Heteroaryl substituted spirocyclic sulfamides for inhibition of gamma secretase
View Patent ↗Compounds of formula I are disclosed: in which X is a 5-membered heteroaryl ring and R is as defined herein. The compounds are inhibitors of the processing of APP by gamma-secretase, and hence are useful in the treatment or prevention of Alzheimer's disease.
1. A compound of formula X(a):
wherein R 1 is H or a hydrocarbon group of up to 5 carbon atoms optionally substituted with up to 3 halogen atoms; and
R is selected from:
(i) CF 3 or a non-aromatic hydrocarbon group of up to 10 carbon atoms, optionally substituted with halogen, CF 3 , CHF 2 , CN, OH, CO 2 H, C 2-6 acyl, C 1-4 alkoxy or C 1-4 alkoxycarbonyl;
(ii) a non-aromatic heterocyclic group consisting of up to 7 ring atoms of which up to 3 are chosen from N, O and S and the remainder are carbon, bearing 0-3 substituents independently selected from oxo, halogen, CN, C 1-6 alkyl, OH, CF 3 , CHF 2 , CH 2 F, C 2-6 acyl, CO 2 H, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;
(iii) phenyl or 6-membered heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CF 3 , CHF 2 , CH 2 F, NO 2 , CN, OCF 3 , C 1-6 alkyl and C 1-6 alkoxy; and
(iv) N(R a ) 2 where each R a independently represents H or C 1-6 alkyl which is optionally substituted with halogen, CF 3 , CHF 2 , CN, OH, CO 2 H, C 2-6 acyl, C 1-4 alkoxy or C 1-4 alkoxycarbonyl; or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 wherein R is phenyl or 6-membered heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CF 3 , CHF 2 , CH 2 F, NO 2 , CN, OCF 3 , C 1-6 alkyl and C 1-6 alkoxy.
3. A compound of claim 2 wherein R is monohalophenyl or dihalophenyl.
4. A compound of claim 1 wherein R 1 is methyl.
5. A compound of claim 1 selected from the group consisting of [6S,9R,11R] 2′,3′,4′,5,5′,6,7,8,9,10-Decahydro-2-(5-(4-fluorophenyl)-1-methyl-pyrazol-3-yl)-5′-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3′-[1,2,5]thiadiazole] 1′,1′-dioxide; [6S,9R,11R] 2′,3′,4′,5,5′,6,7,8,9,10-Decahydro-2-(5-(3,4-difluorophenyl)-1-methyl-pyrazol-3-yl)-5′-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3′-[1,2,5]thiadiazole] 1′,1′-dioxide; [6S,9R,11R] 2′,3′,4′,5,5′,6,7,8,9,10-Decahydro-2-(5-(4-chlorophenyl)-1-methyl-pyrazol-3-yl)-5′-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3′-[1,2,5]thiadiazole] 1′,1′-dioxide; [6S,9R,11R] 2′,3′,4′,5,5′,6,7,8,9,10-Decahydro-2-(5-(2,4-difluorophenyl)-1-methyl-pyrazol-3-yl)-5′-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3′-[1,2,5]thiadiazole] 1′,1′-dioxide; [6S,9R,11R] 2′,3′,4′,5,5′,6,7,8,9,10-Decahydro-2-(5-(3-chloro-4-fluorophenyl)-1-methyl-pyrazol-3-yl)-5′-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3′-[1,2,5]thiadiazole] 1′,1′-dioxide; and [6S,9R,11R] 2′,3′,4′,5,5′,6,7,8,9,10-Decahydro-2-(5-(3,4-dichlorophenyl)-1-methyl-pyrazol-3-yl)-5′-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3′-[1,2,5]thiadiazole] 1′,1′-dioxide; or a pharmaceutically salt thereof.
6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
7. A method of treatment of a subject suffering from Alzheimer's disease which comprises administering to that subject an effective amount of a compound of claim 1 .
8. The compound [6S,9R,11R] 2′,3′,4′,5,5′,6,7,8,9,10-Decahydro-2-(5-(4-fluorophenyl)-1-methyl-pyrazol-3-yl)-5′-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3′-[1,2,5]thiadiazole] 1′,1′-dioxide; or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier.
10. A method of treatment of a subject suffering from Alzheimer's disease which comprises administering to that subject an effective amount of a compound of claim 8 .