2,5-Disubstituted Piperidine Orexin Rceptor Antagonists

• US 20110201632A1
• Filed: 10/15/2009
• Published: 08/18/2011
• Est. Priority Date: 10/21/2008
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Breslin, Michael J., Raheem, Izzat T., Schreier, John D., Cox, Christopher D., Coleman, Paul J., Roecker, Anthony J.
• Granted Patent: US 8,710,076 B2
• Time in Patent Office: Days
• US Class Current: 514/266.22
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

The present invention is directed to 2,5-disubstituted piperidine amide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

Claims

1. A compound of the formula I:

2. The compound of claim 1 of the formula Ia:

3. The compound of claim 1 of the formula Ib:

4. The compound of claim 1 of the formula Ic:

5. The compound of claim 1 wherein A is selected from the group consisting of:

phenyl, pyrazolyl, and thiazolyl.

6. The compound of claim 1 wherein B is independently selected from the group consisting of:

(1) phenyl,

(2) quinoline,

(3) isoquinoline,

(4) benzoxazole,

(5) thienopyridine,

(6) pyridine,

(7) furan,

(8) naphthyridine,

(9) benzothiazole, and

(10) pyrimidine.

7. The compound of claim 6 wherein B is selected from the group consisting of quinoline, isoquinoline and pyridine.

8. The compound of claim 1 wherein R^1a, R^1b and R^1c are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) C_1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl, phenyl or napthyl,

(5) —

O—

C_1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(6) heteroaryl, wherein heteroaryl is selected from triazolyl, oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl, and pyrimidinyl, which is unsubstituted or substituted with halogen, hydroxyl, C_1-6alkyl, —

O—

C_1-6alkyl or —

NO₂,

(7) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, C_1-6alkyl, —

O—

C_1-6alkyl or —

NO₂,

(8) —

O-phenyl, which is unsubstituted or substituted with halogen, hydroxyl, C_1-6alkyl, —

O—

C_1-6alkyl or —

NO₂, and

(9) —

NH—

C_1-6alkyl, or —

N(C_1-6alkyl)(C_1-6alkyl), which is unsubstituted or substituted with halogen, hydroxyl, C_1-6alkyl, —

O—

C_1-6alkyl or —

NO₂.

9. The compound of claim 8 wherein R^1a, R^1b and R^1c are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) C_1-6alkyl,

(4) triazolyl,

(5) oxazolyl,

(6) pyrimidinyl, and

(7) phenyl.

10. The compound of claim 9 wherein R^1c is hydrogen and R^1a and R^1b are independently selected from the group consisting of:

(1) hydrogen,

(2) chloro,

(3) fluororo,

(4) methyl,

(5) triazolyl,

(6) oxazolyl,

(7) pyrimidinyl, and

(8) phenyl.

11. The compound of claim 1 wherein R^2a, R^2b and R^2c are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) C_1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl or napthyl,

(5) —

O—

C_1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(6) heteroaryl, wherein heteroaryl is selected from pyrrolyl, imidazolyl, indolyl, pyridyl, and pyrimidinyl, which is unsubstituted or substituted with halogen, hydroxyl, C_1-6alkyl, —

O—

C_1-6alkyl or —

NO₂,

(7) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, C_1-6alkyl, —

O—

C_1-6alkyl or —

NO₂,

(8) —

O-phenyl, which is unsubstituted or substituted with halogen, hydroxyl, C_1-6alkyl, —

O—

C_1-6alkyl or —

NO₂, and

(9) —

NH—

C_1-6alkyl, or —

N(C_1-6alkyl)(C_1-6alkyl), which is unsubstituted or substituted with halogen, hydroxyl, C_1-6alkyl, —

O—

C_1-6alkyl or —

NO₂.

12. The compound of claim 11 wherein R^2a, R^2b and R^2c are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) C_1-6alkyl, which is unsubstituted or substituted with halogen,

(4) —

O—

C_1-6alkyl, which is unsubstituted or substituted with halogen, and

(5) —

NH—

C_1-6alkyl, or —

N(C_1-6alkyl)(C_1-6alkyl), which is unsubstituted or substituted with halogen.

13. The compound of claim 12 wherein R^2c is hydrogen, and R^2a and R^2b are independently selected from the group consisting of:

(1) hydrogen,

(2) chloro,

(3) fluoro,

(4) bromo,

(5) methoxy,

(6) t-butoxy,

(7) difluoromethyl, and

(8) trifluoromethyl.

14. The compound of claim 1 wherein R³ is C_1-6alkyl.

15. The compound of claim 14 wherein R³ is methyl.

17. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

20. A method for enhancing the quality of sleep in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

21. A method for treating insomnia in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

22. A method for treating or controlling obesity in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

16. A compound which is selected from the group consisting of:

5-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-quinoline;

5-({(2R,5R)-6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-quinoline;

5-({(2S,5S)-6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-quinoline;

5-({(2R,5S)-6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-quinoline;

5-({(2S,5R)-6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-quinoline;

1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-isoquinoline;

1-({(2R,5R)-6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-isoquinoline;

1-({(2S,5R)-6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-isoquinoline;

1-({(2R,5S)-6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-isoquinoline;

1-({(2S,5R)-6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-isoquinoline;

N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}isoquinolin-1-amine;

N-{(2R,5R)-6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}isoquinolin-1-amine;

N-{(2S,5S)-6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}isoquinolin-1-amine;

N-{(2R,5S)-6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}isoquinolin-1-amine;

N-{(2S,5R)-6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}isoquinolin-1-amine;

4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-1,3-benzoxazole;

(2R,5R)-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-1,3-benzoxazole;

(2S,5S)-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-1,3-benzoxazole;

(2R,5S)-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-1,3-benzoxazole;

(2S,5R)-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)-1,3-benzoxazole;

7-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)thieno[3,2-b]pyridine;

(2R,5R)-7-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)thieno[3,2-b]pyridine;

(2S,5S)-7-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)thieno[3,2-b]pyridine;

(2R,5S)-7-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)thieno[3,2-b]pyridine;

(2S,5R)-7-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)thieno[3,2-b]pyridine;

3-methyl-2-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)pyridine;

(2R,5R)-3-methyl-2-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)pyridine;

(2S,5S)-3-methyl-2-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)pyridine;

(2R,5S)-3-methyl-2-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)pyridine;

(2S,5R)-3-methyl-2-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)pyridine;

2-methyl-6-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)pyridine;

(2R,5R)-2-methyl-6-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)pyridine;

(2S,5S)-2-methyl-6-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)pyridine;

(2R,5S)-2-methyl-6-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)pyridine;

(2S,5R)-2-methyl-6-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)pyridine;

8-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2R,5R)-8-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2S,5S)-8-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2R,5S)-8-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2S,5R)-8-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quino line;

8-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5R)-8-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5S)-8-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5S)-8-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5R)-8-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)iso quino line;

5-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5R)-5-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5S)-5-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5S)-5-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5R)-5-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)iso quino line;

5-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2R,5R)-5-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2S,5S)-5-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2R,5S)-5-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2S,5R)-5-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quino line;

4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2R,5R)-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2S,5S)-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2R,5S)-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2S,5R)-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quino line;

6-methyl-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2R,5R)-6-methyl-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quino line;

(2S,5S)-6-methyl-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2R,5S)-6-methyl-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2S,5R)-6-methyl-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

8-fluoro-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2R,5R)-8-fluoro-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2S,5S)-8-fluoro-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2R,5S)-8-fluoro-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2S,5R)-8-fluoro-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

1-chloro-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5R)-1-chloro-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5S)-1-chloro-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5S)-1-chloro-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5R)-1-chloro-4-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5R)-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5S)-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5S)-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5R)-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

7-bromo-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5R)-7-bromo-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5S)-7-bromo-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5S)-7-bromo-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5R)-7-bromo-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

4-methoxy-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5R)-4-methoxy-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5S)-4-methoxy-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5S)-4-methoxy-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5R)-4-methoxy-1-({6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

1-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5R)-1-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5S)-1-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5S)-1-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5R)-1-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

5-({6-methyl-1-[2-(1H-1,2,3-triazol-1-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2R,5R)-5-({6-methyl-1-[2-(1H-1,2,3-triazol-1-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2S,5S)-5-({6-methyl-1-[2-(1H-1,2,3-triazol-1-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2R,5S)-5-({6-methyl-1-[2-(1H-1,2,3-triazol-1-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

(2S,5R)-5-({6-methyl-1-[2-(1H-1,2,3-triazol-1-yl)benzoyl]piperidin-3-yl}oxy)quinoline;

1-{[6-methyl-1-(2-pyridin-3-ylbenzoyl)piperidin-3-yl]oxy}isoquinoline;

(2R,5R)-1-{[6-methyl-1-(2-pyridin-3-ylbenzoyl)piperidin-3-yl]oxy}isoquinoline;

(2S,5S)-1-{[6-methyl-1-(2-pyridin-3-ylbenzoyl)piperidin-3-yl]oxy}isoquinoline;

(2R,5S)-1-{[6-methyl-1-(2-pyridin-3-ylbenzoyl)piperidin-3-yl]oxy}isoquinoline;

(2S,5R)-1-{[6-methyl-1-(2-pyridin-3-ylbenzoyl)piperidin-3-yl]oxy}isoquinoline;

1-{[6-methyl-1-(2-pyrimidin-2-ylbenzoyl)piperidin-3-yl]oxy}isoquinoline;

(2R,5R)-1-{[6-methyl-1-(2-pyrimidin-2-ylbenzoyl)piperidin-3-yl]oxy}isoquinoline;

(2S,5S)-1-{[6-methyl-1-(2-pyrimidin-2-ylbenzoyl)piperidin-3-yl]oxy}isoquinoline;

(2R,5S)-1-{[6-methyl-1-(2-pyrimidin-2-ylbenzoyl)piperidin-3-yl]oxy}isoquinoline;

(2S,5R)-1-{[6-methyl-1-(2-pyrimidin-2-ylbenzoyl)piperidin-3-yl]oxy}isoquinoline;

1-({6-methyl-1-[2-(1H-1,2,4-triazol-5-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5R)-1-({6-methyl-1-[2-(1H-1,2,4-triazol-5-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5S)-1-({6-methyl-1-[2-(1H-1,2,4-triazol-5-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2R,5S)-1-({6-methyl-1-[2-(1H-1,2,4-triazol-5-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

(2S,5R)-1-({6-methyl-1-[2-(1H-1,2,4-triazol-5-yl)benzoyl]piperidin-3-yl}oxy)isoquinoline;

N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}-1,3-b enzothiazol-2-amine;

(2R,5R)-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}-1,3-b enzothiazol-2-amine;

(2S,5S)-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}-1,3-b enzothiazol-2-amine;

(2R,5S)-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}-1,3-benzothiazol-2-amine;

(2S,5R)-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}-1,3-benzothiazol-2-amine;

6-chloro-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}-1,3-b enzothiazol-2-amine;

(2R,5R)-6-chloro-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}-1,3-b enzothiazol-2-amine;

(2S,5S)-6-chloro-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}-1,3-b enzothiazol-2-amine;

(2R,5S)-6-chloro-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}-1,3-b enzothiazol-2-amine;

(2S,5R)-6-chloro-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}-1,3-b enzothiazol-2-amine;

N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}isoquinolin-1-amine;

(2R,5R)-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}isoquinolin-1-amine;

(2S,5S)-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}isoquinolin-1-amine;

(2R,5S)-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}isoquinolin-1-amine;

(2S,5R)-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}isoquinolin-1-amine;

N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}pyrimidin-2-amine;

(2R,5R)-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}pyrimidin-2-amine;

(2S,5S)-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}pyrimidin-2-amine;

(2R,5S)-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}pyrimidin-2-amine;

(2S,5R)-N-{6-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}pyrimidin-2-amine;

or a pharmaceutically acceptable salt thereof.

18. (canceled)

19. (canceled)