Inhibitors of the 11-β-hydroxysteroid dehydrogenase type 1 enzyme

1. A compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof

wherein

one of A 1 , A 2 , A 3 and A 4 is selected from the group consisting of alkylcarbonyl, alkylsulfonyl, and, —S(O) 2 —N(R 5 R 6 ), with the exception that the remaining members of the group consisting of A 1 , A 2 , A 3 and A 4 are each individually selected from the group consisting of hydrogen and alkyl;

D is a bond;

E is selected from the group consisting of a cycloalkyl and aryl, wherein R 4 and E together with the atoms to which they are attached form a cycloalkyl ring;

R 1 is selected from the group consisting of hydrogen and alkyl;

R 2 is selected from the group consisting of hydrogen and alkyl;

R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 3 and R 4 together with the atom to which they are attached form a cycloalkyl ring; and

R 5 and R 6 are each independently selected from the group consisting of hydrogen, and alkyl.

2. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen; and

R 1 and R 2 are hydrogen.

3. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen; and

D is a bond.

4. The compound according to claim 1 , wherein A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen; D is a bond; and

E is aryl.

5. The compound according to claim 1 , wherein A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen; D is a bond;

E is aryl;

R 3 and R 4 are hydrogen; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

6. The compound according to claim 1 , wherein A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen; D is a bond;

E is aryl;

R 3 is hydrogen;

R 4 is alkyl; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

7. The compound according to claim 1 , wherein A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen; D is a bond;

E is aryl;

R 3 and R 4 are alkyl; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

8. The compound according to claim 1 , wherein A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen; D is a bond;

E is aryl; and

R 3 and R 4 together with the atom to which they are attached form a cycloalkyl ring.

9. The compound according to claim 1 , wherein A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen; D is a bond;

E is aryl;

R 3 and R 4 together with the atom to which they are attached form a cycloalkyl ring; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

10. The compound according to claim 1 , wherein A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen; D is a bond;

R 4 and E together with the atoms to which they are attached form a cycloalkyl ring; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

11. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen; and

R 1 and R 2 are hydrogen.

12. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen; and

E is aryl.

13. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen;

E is aryl.

14. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen;

E is aryl;

R 3 and R 4 are hydrogen; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

15. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen;

E is aryl;

R 3 is hydrogen;

R 4 is alkyl; and

A 1 is alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

16. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen;

E is aryl;

R 3 and R 4 are alkyl; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

17. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen;

E is aryl; and

R 3 and R 4 together with the atom to which they are attached form a cycloalkyl.

18. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen;

E is aryl;

R 3 and R 4 together with the atom to which they are attached form a cycloalkyl ring; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

19. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen;

E is aryl.

20. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen;

E is aryl;

R 3 and R 4 are hydrogen; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

21. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen;

E is aryl;

R 3 is hydrogen;

R 4 is alkyl; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

22. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen;

E is aryl;

R 3 and R 4 are alkyl; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

23. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen;

E is aryl;

R 3 and R 4 together with the atom to which they are attached form a cycloalkyl;

R 27 , R 28 , R 29 , R 30 are each independently selected from the group consisting of hydrogen and alkyl; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

24. The compound according to claim 1 , wherein

A 2 , A 3 and A 4 are hydrogen;

R 1 and R 2 are hydrogen;

E is aryl;

R 3 and R 4 together with the atom to which they are attached form a cycloalkyl ring; and

A 1 is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).

25. The compound according to claim 1 selected from the group consisting of

E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxylic acid;

E-4-[(1-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylic acid;

E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylic acid;

E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxylic acid amide;

E-4-[(1-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylic acid amide;

E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylic acid amide;

E-4-({[1-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-1-carboxamide;

E-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;

E-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;

E-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;

E-4-{[(1-phenylcyclopentyl)carbonyl]amino}-adamantane-1-carboxamide;

E-4-({[1-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;

E-4-({[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;

E-4-({[1-(4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;

E-4-({[1-(2-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;

E-4-{[(1-methylcyclohexyl)carbonyl]amino}adamantane-1-carboxamide;

E-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;

E-4-({[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;

E-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;

E-4-({[1-(4-methoxyphenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;

E-4-{[2-(4-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;

E-4-{[2-(3-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide; and

E-4-{[2-(4-hydroxyphenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;

E-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1-carboxamide;

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

26. The compound according to claim 1 selected from the group consisting of

methyl (E)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane -1-carboxylate;

methyl (E)-4-{[(1-phenylcyclopropyl)carbonyl]amino}adamantane-1-carboxylate;

(E)-N-[3-(aminocarbonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxamide;

(E)-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1-carboxylic acid;

N-[(E)-5-(aminosulfonyl)-2-adamantyl]-1-phenylcyclopropanecarboxamide;

(E)-4-[(2-methyl-3-phenylpropanoyl)amino]adamantane-1-carboxamide;

methyl (E)-4-({[1-(4-chlorophenyl)cyclobutyl]carbonyl}amino)adamantane-1-carboxylate;

N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-chlorophenyl)-2-methylpropanamide;

(E)-N-[4-(aminosulfonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxamide;

(E)-4-({2-methyl-2-[4-(pentyloxy)phenyl]propanoyl}amino)adamantane-1-carboxylic acid;

(E)-4-({2-[4-(benzyloxy)phenyl]-2-methylpropanoyl}amino)adamantane-1-carboxylic acid;

(E)-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxylic acid;

4-{[({(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoic acid;

3-{[({(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoic acid;

(E)-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxylic acid;

(E)-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxylic acid; and

(E)-4-({2-[4-cyclohexylmethoxy)phenyl]-2-methylpropanoyl}amino)adamantane-1-carboxylic acid;

or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof. The compound according to claim 1 selected from the group consisting of N-[(E)- 5 -(aminosulfonyl)- 2 -adamantyl]- 1 -phenylcyclopropanecarboxyamide; and N-[(E)- 5 -(aminosulfonyl)- 2 -adamantyl]- 2 -( 4 -chlorophenyl)- 2 -methylpropanamide; or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof.

27. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) of claim 1 in combination with a pharmaceutically suitable carrier.