11β-hydroxysteroid dehydrogenase type 1 active compounds

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is hydrogen, C 1 -C 4 alkyl, or cyclopropyl;

R 2 is adamantyl optionally substituted with 0 to 1 R 18 ;

R 4 is hydrogen, C 1 -C 4 alkyl, trifluoromethyl, halogen, C 1 -C 4 alkyloxy, C 1 -C 4 alkyloxyC 1 -C 4 alkyl, or C 1 -C 4 alkylcarbonyl, wherein the alkyl portion of each is substituted with 0 to 1 R 18 ;

X is —O—;

R 3 is -1,4-cyclohexyl-R 9 , —CH 2 -1,4-cyclohexyl-R 9 , -4-piperidin-1-yl-R 11 , or —CH 2 -4-piperidin-1-yl-R 11 ;

R 9 is hydroxy, cyano, C(O)R 13 , —(CR 14 R 15 ) n C(O)NR 7 R 8 , —(CR 14 R 15 ) n NHC(O)R 16 , —(CR 14 R 15 ) n OR 16 , —(CR 14 R 15 ) n S(O) m R 16 , —(CR 14 R 15 ) n S(O) 2 NR 7 R 8 , —(CR 14 R 15 ) n NR 7 R 8 , —(CR 14 R 15 ) n NR 17 C(O)NR 7 R 8 , —(CR 14 R 15 ) n NR 17 S(O) 2 R 16 , —(CR 14 R 15 ) n C═C—R 16 , —(CR 14 R 15 ) n C≡C—R 16 , —(CR 14 R 15 ) n aryl substituted with 0 to 2 R 20 , or —(CR 14 R 15 ) n hetaryl optionally substituted with 0 to 2 R 19 ;

R 11 is —C(O)NR 7 R 8 , —CH 2 C(O)NR 7 R 8 , —C(O)R 17 , —S(O) 2 R 16 or —S(O) 2 NR 7 R 8 ;

R 13 is hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, C 1 -C 6 alkyloxy, aryl, aryloxy, arylC 1 -C 6 alkyloxy, hetaryl, hetaryloxy or hetarylC 1 -C 6 alkyloxy, wherein the C 1 -C 6 alkyl, cycloalkyl, aryl and hetaryl groups are optionally substituted with one or more R 19 ;

R 14 and R 15 independently are hydrogen, halogen, C 1 -C 6 alkyl or cycloalkyl, wherein each is optionally substituted with 0 to 2 substituents selected independently from the group consisting of halogen, hydroxyl, and oxo;

or R 14 and R 15 , together with the carbon atom to which they are attached, form a cycloalkyl ring;

R 16 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, hetcycloalkyl, aryl, or hetaryl, wherein the C 1 -C 6 alkyl, cycloalkyl, aryl and hetaryl groups are each optionally substituted with one or more R 19 ;

R 17 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylC(O)R 20 , —(CR 14 R 15 ) n NR 17 S(O) 2 R 16 , cycloalkyl, hetcycloalkyl, aryl, or hetaryl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are each optionally are substituted with one or more R 21 ;

R 18 is halogen, hydroxy, oxo, —S(O) 2 C 1 -C 4 alkyl, —S(O) 2 NR 7 R 8 or —C(O)R 13 ;

R 19 is halogen, hydroxy, oxo, —C(O)R 20 , C 1 -C 6 alkylC(O)R 20 , —S(O) n R 16 , —S(O) n NR 7 R 8 , cyclopropyl, —OR 16 , C 1 -C 6 alkyl, aryl, hetaryl, —NR 22 C(O)NR 7 R 8 , —NR 22 S(O) 2 NR 7 R 8 , or —NC(O)NHS(O) 2 R 16 ;

R 20 is hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, C 1 -C 6 alkyloxy, aryl, aryloxy, arylC 1 -C 6 alkyloxy, hetaryl, hetaryloxy or hetarylC 1 -C 6 alkyloxy;

R 21 is halogen, cyano or hydroxy; and

m and n independently are 0, 1 or 2.

2. The compound of claim 1 , wherein R 3 is -1,4-cyclohexyl-R 9 or —CH 2 -1,4-cyclohexyl-R 9 .

3. The compound of claim 2 , wherein R 9 is C(O)R 13 .

4. The compound of claim 3 , wherein R 13 is hydroxy.

5. The compound of claim 2 , wherein R 9 is selected from —CH 2 —O-aryl, —CH 2 —O-hetaryl, —O-aryl, —O-hetaryl, —CH 2 —O—C 1-6 alkyl, or —NHC(O)R 16 , wherein the aryl, hetaryl, and alkyl groups are each optionally substituted with one or more R 19 .

6. The compound of claim 2 , wherein R 9 is —NH—S(O) 2 -aryl, —NH—S(O) 2 -hetaryl, —NH-aryl, —NH-hetaryl, —S(O) 2 -aryl, or —S(O) 2 -hetaryl, where the aryl and hetaryl groups are each optionally substituted with one or more R 19 .

7. The compound of claim 1 , wherein R 3 is -4-piperidin-1-yl-R 11 , or —CH 2 -4-piperidin-1-yl-R 11 .

8. A compound selected from the group consisting of:

4-(1-Cyclopropanecarbonyl-piperidin-4-yloxy)-N-adamantan-2-yl-benzamide;

4-[1-(3-Methyl-butyryl)-piperidin-4-yloxy]-N-adamantan-2-yl-benzamide;

4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-adamantan-1-yl-benzamide;

4-[4-(Cyclopropane-carbonyl-amino)-cyclo-hexyloxy]-N-adamantan-2-yl-benzamide;

N-Adamantan-2-yl-4-(4-hydroxy-cyclohexyloxy)-benzamide;

4-[4-adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid;

N-Adamantan-2-yl-4-[4-(4-methyl-1H-imidazol-2-ylsulfanylmethyl)-cyclohexyloxy]-benzamide;

4-[4-(Pyridin-2-yloxy)-cyclohexyloxy]-N-adamantan-2-yl-benzamide;

4-[4-(Pyrazol-1-yloxy)-cyclohexyloxy]-N-adamantan-2-yl-benzamide;

4-[4-(Pyrazol-1-yl-oxymethyl)-cyclohexyloxy]-N-adamantan-2-yl-benzamide;

4-[4-(Pyridin-2-yloxymethyl)-cyclohexyloxy]-N-adamantan-2-yl-benzamide;

4-(4-Hydroxy-cyclohexyl-methoxy)-N-adamantan-2-yl-benzamide;

4-{4-[4-(Adamantan-2-yl-carbamoyl)-phenoxy]-cyclo-hexylmethoxy}-benzoic acid;

4-{4-[4-(Adamantan-2-yl-carbamoyl)-phenoxy]-cyclo-hexylmethoxy}-benzoic acid allyl ester;

Cis-N-Adamantan-2-yl-4-[4-(pyridine-2-sulfonylamino)-cyclohexyloxy]-benzamide;

Cis-Pyridine-2-sulfonic acid {4-[4-(octahydro-quinoline-1-carbonyl)-phenoxy]-cyclohexyl}-amide;

Cis-N-Adamantan-2-yl-4-[4-(cyclopropanecarbonyl-amino)-cyclohexyloxy]-benzamide;

N-(5-Hydroxy-adamantan-2-yl)-4-(4-hydroxy-cyclohexyl-oxy)-N-methyl-benzamide;

N-(5-Hydroxy-adamantan-2-yl)-4-(4-hydroxy-cyclohexyl-oxy)-N-methyl-benzamide;

N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[4-(pyridine-2-sulfonylamino)-cyclohexyloxy]-benzamide;

4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide;

4-[4-(3-Hydroxy-adamantan-1-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid;

4-{4-[(5-Hydroxy-adamantan-2-yl)-methyl-carbamoyl]-phen-oxy}-cyclohexanecarboxylic acid;

4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(Z)-(5-hydroxy-adamantan-2-yl)-benzamide;

4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(E)-(5-hydroxy-adamantan-2-yl)-benzamide;

N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[1-(pyridine-2-sulfonyl)-piperidin-4-yl-methoxy]-benzamide;

4-{4-[(5-Hydroxy-adamantan-2-yl)-methyl-carbamoyl]-phenoxy-methyl}-piperidine-1-carboxylic acid isopropylamide;

N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-ylmethoxy]-benzamide; and

4-(1-Ethanesulfonyl-piperidin-4-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide;

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

10. A pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier or excipient.