Amido compounds and their use as pharmaceuticals

• US 20070066584A1
• Filed: 09/20/2006
• Published: 03/22/2007
• Est. Priority Date: 09/21/2005
• Status: Abandoned Application

• Current Assignee: Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Zhuo, Jincong, Yao, Wenqing, Qian, Ding-Quan
• Application Number:
  US11/524,361
• Publication Number:
  US 20070066584A1
• Time in Patent Office: Days
• US Class Current: 514/210.200
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/28 Antiandrogens
• CPC Class Codes: A61P 5/42 for decreasing, blocking or antagonising the activity of mineralocorticosteroids
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 211/56 Nitrogen atoms nitro radicals C07D211/38
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/06 : Oxygen atoms
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems

Abstract

The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1, antagonists of the mineralocorticoid receptor (MR), and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with expression or activity of 11-β hydroxyl steroid dehydrogenase type 1 and/or diseases associated with aldosterone excess.

Claims

1. A compound of Formula I

2. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein:

Q is —

C(O)NR^AR^B;

R^A is H, C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of said C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 —

W—

X—

Y-Z; and

R^B is cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 —

W—

X—

Y-Z.

3. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein:

Q is —

C(O)NR^AR^B;

R^A is H, C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of said C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 —

W—

X—

Y-Z; and

R^B is cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 —

W—

X—

Y-Z.

4. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein:

Q is —

C(O)NR^AR^B; and

R^A and R^B together with the N atom to which they are attached form a 4-20 membered heterocycloalkyl ring optionally substituted by 1, 2, 3, 4 or 5 —

W—

X—

Y-Z.

5. The compound of claim 4, or pharmaceutically acceptable salt thereof, wherein:

R^A and R^B together with the N atom to which they are attached form a moiety having the formula;

wherein;

r is 0, 1, 2, 3, 4 or 5; and

t is 1, 2, 3, 4 , or 5.

6. The compound of claim 4, or pharmaceutically acceptable salt thereof, wherein:

R^A and R^B together with the N atom to which they are attached form a moiety having the formula;

wherein;

r1 is 0, 1, 2 or 3;

t1 is 0 or 1; and

U is CH₂, NH or O.

7. The compound of claim 4, or pharmaceutically acceptable salt thereof, wherein:

R^A and R^B together with the N atom to which they are attached form a moiety having the formula;

wherein;

r1 is 0, 1, 2 or 3;

R¹⁷ is C(O)R^b, C(O)NR^cR^d, C(O)OR^a, C_1-6 alkyl, aryl or heteroaryl, wherein each of said C_1-6 alkyl, aryl or heteroaryl is optionally substituted by 1, 2 or 3, halo, C_1-4 alkyl, C_1-4 alkoxy or C_1-4 haloalkyl.

8. The compound of claim 4, or pharmaceutically acceptable salt thereof, wherein:

R^A and R^B together with the N atom to which they are attached form a moiety having the formula;

wherein;

ring A is a 3-14 membered cycloalkyl group or a 3-14 membered heterocycloalkyl group;

r1 is 0, 1, 2 or 3; and

r2 is 0, 1, 2, or 3.

9. The compound of claim 8, or pharmaceutically acceptable salt thereof, wherein ring A is a 5-10 membered heterocycloalkyl group.

10. The compound of claim 4, or pharmaceutically acceptable salt thereof, wherein:

R^A and R^B together with the N atom to which they are attached form a moiety having formula IIa or IIb;

wherein;

Q¹ is O, S, NH, CH₂, CO, CS, SO, SO₂, OCH₂, SCH₂, NHCH₂, CH₂CH₂, CH═

CH, COCH₂, CONH, COO, SOCH₂, SONH, SO₂CH₂, or SO₂NH;

Q² is O, S, NH, CH₂, CO, CS, SO, SO₂, OCH₂, SCH₂, NHCH₂, CH₂CH₂, CH═

CH, COCH₂, CONH, COO, SOCH₂, SONH, SO₂CH₂, or SO₂NH;

ring B is a fused 5- or 6-membered aryl or fused 5- or 6-membered heteroaryl group;

r1 is 0, 1 or 2;

r2 is 0, 1 or 2;

r3 is 0, 1, or 2; and

the sum of r1, r2 and r3 is 0, 1, 2 or 3.

11. The compound of claim 4, or pharmaceutically acceptable salt thereof, wherein R^A and R^B together with the N atom to which they are attached form pyrrolidinyl, piperidinyl, piperizinyl, morpholino, 1,2,3,6-tetrahydro-pyridinyl, 3-oxo-piperazinyl, azepanyl or azocanyl, each optionally substituted by 1, 2 or 3 OH, CN, C_1-4 alkyl, C_1-4 alkoxy, arylalkyl, heterocycloalkyl, aryl, heteroaryl, NR^cC(O)R^d, NR^cC(O)OR^a, C(O)R^b, C(O)NR^cR^d or C(O)OR^a, wherein each of said aryl or heteroaryl is optionally substituted by 1, 2 or 3 halo, CN, C_1-4 alkyl, C_1-4 alkoxy or C_1-4 haloalkyl.

12. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R² is H.

13. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R³ is cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2 or 3 —

W′

—

X′

—

Y′

-Z′

.

14. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R³ is cycloalkyl or heterocycloalkyl, each optionally substituted by OH.

15. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R³ is adamantyl optionally substituted by 1, 2 or 3 —

W′

—

X′

—

Y′

-Z′

.

16. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R³ is adamantyl optionally substituted by OH.

17. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein:

R³ is NR^3aR^3b; and

R^3a and R^3b together with the N atom to which they are attached form a 4-14 membered heterocycloalkyl group which is optionally substituted by 1, 2 or 3 —

W′

—

X′

—

Y′

-Z′

.

18. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R³ is 8-azabicyclo[3.2.1]octanyl optionally substituted by 1, 2 or 3 —

W′

—

X′

—

Y′

-Z′

.

19. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R³ is 8-azabicyclo[3.2.1]octanyl optionally substituted by OH.

20. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each H.

21. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is H.

22. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R² is H.

23. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula III:

24. The compound of claim 23, or pharmaceutically acceptable salt thereof, wherein R³ is cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2 or 3 —

W′

—

X′

—

Y′

-Z.

25. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein —

W—

X—

Y-Z is each, independently, OH, CN, C_1-4 alkyl, C_1-4 alkoxy, arylalkyl, heterocycloalkyl, aryl, heteroaryl, NR^cC(O)R^d, NR^cC(O)OR^a, C(O)R^b, C(O)NR^cR^d or C(O)OR^a, wherein each of said aryl or heteroaryl is optionally substituted by 1, 2 or 3 halo, CN, C_1-4 alkyl, C_1-4 alkoxy or C_1-4 haloalkyl.

26. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein —

W′

—

X′

—

Y′

-Z′

is OH.

27. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein —

W″

—

X″

—

Y″

-Z″

is aryl, C(O)R^b or C(O)OR^a.

29. A composition comprising a compound of claim 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

28. A compound selected from:

4-Hydroxy-N-[(3S)-1-(pyrrolidin-1-ylcarbonyl)piperidin-3-yl]adamantane-1-carboxamide;

4-Hydroxy-N-[(3S)-1-(piperidin-1-ylcarbonyl)piperidin-3-yl]adamantane--carboxamide;

4-Hydroxy-N-[(3S)-1-(morpholin-4-ylcarbonyl)piperidin-3-yl]adamantane-1-carboxamide;

(3S)-N-Cyclohexyl-3-{[(4-hydroxy-1-adamantyl)carbonyl]amino}piperidine-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(4-methoxypiperidin-1-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(4-methylpiperidin-1-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(4-phenylpiperidin-1-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

N-((3S)-1-{[(3R)-3-(Acetylamino)pyrrolidin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

4-Hydroxy-N-((3S)-1-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

N-((3S)-1-{[3-(3-Fluorophenyl)pyrrolidin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

N-{(3S)-1-[(4-Cyanopiperidin-1-yl)carbonyl]piperidin-3-yl}-4-hydroxyadamantane-1-carboxamide;

N-((3S)-1-{[(3R)-3-Cyanopyrrolidin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(4-pyridin-4-ylpiperidin-1-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

(3-endo)-N-[(3S)-1-(Azepan-1-ylcarbonyl)piperidin-3-yl]-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxamide;

(3-endo)-N-[(3S)-1-(Azocan-1-ylcarbonyl)piperidin-3-yl]-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxamide;

4-Hydroxy-N-((3S)-1-{[4-(2-methoxyphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

N-((3S)-1-{[4-(2-Ethoxyphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

N-((3S)-1-{[4-(2-Fluorophenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

N-((3S)-1-{[4-(2-Chlorophenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

4-Hydroxy-N-[(3S)-1-({4-[2-(Trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)piperidin-3-yl]adamantane-1-carboxamide;

4-Hydroxy-N-((3S)-1-{[4-(3-methoxyphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

4-Hydroxy-N-((3S)-1-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

N-((3S)-1-{[4-(3-Chlorophenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

4-Hydroxy-N-[(3S)-1-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)piperidin-3-yl]adamantane-1-carboxamide;

4-Hydroxy-N-((3S)-1-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

N-((3S)-1-{[4-(4-Fluorophenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

N-((3S)-1-{[4-(4-Chlorophenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

N-((3S)-1-{[4-(4-Cyanophenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

4-Hydroxy-N-((3S)-1-{[3-methyl-4-(3-methylphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

N-((3S)-1-{[4-(2,4-Dimethylphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

N-((3S)-1-{[4-(2,5-dimethylphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

N-((3S)-1-{[4-(3,4-Dichlorophenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

N-((3S)-1-{[4-(2,4-Dimethylphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

N-((3S)-1-{[4-(5-Chloro-2-methylphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

4-Hydroxy-N-((3S)-1-{[4-(2-methylphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

N-((3S)-1-{[4-(2-Cyanophenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(4-pyridin-4-ylpiperazin-1-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(4-pyrazin-2-ylpiperazin-1-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

N-((3S)-1-{[4-(3,5-Dichloropyridin-4-yl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

4-Hydroxy-N-[(3S)-1-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)piperidin-3-yl]adamantane-1-carboxamide;

N-[(3S)-1-({4-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)piperidin-3-yl]-4-hydroxyadamantane-1-carboxamide;

N-{(3S)-1-[(4-Acetylpiperazin-1-yl)carbonyl]piperidin-3-yl}-4-hydroxyadamantane-1-carboxamide;

Ethyl 4-[((3S)-3-{[(4-hydroxy-1-adamantyl)carbonyl]amino}piperidin-1-yl)carbonyl]piperazine-1-carboxylate;

N-((3S)-1-{[4-(2-Furoyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

N-{(3S)-1-[(4-Ethylpiperazin-1-yl)carbonyl]piperidin-3-yl}-4-hydroxyadamantane-1-carboxamide;

N-((3S)-1-{[4-(4-Fluorophenyl)piperidin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

N-{(3S)-1-[(4-Cyano-4-phenylpiperidin-1-yl)carbonyl]piperidin-3-yl}-4-hydroxyadamantane-1-carboxamide;

4-Hydroxy-N-((3S)-1-{[4-(3-methoxyphenyl)piperidin-1-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(2-oxo-1,2-dihydro-1′

H-spiro[indole-3,4′

-piperidin]-1′

-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

N-((3S)-1-{[4-(4-Chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

4-Hydroxy-N-((3S)-1-{[(1R)-3-oxo-1′

H,3H-spiro[2-benzofuran-1,3′

-pyrrolidin]-1′

-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

4-Hydroxy-N-((3S)-1-{[(1R)-3-oxo-1′

H,3H-spiro[furo[3,4-c]pyridine-1,3′

-pyrrolidin]-1′

-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(4-hydroxy-4-phenylpiperidin-1-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

4-Hydroxy-N-[(3S)-1-(1′

H,3H-spiro[2-benzofuran-1,4′

-piperidin]-1′

-ylcarbonyl)piperidin-3-yl]adamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

N-[(3S)-1-(1,4′

-Bipiperidin-1′

-ylcarbonyl)piperidin-3-yl]-4-hydroxyadamantane-1-carboxamide;

4-Hydroxy-N-((3S)-1-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

4-Hydroxy-N-((3S)-1-{[4-(1H-indol-1-yl)piperidin-1-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

tert-Butyl {1-[((3S)-3-{[(4-hydroxy-1-adamantyl)carbonyl]amino}piperidin-1-yl)carbonyl]piperidin-4-yl}carbamate;

4-Hydroxy-N-[(3S)-1-({4-[phenyl(propionyl)amino]piperidin-1-yl}carbonyl)piperidin-3-yl]adamantane-1-carboxamide;

N-{(3S)-1-[(4-Benzylpiperidin-1-yl)carbonyl]piperidin-3-yl}-4-hydroxyadamantane-1-carboxamide;

N-{(3S)-1-[(4-Benzyl-4-hydroxypiperidin-1-yl)carbonyl]piperidin-3-yl}-4-hydroxyadamantane-1-carboxamide;

tert-Butyl 8-[((3S)-3-{[(4-hydroxy-1-adamantyl)carbonyl]amino}piperidin-1-yl)carbonyl]-2,8-diazaspiro[4.5]decane-2-carboxylate;

tert-Butyl 4-[((3S)-3-{[(4-hydroxy-1-adamantyl)carbonyl]amino}piperidin-1-yl)carbonyl]piperazine-1-carboxylate;

(3-endo)-3-Hydroxy-N-[(3S)-1-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)piperidin-3-yl]-8-azabicyclo[3.2.1]octane-8-carboxamide;

(3-endo)-3-Hydroxy-N-((3S)-1-{[4-(2-methoxyphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxamide;

(3-endo)-N-((3S)-1-{[4-(2-Ethoxyphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxamide;

(3-endo)-3-Hydroxy-N-((3S)-1-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxamide;

(3-endo)-3-Hydroxy-N-{(3S)-1-[(4-pyrazin-2-ylpiperazin-1-yl)carbonyl]piperidin-3-yl}-8-azabicyclo[3.2.1]octane-8-carboxamide;

4-Hydroxy-N-{(3S)-1-[(3-oxopiperazin-1-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

4-Hydroxy-N-{(3S)-1-[(3-oxo-1′

H,3H-spiro[2-benzofuran-1,4′

-piperidin]-1′

-yl)carbonyl]piperidin-3-yl}adamantane-1-carboxamide;

4-Hydroxy-N-((3S)-1-{[(3R,4R)-3-hydroxy-4-phenylpiperidin-1-yl]carbonyl}piperidin-3-yl)adamantane-1-carboxamide;

1-[((3S)-3-{[(4-Hydroxy-1-adamantyl)carbonyl]amino}piperidin-1-yl)carbonyl]-N,N-dimethylpiperidine-4-carboxamide;

N-((3S)-1-{[2-(Cyclopentylcarbonyl)-2,8-diazaspiro[4.5]dec-8-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

Methyl 8-[((3S)-3-{[(4-hydroxy-1-adamantyl)carbonyl]amino}piperidin-1-yl)carbonyl]-2,8-diazaspiro[4.5]decane-2-carboxylate;

N-((3S)-1-{[4-(Cyclopentylcarbonyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide;

Methyl 4-[((3S)-3-{[(4-hydroxy-1-adamantyl)carbonyl]amino}piperidin-1-yl)carbonyl]piperazine-1-carboxylate;

Ethyl 4-[((3S)-3-{[(4-hydroxy-1-adamantyl)carbonyl]amino}piperidin-1-yl)carbonyl]piperazine-1-carboxylate;

N-[(3S)-1-({4-[(Cyclopentylcarbonyl)amino]piperidin-1-yl}carbonyl)piperidin-3-yl]4-hydroxyadamantane-1-carboxamide;

Methyl {1-[((3S)-3-{[(4-hydroxy-1-adamantyl)carbonyl]amino}piperidin-1-yl)carbonyl]piperidin-4-yl}carbamate;

N-((3S)-1-{[4-(Benzoylamino)piperidin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboxamide; and

4-Hydroxy-N-[(3S)-1-(1′

H-spiro[chromene-2,4′

-piperidin]-1′

-ylcarbonyl)piperidin-3-yl]adamantane-1-carboxamide,

or a pharmaceutically acceptable salt thereof.

30. A method of modulating 11β

HSD1 or MR comprising contacting said 11β

HSD1 or MR with a compound of a compound of Formula I;

31. The method of claim 30 wherein said modulating is inhibiting.

32. A method of treating a disease in a patient, wherein said disease is associated with expression or activity of 11β

HSD1 or MR, comprising administering to said patient a therapeutically effective amount of a compound of Formula I;

33. The method of claim 32 wherein said disease is obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, atherosclerosis, hypertension, hyperlipidemia, cognitive impairment, dementia, depression, glaucoma, cardiovascular disorders, osteoporosis, inflammation, metabolic syndrome, coronary heart disease, type 2 diabetes, hypercortisolemia, androgen excess, or polycystic ovary syndrome (PCOS).