Metabotropic glutamate receptor oxadiazole ligands and their use as potentiators 841
View Patent ↗Compounds of Formula I: wherein R 1 , R 2 , R 3 , R 4 and Q are as described in the specification, pharmaceutically-acceptable salts, methods of making, pharmaceutical compositions containing and methods for using the same.
1. A compound according to Formula I:
wherein
R 1 is halo or C 1-3 haloalkoxyl;
R 2 is hydrogen or C 1-3 alkyl;
R 3 is C 1 or CH 3 ;
R 4 is hydrogen or C 1-3 alkyl;
Q is
R 5 is hydrogen or C 1-3 alkyl,
and n is 1 or 2,
wherein when n is 2 both R 5 moieties can be attached to the same carbon atom, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or combination thereof.
2. A compound, a pharmaceutically acceptable salt, a hydrate or an optical isomer, according to claim 1 , wherein R 1 is chloro or trifluoromethoxyl.
3. A compound, a pharmaceutically acceptable salt, a hydrate or an optical isomer, according to claim 2 , wherein R 1 is chloro.
4. A compound, a pharmaceutically acceptable salt, a hydrate or an optical isomer, according to claim 1 , wherein Q is
5. A compound, a pharmaceutically acceptable salt, a hydrate or an optical isomer, according to claim 4 , wherein Q is
and R 5 is H at each occurrence.
6. A compound, a pharmaceutically acceptable salt, a hydrate or an optical isomer, according to claim 1 , wherein R 1 is chloro or trifluoromethoxyl and Q is
7. A compound, a pharmaceutically acceptable salt, a hydrate or an optical isomer, according to claim 1 , wherein R 1 is chloro and Q is
8. A compound, a pharmaceutically acceptable salt, a hydrate or an optical isomer, according to claim 1 , wherein R 1 is chloro or trifluoromethoxyl and Q is
where R 5 is H at each occurrence.
9. A compound according to claim 1 , wherein Q is
and R 5 is hydrogen or C 1-3 alkyl
or a pharmaceutically acceptable salt, a hydrate, an optical isomer, or a combination thereof.
10. A compound according to claim 1 selected from:
7-chloro-5-(5-piperazin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;
7-chloro-2-(4-chlorobenzyl)-5-(5-piperazin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-2,3-dihydroisoindol-1-one;
7-methyl-5-(5-piperazin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;
2-(4-chlorobenzyl)-7-methyl-5-(5-piperazin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-2,3-dihydroisoindol-1-one;
5-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-[1,2,4]oxadiazol-3-yl]-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;
2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-(5-piperazin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-2,3-dihydro-isoindol-1-one;
2-[(S)-1-(4-chloro-phenyl)-ethyl]-5-{5-[(1S,4S)-1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)methyl]-[1,2,4]oxadiazol-3-yl}-7-methyl-2,3-dihydro-isoindol-1-one;
2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1-one;
2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1-one;
2-(4-chloro-benzyl)-7-methyl-5-[5-(3-methyl-piperazin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1-one;
7-chloro-5-[5-(3,3-dimethyl-piperazin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;
7-methyl-5-[5-(1-piperazin-1-yl-ethyl)-[1,2,4]oxadiazol-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one;
2-(4-chloro-benzyl)-7-methyl-5-[5-(1-piperazin-1-yl-ethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydro-isoindol-1-one, or
2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-[5-(1-piperazin-1-yl-ethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydro-isoindol-1-one,
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
11. A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt, a hydrate or an optical isomer, according to claim 1 and a pharmaceutically acceptable carrier or excipient.
12. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, or a hydrate thereof according to claim 10 and a pharmaceutically acceptable carrier or excipient.
13. A compound that is:
7-chloro-5-(5-piperazin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one, or a pharmaceutically acceptable salt, or a hydrate thereof.
14. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, or a hydrate according to claim 13 and at least one pharmaceutically acceptable carrier or excipient.