US 11,884,682 B2Granted

Compounds and their uses as MIF inhibitors

AssigneeNanjing Immunophage Biotech Co., Ltd.

InventorsGuohuang Fan, Kin Chiu Fong, Hongyu Yang, Jianfei Wang

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Abstract

The present invention provides compounds of Formula I which can be used as macrophage migration inhibitory factor (MIF) inhibitors; methods for the production of the compounds of the invention; pharmaceutical compositions comprising the compounds of the invention; as well as uses and methods for treating a disease mediated by MIF by administering the compounds of the invention.

Claims14

Dependent claims

A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

N-(5-(4-hydroxyphenyl)-1,3,4-oxadia.zol-2-yl)-2,4-dimethoxybenzamide;
2,4-dimethoxy-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2,4-dimethoxy-N-(5-(3-methylthiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
N-(5-(3-fluorothiophen-2-yl)-1,3,4-oxadiazol-2-yl)-2,4-dimethoxybenzamide;
2-ethoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2-fluoro-4-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
methyl 2((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)benzoate;
4-(benzyloxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxa.diazol-2-yl)benzamide;
4-hydroxy-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
4-(2-hydroxyethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazoi-2-yl)benzamide;
4-(2-(benzyloxy)ethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenoxy)acetic acid;
4-(2-(dimethylamino)ethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4oxadiazol-2-yl)benzamide;
2-(3-methoxy-4-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenoxy)-2-methylpropanoic acid;
4-((2H-tetrazol-5-yl)methoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4oxadiazol-2-yl)benzamide;
2-methoxy-4-((2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-2H-tetrazol-5-y)methoxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiaziol-2-yl)benzamide;
2-methoxy-4-((1-((5-methyl-2-oxo 1,3 -dioxol-4-yl)methyl)-1H-tetrazol-5-yl)methoxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yObenzamide;
4-(3-cyanopropyl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
4-(3-(2H-tetrazol-5-yl)propyl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)berizamide;
Cis-4-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl(carbamoyl)phenyl)cyclohexane-1-carboxyl acid;
Trans-4-(3-methoxy-4-((5-(thiophen-2-yl)-oxadiazol-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid;
3′-methoxy4′-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-carboxylic acid;
(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)proline;
1-(3-methoxy-4-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)piperidine-3-carboxylic acid;
2-((3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)amino)-2-methylpropanoic acid;
4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2-methoxy-4-morpholino-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2-methoxy-4-morpholino-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzenesulfonamide;
2-methoxy-N-methyl-4-morpholino-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2-methoxy-4-morpholino-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2,4-dimethoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(trifluoromethoxy)benzamide;
2-hydroxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2,6-difluoro-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
3-methoxy -N-((5-(thioplien-2-yl)- 1,3,4-oxadiazol-2-yl)methyl)isonicotinamide;
2-methoxy-N-((5-(thiophen-2-yl)- 1,3,4-oxadiazol-2-yl)methyl)nicotinamide;
1-methyl-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol -2-yl)methyl)piperidine-4-carboxamide;
2-methoxy-4-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-N-methyl-4-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-y)methyl)benzamide;
N-ethyl-2-methoxy-z1-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-3-morpholino-N-((5-(thiophen-2-yl)- 1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-(2,6-dimethylmorpholino)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(piperidin-1-yl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(piperazin-1-yl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(4-methylpiperazin-1-yl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-methyl)benzamide;
2-methoxy-4-morpholino-N-((5-(thiazol-5-yl)-1,3,4-oxadiazol-2-y1)methyl)benzamide;
N-((5-(isothiazol-5-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-methoxy-4-morpholinobenzamide;
2-methoxy-4-morpholino-N((5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
N-((5-(5-chlorothiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-methoxy-4-morpholinohenzamide;
2-methoxy-4-morpholino-N-(2-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)benzamide;
2-methoxy-4-morpholino-N-(1-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)benzamide;
2-methoxy-N-methyl-4-morpholino-N-(2-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)benzamide;
2-methoxy4-(2-morpholinoethoxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-(2-hydroxyethoxy)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(2-methoxyethoxy)-N-((5-(thiophen-2-yl -1,3,4-oxadiazol-2-yl)methyl)benzamide;
N-(2-methoxy-4-morpholinophenyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole-2-carboxamide;
2-methoxy-4-((1-methylpyrrolidin-3-yl)amino)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(2-(methylamino)ethyl)amino)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-(3-hydroxypyrrolidin-1-yl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-((2-hydroxyethyl)amino)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazial-2-yl)methyl)benzamide;
2-methoxy-4-(2-(methylamino)ethoxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(pyrrolidin-3-yloxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-(2-hydroxypropan-2-yl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-(2-hydroxy-2-methylpropyl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(piperidin-1-ylmethyl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy4-(morpholinomethyl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide.

65 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/053,357Filed 23 Jun 2020
Published: US 2021/0403484 A130 Dec 2021
Granted: 30 Jan 2024
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 498/18
In which the condensed system contains three hetero rings: bridged systems
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…

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US 2021/0403484 A1Pre-grant publication · published 30 Dec 2021
US 11,884,682 B2This patent

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Abstract

A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

N-(5-(4-hydroxyphenyl)-1,3,4-oxadia.zol-2-yl)-2,4-dimethoxybenzamide;
2,4-dimethoxy-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2,4-dimethoxy-N-(5-(3-methylthiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
N-(5-(3-fluorothiophen-2-yl)-1,3,4-oxadiazol-2-yl)-2,4-dimethoxybenzamide;
2-ethoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2-fluoro-4-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
methyl 2((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)benzoate;
4-(benzyloxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxa.diazol-2-yl)benzamide;
4-hydroxy-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
4-(2-hydroxyethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazoi-2-yl)benzamide;
4-(2-(benzyloxy)ethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenoxy)acetic acid;
4-(2-(dimethylamino)ethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4oxadiazol-2-yl)benzamide;
2-(3-methoxy-4-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenoxy)-2-methylpropanoic acid;
4-((2H-tetrazol-5-yl)methoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4oxadiazol-2-yl)benzamide;
2-methoxy-4-((2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-2H-tetrazol-5-y)methoxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiaziol-2-yl)benzamide;
2-methoxy-4-((1-((5-methyl-2-oxo 1,3 -dioxol-4-yl)methyl)-1H-tetrazol-5-yl)methoxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yObenzamide;
4-(3-cyanopropyl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
4-(3-(2H-tetrazol-5-yl)propyl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)berizamide;
Cis-4-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl(carbamoyl)phenyl)cyclohexane-1-carboxyl acid;
Trans-4-(3-methoxy-4-((5-(thiophen-2-yl)-oxadiazol-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid;
3′-methoxy4′-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-carboxylic acid;
(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)proline;
1-(3-methoxy-4-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)piperidine-3-carboxylic acid;
2-((3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)amino)-2-methylpropanoic acid;
4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2-methoxy-4-morpholino-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2-methoxy-4-morpholino-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzenesulfonamide;
2-methoxy-N-methyl-4-morpholino-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2-methoxy-4-morpholino-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide;
2,4-dimethoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(trifluoromethoxy)benzamide;
2-hydroxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2,6-difluoro-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
3-methoxy -N-((5-(thioplien-2-yl)- 1,3,4-oxadiazol-2-yl)methyl)isonicotinamide;
2-methoxy-N-((5-(thiophen-2-yl)- 1,3,4-oxadiazol-2-yl)methyl)nicotinamide;
1-methyl-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol -2-yl)methyl)piperidine-4-carboxamide;
2-methoxy-4-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-N-methyl-4-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-y)methyl)benzamide;
N-ethyl-2-methoxy-z1-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-3-morpholino-N-((5-(thiophen-2-yl)- 1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-(2,6-dimethylmorpholino)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(piperidin-1-yl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(piperazin-1-yl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(4-methylpiperazin-1-yl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-methyl)benzamide;
2-methoxy-4-morpholino-N-((5-(thiazol-5-yl)-1,3,4-oxadiazol-2-y1)methyl)benzamide;
N-((5-(isothiazol-5-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-methoxy-4-morpholinobenzamide;
2-methoxy-4-morpholino-N((5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
N-((5-(5-chlorothiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-methoxy-4-morpholinohenzamide;
2-methoxy-4-morpholino-N-(2-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)benzamide;
2-methoxy-4-morpholino-N-(1-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)benzamide;
2-methoxy-N-methyl-4-morpholino-N-(2-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)benzamide;
2-methoxy4-(2-morpholinoethoxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-(2-hydroxyethoxy)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(2-methoxyethoxy)-N-((5-(thiophen-2-yl -1,3,4-oxadiazol-2-yl)methyl)benzamide;
N-(2-methoxy-4-morpholinophenyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole-2-carboxamide;
2-methoxy-4-((1-methylpyrrolidin-3-yl)amino)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(2-(methylamino)ethyl)amino)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-(3-hydroxypyrrolidin-1-yl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-((2-hydroxyethyl)amino)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazial-2-yl)methyl)benzamide;
2-methoxy-4-(2-(methylamino)ethoxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(pyrrolidin-3-yloxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-(2-hydroxypropan-2-yl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
4-(2-hydroxy-2-methylpropyl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy-4-(piperidin-1-ylmethyl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide;
2-methoxy4-(morpholinomethyl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide.

65 more elements

Facts

Application

17/053,357Filed 23 Jun 2020

Published

US 2021/0403484 A130 Dec 2021

Granted

30 Jan 2024

Term ends

Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 498/18
In which the condensed system contains three hetero rings: bridged systems
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…