Spiropiperidine allosteric modulators of nicotinic acetylcholine receptors

Patent metadata

Field	Value
Publication number	US-12331022-B2
Application number	US-202017606154-A
Country	US
Kind code	B2
Filing date	Apr 27, 2020
Priority date	May 2, 2019
Publication date	Jun 17, 2025
Grant date	Jun 17, 2025

Abstract

The present disclosure relates to compounds of formula I that are useful as modulators of α7 nAChR, compositions comprising such compounds, and the use of such compounds for preventing, treating, or ameliorating disease, particularly disorders of the central nervous system such as cognitive impairments in Alzheimer's disease, Parkinson's disease, and schizophrenia, as well as for L-DOPA induced-dyskinesia and inflammation

First claim

What is claimed is:

1. A compound which is selected from
1-({[2-(difluoromethoxy)pyridin-4-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
2-({[2-(difluoromethoxy)pyridin-4-yl]oxy}methyl)-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-{[(5-phenyl-1,2,4-oxadiazol-3-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
1-({[2-(trifluoromethyl)pyridin-4-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-{[(5-phenyl-1,2,4-oxadiazol-3-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
1-{[3-(2,2,2-trifluoroethoxy)phenoxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-({[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-({[6-(2,2,2-trifluoroethoxy)pyridin-2-yl]methoxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-[({6-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}oxy)methyl]-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-{[(5-chloro-2-methoxyphenyl)sulfanyl]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-{[(5-chloro-2-methoxyphenyl)sulfonyl]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)—N-(5-chloro-2-methoxyphenyl)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxamide;
(1R)-1-{[(5-chloro-2-methoxyphenyl)amino]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)—N-(5-chloro-2-methoxyphenyl)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxamide;
(1R)-1-({[6-(morpholin-4-yl)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-({[4-fluoro-2-(trifluoromethyl)phenyl]sulfanyl}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-{2-[4-fluoro-2-(trifluoromethyl)phenyl]ethyl}-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-{(E)-2-[4-fluoro-2-(trifluoromethyl)phenyl]ethenyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-{[(2,6-dimethoxypyridin-3-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
2-[(5-chloro-2-methoxyphenoxy)methyl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-[(4-fluoro-3-methoxyphenoxy)methyl]-6-azaspiro[2.5]octane-6-sulfonamide;
(1S)-1-[(4-fluoro-3-methoxyphenoxy)methyl]-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-[(4-fluoro-2-methoxyphenoxy)methyl]-6-azaspiro[2.5]octane-6-sulfonamide;
1-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-{[5-fluoro-2-(trifluoromethyl)phenoxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
1-{[2-(difluoromethoxy)phenoxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-({[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1S)-1-{[(5-phenyl-1,2,4-oxadiazol-3-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
1-{[(3-methyl-1-phenyl-1H-pyrazol-5-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
1-{[5-fluoro-2-(trifluoromethyl)phenoxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1S)-1-({[4-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-({[6-(cyclopropylmethoxy)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1S)-1-({[6-(cyclopropylmethoxy)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-({[6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1S)-1-({[6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
4,4-difluoro-1-{[(5-phenyl-1,2,4-oxadiazol-3-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
1-{[3-(difluoromethoxy)phenoxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-{[3-(trifluoromethoxy)phenoxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1S)-1-{[3-(trifluoromethoxy)phenoxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
1-[(2-fluoro-5-methoxyphenoxy)methyl]-6-azaspiro[2.5]octane-6-sulfonamide;
1-{[(6-methoxypyridin-2-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
2-{[3-(difluoromethoxy)phenoxy]methyl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-{[3-(2,2,2-trifluoroethoxy)phenoxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-[(2-fluoro-5-methoxyphenoxy)methyl]-6-azaspiro[2.5]octane-6-sulfonamide;
1-({[2-(2,2,2-trifluoroethoxy)pyridin-4-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-({[2-(2,2,2-trifluoroethoxy)pyridin-4-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-({[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-({[6-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1S)-1-({[6-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
4,4-difluoro-1-({[6-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-({[6-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
1-[(5-chloro-2-methoxyphenoxy)methyl]-6-azaspiro[2.5]octane-6-sulfonamide;
1-({[4-(trifluoromethyl)phenyl]sulfanyl}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-({[4-(trifluoromethyl)phenyl]sulfanyl}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-({[6-(methylsulfonyl)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-({[6-(4-methylpiperazin-1-yl)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-{[(6-cyanopyridin-2-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-{[(6-methylpyridin-2-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-{[(6-cyclopropylpyridin-2-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-({[6-(3-methyl-1H-pyrazol-1-yl)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-{[(6-methoxypyridin-2-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-({[6-(propan-2-yl)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-{[(6-ethoxypyridin-2-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-{[(6-tert-butylpyridin-2-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-({[6-(1,1-difluoroethyl)pyridin-2-yl]oxy}methyl)-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-{[(6-phenylpyridin-2-yl)oxy]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)-1-[(2,4′-bipyridin-6-yloxy)methyl]-6-azaspiro[2.5]octane-6-sulfonamide;
(2R)-2-{[(5-chloro-2-methoxyphenyl)amino]methyl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;
(2R)-2-{[(2,5-dimethylphenyl)amino]methyl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;
1,1-difluoro-2-{[(1-phenyl-1H-tetrazol-5-yl)sulfanyl]methyl}-6-azaspiro[2.5]octane-6-sulfonamide;
(1R)—N-(2-methoxyphenyl)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxamide;
(1R)—N-(3-chlorophenyl)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxamide; and
(1S)—N-(5-chloro-2-methoxyphenyl)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxamide;

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) a compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 2 , further comprising a second therapeutic agent selected from the group consisting of acetylcholinesterase inhibitors; NMDA receptor antagonists; antipsychotics; MAO-B inhibitors; and levodopa.

4. A method of treating a patient with cognitive impairments associated with Alzheimer's disease, Parkinson's disease, and schizophrenia, the method comprising administering to the patient the compound of claim 1 , or a pharmaceutically acceptable salt thereof, in an amount effective to treat the patient.

5. A method of modulating α7 nAChR activity, the method comprising administering an effective amount of a compound of claim 1 to

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Bell Ian M
• Campbell Brian T
• Crowley Brendan M
• Fells James
• Leavitt Kenneth J
• Roecker Anthony J
• Harvey Andrew John
• Huff Belinda C
• Paul Dharam
• Morice Christophe
• Joseph Christophe
• Bazzini Patrick
• Contreras Jean-Marie
• Garrido Fabrice
• Witzel Aurelie

Classifications

• C07D413/12

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

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12

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

• A61K45/06 Primary

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

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title