Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)

1. A compound of formula (I),

or therapeutically suitable salt, ester or prodrug, thereof, wherein

 is a member selected from the group consisting of a single and double bond:

A is a member selected from the group consisting of —C(O)—, —N(R a )—C(O)—, —C(O)—N(R a )—, N(R a )—, —N(R a )—S(O) 2 —, and —S(O) 2 —N(R a )—;

D is a member selected from the group consisting of a bond, —C(O)—, —C(O)—N(R b )—, —N(R b )—, —N(R b )—C(O)—, —N(R b )—S(O) 2 —, —O—, and —S(O) 2 —N(R b )—;

L is a member selected from the group consisting of a bond, —(CH 2 ) m —CR d R e —(CH 2 ) n —, aryl, cycloalkyl, and heterocycle;

m and n are each independently 0, 1, 2, 3 or 4;

R 1 is a member selected from the group consisting of aryl, alkyl, arylalkyl, cycloalkyl and heterocycle;

R a and R b are each independently members selected from the group consisting of hydrogen, alkyl, arylalkyl and heterocyclealkyl and hydroxyalkyl;

R d and R e are each independently members selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, halo, haloalkyl, heterocycle, heterocyclealkyl, hydroxy and hydroxyalkyl, and R d and R e taken together with the atom to which they are attached form cycloalkyl; and

X is a member selected from the group consisting of —CH 2 —, —CHF—, —CF 2 —, —O—, —S— and —CH 2 O—.

2. A compound of formula (II),

or therapeutically suitable salt, ester or prodrug, thereof, wherein

 is a member selected from the group consisting of a single and double bond;

D is a bond or is a member selected from the group consisting of —C(O)—, —C(O)—N(R b )—, —N(R b )—, —N(R b )—C(O)—, —N(R b )—S(O) 2 —, —O—, and —S(O) 2 —N(R b )—;

L is a member selected from the group consisting of a bond, —(CH 2 ) m —CR d R e —(CH 2 ) n —, aryl, cycloalkyl, and heterocycle;

m and n are each independently 0, 1, 2, 3 or 4;

R 1 is a member selected from the group consisting of aryl, alkyl, arylalkyl, cycloalkyl and heterocycle;

R b is a member selected from the group consisting of hydrogen, alkyl, arylalkyl and heterocyclealkyl and hydroxyalkyl;

R d and R e are each independently members selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, halo, haloalkyl, heterocycle, heterocyclealkyl, hydroxy and hydroxyalkyl, and R d and R e taken together with the atom to which they are attached form cycloalkyl; and

X is a member selected from the group consisting of —CH 2 —, —CHF—, —CF 2 —, —O—, —S— and —CH 2 O—.

3. The compound according to claim 2 , that is a member selected from the group consisting of

(5S)-1-(1-(5-thiazolidine-3 -carbonyl)-pyrrolidin-3-yl)-acetyl)-piperidin-4-yl)1,3-dihydro-benzoimidazol-2-one; and

(5S)-1-(4-(4-chlorophenyl)-piperazine-1-yl)-2-(5-(thiazolidine-3-carbonyl)-pyrrolidin-3-yl)-ethanone.

4. A compound of formula (III),

or therapeutically suitable salt, ester or prodrug, thereof, wherein

 is a member selected from the group consisting of a single and double bond;

D is a bond or is a member selected from the group consisting of —C(O)—, —C(O)—N(R b )—, —N(R b )—, —N(R b )—C(O)—, —N(R b )—S(O) 2 —, —O—, and —S(O) 2 —N(R b )—;

L is a member selected from the group consisting of a bond, —(CH 2 ) m —CR d R e —(C 2 ) n —, aryl, cycloalkyl, and heterocycle;

m and n are each independently 0, 1, 2, 3 or 4;

R 1 is a member selected from the group consisting of aryl, alkyl, arylalkyl, cycloalkyl and heterocycle;

R a and R b are each independently members selected from the group consisting of hydrogen, alkyl, arylalkyl and heterocyclealkyl and hydroxyalkyl;

R d and R e are each independently members selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, halo, haloalkyl, heterocycle, heterocyclealkyl, hydroxy and hydroxyalkyl, and R d and R e taken together with the atom to which they are attached form cycloalkyl; and

X is a member selected from the group consisting of —CH 2 —, —CHF—, —CF 2 —, —O—, —S— and —CH 2 O—.

5. The compound according to claim 4 , that is a member selected from the group consisting of

(5S)—N-(4-piperidin-1-yl-phenyl)-2-[5-(thiaxolidine-3-carbonyl)-pyrrolidin-3-ylidene]-acetamide;

(5S)—N-(2-phenoxy-ethyl)-2-5-(thiazolidine-3-carbonyl)-pyrrolidin-3-yl)-acetamide;

(5S)—N,N-dibenzyl-2-((5-thiazolidine-3-carbonyl)-pyrolidin-3-yl)-acetamide;

(5S)—N-(4-chloro-phenyl)-2-(5-(thiazolidine-3-carbonyl)-pyrrolidin-3-yl)-acetamide;

(5S)—N-(2-(1H-indole-3-yl)-ethyl)-2-(5-(thiazolidine-3-carbonyl)-pyrrolidin-3-yl)-acetamide; and

(5S)—N-(3-chlorobenzyl)-2-(5-(thiazolidine-3-carbonyl)-pyrrolidin-3-yl)-acetamide.

6. A compound of formula (V),

or therapeutically suitable salt, ester or prodrug, thereof, wherein

 is a member selected from the group consisting of a single and double bond;

D is a bond or is a member selected from the group consisting of —C(O)—, —C(O)—N(R b )—, —N(R b )—, —N(R b )—C(O)—, —N(R b )—S(O) 2 —, —O—, and —S(O) 2 —N(R b )—;

L is a member selected from the group consisting of a bond, —(CH 2 ) m —CR d R e —(CH 2 ) n —, aryl, cycloalkyl, and heterocycle;

m and n are each independently 0, 1, 2, 3 or 4;

R 1 is a member selected from the group consisting of aryl, alkyl, arylalkyl, cycloalkyl and heterocycle;

R a and R b are each independently members selected from the group consisting of hydrogen, alkyl, arylalkyl and heterocyclealkyl and hydroxyalkyl;

R d and R e are each independently members selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, halo, haloalkyl, heterocycle, heterocyclealkyl, hydroxy and hydroxyalkyl, and R d and R e taken together with the atom to which they are attached form cycloalkyl; and

X is a member selected from the group consisting of —CH 2 —, —CHF—, —CF 2 —, —O—, —S— and —CH 2 O—.

7. The compounds according to claim 6 , that is a member selected from the group consisting of

(2S, 4R)-(4-{[(Pyridin-2-ylmethyl)-amino]-methyl}-pyrrolidin-2-yl)-thiazolidin-3-yl-methanone; and

(2S, 4S)-(4-{[Bis-(3-chloro-benzyl)-amino]-methyl}-pyrrolidin-2-yl)-thiazolidin-3-yl-methanone.

8. A compound of formula (VI),

or therapeutically suitable salt, ester or prodrug, thereof, wherein

 is a member selected from the group consisting of a single and double bond;

D is a bond or is a member selected from the group consisting of —C(O)—, —C(O)—N(R b )—, —N(R b )—, —N(R b )—C(O)—, —N(R b )—S(O) 2 —, —O—, and —S(O) 2 —N(R b )—;

L is a member selected from the group consisting of a bond, —(CH 2 ) m —CR d R e —(CH 2 ) n —, aryl, cycloalkyl, and heterocycle;

m and n are each independently 0, 1, 2, 3 or 4;

R 1 is a member selected from the group consisting of aryl, alkyl, arylalkyl, cycloalkyl and heterocycle;

R a and R b are each independently members selected from the group consisting of hydrogen, alkyl, arylalkyl and heterocyclealkyl and hydroxyalkyl;

R d and R e are each independently members selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, halo, haloalkyl, heterocycle, heterocyclealkyl, hydroxy and hydroxyalkyl, and R d and R e taken together with the atom to which they are attached form cycloalkyl; and

X is a member selected from the group consisting of —CH 2 —, —CHF—, —CF 2 —, —O—, —S— and —CH 2 O—.

9. The compounds according to claim 8 , that is

(3S, 5S)-4-{[5-(Thiazolidine-3-carbonyl)-pyrrolidin-3-ylmethyl]-sulfamoyl}-benzoic acid.

10. A compound of formula (VII),

or therapeutically suitable salt, ester or prodrug, thereof, wherein

is a member selected from the group consisting of a single and double bond;

D is a bond or is a member selected from the group consisting of —C(O)—, —C(O)—N(R b )—, —N(R b )—, —N(R b )—C(O)—, —N(R b )—S(O) 2 —, —O—, and —S(O) 2 —N(R b )—;

L is a member selected from the group consisting of a bond, —(CH 2 ) m —CR d R e —(CH 2 ) n —, aryl, cycloalkyl, and heterocycle;

m and n are each independently 0, 1, 2, 3 or 4;

R 1 is a member selected from the group consisting of aryl, alkyl, arylalkyl, cycloalkyl and heterocycle;

R a and R b are each independently members selected from the group consisting of hydrogen, alkyl, arylalkyl and heterocyclealkyl and hydroxyalkyl;

R d and R e are each independently members selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, halo, haloalkyl, heterocycle, heterocyclealkyl, hydroxy and hydroxyalkyl, and R d and R e taken together with the atom to which they are attached form cycloalkyl; and

X is a member selected from the group consisting of —CH 2 —, —CHF—, —CF 2 —, —O—, —S— and —CH 2 O—.

11. A method of inhibiting DPP-IV comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 .

12. A method of treating disorders by inhibiting DPP-IV comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 .

13. A method of treating diabetes, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 .

14. A method of treating type II diabetes, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 .

15. A method of treating hyperglycemia, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 .

16. A method of treating Syndrome X, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 .

17. A method of treating hyperinsulinemia, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 .

18. A method of treating obesity, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 .

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 , in combination with a pharmaceutically suitable carrier.