US 12,331,022 B2
Spiropiperidine allosteric modulators of nicotinic acetylcholine receptors
Ian M. Bell, Harleysville, PA (US); Brian T. Campbell, Doylestown, PA (US); Brendan M. Crowley, Collegeville, PA (US); James Fells, Hillsborough, NJ (US); Kenneth J. Leavitt, Garnet Valley, PA (US); Anthony J. Roecker, Harleysville, PA (US); Andrew John Harvey, Paddington Spring Hill (AU); Belinda C. Huff, Thebarton (AU); Dharam Paul, Thebarton (AU); Christophe Morice, Illkirch (FR); Christophe Joseph, Illkirch (FR); Patrick Bazzini, Illkirch (FR); Jean-Marie Contreras, Illkirch (FR); Fabrice Garrido, Illkirch (FR); and Aurelie Witzel, Illkirch (FR)
Assigned to Merck Sharp & Dohme LLC, Rahway, NJ (US)
Appl. No. 17/606,154
Filed by Merck Sharp & Dohme LLC, Rahway, NJ (US)
PCT Filed Apr. 27, 2020, PCT No. PCT/US2020/030019
§ 371(c)(1), (2) Date Oct. 25, 2021,
PCT Pub. No. WO2020/223136, PCT Pub. Date Nov. 5, 2020.
Claims priority of provisional application 62/842,099, filed on May 2, 2019.
Prior Publication US 2022/0119351 A1, Apr. 21, 2022
Int. Cl. C07D 221/20 (2006.01); A61K 31/438 (2006.01); A61K 31/444 (2006.01); A61K 45/06 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 413/12 (2006.01)
CPC C07D 221/20 (2013.01) [A61K 31/438 (2013.01); A61K 31/444 (2013.01); A61K 45/06 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 413/12 (2013.01)] 5 Claims
 
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.