Thiadiazine derivatives

Patent metadata

Field	Value
Publication number	US-12194050-B2
Application number	US-201917259975-A
Country	US
Kind code	B2
Filing date	Jul 12, 2019
Priority date	Jul 13, 2018
Publication date	Jan 14, 2025
Grant date	Jan 14, 2025

Abstract

The invention relates to thiadiazine derivatives, or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof, as well as to pharmaceutical compositions containing them and to their use as modulators of α7 nicotinic acetylcholine receptor activity in a mammalian subject Formula (I):

First claim

The invention claimed is:

1. A method for positive allosteric modulation of the α7 nicotinic acetylcholine receptor in a mammal suffering from a disease which requires positive allosteric modulation of the α7 nicotinic acetylcholine receptor comprising administering to a mammal in need thereof an effective amount of at least one compound of formula(I),

wherein
A is saturated, unsaturated or aromatic, monocyclic or bicyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic monocyclic or bicyclic, fused or bridged heterocyclyl, optionally substituted by one or more halogen atoms, C 1-6 alkyl, C 1-6 alkoxy, or haloC 1-6 alkyl;
B is saturated, unsaturated or aromatic, monocyclic or bicyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic monocyclic or bicyclic, fused or bridged heterocyclyl, optionally substituted by one or more halogen atoms, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, CN, C(O)C 1-6 alkyl, or haloC 1-6 alkoxy;
R 1 is C 1-6 alkyl, C 1-6 alkenyl, haloC 1-6 alkyl, C 3-8 cycloalkylC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, or C 4-6 heterocyclyl;
or pharmaceutically acceptable salt, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates or hydrate thereof.

2. The method according to claim 1 , wherein
A is an optionally substituted saturated, unsaturated or aromatic, 4-9 membered monocyclic or bicyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic 4-9 membered monocyclic or bicyclic, fused or bridged heterocyclyl containing 1-3 heteroatoms selected from the group consisting of nitrogen, and oxygen;
B is an optionally substituted saturated, unsaturated or aromatic, 4-9 membered monocyclic or bicyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic 4-9 membered monocyclic or bicyclic, fused or bridged heterocyclyl containing 1-3 heteroatoms selected from the group consisting of nitrogen, and oxygen;
R 1 is C 1-6 alkyl, C 1-6 alkenyl, haloC 1-6 alkyl, C 3-8 cycloalkylC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, or C 4-6 heterocyclyl.

3. The method according to claim 1 , wherein
A is an optionally substituted cyclopentenyl, cyclohexyl, phenyl, cycloheptyl, bicyclo[3.1.0]hexanyl or indazolyl;
B is an optionally substituted phenyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl, benzodioxolyl, 1,2,3,4-tetrahydro-isoquinolinyl, or pyrazolopyridinyl;
R1 is CH 3 , C 2 H 5 , nPr, iPr, nBu, secBu, allyl, —CH 2 —CF 3 , —CH 2 -cyclobutyl, —CH 2 -cyclopropyl, —C 2 H 5 —O—CH 3 , or tetrahydrofuryl.

4. The method according to claim 1 , wherein the compound is selected from the group consisting of:
5-(3,4-dimethoxyphenyl)-2-methyl-N-(3-methylphenyl)-1,1-dioxo-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-(1,3-dimethyl-1H-indazol-5-yl)-2-methyl-N-(3-methylphenyl)-1,1-dioxo-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-2-ethyl-N-(3-methylphenyl)-1,1-dioxo-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-2-ethyl-1,1-dioxo-N-[6-(trifluoromethyl)pyridin-2-yl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
2-ethyl-5-[4-methoxy-3-(trifluoromethyl)phenyl]-N-(3-methoxyphenyl)-1,1-dioxo-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
2-ethyl-5-[4-methoxy-3-(trifluoromethyl)phenyl]-N-(4-methoxyphenyl)-1,1-dioxo-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
2-ethyl-1,1-dioxo-5-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]-N-[6-(trifluoromethyl)pyridin-2-yl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
N-(6-cyanopyridin-2-yl)-2-ethy]-1,1-dioxo-5-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-1,1-dioxo-2-(propan-2-yl)-N-[6-(trifluoromethyl)pyridin-2-yl]-2H1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-1,1-dioxo-2-propyl-N-[3-(trifluoromethyl)phenyl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-1,1-dioxo-2-propyl-N-[6-(trifluoromethyl)pyridin-2-yl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-[4-methoxy-3-(trifluoromethyl)phenyl]-1,1-dioxo-2-propyl-N-[6-(trifluoromethyl)pyridin-2-yl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-(4-methoxy-3-methylphenyl)-1,1-dioxo-2-propyl-N-[6-(trifluoromethyl)pyridin-2-yl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-(3-chloro-4-methoxyphenyl)-1,1-dioxo-2-propyl-N-[6-(trifluoromethyl)pyridin-2-yl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
2-(cyclopropylmethyl)-1,1-dioxo-5-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]-N-[6-(trifluoromethyl)pyridin-2-yl]-2H1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-1,1-dioxo-2-(prop-2-en-1-yl)-N-[6-(trifluoromethyl)pyridin-2-yl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-N-(4-methoxyphenyl)-1,1-dioxo-2-propyl-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-N-(3-methylphenyl)-1,1-dioxo-2-propyl-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-[4-methoxy-3-(trifluoromethyl)phenyl]-1,1-dioxo-2-propyl-N-[3-(trifluoromethyl)phenyl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-N-(6-fluoropyridin-2-yl)-1,1-dioxo-2-(propan-2-yl)-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
N-(6-fluoropyridin-2-yl)-1,1-dioxo-2-(propan-2-yl)-5-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]-2H1λ 6 ,2,6-thiadiazine-3-carboxamide;
2-(cyclopropylmethyl)-N-(6-fluoropyrazin-2-yl)-1,1-dioxo-5-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
2-[(2R)-butan-2-yl]-5-(3,4-dimethoxyphenyl)-1,1-dioxo-N-[6-(trifluoromethyl)pyridin-2-yl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
2-ethyl-5-[4-methoxy-3-(trifluoromethyl)phenyl]-1,1-dioxo-N-[6-(trifluoromethyl)pyridin-2-yl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
1,1-dioxo-2-(propan-2-yl)-5-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]-N-[6-(trifluoromethyl)pyrazin-2-yl]-2H-1λ 6 ,2, 6-thiadiazine-3-carboxamide;
2-(cyclopropylmethyl)-5-(4,4-difluorocyclohexyl)-1,1-dioxo-N-[6-(trifluoromethyl)pyridin-2-yl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
2-(cyclopropylmethyl)-1,1-dioxo-5-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]-N-[2-(trifluoromethyl)pyrimidin-4-yl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide;
or pharmaceutically acceptable salt, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates or hydrate thereof.

5. The method according to claim 1 , wherein the disease is selected from the group consisting of schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, cognitive impairment, net limited to, cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, HIV associated dementia, frontotemporal dementia, Lewy body dementia, vascular dementia, cerebrovascular disease, dementia associated to amyotrophic lateral sclerosis, delirium, traumatic brain injury, senile dementia, mild cognitive impairment, Down's syndrome, depression and cognitive deficit, Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesias, mood disorders, depressive disorders and episodes, bipolar disorders, cyclothymic disorder, substance-induced mood disorder, anxiety disorders, panic disorder and panic attacks, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, phobias, substance use or substance-induced disorders, narcolepsy, dyssomnias, primary hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder, parasomnias, sleep terror disorder, sleepwalking disorder, sleep disorder due to a general medical condition and substance-induced sleep disorder,

Assignees

• Richter Gedeon Nyrt

Inventors

• Ledneczki István
• Éles János
• Tapolcsányi Pál
• Jablonkai Erszébet
• Gábor Eszter
• Visegrádi András
• Némethy Zsolt
• Lévay György István
• Petro József Levente
• Selényi György

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D285/16 Primary

  Thiadiazines; Hydrogenated thiadiazines · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title