Antidiabetic tricyclic compounds

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

A is phenyl;

B is selected from the group consisting of:

(1) phenyl, and

(2) pyridyl;

R 1 is selected from the group consisting of:

(1) halogen,

(2) —CN,

(3) —C 1-6 alkyl,

(4) —(CH 2 ) r OC 1-6 alkyl,

(5) —(CH 2 ) r C 3-6 cycloalkyl, and

(6) —(CH 2 ) r —O—(CH 2 ) r —C 3-6 cycloalkyl,

wherein each CH 2 , —C 1-6 alkyl, —OC 1-6 alkyl and —C 3-6 cycloalkyl is unsubstituted or substituted with one to four substituents selected from halogen, —C 1-6 alkyl and —(CH 2 ) v —C 3-6 cycloalkyl;

R 2 is halogen;

R 3 when present is selected from the group consisting of:

(1) halogen,

(2) —C 1-6 alkyl, and

(3) —(CH 2 ) u —C 3-6 cycloalkyl,

wherein each C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen;

R 4 is —OC 1-6 alkyl, wherein C 1-6 alkyl is unsubstituted or substituted with one, two, three or four substituents selected from R 5 ;

R 5 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —(CH 2 ) s OH, and

wherein each CH 2 and C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen;

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen and (CH 2 ) w OH;

Z is selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —(CH 2 ) s —O—C 1-6 alkyl,

(4) —(CH 2 ) s —OH,

(5) —(CH 2 ) s SO 2 C 1-6 alkyl,

(6) —(CH 2 ) s SO 2 —(CH 2 ) t —C 3-6 cycloalkyl,

(7) —(CH 2 ) s C 3-6 cycloalkyl, and

(8) —(CH 2 ) s —O—(CH 2 ) t —C 3-6 cycloalkyl,

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen;

m is 0, 1, 2 or 3;

n is 1 or 2;

p is 0, 1, 2 or 3;

q is 0,1, 2 or 3, provided that p+q is at least 2;

r is 0, 1, 2 or 3;

s is 0, 1, 2 or 3;

t is 0, 1, 2 or 3;

u is 0, 1, 2 or 3;

v is 0, 1, 2 or 3; and

w is 0, 1, 2 or 3.

2. The compound of claim 1 of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

A is phenyl;

B is selected from the group consisting of:

(1) phenyl, and

(2) pyridyl;

R 1 is selected from the group consisting of:

(1) halogen,

(2) —CN,

(3) —C 1-6 alkyl,

(4) —OC 1-6 alkyl, and

(5) —C 3-6 cycloalkyl,

wherein each —C 1-6 alkyl, —OC 1-6 alkyl and —C 3-6 cycloalkyl is unsubstituted or substituted with one to four substituents selected from halogen;

R 2 is halogen;

R 3 is selected from the group consisting of:

(1) halogen,

(2) —C 1-6 alkyl, and

(3) —C 3-6 cycloalkyl,

wherein each C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen;

R 4 is —OC 1-6 alkyl, wherein C 1-6 alkyl is unsubstituted or substituted with one, two, three or four substituents selected from R 5 ;

R 5 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —(CH 2 ) s OH, and

wherein each CH 2 and C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen;

Z is selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —(CH 2 ) s —O—C 1-6 alkyl,

(4) —(CH 2 ) s —OH, and

(5) —(CH 2 ) s C 3-6 cycloalkyl,

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen;

m is 0, 1, 2 or 3;

n is 1 or 2;

p is 0, 1, 2 or 3;

q is 0,1, 2 or 3, provided that p+q is at least 2; and

s is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein A is:

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein A is

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein B is phenyl, wherein phenyl is unsubstituted or substituted with one, two or three substituents selected from R 3 ;

or a pharmaceutically acceptable salt thereof.

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

(1) halogen, and

(2) —C 1-6 alkyl,

wherein —C 1-6 alkyl is unsubstituted or substituted with one to four substituents selected from halogen; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 wherein R 1 is —C 1-6 alkyl, wherein each —C 1-6 alkyl is substituted with one, two or three substituents selected from halogen; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein R 2 is F; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein R 3 when present is selected from the group consisting of:

(1) halogen, and

(2) —C 1-6 alkyl,

wherein each C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 wherein R 4 is —OC 1-6 alkyl, wherein C 1-6 alkyl is substituted with one substituent selected from R 5 ; or a pharmaceutically acceptable salt thereof.

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

(1) —C 1-6 alkyl,

(2) —OH, and

(3)

wherein each C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 wherein Z is selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —(CH 2 ) s —O—C 1-6 alkyl, and

(4) —(CH 2 ) s —OH,

wherein each CH 2 , and C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen; or a pharmaceutically acceptable salt thereof.

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

(1) —C 1-6 alkyl, and

(2) —(CH 2 ) s OH,

wherein each CH 2 and C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 wherein the absolute stereochemistry at the two stereogenic carbon centers is indicated below:

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 wherein:

A is phenyl;

B is phenyl or pyridyl;

R 1 is selected from the group consisting of:

(1) halogen, and

(2) —C 1-6 alkyl,

wherein —C 1-6 alkyl is unsubstituted or substituted with one to four substituents selected from halogen;

R 2 is halogen;

R 3 when present is selected from the group consisting of:

(1) halogen, and

(2) —C 1-6 alkyl,

wherein each C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen;

R 4 is —OC 1-6 alkyl, wherein C 1-6 alkyl is substituted with one substituent selected from R 5 ;

R 5 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —(CH 2 ) s OH, and

wherein each CH 2 and C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen; and

Z is selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —(CH 2 ) s —O—C 1-6 alkyl, and

(4) —(CH 2 ) s —OH,

wherein each CH 2 , and C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen;

m is 0, 1, 2 or 3;

n is 1 or 2;

p is 0, 1, 2 or 3;

q is 0,1, 2 or 3, provided that p+q is at least 2; and

s is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 wherein:

A is:

B is phenyl or pyridyl;

R 1 is selected from the group consisting of:

(1) halogen, and

(2) —C 1-6 alkyl,

wherein —C 1-6 alkyl is unsubstituted or substituted with one to four substituents selected from halogen;

R 2 is halogen;

R 3 when present is selected from the group consisting of:

(1) halogen, and

(2) —C 1-6 alkyl,

wherein each C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen;

R 4 is —OC 1-6 alkyl, wherein C 1-6 alkyl is substituted with one substituent selected from R 5 ;

R 5 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —OH, and

wherein each C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen;

Z is —(CH 2 ) s —OH;

m is 0, 1, 2 or 3; and

or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1 wherein

A is

B is phenyl;

R 1 is —C 1-6 alkyl, wherein each —C 1-6 alkyl is substituted with one, two or three substituents selected from halogen;

R 2 is F;

R 3 when present is selected from the group consisting of:

(1) halogen, and

(2) —C 1-6 alkyl,

wherein each C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen;

R 4 is —OC 1-6 alkyl, wherein C 1-6 alkyl is substituted with one substituent selected from R 5 ;

R 5 is selected from the group consisting of:

(1) —C 1-6 alkyl, and

(2) —(CH 2 ) s OH,

wherein each CH 2 and C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen;

m is 0, 1, 2 or 3; and

or a pharmaceutically acceptable salt thereof.

18. A compound selected from:

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. A method of treating type 2 diabetes mellitus in a patient in need of treatment comprising the administration to the patient of a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising

(1) a compound of claim 1 or a pharmaceutically acceptable salt thereof;

(2) one or more compounds selected from the group consisting of:

(a) PPAR gamma agonists and partial agonists;

(b) biguanides;

(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(d) dipeptidyl peptidase IV (DP-IV) inhibitors;

(e) insulin or an insulin mimetic;

(f) sulfonylureas;

(g) α-glucosidase inhibitors;

(h) agents which improve a patient's lipid profile, said agents being selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) bile acid sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists, (v) cholesterol absorption inhibitors, (vi) acyl CoA: cholesterol acyltransferase (ACAT) inhibitors, (vii) CETP inhibitors, and (viii) phenolic anti-oxidants;

(i) PPARα/γ dual agonists,

(j) PPARδ agonists,

(k) antiobesity compounds,

(l) ileal bile acid transporter inhibitors;

(m) anti-inflammatory agents;

(n) glucagon receptor antagonists;

(o) GLP-1;

(p) GIP-1;

(q) GLP-1 analogs;

(r) HSD-1 inhibitors;

(s) SGLT 1 inhibitors; and

(t) SGLT 2 inhibitors; and

(3) a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a compound selected from simvastatin, ezetimibe and sitagliptin; and a pharmaceutically acceptable carrier.

23. A compound selected from:

or a pharmaceutically acceptable salt thereof.

24. A compound selected from:

or a pharmaceutically acceptable salt thereof.