Thiadiazine derivatives

Patent metadata

Field	Value
Publication number	US-2025064823-A1
Application number	US-202418947529-A
Country	US
Kind code	A1
Filing date	Nov 14, 2024
Priority date	Jul 13, 2018
Publication date	Feb 27, 2025
Grant date	—

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

1 . A 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 salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates or hydrates thereof.

2 . The compound 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 compound 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 pyrazolo[1,5-a]pyridinyl; R 1 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 compound 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-dirnethyl-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-ethyl-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]-2H-1λ 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-dirnethoxyphenyl)-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]-2H-1λ 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]-2H-1λ 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)cydohexyl]-N-[2-(trifluoromethyl)pyrimidin-4-yl]-2H-1λ 6 ,2,6-thiadiazine-3-carboxamide; or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates or hydrates thereof.

5 .- 13 . (canceled)

14 . A pharmaceutical composition comprising as active ingredient a compound according to claim 1 and at least one pharmaceutically acceptable excipient.

15 . The pharmaceutical composition according to claim 14 , wherein the composition further comprises at least one other active ingredient.

16 . The pharmaceutical composition according to claim 15 , wherein the other active ingredient(s) are selected from the group consisting of acetylcholinesterase inhibitors, NMDA receptor antagonists, beta-secretase inhibitors, antipsychotics, GABA A receptor alpha5 subunit NAMs or PAMs, histamine H 3 receptor antagonists, 5-HT 6 receptor antagonists, M1 or M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, and levodopa.

17 .- 19 . (canceled)

20 . A process for the manufacture of a compound of formula (I) according to claim 1 , the process comprising:
1a) reacting a compound of formula (IIa) or formula (IIb)

with methyl lithium; or
1b) reacting a compound of formula (IIc)

with tributyl(1-ethoxyvinyl)tin; or
1c) reacting a compound of formula (IId)

with acetyl chloride,
to obtain a ketone derivative of formula (I)

2) reacting the ketone derivative of formula (III) with diethyl oxalate to obtain a 2,4-dioxo ester d

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