3-Amino-4-phenylbutanoic acid derivatives 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, or 2;

m is 1 or 2;

p is 1 or 2; with the proviso that m+p is 3;

X is N or CR 2 ;

Ar is phenyl substituted with one to five R 3 substituents;

R 1 and R 2 are each independently selected from the group consisting of

hydrogen,

halogen,

hydroxy,

cyano,

C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,

C 1-10 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,

C 1-10 alkylthio, wherein alkylthio is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,

C 2-10 alkenyl, wherein alkenyl is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,

(CH 2 ) n COOH,

(CH 2 ) n COOC 1-6 alkyl,

(CH 2 ) n CONR 4 R 5 , wherein R 4 and R 5 are independently selected from the group consisting of hydrogen, tetrazolyl, thiazolyl, (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;

or R 4 and R 5 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 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;

(CH 2 ) n —NR 4 R 5 ,

(CH 2 ) n —OCONR 4 R 5 ,

(CH 2 ) n —SO 2 NR 4 R 5 ,

(CH 2 ) n —SO 2 R 6 ,

(CH 2 ) n —NR 7 SO 2 R 6 ,

(CH 2 ) n —NR 7 CONR 4 R 5 ,

(CH 2 ) n —NR 7 COR 7 ,

(CH 2 ) n —NR 7 CO 2 R 6 ,

(CH 2 ) n —COR 6 ,

(CH 2 ) n —C 3-6 cycloalkyl, wherein cycloalkyl 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,

(CH 2 ) n -aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, cyano, hydroxy, NR 7 SO 2 R 6 , SO 2 R 6 , CO 2 H, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,

(CH 2 ) n -heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen, C 1 - 6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, and

(CH 2 ) n -heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, C 1-6 alkyl, 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 1 or R 2 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;

each R 3 is independently selected from the group consisting of

hydrogen,

halogen,

cyano,

hydroxy,

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

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

R 6 is independently selected from the group consisting of tetrazolyl, thiazolyl, (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 6 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;

each R 7 is hydrogen or R 6 ;

each R 8 , R 9 , and R 10 is independently selected from the group consisting of

hydrogen,

cyano,

carboxy,

C 1-6 alkyloxycarbonyl,

C 1-10 alkyl, unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkoxy, carboxy, C 1-6 alkyloxycarbonyl, and phenyl-C 1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens,

(CH 2 ) n -aryl, wherein aryl is 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,

(CH 2 ) n -heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,

(CH 2 ) n -heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,

(CH 2 ) n —C 3-6 cycloalkyl, wherein cycloalkyl 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, and

(CH 2 ) n CONR 4 R 5 , wherein R 4 and R 5 are independently selected from the group consisting of hydrogen, tetrazolyl, thiazolyl, (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;

or R 4 and R 5 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 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;

wherein any methylene (CH 2 ) carbon atom in R 8 , R 9 or R 10 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.

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

3. The compound of claim 1 of structural formula Ib:

4. The compound of claim 3 of structural formula Ic wherein the carbon atom marked with an * has the R configuration

5. The compound of claim 3 of structural formula Id:

6. The compound of claim 3 of structural formula Ie:

7. The compound of claim 1 of structural formula If:

8. The compound of claim 7 of structural formula Ig wherein the carbon atom marked with an * has the R configuration:

9. The compound of claim 7 of structural formula Ih:

10. The compound of claim 7 of structural formula Ii:

11. The compound of claim 1 wherein R 3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, and methyl.

12. The compound of claim 11 wherein R 3 is selected from the group consisting of hydrogen, fluoro, and chloro.

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

hydrogen,

halogen,

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

(CH 2 ) n -aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, CN, hydroxy, NR 7 SO 2 R 6 , SO 2 R 6 , CO 2 H, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, and

C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;

(CH 2 ) n -heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen, 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 1 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.

14. The compound of claim 13 wherein R 1 is selected from the group consisting of

hydrogen,

methyl,

trifluoromethyl,

phenyl,

4-fluorophenyl,

4-(trifluoromethyl)phenyl,

4-(trifluoromethoxy)phenyl, and

5-methyl-1,3,4-oxadiazol-2-yl.

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

hydrogen,

halogen, and

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

16. The compound of claim 15 wherein R 2 is selected from the group consisting of hydrogen and trifluoromethyl.

17. The compound of claim 1 wherein R 8 , R 9 , and R 10 are independently selected from the group consisting of:

hydrogen and

C 1-6 alkyl, unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkoxy, and phenyl-C 1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens.

18. The compound of claim 17 wherein R 8 , R 9 , and R 10 are each independently selected from the group consisting of hydrogen and methyl.

19. The compound of claim 18 wherein R 9 and R 10 are hydrogen.

20. The compound of claim 2 which is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

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

22. 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 .

23. 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 .

24. The pharmaceutical composition of claim 21 further comprising a second active ingredient selected from the group consisting of metformin, rosiglitazone, and pioglitazone.