Phenylimidazole derivatives as PDE10A enzyme inhibitors

1. A compound having the structure I

wherein HET is selected from the group consisting of imidazo[1,2-a]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, and [1,2,4]triazolo[1,5-c]pyrimidine,

and wherein HET may optionally be substituted with up to three substituents R 7 -R 9 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,

-L- is a linker selected from —CH 2 —CH 2 —, —S—CH 2 —, —CH 2 —S— or —CH═CH—,

R 1 is selected from hydrogen, 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,

R 2 -R 6 are selected individually from hydrogen, C 1 -C 6 alkoxy and halogen, and tautomers and pharmaceutically acceptable acid addition salts thereof, and polymorphic forms thereof.

2. The compound of claim 1 wherein at least one of R 7 , R 8 and R 9 is C 1 -C 6 alkyl.

3. The compound of claim 1 wherein -L- is —CH 2 —CH 2 —.

4. The compound of claim 1 wherein -L- is —CH 2 —S—.

5. The compound of claim 1 wherein -L- is —S—CH 2 —.

6. The compound of claim 1 wherein -L- is —CH═CH—.

7. The compound of claim 1 wherein R 1 is hydrogen.

8. The compound of claim 1 wherein R 1 is not hydrogen.

9. The compound of claim 1 wherein R 2 , R 3 , R 4 , R 5 and R 6 are all hydrogen.

10. The compound of claim 1 wherein at least one of R 2 , R 3 , R 4 , R 5 and R 6 is C 1 -C 6 alkoxy.

11. The compound of claim 1 wherein at least one of R 2 , R 3 , R 4 , R 5 and R 6 is halogen.

12. The compound of claim 1 wherein R 7 , R 8 and R 9 are all hydrogen.

13. The compound of claim 2 in which HET is 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine or 5,7-dimethyl-imidazo[1,2-a]pyrimidine.

14. The compound of claim 1 wherein at least one of R 7 , R 8 and R 9 is C 1 -C 6 alkoxy.

15. The compound of claim 1 wherein at least one of R 7 , R 8 and R9 is halogen.

16. The compound of claim 1 , wherein the compound is selected from the group consisting of:

5,7-Dimethyl-2-[1-(3-methyl-butyl)-4-phenyl-1H-imidazol-2-ylsulfanylmethyl]-imidazo[1,2-a]pyrimidine;

5,7-Dimethyl-2-(4-phenyl-1-propyl-1H-imidazol-2-ylsulfanylmethyl)-imidazo[1,2-a]pyrimidine;

2-(1-Cyclopropylmethyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-5,7-dimethyl-imidazo[1,2-a]pyrimidine;

5,7-dimethyl-2-((1-methyl-4-phenyl-1H-imidazol-2-ylthio)methyl)imidazo[1,2-a]pyrimidine;

5,7-Dimethyl-2-[1-(2-morpholin-4-yl-ethyl)-4-phenyl-1H-imidazol-2-ylsulfanylmethyl]-imidazo[1,2-a]pyrimidine:

5,7-Dimethyl-2-[4-phenyl-1-(tetrahydro-pyran-4-ylmethyl)-1H-imidazol-2-ylsulfanylmethyl]-imidazo[1,2-a]pyrimidine;

5,7-Dimethyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]imidazo[1,2-a]pyrimidine;

2-(1-Benzyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-5,7-dimethyl-imidazo[1,2-a]pyrimidine;

trans-5,7-Dimethyl-2-[(E)-2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-vinyl]-imidazo[1,2-a]-pyrimidine;

2-(1-Isopropyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-5,7-dimethyl-imidazo[1,2-a]pyrimidine;

2-(1-Ethyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-5,7-dimethyl-imidazo[1,2-a]pyrimidine;

2-(5,7-Dimethyl-imidazo[1,2-a]pyrimidin-2-ylmethylsulfanyl)-4-phenyl-imidazol-1-ylamine;

2-[4-(3-Methoxy-phenyl)-1-methyl-1H-imidazol-2-ylsulfanylmethyl]-5,7-dimethyl-imidazo[1,2-a]pyrimidine;

2-(1-Methyl-4-phenyl-1H-imidazol-2-ylmethylsulfanyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

2-(1-Methyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-imidazo[1,2-a]pyrimidine;

2-[1-(4-Chloro-benzyl)-4-phenyl-1H-imidazol-2-ylsulfanylmethyl]-5,7-dimethyl-imidazo[1,2-a]pyrimidine;

5,7-Dimethyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine;

5,7-Dimethyl-2-[2-(4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine;

5,7-Dimethyl-2-(4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

5,7-Dimethyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

2-(1-Isobutyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

5,7-Dimethyl-2-[1-(2-morpholin-4-yl-ethyl)-4-phenyl-1H-imidazol-2-ylsulfanylmethyl]-[1,2,4]triazolo[1,5-a]pyrimidine;

5-Methyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-7-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine;

1-{2-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethylsulfanyl)-4-phenyl-imidazol-1-yl]-ethyl}-3-methyl-imidazolidin-2-one;

5,6,7-Trimethyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine;

5-Methyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-7-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine;

2-[4-(3-Methoxy-phenyl)-1-methyl-1H-imidazol-2-ylmethylsulfanyl]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

5,7-Dimethyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylmethylsulfanyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

5,7-Dimethyl-2-{2-[4-phenyl-1-(2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-ethyl}-[1,2,4]triazolo[1,5-a]pyrimidine;

2-[2-(1-Isobutyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

2-[2-(1-Isopropyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-5,7-dimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine;

1-(2-{2-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethyl]-4-phenyl-imidazol-1-yl}-ethyl)-3-methyl-imidazolidin-2-one;

(2-{2-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethyl]-4-phenyl-imidazol-1-yl}-ethyl)-diisopropyl-amine;

5,7-Dimethyl-2-{2-[1-(2-morpholin-4-yl-ethyl)-4-phenyl-1H-imidazol-2-yl]-ethyl}-[1,2,4]triazolo[1,5-a]pyrimidine;

5,7-Dimethyl-2-[2-(4-phenyl-1-propyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine;

1-{2-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethyl]-4-phenyl-imidazol-1-yl}-propan-2-ol;

(S)-1-{2-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethyl]-4-phenyl-imidazol-1-yl}-propan-2-ol;

(R)-1-{2-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethyl]-4-phenyl-imidazol-1-yl}-propan-2-ol;

1-{2-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethyl]-4-phenyl-imidazol-1-yl}-2-methyl-propan-2-ol;

8-Ethyl-5-methyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-c]pyrimidine;

5-Methyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-7-propyl-[1,2,4]triazolo[1,5-a]pyrimidine;

7-Methoxy-5-methyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-c]pyrimidine;

7-Isopropyl-5-methyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine;

2-{2-[4-(2,4-Difluoro-phenyl)-1-methyl-1H-imidazol-2-yl]-ethyl}-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

7-Methoxy-5,8-dimethyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-c]pyrimidine;

5,8-Dimethyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-c]pyrimidine;

2-{2-[4-(2-Methoxy-phenyl)-1-methyl-1H-imidazol-2-yl]-ethyl}-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; and

{5-Methyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-methanol;

and pharmaceutically acceptable acid addition salts thereof.

17. A method of treating a subject suffering from a psychiatric disorder comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof wherein the psychiatric disorder is selected from the group consisting of schizophrenia, schizophreniform disorder and schizoaffective disorder.

18. The method of claim 17 , wherein the psychiatric disorder is schizophrenia.

19. The method of claim 17 , wherein the psychiatric disorder is schizophreniform disorder.

20. The method of claim 17 , wherein the psychiatric disorder is schizoaffective disorder.

21. The method of claim 18 , wherein the schizophrenia is of the paranoid, disorganized, catatonic, undifferentiated or residual type.

22. The method of claim 17 , wherein the compound is administered in combination with a neuroleptic agent.

23. The method of claim 22 , wherein the neuroleptic agent is sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone or osanetant.

24. The method of claim 20 , wherein the schizoaffective disorder is of the delusional type or the depressive type.