Prolylcarboxypeptidase inhibitors

1. A compound of structural formula I-1 or I-2:

or a pharmaceutically acceptable salt thereof; wherein

X is CH or N;

each R 1 is independently selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —(CH 2 ) m —C(O)-aryl,

(3) —(CH 2 ) m —CH(OH)—(CH 2 ) p -aryl,

(4) —(CH 2 ) m —SO 2 -aryl,

(5) —(CH 2 ) m C 2-6 cycloheteroalkyl,

(6) —(CH 2 ) m aryl, and

(7) —(CH 2 ) m heteroaryl,

wherein each CH 2 , alkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from R a ;

each R 2 is selected from the group consisting of:

(1) hydrogen, and

(2) —(CH 2 ) n aryl,

wherein each CH 2 , and aryl is unsubstituted or substituted with one or two substituents selected from R b ;

each R 3 is independently selected from the group consisting of:

(1) hydrogen,

(2) -aryl, and

(3) -heteroaryl,

wherein each aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R c ,

provided that at least one of R 2 and R 3 is not hydrogen;

each R 4 is independently selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens;

each R 5 is independently selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 1-6 alkoxy,

(4) —CF 3 ,

(5) —(CH 2 ) t C 3-7 cycloalkyl,

(6) —(CH 2 ) t C 2-6 cycloheteroalkyl,

(7) —(CH 2 ) t aryl, and

(8) —(CH 2 ) t heteroaryl,

wherein each CH 2 , alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R d ;

each R 6 is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —CF 3 , and

(4) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens;

each R a is independently selected from the group consisting of:

(1) hydrogen,

(2) oxo,

(3) halogen,

(4) —C 1-4 alkyl,

(5) —OC 1-4 alkyl,

(6) —CF 3 ,

(7) —OH,

(8) —OCF 3 ,

(9) —CN, and

(10) —CO 2 —C 1-6 alkyl;

each R b is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C 1-4 alkyl,

(4) —OC 1-4 alkyl,

(5) —CF 3 ,

(6) —OCF 3 ,

(7) —CN, and

(8) —CO 2 —C 1-6 alkyl;

R c is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C 1-4 alkyl,

(4) —OC 1-4 alkyl,

(5) —CF 3 ,

(6) —OCF 3 ,

(7) —CN, and

(8) —CO 2 —C 1-6 alkyl;

each R d is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C 1-4 alkyl,

(4) —OC 1-4 alkyl,

(5) —CF 3 ,

(6) —OCF 3 ,

(7) —CN, and

(8) —CO 2 —C 1-6 alkyl;

m is selected from 0, 1, 2 and 3;

n is selected from 0, 1, 2, and 3;

p is selected from 0, 1, 2 and 3;

r is selected from 0, 1, and 2;

s is selected from 1 and 2; and

t is selected from 0, 1, 2 and 3.

2. The compound of claim 1 wherein each R 1 is independently selected from the group consisting of:

(1) —C 1-6 alkyl, and

(2) —(CH 2 ) m phenyl,

wherein each CH 2 , alkyl and phenyl is unsubstituted or substituted with one to three groups independently selected from R a ; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein R 2 is selected from the group consisting of:

(1) hydrogen, and

(2) -phenyl,

wherein each phenyl is unsubstituted or substituted with one or two substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein R 3 is selected from the group consisting of:

(1) hydrogen,

(2) -phenyl, and

(3) -pyridine,

wherein each phenyl and pyridine is unsubstituted or substituted with one to three substituents selected from Re,

provided that at least one of R 2 and R 3 is not hydrogen;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 5 is —(CH 2 ) t phenyl, wherein each CH 2 and phenyl is unsubstituted or substituted with one to three substituents selected from R d ; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 wherein R 5 is selected from the group consisting of:

(1) —(CH 2 ) 2 -phenyl, and

(2) -phenyl,

wherein each CH 2 and phenyl is unsubstituted or substituted with one to three substituents selected from R d ; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein R 6 is hydrogen; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein r is 0, and s is 1; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 wherein r is 0, and s is 2; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 wherein

each R 1 is independently selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —(CH 2 ) m —C(O)-aryl,

(3) —(CH 2 ) m —CH(OH)—(CH 2 ) p -aryl,

(4) —(CH 2 ) m —SO 2 -aryl,

(5) —(CH 2 ) m C 2-6 cycloheteroalkyl,

(6) —(CH 2 ) m aryl, and

(7) —(CH 2 ) m heteroaryl,

wherein each CH 2 , alkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from R a ;

R 2 is selected from the group consisting of:

(1) hydrogen, and

(2) —(CH 2 ) n aryl,

wherein each CH 2 and aryl is unsubstituted or substituted with one or two substituents selected from R b ;

each R3 is independently selected from the group consisting of:

(1) hydrogen,

(2) -aryl, and

(3) -heteroaryl,

wherein each aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R c ,

provided that at least one of R 2 and R 3 is not hydrogen;

R 5 is —(CH 2 ) t phenyl, wherein each CH 2 and phenyl is unsubstituted or substituted with one to three substituents selected from R d ;

R 6 is hydrogen; and

m is 0, 1 or 2;

n is 0 or 1;

p is 0 or 1; and

t is 0 or 2;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 wherein:

R 1 is independently selected from the group consisting of:

(1) —C 1-6 alkyl, and

(2) —(CH 2 ) m phenyl,

wherein each CH 2 , alkyl and phenyl is unsubstituted or substituted with one to three groups independently selected from R a ;

R 2 is selected from the group consisting of:

(1) hydrogen, and

(2) -phenyl,

wherein each phenyl is unsubstituted or substituted with one or two substituents selected from R b ;

R 3 is selected from the group consisting of:

(1) hydrogen,

(2) -phenyl, and

(3) -pyridine,

wherein each phenyl and pyridine is unsubstituted or substituted with one to three substituents selected from R c ,

provided that at least one of R 2 and R 3 is not hydrogen;

R 5 is -phenyl, wherein phenyl is unsubstituted or substituted with one to three substituents selected from R d ;

R 6 is hydrogen; and

m is 2;

or a pharmaceutically acceptable salt thereof.

12. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

14. A composition comprising a compound according to claim 1 and a compound selected from simvastatin, ezetimibe, taranabant and sitagliptin; and a pharmaceutically acceptable carrier.