Granted Patent B2

US 12,331,022 · App. 17/606,154 · Granted Jun 17, 2025

Inventors: Ian M. Bell (Harleysville, PA); Brian T. Campbell (Doylestown, PA); Brendan M. Crowley (Collegeville, PA); James Fells (Hillsborough, NJ); Kenneth J. Leavitt (Garnet Valley, PA); Anthony J. Roecker (Harleysville, PA); 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); Aurelie Witzel (Illkirch, FR)

Assignee: Merck Sharp & Dohme LLC

C07D221/20A61K31/438A61K31/444A61K45/06C07D401/12C07D401/14C07D413/12

Abstract

Claims (81)

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 a patient in need thereof.

Assignments (6)