11-beta-hydroxysteroid dehydrogenase type 1 active compounds

1. A method of lowering intracellular glucocorticoid levels in a subject, the method comprising administering to a subject a compound of formula I or a pharmaceutically acceptable salt thereof:

wherein:

R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are each H;

one of R 5 and R 6 is H, and the other is selected from the group consisting of —C(═O)—R 12 , —O—R Ib , and —NR 10 R 11 ;

R Ib is hetaryl or arylC 1 -C 6 alkyl;

R 9 is selected from the group consisting of H, halo, OH, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, trihalomethyloxy and C 3 -C 6 cycloalkyl;

R 10 and R 11 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C(O)OC 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl, hetarylC 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, arylcarbonyl, hetarylcarbonyl, arylC 1 -C 6 alkylcarbonyl, hetarylC 1 -C 6 alkylcarbonyl, C 3 -C 10 cycloalkylcarbonyl and C 3 -C 10 hetcycloalkyl-carbonyl, wherein each alkyl, cykloalkyl, hetcycloalkyl, aryl, and hetaryl group is substituted with 0-3 R 18 ;

alternatively, R 10 and R 11 , together with the nitrogen to which they are attached, form a 3-12 membered saturated or partially saturated monocyclic or bicyclic ring consisting of the shown nitrogen, 2-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S(O) n , wherein this ring is substituted with 0-3 groups selected from the group consisting of halo, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 6 spirocycloalkyl, 3-6 membered spirohetcycloalkyl, aryl, hetaryl, arylC 1 -C 6 alkyl, hetarylC 1 -C 6 alkyl, —C(O)R 12 , —S(O) n R 12 , —S(O) n NR 14 R 15 , —N(R 14 )S(O) n R 12 , —N(R 16 )C(═Y)NR 14 R 15 , —C(═NR 17 )NR 17 , OH, oxo, C 1 -C 6 alkyloxy, arylC 1 -C 6 alkyloxy, hetarylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarboxy, arylcarboxy, hetarylcarboxy, arylC 1 -C 6 alkylcarboxy, and hetarylC 1 -C 6 alkylcarboxy, wherein each alkyl, aryl, and hetaryl group is substituted with 0-3 R 18 ;

R 12 is OH, NR 10 R 11 , C 1 -C 6 alkyloxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl-oxy, C 3 -C 10 hetcycloalkyloxy, aryloxy, hetaryloxy, arylC 1 -C 6 alkyloxy, or hetarylC 1 -C 6 alkyloxy;

R 14 and R 15 are independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, aryl, hetaryl, arylC 1 -C 6 alkylene, and hetarylC 1 -C 6 alkylene, wherein the alkyl, alkylene, aryl, and hetaryl groups are independently substituted with 0-3 R 20 ;

alternatively, R 14 and R 15 , together with the nitrogen atom to which they are attached, form a saturated or partially saturated monocyclic, bicyclic, or tricyclic ring consisting of the shown nitrogen, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and sulfur, wherein this ring is substituted with 0-3 substituents selected from the group consisting of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkylene, hetarylC 1 -C 6 alkylene, hydroxy, oxo, C 1 -C 6 alkyloxy, arylC 1 -C 6 alkyloxy, hetarylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC 1 -C 6 alkylcarbonyl, hetarylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarboxy, arylcarboxy, hetarylcarboxy, arylC 1 -C 6 alkyl-carboxy, and hetarylC 1 -C 6 alkylcarboxy;

R 16 is selected from the group consisting of H and C 1 -C 6 alkyl;

R 17 is selected from the group consisting of H, C 1 -C 6 alkyl, 3-10 membered cycloalkyl, halo, OH, cyano, —C(═O)R 12 , —S(═O) n R 12 , S(═O) n NR 14 R 15 , —N(R 14 )S(O) n R 12 , aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are substituted with 0-3 R 20 ;

R 18 is selected from the group consisting of halo, OH, oxo, COOH, S(O) 2 R 12 , C(═O)OC 1 -C 6 alkyl, cyano, C 1 -C 6 alkyloxy, C 3 -C 10 cycloalkyloxy, aryloxy, hetaryloxy, hetarylthio, and arylC 1 -C 6 alkyloxy;

R 20 is selected from the group consisting of H, OH, oxo, halo, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 -alkyloxy, NR 21 R 22 , methylendioxo, dihalomethylendioxo, trihalomethyl, and trihalomethyloxy;

R 21 and R 22 are independently selected from the group consisting of H, C 1 -C 6 alkyl, and arylC 1 -C 6 alkyl;

Rn 1 is H; and Rn 2 is an adamantyl group substituted with 0-3 R 18 ; and

n is 0, 1 or 2.

2. A method of lowering intracellular glucocorticoid levels in a subject, the method comprising administering to a subject a compound, which is a compound selected from the group consisting of:

1-[4-(Adamantan-1-ylcarbamoyl)-phenyl]-pyrrolidine-3-carboxylic acid;

4-(3-Acetylamino-pyrrolidin-1-yl)-N-adamantan-2-yl-benzamide;

4-[3-(4-Chloro-phenyl)-pyrrolidin-1-yl]-N-adamantan-2-yl-benzamide;

4-[3-(Pyridin-2-yloxymethyl)-pyrrolidin-1-yl]-N-adamantan-2-yl-benzamide;

4-(3-Methanesulfonyl-pyrrolidin-1-yl)-N-adamantan-2-yl-benzamide;

4-[(R)-3-(3-Isopropyl-ureido)-pyrrolidin-1-yl]-N-adamantan-2-yl-benzamide;

Morpholine-4-carboxylic acid {(R)-1-[4-(adamantan-2-ylcarbamoyl)-phenyl]-pyrrolidin-3-yl}-amide; and

1-{(R)-1-[4-(adamantan-2-yl-phenyl]-pyrrolidin-3-yl}-3-N,N-dimethyl-sulfamide;

or a pharmaceutically acceptable salt thereof.

3. A method of lowering intracellular glucocorticoid levels in a subject, the method comprising administering to a subject a compound, which is a compound selected from the group consisting of:

4-(3-Acetylamino-pyrrolidin-1-yl)-N-(3-hydroxymethyl-adamantan-1-yl)-benzamide;

4-(3-Acetylamino-pyrrolidin-1-yl)-N-(5-hydroxy-adamantan-2-yl)-benzamide;

4-(3-Acetylamino-pyrrolidin-1-yl)-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide;

N-Adamantan-2-yl-4-((R)-3-benzyloxy-pyrrolidin-1-yl)-benzamide;

4-((R)-3-Benzyloxy-pyrrolidin-1-yl)-N-(1-hydroxy-adamantan-2-yl)-benzamide;

4-((S)-3-Acetylamino-pyr-rolidin-1-yl)-N-adamantan-2-yl-benzamide;

4-(3-Acetylamino-pyrrolidin-1-yl)-N-(3-hydroxy-adamantan-1-yl)-benzamide;

N-{(S)-1-[4-(Adamantan-2-ylcarbamoyl)-phenyl]-pyrrolidin-3-yl}-6-chloro-nicotin-amide;

N-Adamantan-2-yl-4-[(1S,5R)-3-(pyridin-2-yloxy)-8-aza-bicyclo[3.2.1]oct-8-yl]-benzamide; and

2-[4-(Adamantan-2-yl-carbamoyl)-phenyl]-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid isopropylamide;

or a pharmaceutically acceptable salt thereof.