Aminocyclohexanes as dipeptidyl peptidase-IV inhibitors for the treatment of diabetes

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

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

X is selected from the group consisting of :

Ar is phenyl unsubstituted or substituted with one to five R 1 substituents;

each R 1 is independently selected from the group consisting of

halogen,

cyano,

hydroxy,

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

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

C 1-6 alkyloxycarbonyl,

amino,

NHR 2 ,

NR 2 R 2 ,

NHSO 2 R 2 ,

NR 2 SO 2 R 2 ,

NHCOR 2 ,

NR 2 COR 2 ,

NHCO 2 R 2 ,

NR 2 CO 2 R 2 ,

SO 2 R 2 ,

SO 2 NH 2 ,

SO 2 NHR 2 , and

SO 2 NR 2 R 2 ;

each R 2 is independently C 1-6 alkyl, unsubstituted or substituted with one to five substituents independently selected from halogen, CO 2 H, and C 1-6 alkyloxycarbonyl;

R 3 is selected from the group consisting of

hydrogen,

hydroxy,

halogen,

cyano,

CO 2 H,

NR 4 R 5 ,

CONR 4 R 5 ,

CH 2 CONR 4 R 5 ,

OCONR 4 R 5 ,

SO 2 NR 4 R 5 ,

SO 2 R 6 ,

NR 7 SO 2 R 6 ,

NR 7 CONR 4 R 5 ,

NR 7 COR 6 ,

NR 7 CO 2 R 6 ,

1H-tetrazol-5-yl,

C 1-6 alkyloxycarbonyl,

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

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

C 1-6 alkylthio,

C 1-6 alkylsulfonyl, and

(CH 2 ) n -C 3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;

wherein any individual methylene (CH 2 ) carbon atom in (CH 2 ) n 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;

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

hydrogen,

(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 substituents independently selected from halogen and hydroxy 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 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;

each R 6 is independently C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen and hydroxyl; and

R 7 is hydrogen or R 6 .

2. The compound of claim 1 wherein each R 1 is independently selected from the group consisting of fluorine, chlorine, bromine, methyl, trifluoromethyl, and trifluoromethoxy.

3. The compound of claim 1 of structural formulae Ia and Ib having the indicated stereochemical configuration at the two stereogenic cyclohexane carbon atoms marked with an *:

4. The compound of claim 3 of structural formula Ia having the indicated absolute stereochemical configuration at the two stereogenic cyclohexane carbon atoms marked with an *:

5. The compound of claim 3 of structural formulae Ic and Id having the indicated stereochemical configuration at the three stereogenic cyclohexane carbon atoms marked with an *:

6. The compound of claim 5 of structural formula Ic having the indicated absolute stereochemical configuration at the three stereogenic cyclohexane carbon atoms marked with an *:

7. The compound of claim 3 of structural formulae Ie and If having the indicated stereochemical configuration at the three stereogenic cyclohexane carbon atoms marked with an *:

8. The compound of claim 7 of structural formula Ie having the indicated absolute stereochemical configuration at the three stereogenic cyclohexane carbon atoms marked with an *:

9. The compound of claim 8 of structural formula Ig:

10. The compound of claim 8 of structural formula Ih:

11. The compound of claim 8 wherein R 3 is selected from the group consisting of:

hydrogen,

cyano,

CO 2 H,

1H-tetrazol-5-yl,

C 1-3 alkyloxycarbonyl,

CONR 4 R 5 ,

CH 2 CONR 4 R 5 ,

C 1-3 alkyl, wherein alkyl is unsubstituted or substituted with one to five

fluorines,

C 1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with hydroxy or one to five fluorines, and

C 3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one to three substituents 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.

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

R 1

R 2

2-F, 5-F

Me

2-F, 5-F

cyclopropyl

2-F, 5-F

CF 3

2-F, 4-F, 5-F

H

2-F, 4-F, 5-F

Me

2-F, 4-F, 5-F

cyclopropyl

2-F, 4-F, 5-F

CF 3

2-F, 4-F, 5-F

H

2-F, 4-F, 5-F

—OCH 2 CH 2 F

2-F, 4-F, 5-F

—OCH 3

2-F, 4-F, 5-F

—OCH 2 CF 3

2-F, 4-F, 5-F

—OCH 2 CHF 2

2-F, 4-F, 5-F

—CN

2-F, 4-F, 5-F

1H-tetrazol-5-yl

2-F, 4-F, 5-F

—CH 2 CONH 2

2-F, 4-F, 5-F

—CONH 2

or a pharmaceutically acceptable salt thereof.

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

14. The pharmaceutical composition of claim 13 additionally comprising metformin.

15. A method of 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 compounds of claim 1 .