Fused indoles as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

1. A compound of structural formula I:

wherein:

each n is independently 0, 1, 2, or 3;

X is selected from S, S(O), S(O) 2 , CH 2 , CHF, and CF 2 ;

R 1 is hydrogen or —CN;

R 2 is selected from the group consisting of

hydrogen,

C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, CO 2 H,

C 1-6 alkyloxycarbonyl, and

(CH 2 ) n -aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, CO 2 H, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;

R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of

hydrogen,

halogen,

cyano,

hydroxy,

C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five halogens,

C 1-6 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens,

(CH 2 ) n —COOH,

(CH 2 ) n —COOC 1-6 alkyl,

(CH 2 ) n —CONR 7 R 8 ,

(CH 2 ) n —NR 7 R 8 ,

(CH 2 ) n —NR 10 SO 2 R 9 ,

(CH 2 ) n —NR 10 CONR 7 R 8 ,

(CH 2 ) n —NR 10 COR 10 ,

(CH 2 ) n —NR 10 CO 2 R 9 ,

(CH 2 ) n -aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, CO 2 H, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,

wherein any methylene (CH 2 ) carbon atom in R 3 , R 4 , R 5 , and R 6 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five halogens;

R 7 and R 8 are each independently selected from the group consisting of

hydrogen,

(CH 2 ) n -phenyl,

(CH 2 ) n —C 3-6 cycloalkyl, and

C 1-10 alkyl,

wherein alkyl is unsubstituted or substituted with one to five halogens and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens; or

R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;

R 9 is selected from the group consisting of (CH 2 ) n -phenyl, (CH 2 ) n -phenyl, (CH 2 ) n —C 3-6 cycloalkyl, and C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five halogens and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, and wherein any methylene (CH 2 ) carbon atom in R 9 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five halogens; and

each R 10 is hydrogen or R 9 .

2. The compound of claim 1 of structural formula Ia wherein the carbon atom marked with an * has the stereochemical configuration as depicted in formula Ia:

3. The compound of claim 1 wherein X is S, S(O), or S(O) 2 .

4. The compound of claim 3 wherein R 1 is hydrogen.

5. The compound of claim 2 wherein X is S, S(O), or S(O) 2 .

6. The compound of claim 1 wherein X is CH 2 , CHF, or CF 2 .

7. The compound of claim 6 wherein R 1 is hydrogen.

8. The compound of claim 2 wherein X is CH 2 , CHF, or CF 2 .

9. The compound of claim 1 wherein R 2 is hydrogen, methyl, or phenyl.

10. The compound of claim 9 wherein R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, trifluoromethoxy, carboxy, and COOC 1-4 alkyl.

11. The compound of claim 10 wherein R 4 and R 6 are hydrogen.

12. The compound of claim 11 of structural formula II selected from the group consisting of:

(II)

X

R 2

R 3

R 5

S

H

H

Cl

CH 2

H

H

Cl

CH 2

H

H

OCF 3

CH 2

H

H

CF 3

CH 2

H

CO 2 H

H

CH 2

H

CO 2 Et

H

CH 2

H

H

CO 2 H

CH 2

H

H

CO 2 Et

CH 2

H

CF 3

H

CF 2

H

CONHn-Dec

H

CH 2

Me

H

H

CH 2

Ph

H

H.

13. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.

14. A method for treating diabetes in a mammal in need thereof which comprises the administration to the mammal of a therapeutically effective amount of a compound of claim 1 .

15. A method for treating non-insulin dependent (Type 2) diabetes in a mammal in need thereof which comprises the administration to the mammal of a therapeutically effective amount of a compound of claim 1 .

16. A method for treating hyperglycemia in a mammal in need thereof which comprises the administration to the mammal of a therapeutically effective amount of a compound of claim 1 .

17. The pharmaceutical composition of claim 13 further comprising one or more additional active ingredients selected from the group consisting of:

(a) a second dipeptidyl peptidase IV inhibitor;

(b) an insulin sensitizer selected from the group consisting of a PPARγ agonist, a PPARα/γ dual agonist, a PPARα agonist, a biguanide, and a protein tyrosine phosphatase-1B inhibitor;

(c) an insulin or insulin mimetic;

(d) a sulfonylurea or other insulin secretagogue;

(e) an α-glucosidase inhibitor;

(f) a glucagon receptor antagonist;

(g) GLP-1, a GLP-1 mimetic, or a GLP-1 receptor agonist;

(h) GIP, a GIP mimetic, or a GIP receptor agonist;

(i) PACAP, a PACAP mimetic, or a PACAP receptor agonist;

(j) a cholesterol lowering agent such as (i) HMG-CoA reductase inhibitor, (ii) sequestrant, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonist, (v) PPARα/γ dual agonist, (vi) inhibitor of cholesterol absorption, (vii) acyl CoA:cholesterol acyltransferase inhibitor, and (viii) anti-oxidant;

(k) a PPARδ agonist;

(l) an antiobesity compound;

(m) an ileal bile acid transporter inhibitor;

(n) an anti-inflammatory agent; and

(o) an antihypertensive agent.