Heteroaryl-pyrimidinone compounds as PDE2 inhibitors

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, and (CH 2 ) n C 6-10 aryl, said alkyl, cycloalkyl, and aryl optionally substituted with one to three groups of R a ;

R 2 and R 2a are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, (CH 2 )nOR, C(O)OR, N(R) 2 , C 3-10 cycloalkyl, (CH 2 ) n C 5-10 heterocyclyl said alkyl, cycloalkyl, and heterocyclyl optionally substituted with one to three groups of R b ;

R 2 and R 2a can combine with the carbon atom to which they are attached to form a C 2-6 alkenyl, C 3-6 cycloalkyl, or C 4-10 heterocyclyl, said alkenyl, cycloalkyl and heterocyclyl optionally substituted with one to three groups of R b ;

Y is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, and imidazolyl, said group optionally substituted with one to three groups of R b ;

R represents H, or C 1-6 alkyl,

R a is selected from the group consisting of halo, CN, C 1-6 alkyl, (CH 2 ) n OR, (O) p C 1-4 haloalkyl, C(O)OR, —O(CH 2 ) n N(R) 2 , (CHR) n N(R) 2 , NO 2 , SCF 3 , S(O) s CF 3 , S(O) s R, SF 5 , C 3-10 cycloalkyl, O—C 3-10 cycloalkyl, C 5-10 heterocyclyl, and C 6-10 aryl, said alkyl, cycloalkyl, heterocyclyl and aryl optionally substituted with one to three groups of R b ;

R b is selected from the group consisting of halo, C 1-6 alkyl, (CH 2 ) n OR, and (O) p C 1-4 haloalkyl;

n represents 0, 1, 2, 3, or 4;

s represents 0, 1, or 2; and

p represents 0 or 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl represented by structural formulas (a), (b), (c), (d), (e), (f), (g), (h), (i) and (j):

3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted pyridyl represented by structural formula (a), (b), (c) or (j).

4. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted pyrimidinyl represented by structural formula (d), (e), or (f).

5. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted pyrazinyl represented by structural formula (g).

6. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted pyridazinyl represented by structural formula (h) or (i).

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein Y is optionally substituted oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl represented by structural formulas (k), (1), (m), (n), (o), (p), (q), (r), (s), (t), (u), (v), and (w):

8. The compound according to claim 7 , or a pharmaceutically acceptable salt thereof wherein Y is optionally substituted thiazolyl represented by structural formula (k), (1), (m), or (n).

9. The compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein Y is thiadiazolyl represented by structural formula (o).

10. The compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted oxazolyl represented by structural formula (p) or (q).

11. The compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein Y is oxadiazolyl represented by structural formula (r), (s) or (t).

12. The compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted imidazolyl represented by structural formula (u), (v) or (w).

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof wherein R is hydrogen, R 1 is C 1-6 alkyl optionally substituted with 1 to 3 groups of R a , R 2 and R 2a are independently selected from hydrogen, (CH 2 ) n CH 3 , CH 3 , CH(CH3) 2 , (CH 2 ) n OH, C(O)OCH 3 , NHCH 3 , (CH 2 ) n (OCH 3 ), cyclopropyl, cyclobutyl, tetrahydrofuranyl, and R a is selected from OH, halo, (CH 2 ) n CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) n OCH 3 , OC(CH 3 ) 2 , CH 2 F, CHF 2 , CF 3 , OCHF 2 , OCF 3 , SCH 3 , SCF 3 , SF 5 , SOCF 3 , SO 2 CF 3 , SO 2 CH 3 , CH 2 NH 2 , (CH 2 ) n N(CH 3 ) 2 , NO 2 , CN, cyclobutyl, cyclopropyl, and phenyl, said groups, optionally substituted with one to three groups of Rb.

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof wherein one of R 2 and R 2a is hydrogen and the other is selected from the group consisting of (CH 2 ) n CH 3 , CH 3 , CH(CH3) 2 , (CH 2 ) n OH, C(O)OCH 3 , NHCH 3 , (CH 2 ) n (OCH 3 ), cyclopropyl, cyclobutyl, and tetrahydrofuranyl.

15. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof wherein the number of R b present is zero, R 1 is optionally substituted methyl optionally substituted with 1 to 3 groups of R a , and one of R 2 and R 2a is hydrogen and the other is (CH 2 ) n CH 3 .

16. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof wherein Y is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl, said groups optionally substituted with 1 to 3 groups of R a , R is hydrogen, R 1 is methyl optionally substituted with 1 to 3 groups of R a , and one of R 2 and R 2a is hydrogen and the other is selected from (CH 2 ) n CH 3 , CH 3 , CH(CH 3 ) 2 , (CH 2 ) n OH, C(O)OCH 3 , NHCH 3 , (CH 2 ) n (OCH 3 ), cyclopropyl, cyclobutyl, and tetrahydrofuranyl.

17. A compound which is:

2-Methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)thiazol-2-yl)pyrimidin-4(3H)-one,

2-Methyl-6-(2-(1-(4-(trifluoromethyl)phenyl)ethyl)thiazol-4-yl)pyrimidin-4(3H)-one,

2-Methyl-6-(4-(1-(4-(trifluoromethyl)phenyl)ethyl)thiazol-2-yl)pyrimidin-4(3H)-one,

(S)-6-(5-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1,3,4-thiadiazol-2-yl)-2-methylpyrimidin-4(3H)-one,

(R)-6-(5-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1,3,4-thiadiazol-2-yl)-2-methylpyrimidin-4(3H)-one,

(S)-2-methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)-1,3,4-thiadiazol-2-yl)pyrimidin-4(3H)-one,

(R)-2-methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)-1,3,4-thiadiazol-2-yl)pyrimidin-4(3H)-one,

2-Methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)oxazol-2-yl)pyrimidin-4(3H)-one,

(S)-2-methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-4(3H)-one,

(R)-2-methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-4(3H)-one,

2-Methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-4(3H)-one,

2-Methyl-6-(3-(1-(4-(trifluoromethyl)phenyl)ethyl)-1,2,4-oxadiazol-5-yl)pyrimidin-4(3H)one,

2-Methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazol-2-yl)pyrimidin-4(3H)-one,

(S)-6-(1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1H-imidazol-4-yl)-2-methylpyrimidin-4(3H)-one,

(R)-6-(1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1H-imidazol-4-yl)-2-methylpyrimidin-4(3H)-one,

(S)-2-methyl-6-(1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazol-4-yl)pyrimidin-4(3H)-one,

(R)-2-methyl-6-(1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazol-4-yl)pyrimidin-4(3H)-one,

(S)-2-(3,4-dimethoxybenzyl)-6-(1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1H-imidazol-4-yl)pyrimidin-4(3H)-one,

(R)-2-(3,4-dimethoxybenzyl)-6-(1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1H-imidazol-4-yl)pyrimidin-4(3H)-one,

6-(1-(1-(2-Fluoro-4-(trifluoromethyl)phenyl)propyl)-1H-imidazol-4-yl)-2-methylpyrimidin-4(3H)-one,

6-(1-(1-(2-Fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-1H-imidazol-4-yl)-2-methylpyrimidin-4(3H)-one,

2-methyl-6-(4-(1-(4-(trifluoromethyl)phenyl)ethyl)pyridin-2-yl)pyrimidin-4(3H)-one,

(S)-2-Methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)pyridin-3-yl)pyrimidin-4(3H)-one,

(R)-2-Methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)pyridin-3-yl)pyrimidin-4(3H)-one,

6-(5-(Hydroxy(4-(trifluoromethyl)phenyl)methyl)pyridin-3-yl)-2-methylpyrimidin-4(3H)-one,

6-(5-(1-Hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)pyridin-3-yl)-2-methylpyrimidin-4(3H)-one,

2-Methyl-6-(2-(1-(4-(trifluoromethyl)phenyl)ethyl)pyridin-4-yl)pyrimidin-4(3H)-one,

6-(2-(1-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)pyridin-4-yl)-2-methylpyrimidin-4(3H)-one,

2-Methyl-6-(6-(1-(4-(trifluoromethyl)phenyl)ethyl)pyrazin-2-yl)pyrimidin-4(3H)-one,

(S)-6′-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(R)-6′-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(S)-2-methyl-6′-(1-(4-(trifluoromethyl)phenyl)ethyl)-[4,4′-bipyrimidin]-6(1H)-one,

(R)-2-methyl-6′-(1-(4-(trifluoromethyl)phenyl)ethyl)-[4,4′-bipyrimidin]-6(1H)-one,

(S)-6′-(1-(4-(difluoro-methoxy)-3-fluorophenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(R)-6′-(1-(4-(difluoro-methoxy)-3-fluorophenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(S)-6′-(1-(4-(1,1-difluoroethyl)phenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(R)-6′-(1-(4-(1,1-difluoroethyl)phenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(S)-6′-(1-(4-(difluoro-methyl)-3-fluoro-phenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(R)-6′-(1-(4-(difluoro-methyl)-3-fluoro-phenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(S)-6′-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(R)-6′-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(S)-6′-(1-(3-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(R)-6′-(1-(3-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(S)-2-methyl-6′-(1-(4-(trifluoromethoxy)phenyl)ethyl)-[4,4′-bipyrimidin]-6(1H)-one,

(R)-2-methyl-6′-(1-(4-(trifluoromethoxy)phenyl)ethyl)-[4,4′-bipyrimidin]-6(1H)-one,

(S)-6′-(1-(4-(2-hydroxypropan-2-yl)phenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

(R)-6′-(1-(4-(2-hydroxypropan-2-yl)phenyl)ethyl)-2-methyl-[4,4′-bipyrimidin]-6(1H)-one,

2,2′-dimethyl-6′-(1-(4-(trifluoromethyl)phenyl)ethyl)-[4,4′-bipyrimidin]-6(1H)-one,

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19. A method of treating psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, Alzheimer's disease, schizophrenia, migraines, Huntington's disease, Parkinson's disease, Parkinson's disease dementia (PDD), and neurodegenerative disorders comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof.