Benzenesulfonamide Compounds and Their Use as Blockers of Calcium Channels

• US 20100022595A1
• Filed: 04/13/2007
• Published: 01/28/2010
• Est. Priority Date: 04/13/2006
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Sha, Deyou, Islam, Khondaker, Zhou, Xiaoming, Chen, Zhengming, Shao, Bin, Kyle, Donald J., Yao, Jiangchao
• Granted Patent: US 8,791,264 B2
• Time in Patent Office: Days
• US Class Current: 514/329
• 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 I:

9. The compound of claim 1, wherein Z=Z¹ having the Formula IV:

11. The compound of claim 9, having the Formula V:

16. The compound of claim 9, having the Formula VIII:

18. The compound of claim 9, having the Formula IX:

20. The compound of claim 1, wherein Z=Z² having the Formula X:

28. The compound of claim 1, wherein Z=Z³ having the Formula XI:

36. The compound of claim 1, wherein Z=Z⁴ having the Formula XII:

38. The compound of claim 1, wherein Z=Z⁵ having the Formula XIII:

166. A pharmaceutical composition, comprising the compound of claim 1 or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier.

167. A method of treating, preventing or ameliorating a disorder responsive to the blockade of calcium channels in a mammal suffering from said disorder, comprising administering to a mammal in need of such treatment, prevention or amelioration an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

168. The method of claim 167, wherein a disorder responsive to the blockade of N-type calcium channels is treated, prevented or ameliorated.

169. A method for method for treating, preventing or ameliorating stroke, the neuronal damage resulting from head trauma, epilepsy, pain, migraine, a mood disorder, schizophrenia, a neurodegenerative disorder, depression, anxiety, a psychosis, hypertension or cardiac arrhythmia in a mammal, comprising administering to a mammal in need of such treatment, prevention or amelioration an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

170. The method of claim 169, wherein the method is for treating, preventing or ameliorating pain selected from chronic pain, neuropathic pain, acute pain, and surgical pain.

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

172. The method of claim 171, wherein the N-type calcium channel is modulated.

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

174. A method of screening a candidate compound for the ability to bind to a receptor using a radiolabeled compound of claim 173, comprising a) introducing a fixed concentration of the radiolabeled compound to the receptor to form a mixture;

b) titrating the mixture with a candidate compound; and

c) determining the binding of the candidate compound to said receptor.

2. A compound having the Formula I:

3-8. -8. (canceled)

10. (canceled)

12-15. -15. (canceled)

17. (canceled)

19. (canceled)

21-27. -27. (canceled)

29-35. -35. (canceled)

37. (canceled)

39. (canceled)

40. A compound having the Formula I:

41. The compound of claim 40, wherein

R¹, R², q, R³, and Z are as defined in claim 40;

R⁴ and R⁵ are each independently selected from the group consisting of

hydrogen;

alkyl;

alkenyl;

hydroxyalkyl;

haloalkyl;

mercaptoalkyl;

aminoalkyl;

alkylaminoalkyl;

dialkylaminoalkyl;

alkoxyalkyl; and

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

or

R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, mercaptoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, and phenyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy, and

R⁵ is selected from the group consisting of

hydroxyalkyl optionally substituted at one or more carbon atoms with optionally substituted aryl or optionally substituted benzyl;

aminoalkyl;

dialkylaminoalkyl;

diaminoalkyl;

alkoxyalkyl;

alkyl optionally substituted with one or two substituents each independently selected from the group consisting of optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl, and optionally substituted heterocyclo;

optionally substituted heteroaryl;

R¹⁶—

C(O)—

; and

R¹⁶—

SO₂—

, wherein

R¹⁶ is selected from the group consisting of alkyl, alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted benzyl, and 1,2,3,4-tetrahydroquinolinyl or 1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogen atom with alkylcarbonyl or haloalkylcarbonyl;

or

R⁴ and R⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring wherein one or more carbon atoms of the heterocyclic ring are optionally replaced with NR¹⁷, O, or S, wherein R¹⁷ is hydrogen or C_1-3 alkyl;

R⁶ and R⁷ are each independently selected from the group consisting of

hydrogen;

alkyl;

hydroxyalkyl;

alkoxyalkyl;

haloalkyl;

aminoalkyl;

cycloalkyl;

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

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

benzyloxyalkyl;

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

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

or

R⁶ and R⁷ together with the carbon atom to which they are attached form a C_3-7 cycloalkyl ring optionally substituted with one or more substituents each independently selected from the group consisting of hydroxy, amino, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, and ═

O, wherein one or more carbon atoms of the C_3-7 cycloalkyl ring are optionally replaced with NR¹⁷ or O, wherein R¹⁷ is hydrogen or C_1-3 alkyl, to form a heterocyclic ring;

or wherein two adjacent carbon atoms of the C_3-7 cycloalkyl ring can form a bridge —

O—

to form a bicyclic ring;

or wherein one carbon atom of the C_3-7 cycloalkyl ring is linked to a heterocyclic ring to form a spirocyclic ring;

or

R⁷ is hydrogen;

R⁴ is hydrogen, alkyl, or hydroxyalkyl; and

R⁵ and R⁶ together form a bridge —

CH₂—

CH₂—

CH₂—

or —

CH₂—

CHG¹-CHG²-CH₂—

, wherein G¹ and G² are both hydrogen or together with the carbon atoms to which they are attached form a fused phenyl group;

R³² and R³³ are each independently selected from the group consisting of hydroxy, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and alkoxyalkyl;

or

R³³ is hydrogen and R³² is hydroxy, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or alkoxyalkyl;

or

R³² and R³³ together with the carbon atom to which they are attached form a C_3-7 cycloalkyl ring;

or

R³² and R⁴ together with the carbon and nitrogen atoms to which they are attached, respectively, form a 5- or 6-membered heterocyclic ring optionally substituted with one or more substituents each independently selected from the group consisting of hydroxy, hydroxyalkyl, alkyl, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl;

R³³ is hydrogen, hydroxy, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and alkoxyalkyl; and

R⁵, R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aminoalkyl, carboxy, and alkoxycarbonyl;

R⁸ and R⁹ are both hydrogen or together form ═

O;

R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

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;

alkyl;

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 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 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;

R¹⁵ is selected from the group consisting of

phenyl or naphthyl, either of which is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, amino, alkylamino and dialkylamino; and

alkyl substituted with one or two substituents each independently selected from the group consisting of optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclo;

R³⁰ and R³ are each independently selected from the group consisting of

alkyl optionally substituted with one or two substituents independently selected from the group consisting of optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl, and optionally substituted heterocyclo;

hydroxyalkyl optionally substituted at one or more carbon atoms with optionally substituted aryl or optionally substituted benzyl;

aminoalkyl;

dialkylaminoalkyl;

diaminoalkyl;

alkoxyalkyl;

optionally substituted cycloalkyl;

optionally substituted phenyl;

optionally substituted benzyl;

optionally substituted heteroaryl; and

optionally substituted heterocyclo; and

A, B, A-B, D, x, y, m, n, and p are as defined in claim 40.

45. The compound of 40, having the Formula IV:

47. The compound of claim 45, having the Formula V:

60. The compound of claim 47, having the Formula VI:

66. The compound of claim 47, having the Formula VII:

74. The compound of claim 40, having the Formula X:

85. The compound of claim 40, having the Formula XI:

95. The of compound of claim 40, having the Formula XII:

99. The compound of claim 40, having the Formula XIII:

42-44. -44. (canceled)

46. (canceled)

48-59. -59. (canceled)

61-65. -65. (canceled)

67-73. -73. (canceled)

75-84. -84. (canceled)

86-94. -94. (canceled)

96-98. -98. (canceled)

100. (canceled)

101. A compound having the Formula I:

102. The compound of claim 101,

wherein R¹, R², R³, Z and q are as defined in claim 101;

R⁴ and R⁵ are each independently selected from the group consisting of

hydrogen;

alkyl;

alkenyl;

hydroxyalkyl;

haloalkyl;

mercaptoalkyl;

aminoalkyl;

alkylaminoalkyl;

dialkylaminoalkyl;

alkoxyalkyl; and

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

or

R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, mercaptoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, and phenyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy, and

R⁵ is selected from the group consisting of

hydroxyalkyl optionally substituted at one or more carbon atoms with optionally substituted aryl or optionally substituted benzyl;

aminoalkyl;

dialkylaminoalkyl;

diaminoalkyl;

alkoxyalkyl;

alkyl optionally substituted with one or two substituents each independently selected from the group consisting of optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl, and optionally substituted heterocyclo;

optionally substituted heteroaryl;

R¹⁶—

C(O)—

; and

R¹⁶—

SO₂—

, wherein

R¹⁶ is selected from the group consisting of alkyl, alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted benzyl, and 1,2,3,4-tetrahydroquinolinyl or 1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogen atom with alkylcarbonyl or haloalkylcarbonyl;

or

R⁴ and R⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring wherein one or more carbon atoms of the heterocyclic ring are optionally replaced with NR¹⁷, O, or S, wherein R¹⁷ is hydrogen or C_1-3 alkyl;

R⁶ and R⁷ are each independently selected from the group consisting of

hydrogen;

alkyl;

hydroxyalkyl;

alkoxyalkyl;

haloalkyl;

aminoalkyl;

cycloalkyl;

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

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

benzyloxyalkyl;

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

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

or

R⁶ and R⁷ together with the carbon atom to which they are attached form a C_3-7 cycloalkyl ring optionally substituted with one or more substituents each independently selected from the group consisting of hydroxy, amino, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, and ═

O, wherein one or more carbon atoms of the C_3-7 cycloalkyl ring are optionally replaced with NR¹⁷ or 0, wherein R¹⁷ is hydrogen or C_1-3 alkyl, to form a heterocyclic ring;

or wherein two adjacent carbon atoms of the C_3-7 cycloalkyl ring can form a bridge —

O—

to form a bicyclic ring;

or wherein one carbon atom of the C_3-7 cycloalkyl ring is linked to a heterocyclic ring to form a spirocyclic ring;

R⁷ is hydrogen;

R⁴ is hydrogen, alkyl, or hydroxyalkyl; and

R⁵ and R⁶ together form a bridge —

CH₂—

CH₂—

CH₂—

or —

CH₂—

CHG¹-CHG²-CH₂—

, wherein G¹ and G² are both hydrogen or together with the carbon atoms to which they are attached form a fused phenyl group;

R³² and R³³ are each independently selected from the group consisting of hydroxy, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and alkoxyalkyl;

or

R³³ is hydrogen and R³² is hydroxy, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or alkoxyalkyl;

or

R³² and R³³ together with the carbon atom to which they are attached form a C_3-7 cycloalkyl ring;

or

R³² and R⁴ together with the carbon and nitrogen atoms to which they are attached, respectively, form a 5- or 6-membered heterocyclic ring optionally substituted with one or more substituents each independently selected from the group consisting of hydroxy, hydroxyalkyl, alkyl, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl;

R³³ is hydrogen, hydroxy, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and alkoxyalkyl; and

R⁵, R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aminoalkyl, carboxy, and alkoxycarbonyl;

R⁸ and R⁹ are both hydrogen or together form ═

O;

R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

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;

alkyl;

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 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 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;

R¹⁵ is selected from the group consisting of

phenyl or naphthyl, either of which is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, amino, alkylamino and dialkylamino; and

alkyl substituted with one or two substituents each independently selected from the group consisting of optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclo;

R³⁰ and R³¹ are each independently selected from the group consisting of

alkyl optionally substituted with one or two substituents independently selected from the group consisting of optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl, and optionally substituted heterocyclo;

hydroxyalkyl optionally substituted at one or more carbon atoms with optionally substituted aryl or optionally substituted benzyl;

aminoalkyl;

dialkylaminoalkyl;

diaminoalkyl;

alkoxyalkyl;

optionally substituted cycloalkyl;

optionally substituted phenyl;

optionally substituted benzyl;

optionally substituted heteroaryl; and

optionally substituted heterocyclo; and

A, B, A-B, D, x, y, m, n, and p are as defined in claim 101.

109. The compound of claim 101, wherein Z=Z¹ having the Formula IV:

111. The compound of claim 109, having the Formula V:

124. The compound of claim 111, having the Formula VI:

130. The compound of claim 111, having the Formula VII:

138. The compound of claim 101, wherein Z=Z² having the Formula X:

149. The compound of claim 101, wherein Z=Z³ having the Formula XIII:

159. The compound of claim 101, wherein Z=Z⁴ having the Formula XII:

163. The compound of claim 101, wherein Z=Z⁵ having the Formula XIII:

103-108. -108. (canceled)

110. (canceled)

112-123. -123. (canceled)

125-129. -129. (canceled)

131-137. -137. (canceled)

139-148. -148. (canceled)

150-158. -158. (canceled)

160-162. -162. (canceled)

164. (canceled)

165. A compound selected from the group consisting of:

N-(1-{3-[bis(4-fluorophenyl)amino]propyl}piperidin-4-yl)-N-isopropyl-3-trifluoromethylbenzenesulfonamide;

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

(S)—

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

(S)—

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

(S)—

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

(S)—

N-{1-[2-(cyclohexylmethyl-amino)-3-phenyl-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[2-(3-imidazol-1-yl-propylamino)propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethylbenzenesulfonamide;

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

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

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

N-{1-[2-(benzyl-methyl-amino)butyryl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethylbenzenesulfonamide;

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

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

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;

(S)-2-(1-benzyl-2-{4-[isopropyl(3-trifluoromethylbenzene-sulfonyl)amino]-piperidin-1-yl}-2-oxo-ethylamino)-acetamide;

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-{1-[2-amino-3-(4-benzyloxy-phenyl)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[2-(2-benzyloxy-ethylamino)-4-methyl-pentanoyl]-piperidin-4-yl}-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[2-(2-benzyloxy-ethylamino)-4-methyl-pentanoyl]-piperidin-4-yl}-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(2-benzyloxy-ethylamino)-5-methyl-hexanoyl]-piperidin-4-yl}-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(2-benzyloxy-ethylamino)-5-methyl-hexanoyl]-piperidin-4-yl}-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(benzyl-methyl-amino)-propionyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-{1-[3-(2-benzyloxy-ethylamino)-5-methyl-hexanoyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

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;

N-[1-(2-amino-pent-4-ynoyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-[1-(2-amino-3-naphthalen-1-yl-propionyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-[1-(azetidine-3-carbonyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-[1-(4-amino-tetrahydro-pyran-4-carbonyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

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

N-[1-(2-amino-pent-4-enoyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-[1-(3-amino-3-thiophen-2-yl-propionyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;

N-[1-(2-amino-3-benzo[b]thiophen-3-yl-propionyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide; and

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

or a pharmaceutically acceptable salt, prodrug or solvate thereof

175-178. -178. (canceled)