Substituted pyrazolo/imidazolo bicyclic compounds as PDE2 inhibitors

1. A compound represented by structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X represents NH, or O;

R is selected from the group consisting of H and C 1-6 alkyl,

one of R 1 and R 2 is hydrogen and the other is C 1-6 alkyl, said alkyl is optionally substituted with 1 to 3 groups of R a ;

or R 1 and R 2 can combine with the carbon to which they are attached to form a C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, said cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 3 groups of R a , wherein when R 1 and R 2 are combined R a is selected from the group consisting of (CH 2 ) n CF 3 , OCF 3 , C(CH 3 ) 3 , OC(CH 3 ) 3 , CHF 2 , SF 5 , SCF 3 , OCHF 2 , and CH(CH 3 ) 2 ;

R 3 represents halo, C 1-6 alkyl, C 1-4 haloalkyl, (CH 2 ) n OR, C 3-10 cycloalkyl, or CN, said alkyl and cycloalkyl are optionally substituted with 1 to 3 groups of R a ;

R 4 is selected from the group consisting of hydrogen, (CH 2 ) n OR, C 1-6 alkyl, (CH 2 ) n C 1-4 haloalkyl, CN, and N(R) 2 , said alkyl is optionally substituted with one to three groups of R a ;

R a is selected from the group consisting of halo, CN, C 1-6 alkyl, (CH 2 ) n OR, (CH 2 ) n CF 3 , (O) p C 1-4 haloalkyl, N(R) 2 , SCF 3 , SF 5 , C 3-10 cycloalkyl, C 6-10 aryl, and C 4-10 heterocyclyl;

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

provided that when X is NH, then R 1 and R 2 combine with the carbon to which they are attached to form a C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, said cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 3 groups of R a ; and

p represents 0 or 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein X is NH.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 4 is hydrogen.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 4 is selected from the group consisting of H, CH 3 , (CH 2 ) n OH, C(CH 3 ) 2 OH, C(CH 3 ) 3 , CH(CH 3 ) 2 , CH 2 C(CH 3 ) 2 OH, CH 2 CH 3 (CH 2 ) n CHF 2 , (CH 2 ) n CH 2 F, (CH 2 ) n CF 3 , NH 2 , N(CH 3 ) 2 , NHCH 3 , OCH 2 CH 3 , (CH 2 ) n OCH 3 , and CN.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof wherein R 4 is selected from the group consisting of CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 2 OH, C(CH 3 ) 3 , CH 2 CH 3 , (CH 2 ) n OH, CHF 2 , CH 2 F, CH 2 CF 3 , CF 3 , and NH 2 .

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein X is O, and one of R 1 and R 2 is hydrogen and the other is selected from the group consisting CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 2 OH, C(CH 3 ) 2 CH 2 OH, C(CH 3 ) 3 , CH 2 CH 3 , CH(CH 3 )OH, (CH 2 ) 1-4 OH, C(CH 3 ) 2 NH 2 , C(CH 2 CH 3 ) 2 OH, and (CH 2 ) 1-4 OCH 3 .

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein X is NH, and R 1 and R 2 combine with the carbon to which they are attached to form an optionally substituted C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or oxetanyl, said C 3-10 cycloalkyl or C 3-10 heterocycloalkyl are optionally substituted with 1 to 3 groups selected from R a where R a is selected from the group consisting of (CH 2 ) n CF 3 , OCF 3 , C(CH 3 ) 3 , OC(CH 3 ) 3 , CHF 2 , SF 5 , SCF 3 , OCHF 2 , and CH(CH 3 ) 2 .

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is selected from the group consisting of halo, OH, (CH 2 ) n CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) n OCH 3 , CH 2 F, CHF 2 , (CH 2 ) n CF 3 , CN, and cyclopropyl optionally substituted with 1 to 3 groups of R a .

9. A compound which is:

6-Chloro-1-methyl-N-{1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-1-methyl-N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-1-methyl-N-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-1-methyl-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-1-methyl-N-{1-[4-(1-methylethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-1-methyl-N-{1-(4-[1-methylethyl)phenyl]propyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-1-methyl-N-{1-[4-(1H-pyrazol-1-yl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-1-methyl-N-{1-methyl-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-1-methyl-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-amine,

6-Chloro-N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-N-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

1-Methyl-4-({1-[4-(trifluoromethyl)phenyl]cyclopropyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-6-ol,

6-Cyclopropyl-1-methyl-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-N,1-dimethyl-N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-N,1-dimethyl-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-N-ethyl-1-methyl-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-N,1-dimethyl-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-Chloro-1-(1-methylethyl)-N-{1-[4-(trifluoromethyl)phenyl]ethyl}1-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

1-Methyl-6-(trifluoromethyl)-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

1,6-Dimethyl-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

1,6-Dimethyl-N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

N-{1-[3-Fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}-1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

1,6-Dimethyl-N-(1-{4-[(trifluoromethyl)sulfanyl]phenyl}cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

N-{1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}-1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

1,6-Dimethyl-N-{1-[4-(trifluoromethyl)phenyl]cyclobutyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

N,1,6-Trimethyl-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

N,1,6-Trimethyl-N-(1-{4-[(trifluoromethyl)sulfanyl]phenyl}cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

N-{1-[3-Fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}-6-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

1-Methyl-4-({1-[4-(trifluoromethyl)phenyl]cyclopropyl}amino)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile, or

1,6-Dimethyl-4-({1-[4-(trifluoromethyl)phenyl]cyclopropyl}oxy)-1H-pyrazolo[3,4-d]pyrimidine,

or a pharmaceutically acceptable salt thereof.

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

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein

when X is O, R a is selected from the group consisting of (CH 2 ) n CF 3 , OCF 3 , C(CH 3 ) 3 , OC(CH 3 ) 3 , CHF 2 , SF 5 , SCF 3 , OCHF 2 , and CH(CH 3 ) 2 ; R 3 is selected from the group consisting of halo, OH, (CH 2 ) n CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) n OCH 3 , CH 2 F, CHF 2 , (CH 2 ) 1-3 CF 3 , CN, and cyclopropyl optionally substituted with 1 to 3 groups of R a ; R 4 is selected from the group consisting of (CH 2 ) n OH, CH(CH 3 ) 2 , CH 3 , and CH 2 CF 3 ; and one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 2 OH, C(CH 3 ) 2 CH 2 OH, C(CH 3 ) 3 , CH 2 CH 3 , CH(CH 3 )OH, (CH 2 ) n OH, C(CH 3 ) 2 NH 2 , C(CH 2 CH 3 ) 2 OH, and (CH 2 ) n OCH 3 .

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein

when X is NH, R 3 is selected from the group consisting of halo, OH, (CH 2 ) n CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) n OCH 3 , CH 2 F, CHF 2 , (CH 2 ) 1-3 CF 3 , CN, and cyclopropyl optionally substituted with 1 to 3 groups of R a ; R 4 is selected from the group consisting of (CH 2 ) n OH, CH(CH 3 ) 2 , CH 3 , and CH 2 CF 3 , and R 1 and R 2 combine with the carbon to which they are attached to form an optionally substituted C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or oxetanyl, said C 3-10 cycloalkyl or C 3-10 heterocycloalkyl are optionally substituted with 1 to 3 groups selected from R a , where R a is selected from the group consisting of (CH 2 ) n CF 3 , OCF 3 , C(CH 3 ) 3 , OC(CH 3 ) 3 , CHF 2 , SF 5 , SCF 3 , OCHF 2 , and CH(CH 3 ) 2 .