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

1. A compound of formula (I)

wherein:

n is 1;

R 1 is

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 , —(CR d R c ) m —CN, —(CR d R c ) m —OR b , —(CR d R c ) m—SR b ,—(CR d R c ) m —S(O) 2 R Z , —(CR d R c ) m —NR a R b , —(CR d R c ) m —C(O)R b , —(CR d R c ) m —C(O)OR b , —(CR d R c ) m —S(O) 2 NR a R b , —(CR d R c ) m —R c , —N(R a )—(CR d R c ) m —C(O)OR b , —N(R a )—(CR d R c ) m —C(O)OR b , —N(R a )—(CR d R c ) m —C(O)NR a R b , —O—(CR d R c ) m —C(O)R b , —O—(CR d R c ) m —C(O)OR b , and —O—(CR d R c ) m —C(O)NR a R b ;

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

R 4 is —(CR d R c ) m -E-G, wherein E, at each occurrence, is independently O or N(R c ), and G, at each occurrence, is independently phenyl or pyridinyl, wherein each G 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 d , —S(R d ), —S(O)(alkyl), —S(O)(haloalkyl), —S(O) 2 (alkyl), —S(O) 2 (haloalkyl), —NR d R c , —C(O)(R d ), —C(O)OR d , —C(O)NR d R c , —S(O) 2 NR d R c , —R c , —(CR d R c ) m —CN, —(CR d R c ) m —NO 2 , —(CR d R c ) m —OR d , —(CR d R c ) m —S(R d ), —(CR d R c ) m —S(O)(alkyl), —(CR d R c ) m —S(O)(haloalkyl), —(CR d R c ) m —S(O) 2 (alkyl), —(CR d R c ) m —S(O) 2 (haloalkyl), —(CR d R c ) m —NR d R c , —(CR d R c ) m —C(O)(R d ), —(CR d R c ) m —C(O)OR d , —(CR d R c ) m —C(O)NR d R c , —(CR d R c ) m —S(O) 2 NR d R c , and —(CR d R c ) m —R c ;

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 c ) m —R c ;

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

R c , at each occurrence, is heteroaryl wherein heteroaryl is imidiazolyl, triazolyl and tetrazolyl, wherein each R c 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 d ,—S(R d ), —S(O)(alkyl), —S(O)(haloalkyl), —S(O) 2 (alkyl), —S(O) 2 (haloalkyl), —NR d R c , —C(O)(R d ), —C(O)OR d , —C(O)NR d R c , —S(O) 2 NR d R c , —(CR d R c ) m —CN, —(CR d R c ) m —NO 2 , —(CR d R c ) m —OR d , —(CR d R c ) m —S(R d ), —(CR d R c ) m —S(O)(alkyl), —(CR d R c ) m —S(O)(haloalkyl), —(CR d R c ) m —S(O) 2 )(alkyl), —CR d R c ) m —S(O) 2 (haloalkyl), —(CR d R c ) m —NR d R c , —(CR d R c ) m —C(O)(R d ), —(CR d R c ) m —C(O)OR d , —(CR d R c ) m —C(O)NR d R c , and —(CR d R c ) m —S(O) 2 NR d R c ;

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

m is 1;

or a pharmaceutically acceptable salt thereof, or a combination thereof.

2. The compound of claim 1 , wherein R 4 is —CH 2 —O-G or —CH 2 —N(R c )-G, and R 2 and R 3 are C 1-6 alkyl.

3. The compound of claim 1 , wherein R 1 is independently unsubstituted or substituted

R c is hydrogen or methyl, and R 2 and R 3 are methyl.

4. The compound of claim 1 , wherein R 1 is

R c is hydrogen or methyl, and R 2 and R 3 are methyl.

5. The compound of claim 1 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-dimethylpyrrolidin-2-one;

6-{[1-(-(5-hydroxycyclooctyl)- 4,4-dimethyl-5-oxopyrrolidin-3-yl]methoxyl}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 thereof, or a combination thereof.

6. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof, or a combination thereof; and a pharmaceutically acceptable carrier thereof.

7. The compound of claim 1 wherein the compound of formula I is E-4-(4-{[(5-cyanopyridin-2-yl)oxy]methyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)adamantane-1-carbonitrile, or 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 thereof, or a combination thereof.

8. The compound of claim 1 wherein the compound of formula I is E-4-(3,3-dimethyl-2-oxo-4-{[4-(1H-1,2,4-triazol-1-yl)phenoxy]methyl}pyrrolidin-1-yl)adamantane-1-carboxamide, or E-4-(4-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)adamantane-1-carboxamide; or a pharmaceutically acceptable salt thereof, or a combination thereof.

9. The compound of claim 1 wherein the compound of formula I is E-4-[3,3-dimethyl-2-oxo-4-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)pyrrolidin-1-yl]-N′-hydroxyadamantane-1-carboximidamide, or E-4-[3,3-dimethyl-2-oxo-4-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)pyrrolidin-1-yl]adamantane-1-carboxamide; or a pharmaceutically acceptable salt thereof, or a combination thereof.

10. The compound of claim 1 , werein the compound of formula I is 6-[(1-cycloheptyl-4,4-dimethyl-5-oxopyrrolidin-3-yl)methoxy]nicotinonitrile; or a pharmaceutically acceptable salt thereof or a combination thereof.

11. The compound of claim 1 wherein the compound of formula I is 4-(4-{[(5-cyanopyridin-2-yl)oxy]methyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)azepane-1-carboxamide; or a pharmaceutically acceptable salt thereof, or a combination thereof.

12. The compound of claim 1 wherein the compound of formula I is 1-cycloheptyl-3,3-dimethyl-4-(phenoxymethyl)pyrrolidin-2-one; or a pharmaceutically acceptable salt thereof, or a combination thereof.

13. The compound of claim 1 wherein the compound of formula I is 1-cycloheptyl-4-{[(2-fluorophenyl)(methyl)amino]methyl}-3,3-dimethylpyrrolidin-2-one; or a pharmaceutically acceptable salt thereof, or a combination thereof.

14. The compound of claim 1 wherein the compound of formula I is 6-{[1-(5-hydroxycyclooctyl)-4,4-dimethyl-5-oxopyrrolidin-3-yl]methoxy}nicotinonitrile; or a pharmaceutically acceptable salt thereof, or a combination thereof.

15. The compound of claim 1 wherein the compound of formula I is E-4-(4-{[(5-cyanopyridin-2-yl)oxy]methyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)adamantane-1-carboxamide; or a pharmaceutically acceptable salt thereof, or a combination thereof.

16. The compound of claim 1 wherein the compound of formula I is 9-(4-{[(5-cyanopyridin-2-yl)oxy]methyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)bicyclo[3.3.1]nonane-3-carboxamide; or a pharmaceutically acceptable salt thereof, or a combination thereof.

17. The compound of claim 1 wherein the compound of formula I is 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; or a pharmaceutically acceptable salt thereof, or a combination thereof.

18. The compound of claim 1 wherein the compound of formula I is 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; or a pharmaceutically acceptable salt there of, or a combination thereof.

19. The compound of claim 1 wherein the compound of formula I is 6-{[4,4-dimethyl-1-(4-methylbicyclo[2.2.2]oct-1-yl)-5-oxopyrrolidin-3-yl]methoxy}nicotinonitrile; or a pharmaceutically acceptable salt thereof, or a combination thereof.

20. The compound of claim 1 wherein the compound of formula I is 6-{[1-(5-cyanocyclooctyl)-4,4-dimethyl-5-oxopyrrolidin-3-yl]methoxy}nicotinonitrile; or a pharmaceutically acceptable salt thereof, or a combination thereof.