Prolylcarboxypeptidase inhibitors

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

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

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 1-6 alkoxy,

(4) —(CH 2 ) m CO 2 C 1-6 alkyl,

(5) —(CH 2 ) m —C(O)—(CH 2 ) p -halogen,

(6) —(CH 2 ) m —C(O)—(CH 2 ) p CO 2 H,

(7) —(CH 2 ) m —C(O)—(CH 2 ) p N(R f ) 2 ,

(8) —(CH 2 ) m —C(O)—(CH 2 ) p —C 3-7 cycloalkyl,

(9) —(CH 2 ) m —C(O)—(CH 2 ) p —C 2-6 cycloheteroalkyl,

(10) —(CH 2 ) m —C(O)—(CH 2 ) p -aryl,

(11) —(CH 2 ) m —C(O)—(CH 2 ) p -heteroaryl,

(12) —(CH 2 ) 2-3 —NR f —C 1-6 alkyl,

(13) —(CH 2 ) 2-3 —O—C 1-6 alkyl,

(14) —(CH 2 ) 2-3 —S—C 1-6 alkyl,

(15) C 3-7 cycloalkyl,

(16) C 2-6 cycloheteroalkyl,

(17) aryl, and

(18) heteroaryl,

wherein each CH 2 , alkyl, alkoxy, cycloalkyl, 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, and

(3) —C 1-6 alkoxy,

wherein each alkyl and alkoxy is unsubstituted or substituted with one to four substituents selected from R c , or

R 1 and R 2 together with the nitrogen atom to which they are attached form a cycloheteroalkyl ring of 4 to 7 members containing 0-1 additional heteroatoms independently selected from oxygen, sulfur and N—R h , wherein the cycloheteroalkyl ring is unsubstituted or substituted with —C 1-3 alkyl and oxo;

each R 3 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 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, and

(2) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of: hydroxy, halogen and —OC 1-4 alkyl;

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

(1) —C 1-6 alkyl,

(2) —(CH 2 ) n CF 3 ,

(3) —(CH 2 ) n OCF 3 ,

(4) —(CH 2 ) n CONH(C 1-4 alkyl),

(5) —(CH 2 ) n CON(C 1-4 alkyl) 2 ,

(6) —(CH 2 ) 1-2 —S-phenyl,

(7) —(CH 2 ) 1-2 —S—C 1-4 alkyl,

(8) —(CH 2 ) 1-2 —S(O) 2 -phenyl,

(9) —(CH 2 ) 1-2 —S(O) 2 C 1-4 alkyl,

(10) —(CH 2 ) n C 3-7 cycloalkyl,

(11) —(CH 2 ) n C 2-6 cycloheteroalkyl,

(12) —(CH 2 ) n aryl, and

(13) —(CH 2 ) n heteroaryl,

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

provided that at least one of R 6 and R 7 is selected from the group consisting of: —(CH 2 ) n C 3-7 cycloalkyl, —(CH 2 ) n C 2-6 cycloheteroalkyl, —(CH 2 ) n aryl and —(CH 2 ) n heteroaryl;

each R 7 is independently selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —(CH 2 ) n CF 3 ,

(4) —(CH 2 ) n OCF 3 ,

(5) —(CH 2 ) n CONH(C 1-4 alkyl),

(6) —(CH 2 ) n CON(C 1-4 alkyl) 2 ,

(7) —(CH 2 ) 1-2 —S-phenyl,

(8) —(CH 2 ) 1-2 —S—C 1-4 alkyl,

(9) —(CH 2 ) 1-2 —S(O) 2 -phenyl,

(10) —(CH 2 ) 1-2 —S(O) 2 C 1-4 alkyl,

(11) —(CH 2 ) n C 3-7 cycloalkyl,

(12) —(CH 2 ) n C 2-6 cycloheteroalkyl,

(13) —(CH 2 ) n aryl, and

(14) —(CH 2 ) n heteroaryl,

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

R 5 and R 7 together with the carbon atom to which they are attached form a cycloalkyl ring of 3 to 6 members, wherein the cycloalkyl ring is unsubstituted or substituted with one to three substituents selected from R g ;

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

(1) hydrogen,

(2) halogen,

(3) —CN, and

(4) —C 1-4 alkyl, unsubstituted or substituted with one to five fluorines;

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

(1) hydrogen, and

(2) C 1-4 alkyl,

wherein alkyl is unsubstituted or substituted with one to five fluorines;

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

(1) hydrogen, and

(2) C 1-4 alkyl,

wherein alkyl is unsubstituted or substituted with one to five fluorines;

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

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —CF 3 , and

(5) —CN;

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

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —CF 3 ,

(5) —OC 1-6 alkyl, and

(6) —CN;

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

(1) hydrogen,

(2) C 1-6 alkyl, and

(3) —(CH 2 ) 0-2 -cycloalkyl;

wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R b ;

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

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —CF 3 ,

(5) —OC 1-6 alkyl, and

(6) —CN;

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

(1) hydrogen, and

(2) —C 1-6 alkyl;

m is an integer from 0 to 3;

n is an integer from 0 to 3;

p is an integer from 1 to 3; and

q is an integer from 0 to 3.

2. The compound of claim 1 wherein R 3 , R 4 , and R 5 are hydrogen; or a pharmaceutically acceptable salt thereof.

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

(1) —(CH 2 ) n C 3-7 cycloalkyl,

(2) —(CH 2 ) n aryl, and

(3) —(CH 2 ) n heteroaryl,

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

4. The compound of claim 1 wherein R 6 is phenyl, wherein phenyl is unsubstituted or substituted with one to three substituents selected from R d ; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 7 is selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —(CH 2 ) n CF 3 ,

(4) —(CH 2 ) n C 3-7 cycloalkyl,

(5) —(CH 2 ) n aryl, and

(6) —(CH 2 ) n heteroaryl,

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

R 5 and R 7 together with the carbon atom to which they are attached form a cycloalkyl ring of 3 to 6 members, wherein the cycloalkyl ring is unsubstituted or substituted with one to three substituents selected from R g ;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein R 7 is selected from the group consisting of:

(1) phenyl, and

(2) pyridine,

wherein phenyl and pyridine are unsubstituted or substituted with one to three substituents selected from R e ; or a pharmaceutically acceptable salt thereof.

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

(1) hydrogen,

(2) —CO 2 C 1-6 alkyl,

(3) —C(O)—(CH 2 ) p -halogen,

(4) —C(O)—(CH 2 ) p N(R f ) 2 ,

(5) —C(O)—(CH 2 ) p —C 2-6 cycloheteroalkyl,

(6) —C(O)—(CH 2 ) p -heteroaryl, and

(7) —(CH 2 ) 2-3 —O—C 1-6 alkyl,

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

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

(1) hydrogen,

(2) —C 1-6 alkyl, and

(3) —C 1-6 alkoxy,

wherein each alkyl and alkoxy is unsubstituted or substituted with one to four substituents selected from R c , or

R 1 and R 2 form a morpholine ring, wherein the morpholine ring is unsubstituted or substituted with —C 1-3 alkyl and oxo;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 wherein R 1 is —C(O)—(CH 2 )N(R f ) 2 and R 2 is hydrogen; or R 1 and R 2 form a morpholine ring; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 wherein q is 0 or 1; or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 of structural formula (Ia):

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 wherein

R 1 is independently selected from the group consisting of:

(1) hydrogen,

(2) —CO 2 C 1-6 alkyl,

(3) —C(O)—(CH 2 ) p -halogen,

(4) —C(O)—(CH 2 ) p N(R f ) 2 ,

(5) —C(O)—(CH 2 ) p —C 2-6 cycloheteroalkyl,

(6) —C(O)—(CH 2 ) p -heteroaryl, and

(7) —(CH 2 ) 2-3 —O—C 1-6 alkyl,

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

R 2 is selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl, and

(3) —C 1-6 alkoxy,

wherein each alkyl and alkoxy is unsubstituted or substituted with one to four substituents selected from R c , or

R 1 and R 2 form a morpholine ring, wherein the morpholine ring is unsubstituted or substituted with —C 1-3 alkyl and oxo;

R 3 , R 4 , and R 5 are hydrogen;

R 6 is selected from the group consisting of:

(1) —(CH 2 ) n C 3-7 cycloalkyl,

(2) —(CH 2 ) n aryl, and

(3) —(CH 2 ) n heteroaryl,

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

R 7 is selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —(CH 2 ) n CF 3 ,

(4) —(CH 2 ) n C 3-7 cycloalkyl,

(5) —(CH 2 ) n aryl, and

(6) —(CH 2 ) n heteroaryl,

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

R 5 and R 7 together with the carbon atom to which they are attached form a cycloalkyl ring of 3 to 6 members, wherein the cycloalkyl ring is unsubstituted or substituted with one to three substituents selected from R g ; and

q is 0 or 1;

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 wherein

R 1 is —C(O)—(CH 2 )N(R f ) 2 and R 2 is hydrogen, or R 1 and R 2 form a morpholine ring;

R 3 , R 4 , and R 5 are hydrogen;

R 6 is phenyl, wherein phenyl is unsubstituted or substituted with one to three substituents selected from R d ;

R 7 is selected from the group consisting of:

(1) phenyl, and

(2) pyridine,

wherein phenyl and pyridine are unsubstituted or substituted with one to three substituents selected from R e ; and

q is 1;

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

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

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

17. A method of treating a disorder, condition or disease responsive to the inhibition of prolylcarboxypeptidase in a patient in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 1 .

18. The method of claim 17 wherein the disorder, condition, or disease is selected from the group consisting of: obesity, diabetes, metabolic syndrome, a diabetes related disorder or an obesity related disorder.

19. The method of claim 18 wherein the disorder, condition, or disease is obesity.