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US 12,060,339 B2Granted
Dual modulator of mGluR5 and 5-HT2A receptor, and use thereof
AssigneeVivozon Inc.
InventorsDae Kyu Choi, Hyo Jin Kim, Mi Seon Bae, Jin Choi, Hyun Jin Heo, Yong Seok Lee, Geon Ho Lee, Mi Yon Shim, Jin Sun Park, Han Mi Lee
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Abstract
Disclosed are a dual modulator of mGluR5 and 5-HT2AR (5-HT2A receptor), and use thereof. More specifically, disclosed are a compound which acts as modulator of mGluR5 and an antagonist of 5-HT2AR at the same time, and use thereof as therapeutic agent for pain.
Claims11
A compound of the following Formula 1 or a pharmaceutically acceptable salt thereof:
- wherein
- X1 and X2 together with carbon atom to which they are attached form 4- to 7-membered aliphatic ring selected from the group consisting of cyclobutane, cyclopentane, and cycloheptane;
- or a 4- to 6-membered heteroaliphatic ring selected from the group consisting of oxetane, tetrahydrofuran, tetrahydropyran, dioxane, and piperidine;
- X3 is CH or N;
- R1 is hydroxy, halo, alkyl, heterocycloalkyl or heterocycloalkyl-alkyl;
- R2 is hydroxy, halo, alkyl, alkoxy, heterocycloalkyl, hydroxyalkyl, haloalkyl, amino, alkylamino, dialkylamino, cycloalkyl-alkyl, cycloalkylamino, haloalkylamino, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, hydroxyaminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, or 5- or 6-membered heteroaryl;
- R3 is deuterium, halo or alkyl;
- R4 is halo or alkyl;
- R5 is fluoro;
- m is an integer of 0 to 3;
- n is 0 or 1;
- and
- l and p are each independently an integer of 0 to 2;
- q is 1 or 2;
- wherein the heterocycloalkyl or heteroaryl has one or more heteroatoms selected from the group consisting of N, O and S.
12 more elements
A compound selected from the group consisting of:
- N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide;
- N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide;
- N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide;
- N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide;
- N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide;
- N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide;
- N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((3-fluoropyridin-4-yl)ethynyl)benzamide;
- N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((3,4-difluorophenyl)ethynyl)benzamide;
- N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((3,4-difluorophenyl)ethynyl)benzamide;
- N-((4-(cyclopropylamino)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((1-morpholinocyclopentyl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((4-(isopropylamino)tetrahydro-2H-pyran-4-yl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide;
- N-((4-(cyclopropylmethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclopentyl)methyl)benzamide;
- 4-((4-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((1-(pyridin-3-yl)cyclopentyl)methyl)benzamide;
- 2-fluoro-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;
- 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide;
- (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;
- (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;
- (R)-4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)benzamide;
- N-((4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- N-((1,4-dioxan-2-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide;
- 4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)-N-methyltetrahydro-2H-pyran-4-carboxamide;
- 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)benzamide;
- N-((3,3-difluorocyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-(oxetan-2-ylmethyl)benzamide;
- 3-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)propanoic acid;
- 4-((2-fluorophenyl)ethynyl)-N-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)benzamide;
- N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl-d2)benzamide;
- (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;
- N-((5,5-dimethyltetrahydrofuran-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;
- N-((3-ethyloxetan-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- methyl 2-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)acetate;
- N-((1-(2-amino-2-oxoethyl)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- N-((4-(2-amino-2-oxoethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((3-hydroxyoxetan-3-yl)methyl)benzamide;
- 4-((4-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide;
- 3-fluoro-4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-(((1 s,3 s)-3-hydroxycyclobutyl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-(((1r,3r)-3-hydroxycyclobutyl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)methyl)benzamide;
- (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide;
- (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide;
- (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;
- 4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((3-ethyloxetan-3-yl)methyl-d)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((1-morpholinocyclobutyl)methyl)benzamide;
- N-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide;
- (R)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide;
- (S)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide;
- (R)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;
- (S)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;
- N-((3-fluorooxetan-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;
- 4-((4-fluorophenyl)ethynyl)-N-((1-methylcyclohexyl)methyl)benzamide;
- 4-((2-fluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide;
- 4-((4-fluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide;
- 4-((2,4-difluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide;
- 4-((2,4-difluorophenyl)ethynyl)-N-((1-methylcyclopentyl)methyl)benzamide;
- (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;
- (R)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;
- (S)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;
- N-((3-ethyloxetan-3-yl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide;
- (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;
- (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;
- 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)benzamide;
- 4-((4-fluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide;
- (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;
- 4-((2,4-difluorophenyl)ethynyl)-N-(oxetan-2-ylmethyl)benzamide;
- 4-((2,4-difluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide;
- N-((3,3-difluorocyclobutyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide;
- N-((4,4-difluorocyclohexyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide;
- 4-((2,4-difluorophenyl)ethynyl)-N-((3-ethyloxetan-3-yl)methyl)benzamide;
- 4-((2,4-difluorophenyl)ethynyl)-N-((3-fluorooxetan-3-yl)methyl)benzamide;
- (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide;
- and
- 4-((2,4-difluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide;
- or a pharmaceutically acceptable salt thereof.
91 more elements
Dependencies are inferred from the claim text.