Spiropiperidine prolylcarboxypeptidase inhibitors

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

T, U, V and W are C or CH;

each X is independently selected from the group consisting of:

(1) —CH 2 —,

(2) —CH 2 CH 2 —,

(3) —SO 2 —,

(4) —C(O)—, and

(5) —C(O)CH 2 —,

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

each R 1 is independently selected from the group consisting of: pyrrolidine, azabicyclo[2.2.1]heptane, pyridine, pyrazine, pyridazine, pyrimidine, thiophene, benzodioxole, naphthalene, benzofuran, oxazole, thiazole, triazole, benzisoxazole, and imidazopyrimidine, wherein each, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from R b :

each R 2 is independently selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 1-6 alkoxy,

(4) halogen,

(5) oxo, and

(6) —OH;

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

(1) —(CH 2 ) m —C 3-7 cycloalkyl,

(2) —(CH 2 ) m —C 3-7 cycloalkenyl,

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

(4) —(CH 2 ) m —C 3-7 cycloheteroalkenyl,

(5) —(CH 2 ) m -aryl, and

(6) —(CH 2 ) m -heteroaryl,

wherein each CH 2 , cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with one, two or three groups independently selected from R c ;

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

(1) hydrogen,

(2) halogen,

(3) —CN,

(4) —CF 3 ,

(5) —OCF 3 ,

(6) —OH,

(7) —OC 1-6 alkyl, and

(8) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of: —OH, halogen, —C 1-6 alkyl, —CN, —OC 1-6 alkyl, —CO 2 H, and —CO 2 C 1-6 alkyl;

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

(1) —C 1-6 alkyl,

(2) —(CH 2 ) n CO 2 H,

(3) —(CH 2 ) n CO 2 C 1-6 alkyl,

(4) —(CH 2 ) n —OH,

(5) oxo,

(6) —(CH 2 ) n —O—C 1-6 alkyl,

(7) —(CH 2 ) n —N(R d ) 2 , and

(8) —(CH 2 ) n —S—C 1-6 alkyl,

wherein each CH 2 , and alkyl is unsubstituted or substituted with one or two groups independently selected from: —OH, —C 1-6 alkyl, halogen, —CN, —OC 1-6 alkyl, —CO 2 H, and —CO 2 C 1-6 alkyl;

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

(1) hydrogen,

(2) halogen,

(3) —CF 3 ,

(4) —OCF 3 ,

(5) —OC 1-6 alkyl, and

(6) —C 1-6 alkyl,

wherein each alkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of: —OH, —C 1-6 alkyl, halogen, —CN, and —CO 2 C 1-6 alkyl;

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

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —CN,

(5) oxo,

(6) —OH,

(7) —OC 1-6 alkyl,

(8) —CF 3 , and

(9) —OCF 3 ,

wherein alkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of: —OH, —C 1-6 alkyl, halogen, —CN, —OC 1-6 alkyl, —CO 2 H, and —CO 2 C 1-6 alkyl;

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

(1) hydrogen, and

(2) —C 1-6 alkyl;

m is selected from 0, 1, 2, 3 and 4;

n is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3 and 4;

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

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

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

(1) -aryl, and

(2) -heteroaryl,

wherein each aryl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from R c ; or a pharmaceutically acceptable salt thereof.

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

(1) -phenyl, and

(2) -pyridine,

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

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

(1) —CH 2 —,

(2) —CH 2 CH 2 —, and

(3) —SO 2 —,

wherein each CH 2 is unsubstituted or substituted with one or two substituents selected from R a ; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 wherein each X is independently selected from the group consisting of:

(1) —CH 2 —, and

(2) —SO 2 —,

wherein CH 2 is unsubstituted or substituted with one or two substituents selected from R a ; or a pharmaceutically acceptable salt thereof.

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

(1) hydrogen,

(2) halogen, and

(3) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of: —OH, halogen, —C 1-6 alkyl, —CN, —OC 1-6 alkyl, —CO 2 H, and —CO 2 C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 wherein R 4 is hydrogen; or a pharmaceutically acceptable salt thereof.

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

(1) hydrogen,

(2) — 1-6 alkyl,

(3) oxo, and

(4) —OH;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 wherein R 2 is hydrogen; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1

R 1 is pyridine, wherein pyridine is unsubstituted or substituted with one to three groups independently selected from R b ;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 wherein

each X is independently selected from the group consisting of:

(1) —CH 2 —,

(2) —CH 2 CH 2 —, and

(3) —SO 2 —,

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

each R 2 is independently selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) oxo, and

(4) —OH;

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

(1) -aryl, and

(2) -heteroaryl,

wherein each aryl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from R c ;

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

(1) hydrogen,

(2) halogen, and

(3) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of: —OH, halogen, —C 1-6 alkyl, —CN, —OC 1-6 alkyl, —CO 2 H, and —CO 2 C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 wherein:

each X is independently selected from the group consisting of:

(1) —CH 2 —, and

(2) —SO 2 —,

wherein CH 2 is unsubstituted or substituted with one or two substituents selected from R a ;

R 1 is pyridine, wherein pyridine is unsubstituted or substituted with one to three groups independently selected from R b ;

R 2 is hydrogen;

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

(1) -phenyl, and

(2) -pyridine,

wherein each phenyl and pyridine is unsubstituted or substituted with one to three groups independently selected from R c ;

R 4 is hydrogen;

or a pharmaceutically acceptable salt thereof.

13. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

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

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