Heteroaromatic phenylimidazole derivatives as PDE10A enzyme inhibitors
This invention is directed to compounds, which are PDE10A enzyme inhibitors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The present invention also provides processes for the preparation of the compounds of formula I. The present invention further provides a method of treating a subject suffering from a neurodegenerative disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I. The present invention also provides a method of treating a subject suffering from a drug addiction comprising administering to the subject a therapeutically effective amount of a compound of formula I. The present invention further provides a method of treating a subject suffering from a psychiatric disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I.
1. A compound having the structure I
wherein HET1 is
optionally substituted with up to three substituents R2, R3 and R4 individually selected from hydrogen, C 1 -C 6 alkyl; halogen; cyano, halo(C 1 -C 6 )alkyl; aryl, alkoxy and C 1 -C 6 hydroxyalkyl, and wherein * denotes the attachment point,
HET2 is a heteroaromatic group of formula III or IV:
wherein Y can be N, S, O or CH, X can be N or CH, and wherein HET2 may optionally be substituted with up to three substituents R5, R6 and R7 individually selected from hydrogen, C 1 -C 6 alkyl; halogen; cyano, halo(C 1 -C 6 )alkyl; aryl, alkoxy and C 1 -C 6 hydroxyalkyl, and wherein * denotes the attachment point,
-L- is a linker selected from —S—CH 2 —, —CH 2 —S—, —CH 2 —CH 2 —, —CH═CH—, and —C≡C—
R1 is selected from H, C 1 -C 6 alkyl; C 1 -C 6 alkyl(C 3 -C 8 )cycloalkyl; C 1 -C 6 hydroxyalkyl, CH 2 CN, CH 2 C(O)NH 2 , C 1 -C 6 arylalkyl, and C 1 -C 6 alkyl-heterocycloalkyl,
and pharmaceutically acceptable acid addition salts thereof.
2. The compound of claim 1 in which HET2 is selected from the group consisting of thiophene, furane, thiazole, pyrazole, pyridine, pyrimidine and pyrazine.
3. The compound of claim 1 wherein -L- is —S—CH 2 —.
4. The compound of claim 1 wherein -L- is —CH 2 —S—.
5. The compound of claim 1 wherein -L- is —CH 2 —CH 2 —.
6. The compound of claim 1 wherein -L- is —CH═CH—.
7. The compound of claim 1 wherein -L- is —C≡C—.
8. The compound of claim 1 wherein R1 is hydrogen.
9. The compound of claim 1 wherein R1 is not hydrogen.
10. The compound of claim 1 wherein R2, R3 and R4 are all hydrogen.
11. The compound of claim 1 wherein at least one of R2, R3 and R4 is C 1 -C 6 alkyl.
12. The compound of claim 1 wherein at least one of R2, R3 and R4 is halogen.
13. The compound of claim 1 , wherein the compound is selected from the group consisting of:
5,8-Dimethyl-2-{2-[1-methyl-4-(5-methyl-furan-2-yl)-1H-imidazol-2-yl]-ethyl}-[1,2,4]triazolo[1,5-a]pyrazine;
5,8-Dimethyl-2-[2-(1-methyl-4-thiophen-2-yl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrazine;
5,8-Dimethyl-2-[2-(1-methyl-4-thiazol-2-yl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrazine;
5,8-Dimethyl-2-[2-(1-methyl-4-pyridin-3-yl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[,5-a]pyrazine;
2-[2-(4-Furan-3-yl-1-methyl-1H-imidazol-2-yl)-ethyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine;
5,8-Dimethyl-2-[2-(1-methyl-4-thiazol-5-yl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrazine;
and pharmaceutically acceptable acid addition salts thereof.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and one or more pharmaceutically acceptable carriers, diluents and excipients.
15. The compound of claim 1 , wherein the compound is 5,8-Dimethyl-2-{2-[1-methyl-4-(5-methyl-furan-2-yl)-1H-imidazol-2-yl]-ethyl}-[1,2,4]triazolo[1,5-a]pyrazine.
16. The compound of claim 1 , wherein the compound is 5,8-Dimethyl-2-[2-(1-methyl-4-thiophen-2-yl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrazine.
17. The compound of claim 1 , wherein the compound is 5,8-Dimethyl-2-[2-(1-methyl-4-thiazol-2-yl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrazine.
18. The compound of claim 1 , wherein the compound is 5,8-Dimethyl-2-[2-(1-methyl-4-pyridin-3-yl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrazine.
19. The compound of claim 1 , wherein the compound is 2-[2-(4-Furan-3-yl-1-methyl-1H-imidazol-2-yl)-ethyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine.
20. The compound of claim 1 , wherein the compound is 5,8-Dimethyl-2-[2-(1-methyl-4-thiazol-5-yl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrazine.