Benzenesulfonamide compounds and their use as blockers of calcium channels

• US 8,791,264 B2
• Filed: 04/13/2007
• Issued: 07/29/2014
• Est. Priority Date: 04/13/2006
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Chen, Zhengming, Shao, Bin, Yao, Jiangchao, Zhou, Xiaoming
• Primary Examiner(s): ZAREK, PAUL E
• Application Number:
  US12/296,799
• Publication Number:
  US 20100022595A1
• Time in Patent Office: 2,664 Days
• Field of Search: 546/244
• US Class Current: 546/244
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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: C07D 211/58 attached in position 4

Abstract

The invention relates to piperidinyl and hexahydroazepinyl compounds of Formula (I): and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein R¹-R³, Z and q are defined as set forth in the specification. The invention is also directed to the use compounds of Formula (I) to treat, prevent or ameliorate a disorder responsive to the blockade of calcium channels, and particularly N-type calcium channels. Compounds of the present invention are especially useful for treating pain.

Claims

1. A compound having the Formula XI:

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

R¹ and R² are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, alkoxy, haloalkoxy, cyano, nitro, amino, aminoalkyl, alkylamino, dialkylamino, and hydroxy;

q is 1;

R³ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylalkyl, 3-tetrahydrofuranylalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cyanoalkyl, carboxyalkyl, and alkoxycarbonylalkyl;

R⁸ and R⁹ are both hydrogen;

p is 0, 1, 2, 3, or 4;

D is —

NH—

or —

N(alkyl)-, and

R¹⁴ is selected from the group consisting of

phenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

naphthyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

quinolinyl;

pyridyl;

phenyl substituted with phenyl, benzyl, phenoxy, or benzyloxy, wherein each phenyl ring is optionally substituted with one or two substituents independently selected from the group consisting of halogen, haloalkyl, alkoxy, hydroxy, amino and cyano;

alkyl optionally substituted with hydroxy; and

—

NR^14aR^14b, wherein R^14a and R^14b are each independently selected from the group consisting of

hydrogen; and

alkyl;

or R^14a is hydrogen or alkyl, and R^14b is selected from the group consisting of

aryl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

benzyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

heteroaryl selected from pyridyl or benzothiazolyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino; and

heteroarylalkyl selected from pyridylalkyl or benzothiazolylalkyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

or

D is —

C(O)—

, —

CH═

CH—

or absent, and

R¹⁴ is —

NR^14aR^14b, wherein R^14a and R^14b are as defined above.

8. A pharmaceutical composition, comprising the compound of claim 1, 3, 5, or 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. A method for treating or ameliorating pain in a mammal, comprising administering to a mammal in need of such treatment or amelioration an effective amount of a compound of claim 1, 3, 5, or 7, or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein the method is for treating or ameliorating pain selected from chronic pain, neuropathic pain, acute pain, and surgical pain.

11. A method of modulating calcium channels in a mammal, comprising administering to the mammal at least one compound as claimed in claim 1, 3, 5, or 7, or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the N-type calcium channel is modulated.

13. A compound having the Formula XI as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is ³H, ¹¹C, or ¹⁴C radiolabeled.

14. The compound of claim 1, wherein R³ is selected from the group consisting of methyl, ethyl, iso-pentyl, iso-butyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclopropylethyl, methoxymethyl, methoxyethyl, hydroxymethyl, hydroxyethyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl, 2-tetrahydrofuranylethyl, methylsulfonamidomethyl, methylsulfonamidoethyl, aminocarbonylmethyl, and aminocarbonylethyl.

15. The compound of claim 1, wherein R³ is cyclopropyl, methyl, iso-propyl, or iso-butyl.

16. The compound of claim 15, wherein R³ is cyclopropyl.

17. The compound of claim 1, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, alkoxy, haloalkoxy, nitro, amino, alkylamino, and dialkylamino.

18. The compound of claim 17, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, fluoromethyl, cyano, nitro, methoxy and difluoromethoxy.

19. The compound of claim 18, wherein R¹ is hydrogen and R² is trifluoromethyl, or R¹ and R² are both hydrogen.

20. The compound of claim 16, wherein R¹ is hydrogen and R² is trifluoromethyl at the meta-position of the phenyl ring.

21. The compound of claim 1, wherein R¹⁴ is selected from the group consisting of:

phenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino; and

phenyl substituted with phenyl, benzyl, phenoxy or benzyloxy, wherein each phenyl ring is optionally substituted with one or two substituents selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, and cyano; and

D is —

NH—

or —

NH(alkyl)-.

22. The compound of claim 1, wherein R¹⁴ is unsubstituted naphthyl, quinolinyl or pyridyl.

23. The compound of claim 1, wherein D is ═

O and R¹⁴ is —

NR^14aR^14b, wherein R^14a and R^14b each independently selected from the group consisting of hydrogen and alkyl;

or R^14a is hydrogen or alkyl, and R^14b is selected from the group consisting of aryl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy;

benzyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy;

heteroaryl selected from pyridyl or benzothiazolyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy; and

heteroarylalkyl selected from pyridylalkyl or benzothiazolylalkyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy.

24. The compound of claim 1, wherein p is 0 or 1.

3. A compound having the Formula XI:

4. The compound of claim 3, wherein

R¹, R², q, R³, and Z are as defined in claim 3;

R⁸ and R⁹ are both hydrogen or together form ═

O;

R¹⁴ is selected from the group consisting of

phenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

naphthyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

quinolinyl;

pyridyl;

phenyl substituted with phenyl, benzyl, phenoxy, or benzyloxy, wherein each phenyl ring is optionally substituted with one or two substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino and cyano;

alkyl optionally substituted with hydroxy; and

—

NR^14aR^14b, wherein R^14a and R^14b are each independently selected from the group consisting of

hydrogen; and

alkyl;

or

R^14a is hydrogen or alkyl, and R^14b is selected from the group consisting of

aryl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

benzyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, an aminoalkyl, alkylamino, and dialkylamino;

heteroaryl selected from pyridyl or benzothiazolyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino; and

heteroarylalkyl selected from pyridylalkyl or benzothiazolylalkyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

and

and p is as defined in claim 3.

25. The compound of claim 3, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, alkoxy, haloalkoxy, nitro, amino, alkylamino, and dialkylamino.

26. The compound of claim 25, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, fluoromethyl, cyano, nitro, methoxy and difluoromethoxy.

27. The compound of claim 26, wherein R¹ is hydrogen and R² is trifluoromethyl, or R¹ and R² are both hydrogen.

28. The compound of claim 3, wherein R¹⁴ is selected from the group consisting of:

phenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino; and

phenyl substituted with phenyl, benzyl, phenoxy or benzyloxy, wherein each phenyl ring is optionally substituted with one or two substituents selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, and cyano.

29. The compound of claim 3, wherein R¹⁴ is unsubstituted naphthyl, quinolinyl or pyridyl.

30. The compound of claim 3, wherein R⁸ and R⁹ are both hydrogen when R¹⁴ is one of

naphthyl;

quinolinyl;

pyridyl;

phenyl substituted with phenyl optionally substituted with halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano;

phenyl substituted with benzyl optionally substituted with halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano;

phenyl substituted with phenoxy optionally substituted with halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano;

or

phenyl substituted with benzyloxy optionally substituted with halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano.

31. The compound of claim 3, wherein D is ═

O and R¹⁴ is —

NR^14aR^14b wherein R^14a and R^14b are each independently selected from the group consisting of hydrogen and alkyl;

or R^14a is hydrogen or alkyl, and R^14b is selected from the group consisting of aryl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy;

benzyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy;

heteroaryl selected from pyridyl or benzothiazolyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy; and

heteroarylalkyl selected from pyridylalkyl or benzothiazolylalkyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy.

32. The compound of claim 3, wherein R⁸ and R⁹ together form ═

O.

33. The compound of claim 3, wherein R⁸ and R⁹ are both hydrogen or together form ═

O, and D is absent or —

CH═

CH—

.

34. The compound of claim 3, wherein R⁸ and R⁹ together form ═

O and D is C═

O.

35. The compound of claim 3, wherein p is 0 or 1.

5. A compound having the Formula XI:

6. The compound of claim 5,

wherein R¹, R², R³, Z and q are as defined in claim 5;

R¹⁴ is selected from the group consisting of

phenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

naphthyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

quinolinyl;

pyridyl;

phenyl substituted with phenyl, benzyl, phenoxy, or benzyloxy, wherein each phenyl ring is optionally substituted with one or two substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino and cyano;

alkyl optionally substituted with hydroxy; and

—

NR^14aR^14b, wherein R^14a and R^14b are each independently selected from the group consisting of

hydrogen; and

alkyl;

or

R^14a is hydrogen or alkyl, and R^14b is selected from the group consisting of

aryl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

benzyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

heteroaryl selected from pyridyl or benzothiazolyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino; and

heteroarylalkyl selected from pyridylalkyl or benzothiazolylalkyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

and p is as defined in claim 5.

36. The compound of claim 5, wherein R³ is selected from the group consisting of methyl, ethyl, iso-pentyl, iso-butyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclopropylethyl, methoxymethyl, methoxyethyl, hydroxymethyl, hydroxyethyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl, 2-tetrahydrofuranylethyl, methylsulfonamidomethyl, methylsulfonamidoethyl, aminocarbonylmethyl, and aminocarbonylethyl.

37. The compound of claim 36, wherein R³ is cyclopropyl, methyl, iso-propyl, or iso-butyl.

38. The compound of claim 37, wherein R³ is cyclopropyl.

39. The compound of claim 5, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, alkoxy, haloalkoxy, nitro, amino, alkylamino, and dialkylamino.

40. The compound of claim 39, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, fluoromethyl, cyano, nitro, methoxy and difluoromethoxy.

41. The compound of claim 40, wherein R¹ is hydrogen and R² is trifluoromethyl, or R¹ and R² are both hydrogen.

42. The compound of claim 38, wherein R¹ is hydrogen and R² is trifluoromethyl at the meta-position of the phenyl ring.

43. The compound of claim 5, wherein R¹⁴ is selected from the group consisting of:

phenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

phenyl substituted with phenyl, benzyl, phenoxy or benzyloxy, wherein each phenyl ring is optionally substituted with one or two substituents selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, and cyano.

44. The compound of claim 5, wherein R¹⁴ is unsubstituted naphthyl, quinolinyl or pyridyl.

45. The compound of claim 5, wherein R⁸ and R⁹ are both hydrogen when R¹⁴ is one of

naphthyl;

quinolinyl;

pyridyl;

phenyl substituted with phenyl optionally substituted with halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano;

phenyl substituted with benzyl optionally substituted with halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano;

phenyl substituted with phenoxy optionally substituted with halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano;

or

phenyl substituted with benzyloxy optionally substituted with halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano.

46. The compound of claim 5, wherein D is ═

O and R¹⁴ is —

NR^14aR^14b, wherein R^14a and R^14b are each independently selected from the group consisting of hydrogen and alkyl;

or R^14a is hydrogen or alkyl, and R^14b is selected from the group consisting of aryl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy;

benzyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy;

heteroaryl selected from pyridyl or benzothiazolyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy; and

heteroarylalkyl selected from pyridylalkyl or benzothiazolylalkyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, alkoxycarbonyl, and haloalkoxy.

47. The compound of claim 5, wherein R⁸ and R⁹ together form ═

O.

48. The compound of claim 5, wherein R⁸ and R⁹ are both hydrogen or together form ═

O, and D is absent or —

CH═

CH—

.

49. The compound of claim 5, wherein R⁸ and R⁹ together form ═

O and D is C═

O.

50. The compound of claim 5, wherein p is 0 or 1.

7. A compound selected from the group consisting of:

N-{1-[2-(4-fluorophenylamino)acetyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethylbenzenesulfonamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(4-fluorophenyl)-2-oxo-acetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)-amino]-piperidin-1-yl}-N-isopropyl-2-oxo-acetamide;

3-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(4-fluorophenyl)-3-oxo-propionamide;

3-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(2,4-difluorophenyl)-3-oxo-propionamide;

N-(2,4-difluorophenyl)-3-{4-[methyl-(3-trifluoromethylbenzene-sulfonyl)amino]-piperidin-1-yl}-3-oxo-propionamide;

3-{4-[(3-chlorobenzenesulfonyl)-cyclopropylamino]-piperidin-1-yl}-N-(2,4-difluorophenyl)-3-oxo-propionamide;

2-{4-[isopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

N-isobutyl-2-{4-[isopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

2-{4-[cyclopropyl-(toluene-3-sulfonyl)amino]-piperidin-1-yl}-N-isobutylacetamide;

2-{4-[cyclopropyl-(3-fluorobenzenesulfonyl)amino]-piperidin-1-yl}-N-isobutylacetamide;

2-[4-(benzenesulfonyl-cyclopropylamino)-piperidin-1-yl]-N-isobutylacetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N,N-diethylacetamide;

N-(2,6-dimethylphenyl)-2-{4-[isopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

2-{4-[isopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-o-tolyl-acetamide;

N-(2-ethoxyphenyl)-2-{4-[isopropyl-(3 trifluoromethylbenzene-sulfonyl)amino]-piperidin-1-yl}-acetamide;

2-{4-[isopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-m-tolyl-acetamide;

2-{4-[isopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-p-tolyl-acetamide;

N-(4-isopropylphenyl)-2-{4-[isopropyl-(3-trifluoromethylbenzene-sulfonyl)amino]-piperidin-1-yl}-acetamide;

N-(4-cyanophenyl)-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

2-{4-[isopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(4-methoxyphenyl)acetamide;

N-(6-fluorobenzothiazol-2-yl)-2-{4-[isopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

N-(4-fluorophenyl)-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]-piperidin-1-yl}-N-methyl-acetamide;

N-(4-fluorobenzyl)-2-{-4-[1-isopropyl-(3-trifluoromethylbenzene-sulfonyl)amino]-piperidin-1-yl}-acetamide;

2-{4-[isopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(4-trifluoromethoxyphenyl)-acetamide;

2-{4-[isopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(5-trifluoromethylpyridin-2-yl)-acetamide;

N-(4-fluorophenyl)-2-{4-[isopropyl-(3-trifluoromethylbenzene-sulfonyl)amino]-piperidin-1-yl}-acetamide;

2-{4-[cyclopropyl-(toluene-3-sulfonyl)amino]-piperidin-1-yl}-N-(4-fluorophenyl)acetamide;

2-[4-[cyclopropyl-(3-fluorobenzenesulfonyl)amino]-piperidin-1-yl]-N-(4-fluorophenyl)acetamide;

2-[4-(benzenesulfonylmethylamino]-piperidin-1-yl]-N-(4-fluorophenyl)acetamide;

2-[4-(benzenesulfonylcyclopropylamino)-piperidin-1-yl]-N-(4-fluorophenyl)acetamide;

2-{4-[(4-chlorobenzenesulfonyl)cyclopropylamino]-piperidin-1-yl}-N-(4-fluorophenyl)acetamide;

2-{4-[(3-chlorobenzenesulfonyl)cyclopropylamino]-piperidin-1-yl}-N-(4-fluorophenyl)acetamide;

N-(4-fluorophenyl)-2-{4-[methyl-(3-trifluoromethylbenzenesulfonyl)-amino]-piperidin-1-yl}-acetamide;

4-(2-{-4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-acetylamino)benzoic acid ethyl ester;

2-{4-[cyclopropyl-(3-fluorobenzenesulfonyl)amino]-piperidin-1-yl}-N-(4-trifluoromethylphenyl)acetamide;

N-(4-tert-butylphenyl)-2-{4-[cyclopropyl-(3-fluoro-benzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)-amino]-piperidin-1-yl}-N-phenyl-acetamide;

2-{-4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)-amino]-piperidin-1-yl}-N-(2,6-dimethylphenyl)acetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)-amino]-piperidin-1-yl}-N-(4-isopropylphenyl)acetamide;

2-{4-[methyl-(3-trifluoromethylbenzenesulfonyl)-amino]-piperidin-1-yl}-N-(4-trifluoromethylphenyl)acetamide;

N-(3,5-bis-trifluoromethylphenyl)-2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

N-(3,5-bis-trifluoromethylbenzyl)-2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

N-(6-fluorobenzothiazol-2-yl)-2-{4-[methyl-(3-fluoro-benzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

N-(3,5-bis-trifluoromethylphenyl)-2-{4-[(3-chlorobenzenesulfonyl)-cyclopropylamino]-piperidin-1-yl}-acetamide;

N-(3,5-bis-trifluoromethylphenyl)-2-{4-[(4-chlorobenzenesulfonyl)-cyclopropylamino]-piperidin-1-yl}-acetamide;

2-[4-(benzenesulfonyl-methyl-amino)-piperidin-1-yl]-N-(3,5-bis-trifluoromethylphenyl)-acetamide;

N-(3,5-bis-trifluoromethylphenyl)-2-{4-[cyclopropyl-(toluene-3-sulfonyl)amino]-piperidin-1-yl}-acetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(2-ethoxy-4-fluorophenyl)-acetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(4-fluoro-3-trifluoromethylphenyl)-acetamide;

N-(2,4-bis-trifluoromethylphenyl)-2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(3-fluoro-5-trifluoromethylphenyl)-acetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(3,5-difluorophenyl)-acetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(2-fluoro-4-trifluoromethylphenyl)-acetamide;

N-(4-chloro-2-trifluoromethoxyphenyl)-2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

N-(2-chloro-5-trifluoromethylphenyl)-2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]piperidin-1-yl}-acetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(5-fluoro-pyridin-3-yl)-acetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(3,5-dichlorophenyl)-acetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(3,5-dimethylphenyl)-acetamide;

N-(3-cyano-5-fluorophenyl)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

N-(5-chloro-2-methoxyphenyl)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]-piperidin-1-yl}-acetamide;

2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(2-methoxy-5-trifluoromethylphenyl)-acetamide;

N-[1-(2-benzylaminoacetyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethylbenzenesulfonamide;

N-isopropyl-N-{1-[2-(4-methoxy-benzylamino)acetyl]-piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide;

N-cyclopropyl-N-{1-[2-(4-methoxy-benzylamino)acetyl]-piperidin-4yl}-benzenesulfonamide;

N-cyclopropyl-N-{1-[2-(4-fluorobenzylamino)acetyl]-piperidin-4-yl}-benzenesulfonamide;

N-cyclopropyl-N-{1-[2-(4-methoxybenzylamino)acetyl]-piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide;

4-chloro-N-cyclopropyl-N-{1-[2-(4-methoxybenzylamino)acetyl]-piperidin-4-yl}-benzenesulfonamide;

4-chloro-N-cyclopropyl-N-{1-[2-(2-methoxybenzylamino)acetyl]-piperidin-4-yl}-benzenesulfonamide;

N-(4-fluorophenyl)-3-{4-[isopropyl-(3-trifluoromethylbenzene-sulfonyl)amino]-piperidin-1-yl}-propionamide;

3-{4-[isopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-N-(2-methoxyphenyl)-propionamide;

N-isobutyl-3-{4-[isopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}-propionamide;

4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidine-1-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide;

(4-benzenesulfonyl-methyl-amino)-piperidine-1-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide;

N-[1-(2-aminoethyl)-piperidin-4-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;

N-(2,4-difluorophenyl)-3-oxo-3-[4-(3-trifluoromethylbenzenesulfonylamino)-piperidin-1-yl]-propionamide;

N-(4-fluorophenyl)-2-[4-(3-trifluoromethylbenzenesulfonylamino)-piperidin-1-yl]-acetamide;

N-isopropyl-N-{1-[3-(4-methoxy-benzylamino)-propionyl]-piperidin-4-yl}-3-trifluoromethyl-benzenesulfonamide;

N-[1-(2-hydroxy-4-methyl-pentanoyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

2-[4-(benzenesulfonyl-methyl-amino)-piperidin-1-yl]-N-isobutyl-acetamide;

N-isopropyl-N-{1-[3-(4-methoxy-phenylamino)-propionyl]-piperidin-4-yl}-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(4-fluoro-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(4-cyano-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-isopropyl-N-{1-[3-(2-methoxy-phenylamino)-propionyl]-piperidin-4-yl}-3-trifluoromethyl-benzenesulfonamide;

N-isopropyl-N-{1-[3-(3-methoxy-phenylamino)-propionyl]-piperidin-4-yl}-3-trifluoromethyl-benzenesulfonamide;

N-isopropyl-N-[1-(3-o-tolylamino-propionyl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(3-fluoro-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(2-fluoro-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-isopropyl-N-{1-[3-(2-trifluoromethoxy-phenylamino)-propionyl]-piperidin-4-yl}-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(3,5-dimethoxy-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(2,3-dimethoxy-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(2,5-dimethoxy-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(2,6-dimethyl-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(3,4-difluoro-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(2,4-difluoro-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(2-chloro-4-fluoro-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(3-chloro-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(4-chloro-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-isopropyl-N-{1-[3-(3-trifluoromethoxy-phenylamino)-propionyl]-piperidin-4-yl}-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(4-fluoro-3-methoxy-phenylamino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide; and

N-[1-(2-amino-2-methyl-propionyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethylbenzenesulfonamide;

or a pharmaceutically acceptable salt thereof.