Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme

1. A method inhibiting 11-β-HSD-1 enzyme comprising administering to the mammal an effective amount of a selective inhibitor of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme activity, wherein the inhibitor is a compound of formula (I)

wherein

n is 1;

R 1 is cycloalkyl or heterocycle, selected from the group consisting of

each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, haloalkyl, Cl, Br, F, I, —CN, —NO 2 , —OR b , —SR b , —S(O)R Z , —S(O) 2 R Z , —NR a R b , —C(O)R b , —C(O)OR b , —C(O)NR a R b , —S(O) 2 NR a R b , —C(═NOH)NH 2 , —C(═NH)NH 2 , R c , and —(CR d R e ) m —CN;

R 2 and R 3 , at each occurrence, are each independently hydrogen or alkyl;

R 4 is —(CR d R e ) m -E-G, wherein E, at each occurrence, is independently O or N(R e ), -and G, at each occurrence, is independently unsubstituted or substituted phenyl or pyridinyl;

R a , at each occurrence, is independently hydrogen or alkyl;

R b , at each occurrence, is independently hydrogen, alkyl, haloalkyl, R c , or (CR d R e ) m —R c ;

R Z , at each occurrence, is independently alkyl, haloalkyl, R c or —(CR d R e ) m —R c ;

R c , at each occurrence, is independently heteroaryl, wherein the heteroaryl is imidazolyl, triazolyl or tetrazolyl;

R d and R e , at each occurrence, are independently hydrogen or alkyl; and

m is 1;

or a pharmaceutically acceptable salt, or a combination thereof.

2. The method of claim 1 , wherein the compound is selected from the group consisting of:

6-[(1-cycloheptyl-4,4-dimethyl-5-oxopyrrolidin-3-yl)methoxy]nicotinonitrile;

4-(4-{[(5-cyanopyridin-2-yl)oxy]methyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)azepane-1-carboxamide;

1-cycloheptyl-3,3-dimethyl-4-(phenoxymethyl)pyrrolidin-2-one;

1-cycloheptyl-4-{[(2-fluorophenyl)(methyl)amino]methyl}-3,3-dimethyl pyrrolidin-2-one;

6-{[1-(5-hydroxycyclooctyl)-4,4-dimethyl-5 -oxopyrrolidin-3-yl]methoxy}nicotinonitrile;

E-4-(4-{[(5-cyanopyridin-2-yl)oxy]methyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)adamantane-1-carboxamide;

9-(4-{[(5-cyanopyridin-2-yl)oxy]methyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)bicyclo[3.3.1]nonane-3 -carboxamide;

trans ethyl (1R,7S)-4-(4-{[(5-cyanopyridin-2-yl)oxy]methyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)bicyclo[5.1.0]octane-8-carboxylate;

trans ethyl (1S,7R)-4-(4-{[(5-cyanopyridin-2-yl)oxy]methyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)bicyclo[5.1.0]octane-8-carboxylate;

6-{[4,4-dimethyl-1-(4-methylbicyclo[2.2.2]oct-1-yl)-5-oxopyrrolidin-3-yl]methoxy}nicotinonitrile;

6-{[1-(5-cyanocyclooctyl)-4,4-dimethyl-5-oxopyrrolidin-3-yl]methoxy}nicotinonitrile;

E-4-(4-{[(5-cyanopyridin-2-yl)oxy]methyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)adamantane-1-carbonitrile;

E-4-(3,3-dimethyl-2-oxo-4-{[4-(1H-1,2,4-triazol-1-yl)phenoxy]methyl}pyrrolidin-1-yl)adamantane-1-carboxamide;

E-4-(4-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)adamantane-1-carboxamide;

E-4-[3,3-dimethyl-2-oxo-4-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)pyrrolidin-1-yl]-N′-hydroxyadamantane-1-carboximidamide;

E-4-[3,3-dimethyl-2-oxo-4-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)pyrrolidin-1-yl]adamantane-1-carboxamide; and

E-4-[3,3-dimethyl-2-oxo-4-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)pyrrolidin-1-yl]adamantane-1-carboximidamide; or

a pharmaceutically acceptable salt, or a combination thereof.

3. The method of claim 1 , wherein the method is for treating a mammal suffering from a glucocorticoid-related disease selected from the group consisting of Cushing's syndrome, non-insulin dependent type 2 diabetes, obesity, lipid disorder, glaucoma, and metabolic syndrome.

4. The method of claim 2 , wherein the method is for treating a mammal suffering from glucocorticoid-related diseases and conditions selected from the group consisting of Cushing's syndrome, non-insulin dependent type 2 diabetes, obesity, lipid disorder, glaucoma, and metabolic syndrome.

5. The method of claim 1 , wherein the disease is Cushing's syndrome.

6. The method of claim 1 , wherein the disease is non-insulin dependent type 2 diabetes.

7. The method of claim 1 , wherein the disease is obesity.

8. The method of claim 1 , wherein the disease is lipid disorder.

9. The method of claim 1 , wherein the disease is glaucoma.

10. The method of claim 1 , wherein the disease is metabolic syndrome.

11. The method of claim 2 , wherein the disease is Cushing's syndrome.

12. The method of claim 2 , wherein the disease is non-insulin dependent type 2 diabetes.

13. The method of claim 2 , wherein the disease is obesity.

14. The method of claim 2 , wherein the disease is lipid disorder.

15. The method of claim 2 , wherein the disease is glaucoma.

16. The method of claim 2 , wherein the disease is metabolic syndrome.