl, and 2,3-dimethyl pyrazin-5-yl;
and
(e) 5-methyl-1H-imidazol-2-yl;
5-methylthiazol-2-yl;
and pharmaceutically acceptable salts of compounds of Formula (I);
and
(B) at least one pharmaceutically acceptable excipient.

41 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/237,333Filed 31 Dec 2018 · division
Priority: 10 Feb 2016
Published: US 2019/0135791 A19 May 2019
Granted: 8 Sep 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification26 codes

C07D 403/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 25/00
Drugs for disorders of the nervous system

Family

Application62/293,680Us provisional application · filed 10 Feb 2016
Application15/428,710Parent of this division · filed 9 Feb 2017
Application16/046,332Parent of this division · filed 26 Jul 2018
US 10,071,988 B2Parent of this division · filed 11 Sep 2018
US 2019/0135791 A1Pre-grant publication · published 9 May 2019
US 10,233,173 B2Parent of this division
US 2017/0226089 A1Published application
US 2018/0334451 A1Published application
US 10,766,880 B2This patent

From the US filing history. Foreign family members aren’t listed.

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