Mammalian ion channels are becoming increasingly well characterised, and this is especially true of calcium channels. Voltage-gated calcium channels are critical components for the functioning of the nervous system, and they signal a painful event. To date, 7 subtypes of these channels have been identified (L, N, T, O, P, Q and R), each expressed in various combinations by neuronal and non- neuronal cells (Perez-Reyes, E.; Schneider, T. DrugDev. Res., 1994,33, 295-318).

These channels are now recognised as valid targets for pain therapeutics and as neuroprotective agents (Cox, B. ; Denyer, J. C. Expert Opinion on Therapeutic Patents, 1998, 8, 1237-1250).

It has now surprisingly been found that particular compounds of the general formula (1) set out below act as inhibitors of N-type calcium channels. Accordingly, the present invention provides the use, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels, of a compound of formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: Rl is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, -L-Het-Y, -L-X-Y, 5- to 6-membered heteroaryl, -CONH2 or-X-Y, wherein: -X is-CO-,-CO-O-,-CONR-,-O-CO-,-NR-CO-or-NR-CO-NR-, wherein each R is the same or different and represents hydrogen, Cl-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; -Het is-O-,-S-or-NR-, wherein R is as defined above; - L represents a Cl-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety;

- Y is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C1o aryl, 5-to 10- membered heteroaryl, C3-Cs carbocyclyl, 5-to 10-membered heterocyclyl or - L-A, wherein L is as defined above and A represents a C6-Clo aryl, 5-to 10- membered heteroaryl, C3-C8 carbocyclyl or 5-to 10-membered heterocyclyl moiety; each R is the same or different and represents halogen, hydroxy, amino, thio, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, oxo, -Het-L,-Het-A,-X-L or-X-A, wherein Het, L, A and X are as defined above; R3, R4 and R5 are the same or different and are selected from hydrogen, halogen, hydroxy, thio, amino, cyano, nitro, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 alkoxy, Cl-C6 alkylthio, mono (Cl-C6 alkyl) amino and di (Cl-C6 alkyl) amino; and n is from 0 to 4, the alkyl, alkenyl and alkynyl groups and moieties in Rl to R5 being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino and thio substituents; and the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in Ri and R2 being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino, thio, Cl-C6 alkyl, Cl-C6 alkoxy, Cl-C6 alkylthio, mono (Cl-C6 alkyl) amino, di (Cl-C6 alkyl) amino, Cl-C6 haloalkyl, Cl-C6 haloalkoxy, Cl-C6 haloalkylthio, Cl-C6 hydroxyalkyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-S-(C1-C6 alkyl), -(C1-C6 alkyl)-NR'-(C1-C6 alkyl),-CO- (C1-C6 alkyl),-CO-O- (Cl-C6 alkyl) and-CONR'- (C1-C6 alkyl) substituents, wherein R'represents hydrogen or Cl-C6 alkyl.

The present invention further provides the use, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels, of a compound of formula (II), a tautomer thereof or a pharmaceutically acceptable salt thereof,

wherein: one of Rl and R6 is hydrogen and the other is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, 5-to 6-membered heteroaryl, -CONH2 or-X-Y, wherein: - X is -CO-, -CO-O-, -CONR-, -O-CO-, -NR-CO- or -NR-CO-NR-, wherein each R is the same or different and represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; and - Y is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-Clo aryl, 5-to 10- membered heteroaryl, C3-C8 carbocyclyl, 5-to 10-membered heterocyclyl or -L-A, wherein : - L represents a Cl-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety; and -A represents a C6-Clo aryl, 5-to 10-membered heteroaryl, C3-C8 carbocyclyl or 5-to 10-membered heterocyclyl moiety; and R3, R4 and R5 are the same or different and are selected from hydrogen, halogen, hydroxy, thio, amino, cyano, nitro, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 alkoxy, Cl-C6 alkylthio, mono (Cl-C6 alkyl) amino and di (Cl-C6 alkyl) amino, wherein: the alkyl, alkenyl and alkynyl groups and moieties in R1 and R3 to R6 are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino and thio substituents; and the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in R' and R6 are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino, thio, Cl-C6 alkyl, Cl-C6 alkoxy, Cl-C6 alkylthio, mono (CI-C6 alkyl) amino, di (Cl-C6 alkyl) amino, Cl-C6 haloallcyl, Cl-C6 haloalkoxy or Cl-C6 haloalkylthio substituents.

For the avoidance of doubt, the substituents on the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in formulae (I) and (II) are typically unsubstituted.

For the avoidance of doubt, the orientation of the group X in formulae (I) and (II) is such that the left hand side of the depicted group is attached to the piperidinyl ring. Thus, for example, when X is-CONR-, the group-X-Y is-CONR-Y.

For the avoidance of doubt, when R2 is an oxo group the line linking R2 to the piperidinyl ring depicts a double bond. Otherwise, the lines linking the Rl and R2 to the piperidinyl ring depict single bonds.

As used herein, a Cl-C6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms. Examples of Cl-C6 alkyl groups or moieties include methyl, ethyl, iso-propyl, n-propyl, t-butyl, iso-butyl, sec-butyl, n-butyl, 3-methyl-butyl, 1,2-dimethyl-butyl, 1-ethyl-propyl, 2,2-dimethyl- propyl and 3,3-dimethyl-butyl. Further examples of Cl-C6 alkyl groups or moieties include Cl-C4 alkyl groups or moieties, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl. Preferred Cl-C6 alkyl groups include methyl, ethyl, n-propyl, iso-propyl and t-butyl. A divalent alkyl group can be attached via the same carbon atom, via adjacent carbon atoms or via non-adjacent carbon atoms.

As used herein, a C2-C6 alkenyl group is a linear or branched C2-C6 alkylene group. Typically, an alkenyl group or moiety is saturated except for one double bond. Typically, it is an ethenyl, propenyl or butenyl group. Preferably it is an ethenyl group. A divalent alkenyl group can be attached via the same carbon atom, via adjacent carbon atoms or via non-adjacent carbon atoms.

As used herein, a C2-C6 alkynyl group is a linear or branched C2-C6 alkynyl group. Typically, an alkynyl group or moiety is saturated except for one triple bond.

Typically, it is an ethynyl, propynyl or butynyl group. A divalent alkynyl group can be attached via the same carbon atom, via adjacent carbon atoms or via non-adjacent carbon atoms.

As used herein, a C6-Clo aryl group or moiety is typically a phenyl or naphthyl group or moiety. Preferably, it is a phenyl group.

As used herein, a 5-to 10-membered heteroaryl group is a 5-to 10-membered aromatic ring containing at least one heteroatom, for example 1,2 or 3 heteroatoms, selected from O, S and N. Preferred 5-to 10-membered heteroaryl groups are 5-to 6-membered heteroaryl groups. Examples include pyridyl, pyrazinyl, pyrimidinyl,

pyridazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.

Preferred 5-to 6-membered heteroaryl groups are furanyl, thienyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl and imidazolyl. Examples of preferred groups are furanyl, thienyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl and thiadiazolyl groups. Further examples of preferred groups are oxadiazolyl, oxazolyl and isoxazolyl groups. As used herein, a 5-to 10-membered heteroaryl group is typically a monocyclic 5-to 10-membered heteroaryl group.

As used herein, a 5-to 10-membered heteroaryl group or moiety is a monocyclic group or moiety or a bicyclic fused group or moiety. Preferred bicyclic fused groups and moieties are 5-to 10-membered moieties in which a 5-to 6- membered ring is fused to a phenyl ring, to form a 9-to 10-membered heteroaryl group. Examples of suitable such 5-to 6-membered heteroaryl groups are pyridyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl and thiozolyl groups. As used herein, a 9-to 10-membered heteroaryl group or moiety is therefore typically a 5-to 6- membered heteroaryl group fused to a phenyl ring. Examples of such 9-to 10- membered heteroaryl groups and moieties are benzimidazolyl, benzoxazolyl, quinolinyl, indolyl, benzofuranyl, benzothiophenyl and benzothiazolyl. A preferred such group is benzoxazolyl.

As used herein, a halogen is typically fluorine, chlorine, bromine or iodine and is preferably fluorine, chlorine or bromine. As used herein, a said Cl-C6 alkoxy group is typically a said Cl-C6 alkyl group attached to an oxygen atom. A said Cl-C6 alkylthio group is typically a said Cl-C6 alkyl group attached to a thio group.

As used herein, a Cl-C6 haloalkyl group is typically a said Cl-C6 alkyl group, substituted by one or more said halogen atoms. Typically, it is substituted by 1,2 or 3 said halogen atoms. Examples of haloalkyl groups include perhaloalkyl groups such as-CX3 wherein X is a said halogen atom. Preferred haloalkyl groups are fluoroalkyl groups such as-CF3,-CHF2 and-CH2F.

As used herein, a Cl-C6 haloalkoxy group is typically a said Cl-C6 alkoxy group substituted by one or more said halogen atoms. Typically, it is substituted by 1,2 or 3 said halogen atoms. Preferred haloalkoxy groups include perhaloalkoxy groups such as-OCX3 wherein X is a said halogen atom.

As used herein, a Cl-C6 hydroxyalkyl group is typically a said Cl-C6 alkyl group substituted by one or more hydroxy groups. Typically, it is substituted by 1,2 or 3 hydroxy groups. Preferred hydroxyalkyl groups are monohydroxyalkyl groups.

As used herein, a Cl-C6 haloalkylthio group is typically a said Cl-C6 alkylthio group substituted by one or more said halogen atoms. Typically, it is substituted by 1,2 or 3 said halogen atoms. Preferred haloalkylthio groups include perhaloalkylthio groups such as-SCX3 wherein X is a said halogen atom.

As used herein, a C3-C8 carbocyclyl group or moiety is a non-aromatic saturated or unsaturated hydrocarbon ring, having from 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Typically, the carbocyclyl group is saturated, for example a C3-C6 cycloalkyl group. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. A preferred carbocyclyl group is cyclopropyl. As used herein, a C3-C8 carbocyclyl group or moiety is typically a monocyclic C3-C8 carbocyclyl group or moiety.

As used herein, a 5-to 10-membered heterocyclyl group or moiety is a non- aromatic, saturated or unsaturated Cs-CIo carbocyclic ring in which one or more, for example 1,2 or 3, of the carbon atoms are replaced by a heteroatom selected from N, O and S. Saturated heterocyclyl groups are preferred. Examples of suitable heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolanyl, dithiolanyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, dithianyl, morpholinyl and thiomorpholinyl. Preferred heterocyclic groups are pyrrolidinyl and piperidinyl. An example of a preferred heterocyclic group is piperidinyl.

As used herein, a 5-to 1 0-membered heterocyclyl group or moiety is a monocyclic group or moiety or a bicyclic fused group or moiety. Preferred bicyclic fused groups and moieties are 5-to 10-membered moieties in which a 5-to 6- membered ring is fused to a phenyl ring, to form a 9-to 10-membered heterocyclic group. Examples of suitable such 5-to 6-membered heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl. As used herein, a 9-to 10-membered heterocyclic group or moiety is therefore typically a 5-to 6-membered heterocyclyl group fused to a phenyl ring. Examples of such 9-to 10-membered heterocyclyl groups and moieties

are 1, 3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, 1,3- dihydrobenzo [c] thiophenyl, 2,3-dihydrobenzo [b] thiophenyl, 1,3-dihydroisoindolyl, 2,3-dihydroindolyl, 1,2, 3, 4-tetrahydroisoquinolinyl, 1,2, 3, 4-tetrahydroquinolinyl, isochromanyl, isothiochromanyl and thiochromanyl. A preferred such group is 1, 3-dihydroisoindolyl and, in particular, 1, 3-dihydroisoindol-2-yl.

Typically, the alkyl, alkenyl and alkynyl groups and moieties in Rl to R6, in the formulae (I) and (II), are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine or hydroxy substituents.

Preferably, the alkyl, alkenyl and alkynyl groups and moieties in Rl to R6, in the formulae (I) and (II), are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine or chlorine.

Typically, R', in the formula (1), is hydrogen or Cl-C4 alkyl. Preferably, R'is hydrogen or Cl-C2 alkyl. More preferably, R'is hydrogen or methyl.

Typically, the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in Rl and R2, in the formula (I), are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, hydroxy, amino, thio, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 alkylthio, mono (CI-C4 alkyl) amino, di (Cl-C4 alkyl) amino, Cl-C4 haloalkyl, Cl-C4 haloalkoxy, Cl-C4 haloalkylthio, Cl-C4 hydroxyalkyl,-(Cl-C4 alkyl)-O-(Cz-C alkyl), -(C1-C4 alkyl)-S-(C1-C4 alkyl), -(C1-C4 alkyl)-NR'-(C1-C4 alkyl), -CO-(C1-C4 alkyl),-CO-O- (CI-C4 alkyl) and-CONR'- (Cl-C4 alkyl) substituents, wherein R'is as defined above.

Further, typically only one of the substituents on an aryl, heteroaryl, carbocyclyl or heterocyclyl group or moiety is a-(Cl-C4 alkyl)-O-(Cz-C4 alkyl), <BR> <BR> <BR> <BR> -(Cl-C4 alkyl)-S-(Cz-C4 alkyl),-(Cl-C4 alkyl)-NR'-(Cz-C4 alkyl),-CO-(CI-C4 alkyl), - CO-O- (Cl-C4 alkyl) or-CONR'- (Ci-C4 alkyi) substituent.

Preferably, the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in Rl and R2, in the formula (I), are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, Cl-C4 alkyl, Ci-C4 alkoxy, Cl-C4 haloalkyl, Cl-C4

haloalkoxy, Cl-C2 hydroxyalkyl,- (Ci-C2 alkyl)-O- (Ci-C2 alkyl), or-CO-O- (Cl-C4 alkyl) substituents.

More preferably, the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in Rl and R2, in the formula (I), are unsubstituted or are substituted by a single methyl, ethyl, t-butyl, trifluoromethyl,-CH2-OH,-CH2-O-CH3 or -CO-O-t-butyl substituent.

Typically, each R in the moiety X or Het, in the formulae (I) and (II), is the same or different and represents hydrogen or Cl-C6 alkyl. Preferably, each R is the same or different and represents hydrogen or Cl-C2 alkyl. More preferably, each R is the same or different and represents hydrogen or methyl.

Typically, Het, in the formula (I), represents-O-,-S-or-NR-, wherein R is as defined above. Preferably, Het represents-O-or-NR-, wherein R is as defined above. More preferably, Het represents-O-,-NH-or-NMe-.

Typically, L, in the formulae (I) and (II), represents a Cl-C6 alkyl moiety.

Preferably, L represents a Cl-C4 alkyl moiety. More preferably, L represents a Cl-C2 alkyl moiety.

Typically, A, in the formulae (I) and (II) represents a phenyl, 5-to 6- membered heteroaryl, C3-C6 carbocyclyl or 5-to 6-membered heterocyclyl moiety.

Preferably, A represents a phenyl, 5-to 6-membered heteroaryl or C3-C6 carbocyclyl moiety. More preferably, A represents thienyl, furanyl or phenyl. An example of a more preferred A group is phenyl.

Typically, X, in the formulae (I) and (II) is-CO-,-CO-O-,-CONR-,-O-CO- or-NR-CO-, wherein R is as defined above. Preferably, X is-CO-,-CO-O-or -CONR-, wherein R is as defined above. More preferably, X is-CO-,-CO-O-, - CONH-or-CONMe-.

When Y is-L-A, it is typically- (Cl-C6 alkyl) -A where A is as defined above.

It is preferably- (Ci-C4 alkyl) -A, where A is a phenyl, 5-to 6-membered heteroaryl or C3-C6 carbocyclyl moiety. It is more preferably- (Cl-C2 alkyl)-thienyl,- (Cl-C2 alkyl)-furanyl or- (Cl-C2 alkyl) -phenyl. An example of a more preferred group is - (Cl-C2 alkyl) -phenyl.

Typically, Y, in the formulae (I) and (II) is Cl-C6 alkyl, phenyl, 5-to

6-meinbered heteroaryl, C3-C6 carbocyclyl, 5-to 10-membered heterocyclyl or-L-A, wherein L and A are as defined above. Examples of typical Y groups are Cl-C6 alkyl, phenyl, 5-to 6-membered heteroaryl, C3-C6 carbocyclyl, 5-to 6-membered heterocyclyl and-L-A, wherein L and A are as defined above. Preferably, Y is Cl-C6 alkyl, C3-C6 carbocyclyl, 5-to 6 membered heterocyclyl, 9-to 10-membered heterocyclyl or-L-A, wherein L and A are as defined above. Examples of preferred Y groups are Cl-C6 alkyl, C3-C6 carbocyclyl and-L-A, wherein L and A are as defined above. More preferably, Y is Cl-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, pyrrolidinyl, 1, 3-dihydroisoindolyl,- (Cl-C2 alkyl)-thienyl, -(Cl-C2 alkyl)-furanyl or-(Cl-C2 alkyl) -phenyl. Examples of more preferred Y groups are Cl-C6 alkyl, cyclopropyl, cyclobutyl and-(cz-c2 alkyl)-phenyl.

Examples of more preferred Y groups are Cl-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, 1, 3-dihydroisoindolyl,-(Cl-C2 alkyl)-thienyl,-(Cl-C2 alkyl)- furanyl or- (Ci-C2 alkyl) -phenyl. Further examples of more preferred Y groups are Ci-C6 alkyl, cyclopropyl, cyclobutyl and- (Cl-C2 alkyl) -phenyl.

When Y is a heterocyclyl moiety which comprises nitrogen, it may be attached to X via either a carbon or nitrogen atom. Typically, when X is-CO-O-, -CONR-, -O-CO-, -NR-CO- or -NR-CO-NR- and Y is a heterocyclyl moiety which comprises nitrogen, Y is attached to X via a carbon atom.

When Rl or R6, in the formulae (I) and (II) is-X-Y, it is typically-CO-Y, -CO-O-Y, -CONR-Y, -O-CO-Y or-NR-CO-Y, wherein Y is Cl-C6 alkyl, phenyl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl, 5-to'6-membered heterocyclyl or - L-A, wherein L, A and R are as defined above. It is preferably,-CO-Y,-CO-O-Y or -CONR-Y, wherein Y is Cl-C6 alkyl, C3-C6 carbocyclyl, 5-to 6 membered heterocyclyl, 9-to 10-membered heterocyclyl or-L-A, wherein L, A and R are as defined above. Examples of preferred groups are-CO-Y,-CO-O-Y or-CONR-Y, wherein Y is Cl-C6 alkyl, C3-C6 carbocyclyl or-L-A, wherein L, A and R are as defined above. It is more preferably-CO-Y,-CO-O-Y,-CONH-Y or-CONMe-Y, wherein Y is Cl-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, pyrrolidinyl, 1, 3-dihydroisoindolyl,-(Cl-C2 alkyl)-thienyl,-(Cl-C2 alkyl) -furanyl or -(Cl-C2 alkyl) -phenyl. Examples of more preferred groups are-CO-Y,-CO-O-Y,

- CONH-Y or-CONMe-Y, wherein Y is Cl-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, 1, 3-dihydroisoindolyl, -(C1-C2 alkyl)-thienyl, -(C1-C2 alkyl)- furanyl or -(C1-C2 alkyl)-phenyl. Further examples of more preferred groups are -CO-Y, -CO-O-Y, -CONH-Y and-CONMe-Y, wherein Y is Cl-C6 alkyl, cyclopropyl, cyclobutyl or- (Cl-C2 alkyl) -phenyl.

Typically, R1, in the formula (I), is Cl-C6 alkyl, cyano, -L-Het-Y, -L-X-Y, 5- to 6-membered heteroaryl,-CONH2 or-X-Y, wherein X, Y, Het and L are as defined above. Preferably, RI is Cl-C4 alkyl, cyano, -(C1-C2 alkyl)-NR-(C1-C6 alkyl), -(C1-C2 alkyl)-NR-(C3-C6 carbocyclyl), oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, imidazolyl, benzoxazolyl, -CONH2, -CO-Y, -CO-O-Y, -CO-NH-Y or-CO-NMe-Y, wherein Y is Cl-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, pyrrolidinyl, 1, 3-dihydroisoindolyl, -(C1-C2 alkyl)-thienyl, - (Ci-C2 alkyl) -furanyl or- (CI-C2 alkyl) -phenyl and R is hydrogen or methyl.

When R2 is-X-L, it is typically-CO-L, -CO-O-L or-CONR-L, wherein R and L are as defined above. It is preferably-CO-O- (Cl-C6 alkyl) and more preferably-CO-O- (Cl-C4 alkyl).

Typically, R2, in the formula (I), represents fluorine, chlorine, bromine, hydroxy, amino, thio, Ci-C6 alkyl, oxo, -Het-L, -Het-A,-X-L or X-A, wherein Het, L, A and X are as defined above. Preferably, R2 represents fluorine, chlorine, hydroxy, Cl-C6 alkyl, oxo, -Het-L or-X-L, wherein Het represents -O-, -NH- or - NMe-, X represents -CO-, -CO-O-, -CONH- or -CONMe- and L represents Cl-C6 alkyl. More preferably, R2 represents fluorine, chlorine, hydroxy, Cl-C4 alkyl, oxo or -CO-O-(C1-C4 alkyl).

Typically, in the formulae (I) and (II), only one of R3 to R5 represents a nitro or cyano group.

Typically, R3, R4 and R5, in the formulae (1) and (II), are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, hydroxy, thio, amino, cyano, Cl-C4 alkyl, C2-C4 alkenyl, Cl-C4 alkoxy, Cl-C4 alkylthio, mono (CI-C4 alkyl) amino and di (Cl-C4 alkyl) amino.

Preferably, R3, R4 and R5 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, cyano, Cl-C4 alkyl, C2-C4 alkenyl, Cl-C2 alkoxy, Cl-C2 alkylthio, mono (CI-C2 alkyl) amino and di (Ci-C2 alkyl) amino.

More preferably, R3, R4 and R5 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, cyano, Cl-C4 alkyl, Cl-C2 alkoxy or ethenyl. Examples of more preferred R3, R4 and R5 groups are hydrogen, fluorine, chlorine, bromine, cyano, Cl-C4 alkyl or ethenyl.

Typically, n, in the formula (I), represents 0,1 or 2.

Preferred compounds of formula (I) are those wherein: Rl is Cl-C6 alkyl, cyano,-L-Het-Y,-L-X-Y, 5-to 6-membered heteroaryl, - CONH2 or-X-Y, wherein: -X is-CO-,-CO-O-,-CONR-,-O-CO-or-NR-CO-, wherein R represents hydrogen or Cl-C6 alkyl ; -Het represents-O-,-S-or-NR-, wherein R is as defined above; - L represents a Cl-C6 alkyl moiety; and - Y is Cl-C6 alkyl, phenyl, 5-to 6-membered heteroaryl, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl or-L-A, wherein L ia as defined above and A represents a phenyl, 5-to 6-membered heteroaryl, C3-C6 carbocyclyl or 5-to 6-membered heterocyclyl moiety; R2 represents fluorine, chlorine, bromine, hydroxy, Cl-C6 alkyl,-Het-L,-Het- A, -X-L or X-A, wherein Het, L, A and X are as defined above; R3, R4 and R5are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, hydroxy, thio, amino, cyano, Cl-C4 alkyl, C2-C4 alkenyl, Cl-C4 alkoxy, Cl-C4 alkylthio, mono (Cl-C4 alkyl) amino and di (Cl-C4 alkyl) amino; and n represents 0,1 or 2, the alkyl, alkenyl and alkynyl groups and moieties in Rl to R5 being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine or hydroxy substituents; and the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in Ri and R beingunsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, hydroxy, amino, thio, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 alkylthio,

mono (Cl-C4 alkyl) amino, di (CI-C4 alkyl) amino, Cl-C4 haloalkyl, Cl-C4 haloalkoxy, Cl-C4 haloalkylthio, Cl-C4 hydroxyalkyl, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -(C1-C4 alkyl)-S-(C1-C4 alkyl), -(C1-C4 alkyl)-NR'-(C1-C4 alkyl), -CO-(C1-C4 alkyl), -CO-O-(C1-C4 alkyl) and -CONR'-(C1-C4 alkyl) substituents, wherein R'is hydrogen or Cl-C4 alkyl.

Particularly preferred compounds of formula (I) are those wherein: R1 is C1-C4 alkyl, cyano, -(C1-C2 alkyl)-NR-(C1-C6 alkyl), -(C1-C2 alkyl)-NR- (C3-C6 carbocyclyl), oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, imidazolyl, benzoxazolyl,-CONH2,-CO-Y,-CO-O-Y,-CO-NH-Y or -CO-NMe-Y, wherein Y is Cl-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, pyrrolidinyl, 1, 3-dihydroisoindolyl, -(C1-C2 alkyl) -thienyl, - (Cl-C2 alkyl) -furanyl or- (Cl-C2 alkyl)-phenyl and R is hydrogen or methyl; R represents fluorine, chlorine, hydroxy, Cl-C4 alkyl, oxo or -CO-O-(C1-C4 alkyl) ; R3, R4 and R5 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, cyano, Cl-C4 alkyl, Cl-C2 alkoxy or ethenyl; and n represents 0,1 or 2, the alkyl, alkenyl and alkynyl groups and moieties in Ri to RS being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine or chlorine; and the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in R being unsubstituted or are substituted by a single methyl, ethyl, t-butyl, trifluoromethyl,-CH2-OH,-CH2-O-CH3 or-CO-O-t-butyl substituent.

Typically, in formula (II), the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in Rl and R6 are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, hydroxy, amino, thio, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 alkylthio, mono (C1-C4 alkyl) amino, di (Cl-C4 alkyl) amino, Cl-C4 haloalkyl, Cl-C4 haloalkoxy or Cl-C4 haloalkylthio substituents. Preferably, the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in Rl and R6 are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, Cl-C4 alkyl, Cl-C4

alkoxy, Cl-C4 haloalkyl or Cl-C4 haloalkoxy substituents. Examples of preferred substitutuents are fluorine, chlorine, bromine, Cl-C2 alkyl, Cl-C2 alkoxy, Cl-C2 haloalkyl and Cl-C2 haloalkoxy substituents. More preferably, the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in Rl and R2 are unsubstituted or are substituted by a single methyl, ethyl or t-butyl substituent. Examples of more preferred substituents are a single methyl or ethyl substituent.

Typically, in formula (II), one of Rl and R6 is hydrogen and the other is Cl-C6 alkyl, cyano, 5-to 6-membered heteroaryl,-CONH2 or-X-Y, wherein X and Y are as defined above.

Preferably, in formula (II), one of Rl and R6 is hydrogen and the other is Cl-C4 alkyl, cyano, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, - CONH2,-CO-Y,-CO-O-Y,-CO-NH-Y or-CO-NMe-Y, wherein Y is Cl-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, 1, 3-dihydroisoindolyl,- (Ci-C2 alkyl)-thienyl,-(Cl-C2 alkyl) -furanyl or- (Cl-C2 alkyl) -phenyl. Examples of preferred groups are those wherein one of R1 and R2 is hydrogen and the other is Cl-C4 alkyl, cyano, oxadiazolyl, oxazolyl, isoxazolyl,-CONH2,-CO-Y,-CO-O-Y, -CO-NH-Y or-CO-NMe-Y, wherein Y is C1-C6 alkyl, cyclopropyl, cyclobutyl or -(C1-C2 alkyl) -phenyl.

Preferred compounds of formula (II) are those wherein: one of Rl and R6 is hydrogen and the other is Cl-C6 alkyl, cyano, phenyl, 5- to 6-membered heteroaryl, -CONH2 or-X-Y, wherein: - X is -CO-, -CO-O-, -CONR-, -O-CO- or -NR-CO-, wherein R is hydrogen or Cl-C6 alkyl ; and - Y is Cl-C6 alkyl, phenyl, 5-to 6-membered heteroaryl, C3-C6 carbocyclyl, 5-to 10-membered heterocyclyl or-L-A, wherein: - L represents a Cl-C6 alkyl moiety; and - A represents a phenyl, 5-to 6-membered heteroaryl, C3-C6 carbocyclyl or 5-to 6-membered heterocyclyl moiety; and R3, R4 and R5 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, hydroxy, thio, amino, cyano, Cl-C4 alkyl, C2-C4 alkenyl, Cl-C4 alkoxy, Cl-C4 alkylthio, mono (Ci-C4 alkyl) amino and di (CI-C4 alkyl) amino, wherein:

the alkyl, alkenyl and alkynyl groups and moieties in Rl and R3 to R6 are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine or hydroxy substituents; and the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in Rl and R6 are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, hydroxy, amino, thio, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 alkylthio, mono (CI-C4 alkyl) amino, di (Cl-C4 alkyl) amino, Cl-C4 haloalkyl, Cl-C4 haloalkoxy or Cl-C4 haloalkylthio substituents.

Examples of preferred compounds of formula (II) are the preferred compounds of formula (II) as defined above wherein Y is Cl-C6 alkyl, phenyl, 5-to 6-membered heteroaryl, C3-C6 carbocyclyl, 5-to 6-membered heterocyclyl or-L-A, wherein L and A are as defined for said preferred compounds.

More preferred compounds of formula (II) are those wherein: one of Rl and R6 is hydrogen and the other is Cl-C6 alkyl, cyano, phenyl, 5-to 6-membered heteroaryl,-CONH2 or-X-Y, wherein: X is-CO-,-CO-0-or-CO-NR-, wherein R represents hydrogen or Cl-C4 alkyl ; and - Y is Cl-C6 alkyl, C3-C6 carbocyclyl, 5-to 6-membered heterocyclyl, 9-to 10-membered heterocyclyl or-L-A, where L represents a Cl-C4 alkyl moiety and A represents a phenyl, 5-to 6-membered heteroaryl or C3-C6 carbocyclyl moiety; and R3, R4 and R5 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, cyano, Cl-C4 alkyl, C2-C4 alkenyl, Cl-C2 alkoxy, Cl-C2 alkylthio, mono (Cl-C2 alkyl) amino and di (Cl-C2 alkyl) amino, wherein: the alkyl and alkenyl groups and moieties in Rl and R3 to R6 are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine or chlorine substituents ; and the phenyl, heteroaryl and carbocyclyl groups and moieties in Rl and R6 are unsubstituted or substituted by one, two or three unsubstituted substituents which are

the same or different and are selected from fluorine, chlorine, bromine, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 haloalkyl or Cl-C4 haloalkoxy substituents.

Examples of more preferred compounds of formula (II) are those more preferred compounds of formula (II) as defined above wherein Y is Cl-C6 alkyl, C3-C6 carbocyclyl or-L-A, where L represents a Cl-C4 alkyl moiety and A represents a phenyl, 5-to 6-membered heteroaryl or C3-C6 carbocyclyl moiety, and wherein the phenyl, heteroaryl and carbocyclyl groups and moieties in Rl and R6 are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, Cl-C2 alkyl, Cl-C2 alkoxy, Cl-C2 haloalkyl or Cl-C2 haloalkoxy substituents.

Particularly preferred compounds of formula (II) are those wherein: one of Rl and R6 is hydrogen and the other is Cl-C4 alkyl, cyano, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,-CONH2,-CO-Y,-CO-O-Y,-CO-NH-Y or-CO-NMe-Y, wherein Y is Cl-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, 1, 3-dihydroisoindolyl,-(Cl-C2 alkyl)-thienyl,-(Cl-C2 alkyl)-furanyl or - (Ci-C2 alkyl) -phenyl; and R3, R4 and R5 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, cyano, Cl-C4 alkyl or ethenyl, wherein: the alkyl, alkenyl and alkynyl groups and moieties in Rl and R3 to R6 are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine or chlorine substituents; and the phenyl, heteroaryl and carbocyclyl groups and moieties in Rl and R6 are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 haloalkyl or Ci-C4 haloalkoxy substituents.

Examples of particularly preferred compounds of formula (II) are the particularly preferred compounds of formula (II) as defined above wherein one of R and R6 is hydrogen and the other is Cl-C4 alkyl, cyano, oxadiazolyl, oxazolyl, isoxazolyl,-CONH2,-CO-Y,-CO-O-Y,-CO-NH-Y or-CO-NMe-Y, wherein Y is Cl-C6 alkyl, cyclopropyl, cyclobutyl or- (Ci-C2 alkyl) -phenyl, and wherein the phenyl, heteroaryl and carbocyclyl groups and moieties in Rl and R6 are unsubstituted or substituted by one, two or three unsubstituted substituents which are

the same or different and are selected from fluorine, chlorine, bromine, Cl-C2 alkyl, Cl-C2 alkoxy, Cl-C2 haloalkyl or C1-C2 haloalkoxy substituents.

The present invention also provides a compound of formula (III), a tautomer thereof or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body, wherein: R1, R2, R3, R4, RS and n are as defined for formula (1), provided that when R is a to the nitrogen of the piperidinyl ring and n is 0, then: (a) R1 is neither -CO-O-CH2-CH3 nor -CO-O-CH (CH3) 2 ; and either (b) (i) when the phenyl ring substituted by R3, R4 and R5 is a para- fluorophenyl group, then Rl is not a 5-membered heteroaryl group; or (ii) Rl is a 1, 3-oxazol-2-yl, 1, 2-isoxazol-3-yl, 1, 2,4-oxadiazol-3-yl or 1, 2-imidazol-2-yl group.

Preferably, in the compounds of formula (III), provisos (a) and (b) (i) apply.

Thus, preferably, Rl, R2, R3, R4, R5 and n are as defined for formula (I), provided that, when Rl is a to the nitrogen of the piperidinyl ring and n is 0, Rl is neither -CO-O-CH2-CH3 nor-CO-O-CH (CH3) 2 and when the phenyl ring substituted by R3, R4 and R5 is a para-fluorophenyl group, then Rl is not a 5-membered heteroaryl group. In a preferred embodiment of proviso (a), Rl is not a-CO-O- (Cl-C6) alkyl group.

More preferably, in the compounds of formula (III), R1, R2, R3, R4, R5 and n are as defined for formula (I) provided that R1 is not -CO-O-CH2-CH3, -CO-O-CH (CH3) 2 or a 5-membered heteroaryl group. Particularly preferably, in the compounds of formula (III), R1, R, R3, R4, R and n are as defined for formula (I) provided that Rl is not-CO-O-(Cz-C6 alkyl) or a 5-to 6-membered heteroaryl group.

In a particularly preferred embodiment, in the compounds of formula (III), R2, R3, R4, R5 and n are as defined for formula (1) and Rl is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano,-L-Het-Y,-L-X-Y,-CONH2 or-X-Y, wherein: X is-CO-,-CONR-,-0-CO-,-NR-CO-or-NR-CO-NR-, wherein each R is the same or different and represents hydrogen, Cl-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl ; - Het is -O-, -S- or -NR-, wherein R is as defined above; - L represents a Cl-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety; - Y is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-Clo aryl, 5-to 10- membered heteroaryl, C3-C8 carbocyclyl, 5-to 10-membered heterocyclyl or -L-A, wherein L is as defined above and A represents a C6-Clo aryl, 5-to 10- membered heteroaryl, C3-C8 carbocyclyl or 5-to 10-membered heterocyclyl moiety, wherein the substituents on Rl are as defined for formula (I).

In a further preferred embodiment, in the compounds of formula (III): R1 is C1-C4 alkyl, cyano, -(C1-C2 alkyl)-NR-(C1-C6 alkyl), -(C1-C2 alkyl) -NR- (C3-C6 carbocyclyl), -CONH2, -CO-Y,-CO-NH-Y or-CO-NMe-Y, wherein Y is Cl-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, pyrrolidinyl, 1, 3-dihydroisoindolyl,-(Cl-C2 alkyl)-thienyl,-(Cl-C2 alkyl)-furanyl or -(C1-C2 alkyl) -phenyl and R is hydrogen or methyl; R ? represents fluorine, chlorine, hydroxy, Ci-C4 alkyl, oxo or -CO-O-(Cz-C4 alkyl) ; R3, R4 and R5 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, cyano, Cl-C4 alkyl, Cl-C2 alkoxy or ethenyl; and n represents 0,1 or 2, the alkyl, alkenyl and alkynyl groups and moieties in R1 to R5 being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine or chlorine; and the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in R being unsubstituted or are substituted by a single methyl, ethyl, t-butyl, trifluoromethyl,-CH2-OH,-CH2-O-CH3 or-CO-O-t-butyl substituent.

The present invention also provides a compound of formula (IV), a tautomer thereof or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body,

wherein: Rl, R3, and R5 and R6 are as defined for formula (II), provided that: (a) Rl is neither-CO-O-CH2-CH3 nor-CO-O-CH (CH3) 2; and either (b) (i) when the phenyl ring substituted by R3, R4 and R5 is a para- fluorophenyl group, then Rl is not a 5-membered heteroaryl group; or (ii) Rl is a 1, 3-oxazol-2-yl, 1, 2-isoxazol-3-yl or 1, 2,4-oxadiazol-3-yl group.

Preferably, in the compounds of formula (IV), provisos (a) and (b) (i) apply.

Thus, preferably, Rl, R3, R4, RS and R6 are as defined for formula (II), provided that Rl is not-CO-O-CH2-CH3 or-CO-O-CH (CH3) 2 and when the phenyl ring substituted by R3, R4 and R5 is a para-fluorophenyl group, then Rl is not a 5-membered heteroaryl group.

More preferably, in the compounds of formula (IV), Rl, R'and R6 are as defined for formula (II) provided that Rl is not-CO-O-CH2-CH3,-CO-O- CH (CH3) 2 or a 5-membered heteroaryl group. Particularly preferably, in the compounds of formula (IV), Rl, R3, R4, R5 and R6 are as defined for formula (II) provided that Rl is not-CO-O-(CI-C6 alkyl) or a 5-to 6-membered heteroaryl group.

The present invention also provides a compound of formula (IVA), a tautomer thereof or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body,

wherein: R1, R3, R4, R5 and R6 are as defined for formula (II), provided that: (a) when the phenyl ring substituted by R3, R4 and R5 is a para-fluorophenyl group, then Rl is not a 5-membered heteroaryl group; or (b) Rl is a 1, 3-oxazol-2-yl, 1, 2-isoxazol-3-yl or 1, 2,4-oxadiazol-3-yl group.

Preferably, in the compounds of formula (IVA), proviso (a) applies. Thus, preferably, Rl, R3, R4, R5 and R6 are as defined for formula (II), provided that when the phenyl ring substituted by R3, R4 and R5 is a para-fluorophenyl group, then Rl is not a 5-membered heteroaryl group.

Typically, in the compounds of formula (III), (IV) and (IVA), the phenyl ring substituted by R3, R4 and R5 is not a para-fluorophenyl group. Preferably, the phenyl ring substituted by R3, R4 and R5 is not a para-halophenyl group. More preferably, the phenyl ring substituted by R3, R4 and R5 is not a phenyl group substituted by a halogen substituent. Most preferably, the phenyl ring substituted by R3, R4 and W is not a phenyl group substituted by a halogen, haloalkyl or haloalkoxy substituent.

More preferably still, R3, R4 and RS are the same or different and are selected from hydrogen, thio, amino, cyano, nitro, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 alkylthio, mono (CI-C6 alkyl) amino and di (CI-C6 alkyl) amino, provided that R3, R4 and R5 are not all hydrogen.

Examples of particularly preferred compounds of formulae (I) to (IVA) are: 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-3-carboxylic acid ethyl ester 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl ester; 2-Methyl-1- (4-trifluoromethyl-benzenesulfonyl)-piperidine ; 1-(2, 4, 6-Trimethyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl ester; 1-(2, 4, 6-Triisopropyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl ester; 1- (4-Bromo-2-methyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl ester; 1-(4-Bromo-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl ester;

1- (3, 5-Bis-trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxyl ic acid ethyl ester; 1- (4-Bromo-2-trifluoromethyl-benzenesulfonyl)-piperidine-2-car boxylic acid ethyl ester; 1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidine-2-ca rboxylic acid ethyl ester; 2-Ethyl-1- (4-trifluoromethyl-benzenesulfonyl)-piperidine ; (2R)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl ester; (2S)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl ester; 2- (4-Cyano-benzenesulfonyl)-cyclohexanecarboxylic acid ethyl ester; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid tert-butyl ester; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid methyl ester; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl-methyl- amide; 2-Isoxazol-3-yl-1- (4-trifluoromethyl-benzenesulfonyl)-piperidine ; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid isopropyl ester; 1-(4-Vinyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl ester; 1-(4-Difluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl ester; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid amide ; 1- (4-Fluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl ester; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid tert-butylamide; 1- (2-Bromo-4-trifluoromethyl-benzenesulfonyl)-piperidine-2-car boxylic acid ethyl ester; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carbonitril e ; 1- (2, 6-Dichloro-4-trifluoromethyl-benzenesulfonyl)-piperidine-2-c arboxylic acid ethyl ester; 1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidine-3- carboxylic acid ethyl ester ; 2- (5-Methyl- [1, 2,4] oxadiazol-3-yl)-l- (4-trifluoromethyl-benzenesulfonyl)- piperidine ; 1-(2-Methyl-4-trifluoromethyl-benzenesulfonyl)-piperidine-2- carboxylic acid ethyl ester;

(2S)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid tert-butyl ester ; (3R)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-3-carboxylic acid ethyl ester; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-3-carboxylic acid tert-butyl ester; 2- (5-Ethyl-oxazol-2-yl)-1- (4-trifluoromethyl-benzenesulfonyl)-piperidine ; (2S)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid tert- butylamide; (2S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidi ne-2-carboxylic acid ethyl ester; (2S)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid benzyl ester ; (2S)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethylamide ; (2S)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid benzylamide; (2S)-1-(4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carb oxylic acid cyclopropylamide; (3R)-I- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-3-carboxylic acid tert-butyl ester; (2S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidi ne-2-carboxylic acid tert-butyl ester; <BR> <BR> <BR> (3R)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidi ne-3-carboxylic acid ethyl ester; (3R)-1-(2-Bromo-4-trifluoromethyl-benzenesulfonyl)-piperidin e-3-carboxylic acid ethyl ester; <BR> <BR> <BR> (3R)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidi ne-3-carboxylic acid tert-butyl ester; <BR> <BR> <BR> (3R)-1-(2-Bromo-4-trifluoromethyl-benzenesulfonyl)-piperidin e-3-carboxylic acid tert-butyl ester; 2- (5-Methyl-oxazol-2-yl)-1- (4-trifluoromethyl-benzenesulfonyl)-piperidine ; (2S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2-(5-met hyl-oxazol-2-yl)- piperidine ;

(2S)-1-(2-Bromo-4-trifluoromethyl-benzenesulfonyl)-piperidin e-2-carboxylic acid ethyl ester; (2S)-1-(2-Bromo-4-trifluoromethyl-benzenesulfonyl)-piperidin e-2-carboxylic acid tert-butyl ester; (2S)-1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2- (5-ethyl-oxazol-2-yl)- piperidine ; (2S)-2- (5-Ethyl-oxazol-2-yl)-1- (4-trifluoromethyl-benzenesulfonyl)-piperidine ; (2S)-1- [1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidin-2-yl] -butan-1-one ; 1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidine-2-ca rboxylic acid dimethylamide ; (S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2-(5-ethy l-thiazol-2-yl)- piperidine; (S)-1- (4-Trifluorometliyl-benzenesulfonyl)-piperidine-2-carboxylic acid methyl ester; (S)-1-(4-Difluoromethyl-benzenesulfonyl)-2-(5-ethyl-thiazol- 2-yl)-piperidine ; (S)-l- (2-Cliloro-4-trifluoromethyl-benzenesulfonyl)-2- (5-methyl-thiazol-2-yl)- piperidine ; (S)-2- (5-Methyl-oxazol-2-yl)-1- (4-trifluoromethyl-benzenesulfonyl)-piperidine ; (R)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid tert- butylamide; (R)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid tert-butyl ester ; (R)-2- (5-Methyl-oxazol-2-yl)-1- (4-trifluoromethyl-benzenesulfonyl)-piperidine ; (S)-1- (4-Difluoromethyl-benzenesulfonyl)-2- (5-methyl-oxazol-2-yl)-piperidine ; (S)-2- (5-Methyl-thiazol-2-yl)-1- (4-trifluoromethyl-benzenesulfonyl)-piperidine ; (S)-1-(4-Difluoromethyl-benzenesulfonyl)-2-(5-methyl-thiazol -2-yl)-piperidine ; (S)-2-(5-tert-Butyl-oxazol-2-yl)-1-(4-trifluoromethyl-benzen esulfonyl)-piperidine ; (S)-2-(5-tert-Butyl-oxazol-2-yl)-1-(2-chloro-4-trifluorometh yl-benzenesulfonyl)- piperidine ; (S)-2- (5-Methyl- [1, 3,4] thiadiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)- piperidine;

(S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2-(5-meth yl-[1, 3,4] thiadiazol-2- yl)-piperidine ; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (2-thiophen-2- yl-ethyl)-amide ; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (5-methyl- furan-2-ylmethyl)-amide ; Piperidin-1-yl- [1- (4-trifluoromethyl-benzenesulfonyl)-piperidin-2-yl]-methanon e ; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid sec-butylamide; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid cyclopentylamide; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid isopropylamide; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid cyclopropylamide; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (3-methyl- butyl) -amide; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethylamide ; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid propylamide; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid butylamide; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (3,3-dimethyl- butyl) -amide; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid isobutyl-amide; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (1,2-dimethyl- propyl)-amide ; 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (1-ethyl- propyl) -amide; (1, 3-Dihydro-isoindol-2-yl)- [1- (4-trifluoromethyl-benzenesulfonyl)-piperidin-2-yl]- methanone; (S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidin e-2-carboxylic acid tert-butylamide; (S)-1- (4-Difluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid tert- butylamide; (S)-2- (5-tert-Butyl-oxazol-2-yl)-1- (4-difluoromethyl-benzenesulfonyl)-piperidine ;

(S)-1-(2-Chloro-4-difluoromethyl-benzenesulfonyl)-piperidine -2-carboxylic acid methyl ester; (S)-2- (5-tert-Butyl-thiazol-2-yl)-1- (4-trifluoromethyl-benzenesulfonyl)-piperidine ; <BR> <BR> <BR> (S)-2- (5-tert-Butyl-thiazol-2-yl)-l- (2-chloro-4-trifluoromethyl-benzenesulfonyl)- piperidine ; (S)-2- (5-tert-Butyl-thiazol-2-yl)-1- (4-difluoromethyl-benzenesulfonyl)-piperidine ; (S)-1-(2-Chloro-4-difluoromethyl-benzenesulfonyl)-piperidine -2-carboxylic acid ethyl ester; (S)-1-(2-Chloro-4-difluoromethyl-benzenesulfonyl)-piperidine -2-carboxylic acid tert-butylamide; (S)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (2,2- dimethyl-propyl) -amide; (S)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid isopropylamide; (S)-1- (4-Difluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid isopropylamide; (S)-1- (4-Difluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (2,2- dimethyl-propyl) -amide; (S)-2- (5-tert-Butyl- [1, 3,4] oxadiazol-2-yl)-l- (2-chloro-4-trifluoromethyl- benzenesulfonyl)-piperidine ; (S)-1- (2-Chloro-4-difluoromethyl-benzenesulfonyl)-2- (5-methyl- [ 1, 3,4] thiadiazol-2- yl) -piperidine; (R)-1- (4-Difluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid isopropylamide; (R)-1- (4-Difluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid tert- butylamide; (R)-1- (4-Difluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (2,2- dimethyl-propyl)-amide ; (R)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidin e-2-carboxylic acid isopropylamide; (R)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidin e-2-carboxylic acid tert-butylamide ;

(R)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidin e-2-carboxylic acid (2,2-dimethyl-propyl)-amide ; (R)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid isopropylamide; (R)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (2,2- dimethyl-propyl)-amide ; (S)-2- (5-tert-Butyl- [1, 3,4] oxadiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)- piperidine; (S)-1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2- (5-trifluoromethyl- [1,3, 4] oxadiazol-2-yl) -piperidine ; (S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidin e-2-carboxylic acid (2, 2-dimethyl-propyl)-amide ; (S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidin e-2-carboxylic acid isopropylamide; (S)- [1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidin-2-ylm ethyl]- dimethyl-amine ; (S)- [1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidin-2-ylm ethyl]- cyclopropyl-amine ; (S)-tert-Butyl- [1- (2-chloro-4-trifluoromethyl-benzenesulfonyl)-piperidin-2- ylmethyl] -amine; (S)-2- (5-tert-Butyl- [1, 3,4] thiadiazol-2-yl)-1-(2-chloro-4-trifluoromethyl- benzenesulfonyl)-piperidine ; (S)-2- (5-tert-Butyl- [1, 3,4] thiadiazol-2-yl)-1- (4-trifluoromethyl-benzenesulfonyl)- piperidine ; (S)-2- (5-tert-Butyl- [ 1, 3,4] thiadiazol-2-yl)-1-(4-difluoromethyl-benzenesulfonyl)- piperidine ; 1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-1, 2,3, 4,5, 6-hexahydro- [2,3'] bipyridinyl; 1- (4-Trifluoromethyl-benzenesulfonyl)-1, 2,3, 4,5, 6-hexahydro- [2, 3'] bipyridinyl ; (S)-tert-Butyl- [1- (4-difluoromethyl-benzenesulfonyl)-piperidin-2-ylmethyl]-ami ne ; (S)- [l- (4-Difluoromethyl-benzenesulfonyl)-piperidin-2-ylmethyl]-dim ethyl-amine ; (S)-2- [l- (4-Difluoromethyl-benzenesulfonyl)-piperidin-2-yl]-benzooxaz ole ;

(R)-2- (5-tert-Butyl- [ 1, 3,4] oxadiazol-2-yl)-1-(2-chloro-4-trifluoromethyl- benzenesulfonyl)-piperidine ; (R)-3- (5-tert-Butyl- [ 1, 3,4] oxadiazol-2-yl)-1-(2-chloro-4-trifluoromethyl- benzenesulfonyl)-piperidine ; (S)-2-(5-tert-Butyl-1H-imidazol-2-yl)-1-(2-chloro-4-trifluor omethyl- benzenesulfonyl)-piperidine ; (R)-1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2- (5-methyl- [1, 3,4] thiadiazol-2- yl)-piperidine ; (S)-2- (5-tert-Butyl-lH-imidazol-2-yl)-1- (4-trifluoromethyl-benzenesulfonyl)- piperidine ; (S)-1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2- (5-methyl- [1, 3,4] oxadiazol-2- yl)-piperidine ; 1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2-(5-methoxym ethyl- [1, 3, 4] thiadiazol-2-yl)-piperidine ; (S)- {5- [1- (2-Chloro-4-trifluoromethyl-benzenesulibnyl)-piperidm-2-yl]- [1,3, 4] thiadiazol-2-yl}-methanol ; (2S, 4R)-1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2- (5-methyl- [1,3, 4] thiadiazol-2-yl)-piperidin-4-ol ; (S)-1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2- (5-methoxymethyl- [1, 3,4] oxadiazol-2-yl) -piperidine; (R)-1- (2-Cliloro-4-trifluoromethyl-benzenesulfonyl)-3- (5-methyl- [1, 3,4] thiadiazol-2- yl)-piperidine ; (S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-4, 4-difluoro-2-(5- methoxymethyl- [1, 3,4] thiadiazol-2-yl)-piperidine ; 4- (5-tert-Butyl- [1, 3,4] oxadiazol-2-yl)-1-(2-chloro-4-trifluoromethyl- benzenesulfonyl)-piperidine ; 2- [l- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidin-3-yl] -benzooxazole ; 4- (5-tert-Butyl- [1, 3,4] oxadiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)- piperidine ; (S)-2-(5-tert-Butyl-[1, 2,4] oxadiazol-3-yl)-1-(2-chloro-4-trifluoromethyl- benzenesulfonyl)-piperidine ; and

(S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2-(5-meth yl-[1, 2,4] oxadiazol-3- yl)-piperidine.

Certain compounds of the invention are believed to be novel. The present invention therefore also provides such novel compounds. Thus, the present invention provides a compound of formula (V), a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3, R4, R5 and n are as defined for formula (I), provided that when n is 0 then: (a) Rlis neither-CO-O-CH2-CH3 nor-CO-O-CH (CH3) 2, and either (b) (i) when the phenyl ring substituted by R3, R4 and W is a para- fluorophenyl group, then Rl is not a 5-membered heteroaryl, amido, methyl ester, methyl amido, cyano or 2-hydroxypropylamido group; or (ii) Rl is a 1, 3-oxazol-2-yl, 1, 2-isoxazol-3-yl, 1, 2,4-oxadiazol-3-yl or 1,3- imidazoly-2-yl group.

Preferably, in the compounds of formula (V), provisos (a) and (b) (i) apply.

Thus, preferably, Rl, R2, R3, R4, RS and n are as defined for formula (I), provided that, when n is 0, then Rl is neither-CO-O-CH2-CH3 nor-CO-O-CH (CH3) 2, and when the phenyl ring substituted by R3, W and R5 is a para-fluorophenyl group, then Rl is not a 5-membered heteroaryl, amido, methyl ester, methyl amido, cyano or 2-hydroxypropylamido group. In a preferred embodiment of proviso (a), Rl is not a -CO-O-(C1-C6) alkyl group.

More preferably, in the compounds of formula (V), Rl, R2, R3, R4, R5 and n are as defined for formula (provided that Rl is not-CO-O-CH2-CH3,-CO-O- CH (CH3) 2, a 5-membered heteroaryl, amido, methyl ester, methyl amido, cyano or 2-hydroxypropylamido group. Particularly preferably, in the compounds of formula (V), RI, R2, R3, R4, R5 and n are as defined for formula (I) provided that Rl is not

-CO-O-(Cz-C6 alkyl), a 5-to 6-membered heteroaryl,-CO-NH2,-CO-NH- (Ci-C6 alkyl) or cyano group.

In a particularly preferred embodiment, in the compounds of formula (V), R2, R3, R4, R5 and n are as defined for formula (I) and R1 is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-Het-Y, -L-X-Y or-X-Y, wherein: X is-CO-,-0-CO-,-NR-CO-or-NR-CO-NR-, wherein each R is the same or different and represents hydrogen, Cl-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; - Het is -O-, -S- or -NR-, wherein R is as defined above; - L represents a Cl-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety; - Y is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-Clo aryl, 5-to 10- membered heteroaryl, C3-C8 carbocyclyl, 5-to 10-membered heterocyclyl or -L-A, wherein L is as defined above and A represents a C6-Clo aryl, 5-to 10- membered heteroaryl, C3-C8 carbocyclyl or 5-to 10-membered heterocyclyl moiety, wherein the substituents on Rl are as defined for formula (I).

In a further preferred embodiment, in the compounds of formula (V): R1 is C1-C4 alkyl, -(C1-C2 alkyl)-NR-(C1-C6 alkyl), -(C1-C2 alkyl)-NR-(C3-C6 carbocyclyl) or-CO-Y, wherein Y is Cl-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, pyrrolidinyl, 1, 3-dihydroisoindolyl, -(C1-C2 alkyl) -thienyl, -(C1-C2 alkyl) -furanyl or- (Cl-C2 alkyl) -phenyl and R is hydrogen or methyl; R2 represents fluorine, chlorine, hydroxy, Cl-C4 alkyl, oxo or -CO-O-(C1-C4 alkyl) ; R3, R4 and R5 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, cyano, C1-C4 alkyl, C1-C2 alkoxy or ethenyl; and n represents 0,1 or 2, the alkyl, alkenyl and alkynyl groups and moieties in Rl to R5 being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine or chlorine; and the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in R being unsubstituted or are substituted by a single methyl, ethyl, t-butyl, trifluoromethyl,-CH2-OH,-CH2-O-CH3 or-CO-O-t-butylsubstituent.

The present invention also provides a compound of formula (VI), a tautomer thereof or a pharmaceutically acceptable salt thereof,

wherein: Rl, R3, and R5 and R6 are as defined for formula (II), provided that: (a) Rl is neither-CO-O-CH2-CH3 nor-CO-O-CH (CH3) 2, and either (b) (i) when the phenyl ring substituted by R3, R4 and R5 is a para- fluorophenyl group, then Rl is not a 5-membered heteroaryl, amido, methyl ester, methyl amido, cyano or 2-hydroxypropylamido group, or (ii) Rl is a 1, 3-oxazol-2-yl, 1, 2-isoxazol-3-yl or 1, 2,4-oxadiazol-3-yl group.

Preferably, in the compounds of formula (VI) provisos (a) and (b) (i) apply.

Thus, preferably, Rl, R3, R4, R5 and R6 are as defined for formula (II), provided that Rl is neither-CO-O-CH2-CH3 nor-CO-O-CH (CH3) 2, and when the phenyl ring substituted by R3, R4 and R5 is a para-fluorophenyl group, then Ru ils not a 5- membered heteroaryl, amido, methyl ester, methyl amido, cyano or 2- hydroxypropylamido group.

More preferably, in the compounds of formula (VI), Ru, R3, R4, R5 and R6 are as defined for formula (II) provided that R1 is not-CO-O-CH2-CH3, -CO-O-CH (CH3) 2, a 5-membered heteroaryl, amido, methyl ester, methyl amido, cyano or 2-hydroxypropylamido group. Particularly preferably, in the compounds of formula (VI), R1, R3, R4, R5 and R6 are as defined for formula (II) provided that Ru ils not -CO-O-(C1-C6 alkyl), a 5-to 6-membered heteroaryl,-CO-NH2,-CO-NH-(C1-C6 alkyl) or cyano group.

Thus, the present invention provides a compound of formula (VIA), a tautomer thereof or a pharmaceutically acceptable salt thereof,

wherein: Ru, R3, R4, RS and R6 are as defined for formula (II), provided that either: (a) (i) when the phenyl ring substituted by R3, R4 and R'is a para- trifluoromethylphenyl group, neither R1 nor R2 is-CO-O-CH2-CH3 ; and (ii) when the phenyl ring substituted by R3, R4 and R 5 is a para- fluorophenyl group, then R1 is not a 5-membered heteroaryl, carboxylic acid, amido, methyl ester, methyl amido, cyano or 2-hydroxypropylamido group, or (b) (i) when the phenyl ring substituted by R3, R4 and R5 is a para- trifluoromethylphenyl group, neither R1 nor R2 is-CO-O-CH2-CH3 ; and (iii) Ru ils a 1, 3-oxazol-2-yl, 1, 2-isoxazol-3-yl or 1, 2,4-oxadiazol-3-yl group.

Preferably, in the compounds of formula (VIA), proviso (a) applies. Thus, preferably, Ru, R3, R4, RS and R6 are as defined for formula (II), provided that: (i) when the phenyl ring substituted by R3, R4 and R5 is a para-trifluoromethylphenyl group, neither R1 nor R2 is-CO-O-CH2-CH3 ; and (ii) when the phenyl ring substituted by R3, R4 and R5 is a para-fluorophenyl group, then Ru ils not a 5- membered heteroaryl, carboxylic acid, amido, methyl ester, methyl amido, cyano or 2-hydroxypropylamido group.

Typically, in the compounds of formula (V), (VI) and (VIA), the phenyl ring substituted by R3, R4 and R5 is not a para-trifluoromethylphenyl or para- fluorophenyl group. Preferably, the phenyl ring substituted by R3, R4 and R5 is not a para-trihalomethylphenyl or para-halophenyl group. More preferably, the phenyl ring substituted by R3, R4 and R5 is not a phenyl group substituted by a trihalomethyl or halogen substituent. Most preferably, the phenyl ring substituted by R3, R4 and R5 is not a phenyl group substituted by a halogen, haloalkyl or haloalkoxy substituent.

More preferably still, R3, R4 and R5 are the same or different and are selected from hydrogen, thio, amino, cyano, nitro, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylthio,

mono (Cl-C6 alkyl) amino and di (Cl-C6 alkyl) amino, provided that R3, R4 and RS are not all hydrogen.

Typically, in the compounds of formula (V) and (VI) when Ru ils a 1,3- oxazol-2-yl, 1, 2-isoxazol-3-yl, 1, 2,4-oxadiazol-3-yl or 1, 3-imidazol-2-yl group it is unsubstituted or substituted by one or two unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, Cl-C4 alkyl, C1-C4 alkoxy, Cl-C4 haloalkyl, Ci-C4 haloalkoxy, Cl-C4 hydroxyalkyl and- (CI-C2 alkyl)-O-(Cl-C2 alkyl) substituents. Preferably, when R'is a 1, 3-oxazol-2-yl, 1,2- isoxazol-3-yl, 1, 2,4-oxadiazol-3-yl or 1, 3-imidazol-2-yl group it is unsubstituted or substituted by a single methyl, ethyl, t-butyl, trifluoromethyl, -CH2-OH or - CH2-O-CH3 substituent.

Typically, in the compounds of formula (VIA) when R1 is a 1, 3-oxazol-2-yl, 1, 2-isoxazol-3-yl or 1, 2,4-oxadiazol-3-yl group it is unsubstituted or substituted by one or two unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, C1-C4 alkyl, C1-C4 alkoxy, Ci-C4 haloalkyl or C1-C4 haloalkoxy substituents. Examples of the typical substuituents are fluorine, chlorine, bromine, C1-C2 alkyl, C1-C2 alkoxy, Cl-C2 haloalkyl or C1-C2 haloalkoxy substituents. Preferably, when R'is a 1, 3-oxazol-2-yl, 1, 2-isoxazol-3-yl, 1,2, 4- oxadiazol-3-yl or 1, 3-imidazol-2-yl group it is unsubstituted or substituted by a single methyl, ethyl or t-butyl substituent. Further, when R1 is à 1, 3-oxazol-2-yl, 1, 2-isoxazol-3-yl or 1, 2,4-oxadiazol-3-yl group it is preferably unsubstituted or substituted by a single methyl, ethyl or t-butyl substituent. Examples of preferred substituents are a single methyl or ethyl substituent.

Typically, the compounds of formulae (V), (VI) and (VIA) do not include 2- piperidine carboxylic acid-1- [ (4-fluorophenyl) sulphonyl] -phenyl methyl ester.

As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e. g. sodium or potassium) and alkali earth metal (e. g. calcium or

magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.

The compounds of the invention can contain one or more chiral centre. For the avoidance of doubt, the chemical structures depicted herein are intended to embrace all stereoisomers of the compounds shown, including racemic and non- racemic mixtures and pure enantiomers and/or diastereoisomers.

Preferred compounds of the invention are optically active isomers. Thus, for example, preferred compounds of formula (I) containing only one chiral centre include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form and enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer.

The present invention also provides a pharmaceutical composition comprising a compound of formula (III), (IV) or (IVA), as defined above, a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

For the avoidance of doubt, the said pharmaceutically acceptable carrier or diluent is not DMSO.

Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention. Preferred pharmaceutical compositions are sterile and pyrogen free.

Further, the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer. Preferably, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of formula (III), (VI) or (VIA) or a tautomer thereof.

The compounds of formulae (I) to (VIA) may be prepared by conventional routes, for example those set out in any of Schemes 1,2 or A to F shown below.

Scheme 1

Compounds of formula (I) may be prepared by the reaction of a piperidine (I') and a phenyl sulphonyl chloride (I"), wherein R'to W and n are as defined above.

The coupling of the piperidine and the sulphonyl chloride may be performed at room temperature in a suitable solvent, such as toluene or dichloromethane, in the presence of a base, for example triethylamine, N-ethylmorpholine or diisopropylethylamine.

Both piperidine (I') and phenyl sulphonyl chloride (I") are either known compounds or can be prepared by the skilled person using known methods.

A similar approach for preparing compounds of formula (II) is shown in Scheme 2.

Scheme 2 wherein Rl and R3 to R6 are as defined above.

Alternative ways of preparing some of the compounds of the present invention are detailed in Schemes A to F.

Scheme A 0 ! S02CI-,-o Ir r 0 r R5tR3 base Wq NXS » Nu R4 R5 Ra O O lui An Y-1 H0"r-bi LrJr -OH HO/jX r 1) in situ acid activation N O o L OS Rs 2) YM qOS Ra R4 (3) (2)

In order to generate compounds of general formula (2) a multi-step reaction sequence as described in Scheme A may be employed. Herein, ethyl-piperidine carboxylate (or carboxylate hydrochloride), whereby either q = 4 and r = 0, or q = 3 and r = 1, which may or may not have a defined stereochemical centre, is reacted with a sulphonyl chloride. Typically the reaction takes place in a solvent such as dichloromethane in the presence a non-nucleophilic organic amine base such as triethylamine, N-ethylmorpholine or diisopropylethylamine. Saponification of the ethyl ester may be accomplished using standard methods familiar to one skilled in the art, typically employing an aqueous metal hydroxide base such as LiOH or NaOH in the presence of water miscible solvents such as tetrahydrofuran and MeOH.

After activating the resultant carboxylic acid it may be utilized for the synthesis of a variety of products by reaction with a nucleophile of type Y-M.

In order to generate a ketone, Y-M (wherein Y is as defined above) may be an organometallic agent such as an organolithium compound (whereby M is Li) or a Grignard reagent (whereby M is MgHal). Reaction with an organometallic agent must be accomplished by first generating a suitable leaving group on the carboxylic acid. A typical method for achieving this would be to use a chlorinating reagent such as oxalyl chloride or thionyl chloride, in a solvent such as dichloromethane (with catalytic DMF added) to generate of the acid chloride species in situ. Reaction with

the organometallic agent can then be carried out in suitable solvent such as tetrahydrofuran. Alternative methods for preparing ketones of formula (2) include conversion of acids of formula (3) either to the Weinreb amide or the 2-pyridine carbothiolate as described by Wu et al., (R Med. Chem., 2002,45 (16), 3558-3568).

Esters of formula (2) may be prepared from acids of formula (3) by standard methods such as refluxing with alcohols of formula YOH (wherein Y is as defined above) in the presence of catalytic concentrated HC1. For the generation of t-butyl esters Y-M is dimethylformamide di-tert-butyl acetal and the reaction typically carried out using toluene as solvent.

Furthermore, an amide, such as t-butyl amide, may be generated from the carboxylic acid intermediate, by reacting with primary or secondary amines (of generic formula RYN-H, wherein R and Y are as defined above). Typically activation of the acid and subsequent coupling is effected using standard amide coupling reagents, familiar to one skilled in the art, such as EDC. HCl/HOBt, HATU or HBTU.

Heterocyclic compounds of general formula (4), wherein and R8 is Cl-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl may be generated from intermediate acids of formula (3) by employing the reaction sequences outlined in Schemes B to D.

Scheme B o o 0 p] Rg R8 l NHZ H N. O OH OH oxidation O's R3 qos R3 R5 R4 R5 R4 (3) R8 0 w R8-"N Ir R8\ ^N N II EI I r q N\ o q s, Jq N. O % S R3 O S R R5 R4 R5 R4 W=OorS

The acid may be coupled to primary amines of general formulae RICH (OH) CH2NH2. Typically the reaction is effected using standard amide coupling conditions, familiar to one skilled in the art, such as EDC. HCVHOBt, HATU or HBTU. The resultant hydroxy-amide may then be oxidized to the keto-amide by employing 1, 1, l-triacetoxy-l, 1-dihydro-1, 2-benziodoxol-3 (1H)-one as described by Dess, D. B. and Martin, J. C., J. Org. Chem., 1983, 48 (22), 4155-6, or dimethyl sulphoxide as described by Omura, K. et al., J. Org. Chem., 1976,41 (6), 757-62.

Cyclisation to the oxazole (W =O) may be accomplished by heating in neat POC13.

The thiazole (W=S) may be generated by using 2,4-bis (4-methoxyphenyl) -2,4- dithioxo-1, 3,2, 4-dithiadiphosphetane as described by Scheibye, S. et al., Bull. Soc.

Chim. Belg., 1978,87 (3), 229-38, to generate the thioketone in situ, which then spontaneously cyclises to yield the desired thiazole.

Scheme C 0 0 H2N, N 0 H N NH2NH2 N 0 R8 ci ° < R8) tCI R5R4 R4 R3 R5 R4 R5 R4 (3) R8 R8 N O//-S J 0 H Lawesson's reagent R3 toluene, heat q N, SO 0 % R3 R5 R4 R5 R4 R5UR4 R5 R4 R5 R4 (5)

Intermediate acid (3) may be further utilized to synthesize heterocyclic compounds of general formulae (5). Hydrazine may be coupled to the acid using a standard amide coupling procedure, familiar to one skilled in the art. Typically iso- butylchloroformate was employed, in a suitable solvent such as tetrahydrofuran, using a non-nucleophilic base such as N-ethylmorpholine. The resulting hydrazide may then be coupled to an acid chloride, such as acetyl chloride. Heating with Lawesson's reagent in toluene may generate the thiohydrazide which spontaneously cyclises to the desired thiadiazole.

Scheme D 0 0 1 l NC l Jr HzN Jr Jr NH40H reduction NH20H. HCI s I s a N, s R3 R3 0 R3 R5 R4 R5 Rq R5 R4 (3) R8 R8 N OqR8 X NHOH HNoO N=t HN Ir 0 HN Ir Ir ! q N. S'o he R3 p R3 R3 0 R3 R3 0 R5 R4 R5 R4

The intermediate carboxylic acid (3) may be converted to the corresponding amide by employing standard methods familiar to one skilled in the art. A typical procedure uses ethyl chloroformate in a suitable solvent such as THF, in the presence of an organic base such as triethylamine followed by ammonium hydroxide.

Reduction of the amide to a nitrile may typically be accomplished using diphosgene and trimethylphosphate as described by Echavarren, A. et al., Helv. Chim. Acta, 1988,71, 685-97. Refluxing with hydroxylamine hydrochloride, in a protic solvent such as ethanol, in the presence of an inorganic base such as sodium carbonate yields the hydroxyamidine. Acylation of this intermediate may be accomplished using standard methods familiar to one skilled in the art, for example by reacting with an acid chloride, in the presence of an organic base such as triethylamine. Cyclisation of this intermediate to the oxadiazole may be typically accomplished by heating in pyridine.

Scheme E 0 0 0 deprotection r-- r r [NP [NP [NH [LNP [LNp [H 16) SO2CI 0 R5 R3 y in R4 N a N. S O , n s R5 R4 As an alternative to Scheme A, Scheme E employs a suitably protected piperidine carboxylic acid of general formula (6), whereby P is, for example, t- butyloxycarbonyl or benzyloxycarbonyl. This may be subjected to similar conditions as described for the generation of ketones, esters and amides in Scheme A. The N piperdine protected ketone, ester or amide may then be de-protected using standard conditions, familiar to one skilled in the art. The sulphonyl chloride may then be coupled to the free amine in an analogous manner to previously described in Scheme A.

Scheme F 0 several steps Het deprotection Het [NP [NP [NH NP q NP qL NH c qNP (6) so2cl Het R8 R8 R8 R5 R3 W NS N Het =-I N N R4 p % R3 W W=OorS R5 » R4 (4)

As an alternative to Schemes B to D, Scheme F employs a suitably protected piperidine carboxylic acid of general formula (5), whereby P is, for example, t-butyloxycarbonyl or benzyloxycarbonyl. This may be subjected to similar conditions as described for the generation of heterocycles in Schemes B to D, to yield the N-piperdine protected heterocycle. Deprotection may be accomplished using standard conditions, familiar to one skilled in the art. The sulphonyl chloride may then be coupled to the free amine in an analogous manner to previously described in Scheme A.

Similarly, a variety of other heterocycles may be synthesized from acids of general formula (2) or (5), by employing methods, familiar to one skilled in the art as outlined, for example, in Joule, J. A. and Mills, K. A. , Heterocyclic Chemistry (Fourth edition), 2000, Blackwell Science Ltd, Oxford, UK, ISBN 0-632-05453-0.

The thus obtained compounds of formulae (I), (II) and (III) may be salified by treatment with an appropriate acid or base. Racemic mixtures obtained by any of the above processes can be resolved by standard techinques, for example elution on a chiral chromatography column.

The compounds of the invention are found to be inhibitors of N-type calcium channels. Further, many preferred compounds of the invention exhibit selectivity

over L-type calcium channels. The compounds of the invention are therefore therapeutically useful.

The compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferred pharmaceutical compositions of the invention are compositions suitable for oral administration, for example tablets and capsules.

The compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories.

One preferred route of administration is inhalation. The major advantages of inhaled medications are their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed.

Preferred pharmaceutical compositions of the invention therefore include those suitable for inhalation. The present invention also provides an inhalation device containing such a pharmaceutical composition. Typically said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler. Typically, said propellant is a fluorocarbon.

Further preferred inhalation devices include nebulizers. Nebulizers are devices capable of delivering fine liquid mists of medication through a"mask"that fits over the nose and mouth, using air or oxygen under pressure. They are frequently used to treat those with asthma who cannot use an inhaler, including infants, young children and acutely ill patients of all ages.

Said inhalation device can also be, for example, a rotary inhaler or a dry powder inhaler, capable of delivering a compound of the invention without a propellant.

Typically, said inhalation device contains a spacer. A spacer is a device which enables individuals to inhale a greater amount of medication directly into the

lower airways, where it is intended to go, rather than into the throat. Many spacers fit on the end of an inhaler; for some, the canister of medication fits into the device.

Spacers with withholding chambers and one-way valves prevent medication from escaping into the air. Many people, especially young children and the elderly, may have difficulties coordinating their inhalation with the action necessary to trigger a puff from a metered dose inhaler. For these patients, use of a spacer is particularly recommended.

Another preferred route of administration is intranasal administration. The nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently, more so than drugs in tablet form. Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. Drugs can be delivered nasally in smaller doses than medication delivered in tablet form.

By this method absorption is very rapid and first pass metabolism is bypassed, thus reducing inter-patient variability. Nasal delivery devices further allow medication to be administered in precise, metered doses. Thus, the pharmaceutical compositions of the invention are typically suitable for intranasal administration. Further, the present invention also provides an intranasal device containing such a pharmaceutical composition.

A further preferred route of administration is transdermal administration. The present invention therefore also provides a transdermal patch containing a compound of the invention, or a pharmaceutically acceptable salt thereof. Also preferred is sublingual administration. The present invention therefore also provides a sub- lingual tablet comprising a compound of the invention or a pharmaceutically acceptable salt thereof.

A compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e. g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e. g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e. g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e. g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting

agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.

Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e. g. sterile water, olive oil, ethyl oleate, glycols, e. g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

The compounds of the present invention are therapeutically useful in the treatment or prevention of conditions mediated by N-type calcium channels.

Accordingly, the present invention provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels. Also provided is a method of treating a patient suffering from or susceptible to a condition mediated by N-type calcium channels, which method comprises administering to said patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

These compounds are useful as calcium channel antagonists thereby inhibiting in a subject the onset of a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder.

N-type calcium channels are known to be closely involved in the mediation of pain transmission. Typically, the compounds of the invention are therefore used as analgesic agents. N-type calcium channels have been identified as being particularly important in the transmission of pain signals in the spinal cord (Chaplan S. R. , Pogrel

J, W. , Yaksh T. L. J. Pharm. Exp. Ther. , 1994, 269, 1117-1123; Diaz, A. , Dickenson, A. H. Pain, 1997, 69, 93-100). Indeed, a series of recent clinical studies has provided confirmation of the important role of N-type calcium channels in pain transmission (Mathur, V. S.; McGuire, D.; Bowersox, S. S.; Miljanich, G. P.; Luther, R. R. Pharmaceutical News, 1998, 5, 25-29). The compounds of the invention are accordingly particularly effective in alleviating pain. Typically, therefore, said medicament is for use in alleviating pain and said patient is suffering from or susceptible to pain. The compounds of the invention are effective in alleviating both chronic and acute pain.

Acute pain is generally understood to be a constellation of unpleasant sensory, perceptual and emotional experiences of certain associate autonomic (reflex) responses, and of psychological and behavioural reactions provoked by injury or disease. A discussion of acute pain can be found at Halpern (1984) Advances in Pain Research and Therapy, Vol. 7, p. 147. Tissue injury provokes a series of noxious stimuli which are transduced by nociceptors to impulses transmitted to the spinal cord and then to the upper part of the nervous system. Examples of acute pains which can be alleviated with the compounds of the invention include musculoskeletal pain, for example joint pain, lower back pain and neck pain, dental pain, post-operative pain, obstetric pain, for example labour pain, acute headache, neuralgia, myalgia, and visceral pain.

Chronic pain is generally understood to be pain that persists beyond the usual course of an acute disease or beyond a reasonable time for an injury to heal. A discussion of chronic pain can be found in the Halpern reference given above.

Chronic pain is sometimes a result of persistent dysfunction of the nociceptive pain system. Examples of chronic pains which can be alleviated with the compounds of the invention include trigeminal neuralgia, post-herpetic neuralgia (a form of chronic pain accompanied by skin changes in a dermatomal distribution following damage by acute Herpes Zoster disease), diabetic neuropathy, causalgia,"phantom limb"pain, pain associated with osteoarthritis, pain associated with rheumatoid arthritis, pain associated with cancer, pain associated with HIV, neuropathic pain, migraine and other conditions associated with chronic cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, spinal cord injury

pain, central pain, post-herpetic pain, noncardiac chest pain, irritable bowel syndrome and pain associated with bowel disorders and dyspepsia.

Some of the chronic pains set out above, for example, trigeminal neuralgia, diabetic neuropathic pain, causalgia, phantom limb pain and central post-stroke pain, have also been classified as neurogenic pain. One non-limiting definition of neurogenic pain is pain caused by dysfunction of the peripheral or central nervous system in the absence of nociceptor stimulation by trauma or disease. The compounds of the invention can, of course, be used to alleviate or reduce the incidence of neurogenic pain.

Since blockers of N-type calcium channels inhibit the release of excitatory amino acids, they can be used inter alia to inhibit damage to neuronal cells during anoxia, and function as neuroprotective agents, useful in the treatment of cerebral ischaemia or central nervous system injuries (Cox, B.; Denyer, J. C. Expert Opinion on Tl2erapeutic Patents, 1998, 8, 1237-1250). The compounds can also be utilised for the treatment of eye diseases (Chu, T-C; Potter, D. E. Research Communications in Pharmacology and Toxicology, 2001, 6, 263-275).

Examples of cerebral ischaemias which can be treated or prevented with the compounds of the invention include transient ischaemic attack, stroke, for example thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke or lacunar stroke, subarachnoid haemorrhage, cerebral vasospasm, peri-natal asphyxia, drowning, cardiac arrest and subdural haematoma.

Examples of central nervous system injuries which can be treated with the compounds of the invention include traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injuries, raised intracranial pressure, cerebral oedema, hydrocephalus and spinal cord injury.

Examples of eye diseases which can be treated or prevented with the compounds of the invention include drug-induced optic neuritis, cataract, diabetic neuropathy, ischaemic retinopathy, retinal haemorrhage, retinitis pigmentosa, acute glaucoma, in particular acute normal tension glaucoma, chronic glaucoma, in particular chronic normal tension glaucoma, macular degeneration, retinal artery occlusion and retinitis.

By virtue of their inhibition of neurotransmitter release the compounds of the invention can be used in the treatment of seizure disorders. Examples of seizure disorders which can be treated or prevented with the compounds of the invention include epilepsy and post-traumatic epilepsy, partial epilepsy (simple partial seizures, complex partial seizures, and partial seizures secondarily generalised seizures), generalised seizures, including generalised tonic/clonic seizures (grand mal), absence seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, and tonic seizures, Lennox Gastaut, West Syndrome (infantile spasms), multiresistant seizures and seizure prophylaxis (antiepileptogenic).

Furthermore the compounds of the invention can be utilised in the treatment of tinnitus, itch such as pruritoceptive, neuropathic, neurogenic and psychogenic itch, as well as urinary tract disorders such as urinary incontinence, and irritable bowel syndrome.

The compounds of the invention may also have application in disorders which are generally associated with blocking of L-type calcium channels, such as cardiovascular, antiasthmatic and antibronchoconstriction disorders for example in the prevention and treatment of disorders such as hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, premature labour, gastrointestinal motility disorders and cardiovascular disorders wherein the cardiovascular disorder is selected from the group consisting of hypertension, myocardial ischemia, angina, congestive heart failure, myocardial infarction and stroke.

The compounds of the invention can be utilised in the treatment of hypersensitivity disorders such as urinary tract disorders. Examples of urinary tract disorders include in particular bladder dysfunctions such as overactive (or unstable) bladder (OAB) more specifically urinary incontinence, urgency, frequency, urge incontinence, nocturia; bladder hyper-reflexia; urinary tract inflammation specifically bladder inflammation e. g interstitial cystitis; and urinary tract infection.

The compounds of the invention may, where appropriate, be used prophylactically to reduce the incidence of such conditions.

The compounds of the invention can also be utilised in the treatment of anxiety-related disorders and mood disorders, Bipolar disorder and post traumatic stress disorders.

The compounds of the invention the invention can also be used in the treatment of lower urinary tract symptoms (LUTS). LUTS comprises three groups of symptoms, which are irritative, which comprises urgency, frequency and nocturia and which can be associated with OAB and benign prostatic hyperplasia (BHP), obstructive and post micturition symptoms.

The compounds of the invention may, where appropriate, be used prophylactically to reduce the incidence of such conditions.

A therapeutically effective amount of a compound of the invention is administered to a patient. A typical dose is from about 0.001 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration. Preferably, daily dosage levels are from 5 mg to 2 g.

The following Examples illustrate the invention. They do not, however, limit the invention in any way. In this regard, it is important to understand that the particular assays used in the Examples section are designed only to provide an indication of activity in inhibiting N-type calcium channels. There are many assays available to determine the activity of given compounds as N-type calcium channel antagonists, and a negative result in any one particular assay is therefore not determinative.

EXAMPLES Example 1 (2S)-tert-Butyl-l- (4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylate Step 1 To a solution of (2S)-ethyl-2-piperidinecarboxylate hydrochloride (0.200g, 1. 03mmol) (ref : PCT hit. Appl. (2002), W00200653) in dichloromethane (lOmL) was added 4-trifluoromethylbenzenesulphonyl chloride (0.240g, 0. 98mmol) followed by triethylainine (0.29mL, 2. 06mmol) and the reaction mixture was stirred at room temperature for 15h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate followed by brine. The organic layer was dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to afford (2-ethyl-1- (4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylate as a colourless oil (0.152g, 40%). HPLC (Method A) retention time 4. 32min (Solvent: MeCN/H20/0.05% HCOzH, 5-95% gradient H20-6 min. Column : Waters Xterra 50 x 4.60 mm i. d., C18 reverse phase. Flow rate: 1.5 mL/min. ). Mass spectrum (ES+) m/z 366 (M+H).

Step 2 A mixture of (2S)-ethyl-1-(4-kifluoromethylbenzenesulphonyl) piperidine-2- carboxylate (0. 638g, 1. 75mmol) and lithium hydroxide monohydrate (0.077g, 1. 83mmol) in ethanol (8mL) and water (2mL) was stirred at room temperature for 30h. The solvent was removed in vacuo and the residue dissolved in water. The aqueous layer was acidified and extracted with dichloromethane. The organic layer was washed with brine and dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to afford (2S)-1- (4-trifluoromethylbenzene sulphonyl) piperidine-2-carboxylic acid as a colourless oil (0.49g, 83%). HPLC (Method A) retention time 3.78min. Mass spectrum (ES-) m/z 336 (M-H).

Step 3 To a solution of (25)-1-(4-kifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid (0.092g, 0. 28mmol) in toluene (2mL) was added dimethylformamide di-tert-

butyl acetal (0.56mL, 2.34mmol) in three portions over 20h whilst heating at reflux.

The solvent was removed in vacuo and the residue filtered through florisil eluting with isohexane/ethyl acetate (1: 1) to afford the title product as a yellow solid (0.094mg, 88%). HPLC (Method B) retention time 4. 66min. (Solvent: MeCN/H20/0. 05% NH40H, 5-95% gradient H2O-6 min. Column: Waters Xterra 50 x 4.60 mm i. d., C18 reverse phase. Flow rate: 1.5 mL/min. ). Mass spectrum (ES+) m/z 338 (M-tBu+H).

Example 2 tert-Butyl-1-(4-kifluoromethylbenzenesulphonyl) piperidine-2-carboxylate Step l Using an analogous method to that described for Example 1, Step 1 starting from ethyl-2-piperidinecarboxylate hydrochloride (1.98g, 10. 2mmol) and purifying by flash column chromatography, eluting with isohexane/ethyl acetate (4: 1) gave Ethyl- 1- (4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylate as a pale yellow oil (2.95g, 79%). HPLC (Method B) retention time 4. 29min. Mass spectrum (ES+) ynlz 366 (M+H).

Step 2 To a solution of ethyl-1- (4-trifluoromethylbenzenesulphonyl) piperidine-2- carboxylate (l. OOg, 2. 7mmol) in tetrahydrofuran (20mL) and methanol (lOmL) was added 2M aqueous sodium hydroxide (2.75mL, 5. 5mmol) and the reaction mixture stirred at room temperature for 15h. The solvent was removed in vacuo and the residue dissolved in ethyl acetate. The solution was washed with 10% aqueous hydrochloric acid followed by brine. The organic layer was dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to afford a colourless oil, which on standing began to solidify and was triturated with isohexane to afford 1- (4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid as a colourless solid (0.823g, 89%). HPLC (Method B) retention time 2. 51min. Mass spectrum (ES- ) m/z 336 (M-H).

Step 3

Using an analogous method to that described for Example 1, Step 3 starting from 1- (4-trifluorometliylbenzenesulphonyl) piperidine-2-carboxylic acid (0. 135g, 0. 4mmol) and triturating the residue with isohexane gave the title compound as a colourless solid (0.073g, 46%). HPLC (Method A) retention time 4.60min. Mass spectrum (ES+) m/z 338 (M-tBu+H).

Example 3 (2S)-tert-Butyl-l- (2-chloro-4-trifluoromethylbenzenesulphonyl) piperidine-2- carboxylate Step 1 Using an analogous method to that described for Example 1, Stepl starting from (2S)-(-)-ethyl-2-piperidinecarboxylate hydrochloride (0.367g, 1. 90mmol) and 2-chloro-4- (trifluoromethyl) benzenesulphonyl chloride (0.530g, 1. 90mmol) and purifying by flash column chromatography, eluting with isohexane/ethyl acetate (9: 1) gave (2S)-ethyl-l- (2-chloro-4-trifluoromethylbenzenesulphonyl) piperidine-2- carboxylate as a colourless oil (0. 310g, 40%). HPLC (Method B) retention time 4. 54min. Mass spectrum (ES+) m/z 400 (M+H).

Step 2 Using an analogous method to that described for Example 2, Step 2 starting from (2S)-ethyl-l- (2-chloro-4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylate gave (2S)-1-(2-Chloro-4-kifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid as a colourless oil (0.097g, 89%). HPLC (Method B) retention time 2. 53min.

Mass spectrum (ES-) nilz 370 (M-H).

Step 3 Using an analogous method to that described for Example 1, Step 3 starting from (2S)-1- (2-chloro-4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid (0.097g, 0. 26mmol) and purifying by flash column chromatography, eluting with isohexane/ethyl acetate (9: 1) gave the title compound as a pale yellow oil (0.093g, 83%). HPLC (Method B) retention time 4. 74min. Mass spectrum (ES+) walz 372 (M- tBu+H).

Example 4 (2S)-tert-Butyl-1-(2-bromo-4-trifluoromethylbenzenesulphonyl ) piperidine-2- carboxylate Step 1 Using an analogous method to that described for Example 1, Step 1 starting from (2S)-ethyl-2-piperidinecarboxylate hydrochloride (0. 50g, 2. 58mmol) and 2-bromo-4- (trifluoromethyl) benzenesulphonyl chloride (0.84g, 2. 58mmol) and purifying by flash column chromatography, eluting with isohexane/ethyl acetate (19: 1) gave (2S)- ethyl-1-(2-bromo-4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylate as a colourless oil (0.554g, 48%). HPLC (Method B) retention time 4.62min. Mass spectrum (ES+) m/z 444/446 (M+H).

Step 2 Using an analogous method to that described for Example 2, Step 2 starting from (2S)-ethyl-1-(2-bromo-4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylate (0. 50g, 1. 13mmol) gave (2S)-1- (2-bromo-4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid as a colourless solid (0.353g, 75%). HPLC (Method B) retention time 2.52min. Mass spectrum (ES-) m/z 414/416 (M-H).

Step 3 Using an analogous method to that described for Example 1, Step 3 starting from (2æ-1-(2-bromo-4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid (0. 104g, 0. 25mmol) and purifying by flash column chromatography, eluting with isohexane/ethyl acetate (19: 1) gave the title compound as a colourless oil (0.095g, 81%). HPLC (Method B) retention time, 4.86 min. Mass spectrum (ES+) m/z 416/418 (M-tBu+H).

Example 5 (3R)-Ethyl-1- (4-trifluoromethylbenzenesulphonyl) piperidine-3-carboxylate Using an analogous method to that described for Example 1, Step 1 starting from (3R)-ethyl-3-piperidinecarboxylate (0.120g, 0. 76mmol) gave the title compound as a

colourless solid (0.176g, 63%). HPLC (Method A) retention time 4.28 min. Mass spectrum (ES+) m/z 366 (M+H).

Example 6 Ethyl-1- (2-chloro-4-trifluoromethylbenzenesulphonyl) piperidine-3-carboxylate Using an analogous method to that described for Example 1, Step 1 starting from ethyl-3-piperidinecarboxylate (0. 089g, 0. 57mmol) and 2-chloro-4- (trifluoromethyl) benzenesulphonyl chloride (0. 158g, 0. 57mmol) gave the title compound as a colourless oil (0. 139g, 61%). HPLC (Method B) retention time 4. 49min. Mass spectrum (ES+) rnlz 400 (M+H).

Example 7 (3R)-tert-Butyl-1-(2-bromo-4-trifluoromethylbenzenesulphonyl ) piperidine-3- carboxylate Step 1 Using an analogous method to that described for Example 1, Step 1 starting from (3R)-ethyl-3-piperidinecarboxylate (0.483g, 3.07mmol) and 2-bromo-4- (trifluoromethyl) benzenesulphonyl chloride (0.994g, 3. 07mmol) gave (3R)-ethyl-l- (2-bromo-4-trifluoromethylbenzenesulphonyl) piperidine-3-carboxylate as a colourless oil (1.36g, 99%). HPLC (Method B) retention time 4. 38min. Mass spectrum (ES+) m/z 444/446 (M+H).

Step 2 Using an analogous method to that described for Example 2, Step 2 starting from (3R)-ethyl-1-(2-bromo-4-trifluoromethylbenzenesulphonyl) piperidine-3-carboxylate gave (3R)-1-(2-Bromo-4-trifluoromethylbenzenesulphonyl) piperidine-3-carboxylic acid as a pale yellow solid (0.985g, 82%). HPLC (Method B) retention time 2. 5 lmin.

Mass spectrum (ES-) m/z 414/416 (M-H).

Step 3 Using an analogous method to that described for Example 1, Step 3 starting from (3R)-1-(2-bromo-4-trifluoromethylbenzenesulphonyl) piperidine-3-carboxylic acid

and purifying by flash column chromatography, eluting with isohexane/ethyl acetate (19: 1) gave the title compound as a colourless oil (0. 053g, 40%). HPLC (Method B) retention time, 4.65 min. Mass spectrum (ES+) mlz 472/474 (M+H).

Example 8 2- (5-Ethyloxazol-2-yl)-l- (4-trifluoromethylbenzenesulphonyl) piperidine Step 1 To a solution of 1- (4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid (0.471g, 1.39mmol) in tetrahydrofuran (5mL) was added EDC. HC1 (0.237g, 1.53mmol), followed by 1-hydroxybenzotriazole (0. 188g, 1.39mmol), 1-amino-2- butanol (0.121g, 1. 39mmol) and N-ethylmorpholine (0.355mL, 2. 78mmol). The reaction was stirred for 3h at room temperature and then concentrated in vacuo. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate then water followed by brine. The organic layer was dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to afford 1- (4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid (2- hydroxybutyl) amide as a pale yellow oil (0.459g, 81%). HPLC (Method B) retention time 3. 73min. Mass spectrum (ES+) mlz 409 (M+H), (ES-) mlz 407 (M-H).

Step 2 To a solution of 1- (4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid (2-hydroxybutyl) amide (0.165g, 0. 40mmol) in dichloromethane (1. 6mL) at-78°C was added 1, 1, 1-triacetoxy-1, 1-dihydro-1, 2-benziodoxol-3 (1H)-one (Acros, 15% wt in dichloromethane) (1.14mL, 0. 40mmol). The reaction was allowed to warm to room temperature and quenched with water. The reaction mixture was extracted with dichloromethane and the combined organic layers were dried over MgS04. The MgS04 was removed by filtration to afford 1- (4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid (2-oxobutyl) amide as a white solid (O. 1 OOg, 62%).

HPLC (Method A) retention time 3. 85min. Mass spectrum (ES+) mlz 407 (M+H), (ES-) milz 405 (M-H).

Step 3 1- (4-Trifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid (2-

oxobutyl) amide (0.334g, 0. 82mmol) was dissolved in phosphorus oxychloride (2.46mL, 26. 5mmol) and heated to 110°C. The reaction was quenched by addition to an ice/saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with dichloromethane and the organic layer dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to dryness. The residue was purified by flash column chromatography eluting with isohexane/ethyl acetate 4: 1 to afford a colourless oil (0. 118g, 37%). HPLC (Method A) retention time 4. 38min.

Mass spectrum (ES+) m/z 389 (M+H).

Example 9 (25)-1-(2-Chloro-4-trifluoromethylbenzenesulphonyl)-2-(5-met hyloxazol-2- yl) piperidine Step I To a solution of (2S)-l- (carbobenzyloxy)-2-piperidinecarboxylic acid (3. 0g, 12. 0mmol) in tetrahydrofuran (30mL) was added EDC. HC1 (2.053g, 13. 25mmol), 1- hydroxybenzotriazole (1.63g, 12. 0mmol), 1-amino-2-propanol (0. 900g, 12. 0mmol) and N-ethylmorpholine (3.06mL, 24. 0mmol). The reaction was stirred for 16h at room temperature, concentrated in vacuo, diluted with diethyl ether and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to afford a colourless oil. The oil was dissolved in diethyl ether, washed with saturated aqueous potassium carbonate and the organic layer dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to afford (2S)-benzyl-2-(2- hydroxypropylcarbamoyl) piperidine-l-carboxylate as a colourless oil (2.625g, 72%).

HPLC (Method B) retention time 3.23min. Mass spectrum (ES+) m/z 321 (M+H).

Step 2 To a solution of (2S)-benzyl-2-(2-hydroxypropylcarbamoyl) piperidine-1-carboxylate (2.625g, 8. 58mmol) in dichloromethane (26.2mL) was added 1, 1, 1-triacetoxy-1, 1- dihydro-1, 2-benziodoxol-3 (1H)-one (Acros, 15% wt in dichloromethane) (24.26mL, 8. 58mmol) at 0°C. The reaction was allowed to warm to room temperature over 16h.

The reaction was quenched with saturated aqueous sodium bicarbonate solution. The

organic layer was washed with saturated aqueous potassium carbonate and dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to dryness.

The residue was purified by flash column chromatography eluting with ethyl acetate/methanol (95: 5). The residue was dissolved in dichloromethane, washed with 2M aqueous sodium hydroxide and dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to afford (2S)-Benzyl-2-(2-oxopropylcarbamoyl) piperidine-1-carboxylate as a colourless oil (2.088g, 80%). HPLC (Method B) retention time 3. 35min. Mass spectrum (ES+) m/z 319 (M+H).

Step 3 (2S)-Benzyl-2-(2-oxopropylcarbamoyl) piperidine-1-carboxylate (2. 088g, 6. 87mmol) was dissolved in phosphorus oxychloride (20.6mL, 222mmol) and heated to 90°C for lh then stirred at room temperature for a further 16h. The reaction was quenched by addition to an ice/saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with dichloromethane and dried over MgS04. The MgS04 was removed by filtration and the filtrate was evaporated to dryness. Following prolonged standing dichloromethane was added to the residue and the resulting suspension was basified with 2M aqueous sodium hydroxide. The resulting solution was extracted with dichloromethane and dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to afford (2S)-2- (5-Methyloxazol-2- yl) piperidine. (0. 100g, 9%). HPLC (Method B) retention time 2. 65min. Mass spectrum (ES+) mlz 167 (M+H), (ES-) milz 165 (M-H).

Step 4 To a solution of (2S)-2- (5-methyloxazol-2-yl) piperidine (0.071g, 0. 43mmol) in dichloromethane (2mL) was added 2-chloro-4-trifluoromethylbenzenesulphonyl chloride (0. 119g, 0. 43mmol) followed by triethylamine (0.124mL, 0. 86mmol) and the reaction mixture was stirred at room temperature for 15h. The reaction was diluted with dichloromethane and washed with saturated aqueous potassium carbonate followed by brine. The organic layer was dried over MgS04. The MgS04 was removed by filtration and the filtrate was evaporated to afford the title compound as a pale yellow oil (0. 119g, 68%). HPLC (Method B) retention time

4. 22min. Mass spectrum (ES+) m/z 409 (M+H).

Example 10 (2S)-1- (2-Chloro-4-trifluoromethylbenzenesulphonyl)-2- (5-ethyloxazol-2- yl) piperidine Step I Using an analogous method to that described for Example 9, Step 1, starting from 1- amino-2-butanol (1.044g, 12. 0mmol), (2S)-Benzyl-2- (2-hydroxybutylcarbamoyl) piperidine-1-carboxylate was obtained as a yellow oil (3.124g, 82%). HPLC (Method B) retention time 3. 38min. Mass spectrum (ES+) only 335 (M+H).

Step 2 Using an analogous method to that described for Example 9, Step 2, starting from (2S)-benzyl-2-(2-hydroxybutylcarbamoyl) piperidine-1-carboxylate (3.124g, 9. 82mmol) (2S)-Benzyl-2-(2-oxobutylcarbamoyl) piperidine-1-carboxylate was obtained as a pale yellow oil (2.607g, 84%). HPLC (Method B) retention time 3. 51min. Mass spectrum (ES+) tnlz 333 (M+H).

Step 3 Using an analogous method to that described for example 9, step 3, starting from (2S)-benzyl-2-(2-oxobutylcarbamoyl) piperidine-1-carboxylate (2.607g, 8. 25mmol), quenching with water and purifying by flash column chromatography, eluting with ethyl acetate/methanol (95: 5) gave (2S)-Benzyl-2- (5-ethyloxazol-2-yl) piperidine-l- carboxylate (0.324g, 13%). HPLC (Method B) retention time 2. 65min. Mass spectrum (ES+) mlz 167 (M+H), (ES-) mlz 165 (M-H).

Step 4 (2S)-Benzyl-2-(5-ethyloxazol-2-yl)piperidine-1-carboxylate (0.324g, 1.03mmol) was dissolved in ethanol (20mL) with 10% palladium on charcoal (0. 050g), and subjected to hydrogenation (1 atm) over a period of 7h. The catalyst was removed by filtration and washed with water. The aqueous ethanol filtrate was evaporated to afford (2S)-2- (5-Ethyloxazol-2-yl) piperidine as a yellow solid in quantitative yield (0. 190g). HPLC

(Method B) retention time 3.03min. Mass spectrum (ES+) m/z 181 (M+H).

Step 5 Using an analogous method to that described for example 9, step 4, starting from (2S)-2- (5-ethyloxazol-2-yl) piperidine (0.095g, 0. 528mmol), stirring the reaction for 3h and purifying by flash column chromatography, eluting with dichloromethane gave the title compound as a yellow solid (0.075g, 34%). HPLC (Method B) retention time 4. 63min. Mass spectrum (ES+) m/z 423 (M+H).

Example 11 (2S)-2- (5-Ethyloxazol-2-yl)-1- (4-trifluoromethylbenzenesulphonyl) piperidine Using an analogous method to that described for example 9, step 4, starting from (2S)-2- (5-ethyloxazol-2-yl) piperidine (0.095g, 0. 528mmol) and 4- trifluoromethylbenzenesulphonyl chloride (0.129g, 0. 528mmol) and purifying by flash column chromatography, eluting with dichloromethane and then dichloromethane/methanol (95: 5) gave the title compound as a pale yellow oil (0.086g, 42%). HPLC (Method A) retention time 4. 43min. Mass spectrum (ES+) m/z 389 (M+H).

Example 12 Methyl-l- (4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylate To a solution of 1- (4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid (0.102g, 0. 30mmol) in methanol (3mL), was added concentrated hydrochloric acid (2 drops) and the reaction was heated to reflux for 16h. The solvent was removed ira vacuo and the residue filtered through florisil eluting with ethyl acetate. The residue was triturated with isohexane and diethyl ether to afford the title compound as a white solid (0. 051g, 48%). HPLC (Method A) retention time 4. 22min. Mass spectrum (ES+) ynlz 352 (M+H).

Example 13 Isopropyl-l- (4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylate To a solution of 1- (4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid

(0.102g, 0. 30mmol) in isopropanol (3mL) was added concentrated hydrochloric acid (2 drops) and the reaction was stirred at 90°C for 20h. The solvent was removed in vacuo and the residue dissolved in ethyl acetate. The organic layer was washed with 10% aqueous sodium hydroxide followed by water and brine. The organic extract was filtered through florisil and dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to afford the title compound as a pale yellow gum (0.033g, 29%). HPLC (Method A) retention time 4. 43min. Mass spectrum (ES+) m/z 380 (M+H).

Example 14 (2S)-1-[1-(2-Chloro-4-trifluoromethylbenzenesulphonyl) piperidin-2-yl] butan-1-one To a solution of (2S)-1-(2-chloro-4-trifluoromethylbenzenesulphonyl) piperidine-2- carboxylic acid (0. 115g, 0. 31mmol) in dichloromethane (3mL) under nitrogen was added oxalyl chloride (0.033mL, 0. 37mmol) followed by dimethylformamide (2 drops). The reaction was stirred at room temperature for 30min then evaporated to dryness in vacuo. The residue was dissolved in tetrahydrofuran (2mL) and propyl magnesium chloride (2M solution in diethyl ether, 0.16mL, 0. 32mmol) was added.

The reaction was stirred under nitrogen for 16h. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate then 5% aqueous citric acid followed by brine. The organic layer was dried over MgS04.

The MgS04 was removed by filtration and the filtrate evaporated to dryness. The residue was purified by flash column chromatography eluting with isohexane/ethyl acetate (9: 1) to afford the title compound (0. 008g, 7%). HPLC (Method B) retention time 4. 61min. Mass spectrum (ES+) m/z 398 (M+H).

Example 15 Ethyl-1- (4-difluoromethylbenzenesulphonyl) piperidine-2-carboxylate Step I To a stirring suspension of 4-styrenesulphonic acid sodium salt (0.618g, 3. 0mmol) in dichloromethane (6mL) and dimethylformamide (lmL) was added oxalyl chloride (0.4mL, 4. 5mmol) dropwise. The reaction was stirred at room temperature for 2. 5h.

The reaction was diluted with toluene and the solvent removed ira vacuo. The

residue was re-suspended in dichloromethane (15mL). Ethyl-2-piperidinecarboxylate hydrochloride (0.580g, 3. 0mmol) and triethylamine (1.26mL, 9. 0mmol) were added and the reaction stirred at room temperature for 16h. The solvent was removed in vacuo and ethyl acetate added to the residue. The organic layer was washed with 5% aqueous citric acid, water, 10% aqueous sodium bicarbonate solution, water and brine. The organic layer was dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to afford ethyl-1- (4- vinylbenzenesulphonyl) piperidine-2-carboxylate as a pale yellow gum (0. 180g, 19%). HPLC (Method A) retention time 4.17min. Mass spectrum (ES+) m/z 324 (M+H).

Step 2 To a solution of ethyl-1- (4-vinylbenzenesulphonyl) piperidine-2-carboxylate (0.244g, 0. 755mmol) and sodium periodate (0.662g, 3. 095mmol) in carbon tetrachloride (2. 5mL), acetonitrile (2. 5mL) and water (3.6mL) was added ruthenium (III) chloride (0.003g, 0. 015mmol) and the reaction mixture was stirred at room temperature for 16h. The reaction was diluted with water and extracted with ethyl acetate (x2). The combined organic layers were filtered through florisil and evaporated to afford ethyl- 1- (4-formylbenzenesulphonyl) piperidine-2-carboxylate as a pale yellow oil (0.087g, 36%). HPLC (Method A) retention time 3.80min. Mass spectrum (ES+) only 326 (M+H).

Step 3 To a solution of ethyl-1- (4-formylbenzenesulphonyl) piperidine-2-carboxylate (0.035g, O. lmmol) in dichloromethane (2mL) was added dimethylaminosulphur trifluoride (0.2mL, 1. 5mmol). The reaction mixture was stirred at roomtemperature for 64h. The solvent was removed in vacuo and the residue was purified by flash column chromatography eluting with isohexane/ethyl acetate (2: 1). The residue was dissolved in methanol, treated with decolourising charcoal, filtered and evaporated to dryness to afford the title compound as a pale yellow gum (0.028g, 81%). HPLC (Method A) retention time 4. 05min. Mass spectrum (ES+) only 348 (M+H).

Example 16 Ethyl-1- (4-fluoromethylbenzenesulphonyl) piperidine-2-carboxylate Step 1 To a solution of ethyl-1- (4-formylbenzenesulphonyl) piperidine-2-carboxylate (0.047g, 0. 14mmol) in methanol (2mL) at 0°C was added sodium borohydride (0.006g, 0. 15mmol) portion-wise over a period of 30min and the reaction mixture stirred for 1. 5h. The reaction was diluted with water and the methanol removed in vacuo. The aqueous solution was extracted with ethyl acetate. The organic extract was washed with brine and dried over MgS04. The MgS04 was removed by filtration and the filtrate evaporated to afford Ethyl-1- (4- hydroxymethylbenzenesulphonyl) piperidine-2-carboxylate as a colourless gum (0.038g, 83%). HPLC (Method A) retention time 3.44min. Mass spectrum (ES+) m/z 328 (M+H).

Step 2 Using a method analogous to that described for Example 15, step 3, starting from ethyl-1- (4-hydroxymethylbenzenesulphonyl) piperidine-2-carboxylate (0.038g, 0. 1 lmmol) gave the title compound as a colourless gum (0.025g, 69%). HPLC (Method A) retention time 3.95min. Mass spectrum (ES+) nalz 330 (M+H).

The following compounds were prepared by utilising the procedures illustrated in the preparation of Examples 1-16 above: rfne Example LC-MS ES+) m/z HPLC number Compound name retention +H) System time (min) ttme (mm)''" (S)-1- (2-Chloro-4- 55 trifluoromethyl-benzenesulfonyl)-4. 67 439 B 2- (5-ethyl-thiazol-2-yl)-piperidine (S)-1- (4-Trifluoromethyl- 56 benzenesulfonyl)-piperidine-2-4. 25 352 B carboxylic acid methyl ester (S)-1- (4-Difluoromethyl- 57 benzenesulfonyl)-2- (5-ethyl-2. 00 387 A thiazol-2-yl)-piperidine (S)-1- (2-Chloro-4- 58 trifluoromethyl-benzenesulfonyl)-4. 66 425 B 2- (5-methyl-thiazol-2-yl)- piperidine (S)-2- (5-Methyl-oxazol-2-yl)-l- 59 (4-trifluoromethyl-4. 18 375 B benzenesulfonyl)-piperidine (R)-1- (4-Trifluoromethyl- 60 benzenesulfonyl)-piperidine-2-4. 31 393 B carboxylic acid tert-butylamide (R)-1- (4-Trifluoromethyl- 61 benzenesulfonyl)-piperidine-2-4. 64 394 B carboxylic acid tert-butyl ester (R)-2- (5-Methyl-oxazol-2-yl)-l- 62 (4-trifluoromethyl-4. 18 375 B benzenesulfonyl)-piperidine (S)-1- (4-Difluoromethyl- 63 benzenesulfonyl)-2- (5-methyl- 3. 93 357 B oxazol-2-yl)-piperidine (S)-2- (5-Methyl-thiazol-2-yl)-1- 64 (4-trifluoromethyl-4. 39 391 B benzenesulfonyl)-piperidine (S)-1- (4-Difluoromethyl- 65 benzenesulfonyl)-2- (5-methyl- 4. 14 373 B thiazol-2-yl)-pip eridine (S)-2- (5-tert-Butyl-oxazol-2-yl)- 66 1- (4-trifluoromethyl- 4. 58 417 A benzenesulfonyl)-piperidine (S)-2- (5-tert-Butyl-oxazol-2-yl)- 67 1-(2-chloro-4-trifluoromethyl-4. 78 451 B benzenesulfonyl)-piperidine (S)-2- (5-Methyl- [1, 3, 4] thiadiazol- 68 2-yl)-l- (4-trifluoromethyl- 3. 97 392 B benzenesulfonyl)-piperidine (S)-1-(2-Chloro-4-trifluoromethyl 69-benzenesulfonyl)-2- (5-methyl- 4. 14 426 A [1, 3, 4] thiadiazol-2-yl)-piperidine 1- (4-Trifluoromethyl-benzene 70 sulfonyl)-piperidine-2-carboxylic 4. 22 447 A acid (2-thiophen-2-yl-ethyl)- amide 1- (4-Trifluoromethyl- 71 benzenesulfonyl)-piperidine-2-4. 16 431 A carboxylic acid (5-methyl-furan- 2-ylmethyl)-amide Piperidin-1-yl- [1- (4-trifluoro 72 methyl-benzenesulfonyl)-4. 21 405 A piperidin-2-yl]-methanone 1- (4-Trifluoromethyl- 73 benzenesulfonyl)-piperidine-2-4. 12 393 A carboxylic acid sec-butylamide 1- (4-Trifluoromethyl- 74 benzenesulfonyl)-piperidine-2-4. 18 405 A carboxylic acid cyclopentylamide 1- (4-Trifluoromethyl- 75 benzenesulfonyl)-piperidine-2-3. 98 379 A carboxylic acid isopropylamide 1- (4-Trifluoromethyl- 76 benzenesulfonyl)-piperidine-2-3. 83 377 A carboxylic acid cyclopropylamide 1- (4-Trifluoromethyl-benzene 77 sulfonyl)-piperidine-2-carboxylic 4.28 407 B acid (3-methyl-butyl)-amide 1- (4-Trifluoromethyl- 78 benzenesulfonyl)-piperidine-2-4. 29 365 A carboxylic acid ethylamide 1- (4-Trifluoromethyl- 79 benzenesulfonyl)-piperidine-2-3. 99 379 A carboxylic acid propylamide 1- (4-Trifluoromethyl- 80 benzenesulfonyl)-piperidine-2-4. 16 393 A carboxylic acid butylamide 1- (4-Trifluoromethyl-benzene 81 sulfonyl)-piperidine-2-carboxylic 4.4 421 A acid (3,3-dimethyl-butyl)-amide 1- (4-Trifluoromethyl- 82 benzenesulfonyl)-piperidine-2-4. 14 393 A carboxylic acid isobutyl-amide 1- (4-Trifluoromethyl-benzene 83 sulfonyl)-piperidine-2-carboxylic 4.26 407 A acid (1, 2-dimethyl-propyl)-amide 1- (4-Trifluoromethyl-benzene 84 sulfonyl)-piperidine-2-carboxylic 4.24 407 A acid (l-ethyl-propyl)-amide (1, 3-Dihydro-isoindol-2-yl)- [1- (4- 85 trifluoromethyl-benzenesulfonyl)-4. 31 439 A piperidin-2-yl]-methanone (S)-1-(2-Chloro-4-trifluoromethyl 86-benzenesulfonyl)-piperidine-2-4. 5 428 A carboxylic acid tert-butylamide (S)-1- (4-Difluoromethyl- 87 benzenesulfonyl)-piperidine-2-4. 02 375 A carboxylic acid tert-butylamide (S)-2- (5-tert-Butyl-oxazol-2-yl)- 88 1- (4-difluoromethyl- 4. 34 399 B benzenesulfonyl)-piperidine (S)-1- (2-Chloro-4-difluoromethyl- 89 benzenesulfonyl)-piperidine-2-4. 21 368 B carboxylic acid methyl ester (S)-2- (5-tert-Butyl-thiazol-2-yl)- 90 1- (4-trifluoromethyl- 4. 92 433 B benzenesulfonyl)-piperidine (S)-2- (5-tert-Butyl-thiazol-2-yl)- 91 1- (2-chloro-4-trifluoromethyl- 5. 09 467 B benzenesulfonyl)-piperidine (S)-2- (5-tert-Butyl-thiazol-2-yl)- 92 1- (4-difluoromethyl- 4. 46 415 A benzenesulfonyl)-piperidine (S)-l- (2-Chloro-4-difluoromethyl- 93 benzenesulfonyl)-piperidine-2-4. 36 382 B carboxylic acid ethyl ester (S)-1- (2-Chloro-4-difluoromethyl- 94 benzenesulfonyl)-piperidine-2-4. 27 409 B carboxylic acid tert-butylamide (S)-1- (4-Trifluoromethyl- 95 benzenesulfonyl)-piperidine-2- carboxylic acid (2, 2-dimethyl- propyl)-amide (S)-1- (4-Trifluoromethyl- 96 benzenesulfonyl)-piperidine-2-4. 08 379 A carboxylic acid isopropylamide (S)-1- (4-Difluoromethyl- 97 benzenesulfonyl)-piperidine-2-3. 85 361 A carboxylic acid isopropylamide (S)-1- (4-Difluoromethyl- 98 benzenesulfonyl)-piperidine-2-4. 16 389 A carboxylic acid (2, 2-dimethyl- propyl)-amide (S)-2- (5-tert-Butyl- 99 [1, 3, 4] oxadlazol-2-yl)-1-(2-4. 52 452 A chloro-4-trifluoromethyl- benzenesulfonyl)-piperidine (S)-l- (2-Chloro-4-difluoromethyl- 100 benzenesulfonyl)-2- (5-methyl- 3. 98 408 B [1, 3, 4] thiadiazol-2-yl)-piperidine (R)-1- (4-Difluoromethyl- 101 benzenesulfonyl)-piperidine-2-3. 78 361 B carboxylic acid isopropylamide (R)-1- (4-Difluoromethyl- 102 benzenesulfonyl)-piperidine-2-4. 04 375 B carboxylic acid tert-butylamide (R)-1- (4-Difluoromethyl- 103 benzenesulfonyl)-piperidine-2-4. 10 389 B carboxylic acid (2, 2-dimethyl- propyl)-amide (R)-l- (2-Chloro-4- 104 trifluoromethyl-benzenesulfonyl)-4. 18 413 B piperidine-2-carboxylic acid isopropylamide (R)-1-(2-Chloro-4- 105 fluoromethyl-benzenesulfonyl)-q., 42 427 B piperidine-2-carboxylic acid tert- butylamide (R)-l- (2-Chloro-4- 106 trifluoromethyl-benzenesulfonyl)-4 48 441 B piperidine-2-carboxylic acid (2, 2- dimethyl-propyl)-amide (R)-1- (4-Trifluoromethyl- 107 benzenesulfonyl)-piperidine-2-4. 01 379 B carboxylic acid isopropylamide (R)-1- (4-Trifluoromethyl- 108 benzenesulfonyl)-piperidine-2-4. 32 407 B carboxylic acid (2, 2-dimethyl- propyl)-amide (S)-2- (5-tert-Butyl- [1, 3, 4] 109 oxadiazol-2-yl)-1- (4-trifluoro 4. 24 418 A methyl-benzenesulfonyl)- piperidine (S)-1- (2-Chloro-4- 110 trifluoromethyl-benzenesulfonyl)-4. 41 464 A 110 .. r, i 4. 41 464 A 2- (5-trifluoromethyl- [1, 3, 4] oxadiazol-2-yl)-piperidine (S)-1- (2-Chloro-4- 111 trifluoromethyl-benzenesulfonyl)-4. 58 442 B piperidine-2-carboxylic acid (2, 2- dimethyl-propyl)-amide (S)-1- (2-Chloro-4- 112 trifluoromethyl-benzenesulfonyl)-4 26 414 B piperidine-2-carboxylic acid isopropylamide (S)- [l- (2-Chloro-4- 113 trifluoromethyl-benzenesulfonyl)-q,, 4 386 B piperidin-2-ylmethyl]-dimethyl- amine (S)- [1- (2-Chloro-4- 114 trifluoromethyl-benzenesulfonyl)-4 4 398 B piperidin-2-ylmethyl]- cyclopropyl-amine (S)-tert-Butyl- [1- (2-chloro-4- 115 trifluoromethyl-benzenesulfonyl)-4. 51 414 B piperidin-2-ylmethyl]-amine (S)-2- (5-tert-Butyl- 116 [1, 3, 4] thiadiazol-2-yl)-1-(2-4 49 468 B chloro-4-trifluoromethyl- benzenesulfonyl)-piperidine (S)-2- (5-tert-Butyl- 117 [1, 3, 4] thiadiazol-2-yl)-1-(4-4. 30 434 B trifluoromethyl-benzenesulfonyl)- piperidine (S)-2- (5-tert-Butyl- 118 [1, 3, 4] thiadiazol-2-yl)-1-(4-4. 11 416 B difluoromethyl-benzenesulfonyl)- piperidine 1- (2-Chloro-4-trifluoromethyl- 119 benzenesulfonyl)-1, 2, 3, 4, 5, 6- 4. 20 405 B hexahydro- [2, 3'] bipyridinyl s 1- (4-Trifluoromethyl- 120 benzenesulfonyl)-1, 2, 3, 4, 5, 6- 4. 05 371 B hexahydro- [2, 3'] bipyridinyl (S)-tert-Butyl- [l- (4- 121 difluoromethyl-benzenesulfonyl)-4. 11 361 B piperidin-2-ylmethyl]-amine (S)- [1- (4-Difluoromethyl- 122 benzenesulfonyl)-piperidin-2-3. 92 333 B ylmethyl]-dimethyl-amine (S)-2- [1- (4-Difluoromethyl- 123 benzenesulfonyl)-piperidin-2-yl]-4. 33 393 B benzooxazole (R)-2- (5-tert-Butyl- 124 [1, 3, 4] oxadiazol-2-yl)-l- (2- 6. 87 452 B lz4 <i, t.,.-fi 1 D. o/ 4jz Jo chloro-4-trifluoromethyl- benzenesulfonyl)-piperidine (R)-3- (5-tert-Butyl- 125 [1, 3, 4] oxadiazol-2-yl)-1-(2-4 39 452 B chloro-4-trifluoromethyl- benzenesulfonyl)-piperidine (S)-2- (5-tert-Butyl-1 H-imidazol- 126 2-yl)-l- (2-chloro-4- 4. 56 450 B trifluoromethyl-benzenesulfonyl)- piperidine (R)-1-(2-Chloro-4- 127 trifluoromethyl-benzenesulfonyl)-3 67 42 B 2- (5-methyl- [1, 3, 4] thiadiazol-2- yl)-piperidine (S)-2- (5-tert-Butyl-lH-imidazol- 128 2-yl)-l- (4-trifluoromethyl- 3. 8 416 B benzenesulfonyl)-piperidine (S)-1- (2-Chloro-4- 12 trifluoromethyl-benzenesulfonyl)- i'7 -ji rii 'i J. OJ-riU A 2- (5-methyl- [ 1, 3, 4] oxadiazol-2- yl)-piperidine 1- (2-Chloro-4-trifluoromethyl- 130 benzenesulfonyl)-2- (5- 4. 19 456 B methoxymethyl- [1, 3, 4] thiadiazol- 2-yl)-piperidine (S)- {5- [l- (2-Chloro-4- 131 trifluoromethyl-benzenesulfonyl)-3 77 iji..,. nrii--1 J.//442 Jo piperidin-2-yl]- [1, 3, 4] thiadiazol- 2-yl}-methanol (2S, 4R)-l- (2-Chloro-4- 132 trifluoromethyl-benzenesulfonyl)-3. 49 442 B 2- (5-methyl- [1, 3, 4] thiadiazol-2- yl)-piperidin-4-ol (S)-1- (2-Chloro-4- 133 trifluorometliyl-benzenesulfonyl)-4. 02 440 B 2- (5-methoxymethyl- [1, 3, 4] oxadiazol-2-yl)-piperidine (R)-l- (2-Chloro-4- 134 trifluoromethyl-benzenesulfonyl)- 3- (5-methyl- [l, 3, 4] thiadiazol-2- yl)-piperidine (S)-1- (2-Chloro-4- 135 trifluoromethyl-benzenesulfonyl)-4 18 ijj....,--, i i 1 4. 1o 42 o 4, 4-difluoro-2- (5-methoxymethyl- [1, 3, 4] thiadiazol-2-yl)-piperidine 4- (5-tert-Butyl- [1, 3, 4] oxadiazol- 2-yl)-1-(2-chloro-4- trifluoromethyl-benzenesulfonyl)- piperidine 2- [l- (2-Chloro-4-trifluoromethyl- 137 benzenesulfonyl)-piperidin-3-yl]-4. 57 445 B benzooxazole 4- (5-tert-Butyl- [ 1, 3, 4] oxadiazol- 138 2-yl)-l- (4-trifluoromethyl- 4. 04 418 B benzenesulfonyl)-piperidine (S)-2- (5-tert-Butyl- [l, 2, 4] oxadiazol-3-yl)-l- (2- chloro-4-trifluoromethyl- benzenesulfonyl)-piperidine (S)-1- (2-Chloro-4- 140 trifluoromethyl-benzenesulfonyl)- 2- (5-methyl- [1, 2, 4] oxadiazol-3- yl)-piperidine

BIOLOGICAL SCREENING N-type calcium channel inhibition in IMR32 cells The human neuroblastoma cell line IMR32 has been used by a number of groups to investigate calcium ion channels either by electrophysiological or fluorescent techniques in low throughput assays (Carbone, E., et al. (1990) Pfluges Arch 416: 170-179; Rafferty, M. , et al. (2000) Patent WO 00/06559 ; Seko, T. , et al. , (2001) Bioorg Med Chem Lett 11: 2067-2070).

It has been shown that undifferentiated IMR32 cells constitutively express L-type calcium channels, whilst differentiated IMR32 cells express both N-and L-type channels. Therefore, undifferentiated IMR32 cells can be used to assay the L-type calcium channel and differentiated cells assayed in the presence of 5 uM nitrendipine can be used to study the N-type channels.

The Molecular Devices Corp FLEXstation was utilised to develop a medium throughput assay with undifferentiated and differentiated IMR32 cells labelled with Fluo-4. Opening of voltage-activated calcium channels was stimulated by depolarisation of cells with KC1, which was added by the FLEXstation's fluidics system. The resulting influx of calcium into the cells was recorded by an increase in fluorescence. The assays were validated with known ion channel blockers.

IMR32 cells were grown in EMEM supplemented with 10% foetal bovine serum, 2 mM luta. mine, 1 % NEAA, 100 U/ml penicillin and 100 Rg/ml streptomycin. To differentiate the IMR32 cells, 1 mM dibutyryl cAMP and 2. 5, uM bromodeoxyuridine were added to the cell culture media and cells maintained for 7-9 days.

Cells were detached from tissue culture surfaces using an enzyme free cell dissociation buffer (Invitrogen) after washing with a Ca2+/Mg2+ free Hanks buffered saline solution (HBSS). The cells were then resuspended in assay buffer (HBSS containing Ca2+/Mg2+ and supplemented with 20 mM HEPES, pH 7.4) to give a total volume of 40 ml. 2 uM Fluo-4 and 50 ßM probenecid were added and then the cells

were incubated at 25 °C for 30 min. Following centrifugation in a Heraeus Megafuge 1.0 (rotor 2704) for lmin at 1000 rpm, the cell pellet was resuspended in 40 ml assay buffer supplemented with 50 RM probenecid and incubated at 25 °C for a further 30 min. The cells were centrifuged as before and again resuspended in assay buffer supplemented with probenecid. 200,000 cells were aliquoted into each well of a 96- well plate containing 0. 001-100 pM compound to be tested (for the N-type assay 5 FM nitrendipine was also added to each well), in triplicate. The final volume of compound and cells in assay buffer was 200 RI. The plate containing cells was centrifuged at 300 rpm for 1 min with no brake in a Heraeus Labofuge 400E (rotor 8177).

The plate was then assayed using the FLEXstation (Molecular Devices Corp). The excitation and emission wavelengths were 494 and 525 nm, respectively. The calcium response was stimulated by the addition of 50 1250 mM KC1 (50 mM final concentration) by the FLEXstation fluidics system. SOFTmax Pro (Molecular Devices Corp) was used to calculate the change in fluorescence caused by calcium influx for each well and hence the ICSO for each compound. The results are shown in the following Table. Example Compound Name CAVN- Number IMR-M 1 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-3- carboxylic acid ethyl ester 2 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- carboxylic acid ethyl ester 3 2-Methyl-1-(4-trifluoromethyl-benzenesulfonyl)-piperidine 3.51 4 1- (2, 4, 6-Trimethyl-benzenesulfonyl)-piperidine-2-carboxylic 2. 25 acid ethyl ester 5 1-(2, 4, 6-Triisopropyl-benzenesulfonyl)-piperidine-2- carboxylic acid ethyl ester 6 1- (4-Bromo-2-methyl-benzenesulfonyl)-piperidine-2- carboxylic acid ethyl ester 7 1- (4-Bromo-benzenesulfonyl)-piperidine-2-carboxylic acid 0 90 ethyl ester 1-(3,5-Bis-trifluoromethyl-benzenesulfonyl)-piperidine-2- 6.61 carboxylic acid ethyl ester 9 1-(4-Bromo-2-trifluoromethyl-benzenesulfonyl)-piperidine- 1.15 2-carboxylic acid ethyl ester 10 1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidine-0 19 2-carboxylic acid ethyl ester 11 2-Ethyl-1- (4-trifluoromethyl-benzenesulfonyl)-piperidine 3.27 12 (2R)-l- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 2. 00 carboxylicacid ethyl ester 13 (2S)-1-(4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-0 27 carboxylic acid ethyl ester 14 2-(4-Cyano-benzenesulfonyl)-cyclohexanecarboxylic acid 3 1 ethyl ester 15 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 0. 23 carboxylic acid tert-butyl ester 16 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 1. 55 carboxylic acid methyl ester 17 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 13. 31 carboxylic acid ethyl-methyl-amide 18 2-Isoxazol-3-yl-1-(4-trifluoromethyl-benzenesulfonyl)-2. 12 piperidine 19 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 0. 16 carboxylic acid isopropyl ester 20 1- (4-Vinyl-benzenesulfonyl)-piperidine-2-carboxylic acid 2. 93 ethyl ester 21 1- (4-Difluoromethyl-benzenesulfonyl)-piperidine-2- 0. 66 carboxylic acid ethyl ester 22 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 11. 00 carboxylic acid amide 23 1-(4-Fluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic 1 50 acid ethyl ester 24 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 1. 67 carboxylic acid tert-butylamide 25 1- (2-Bromo-4-trifluoromethyl-benzenesulfonyl)-piperidine- 2-carboxylic acid ethyl ester 26 1-(4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-4 24 carbonitrile 27 1-(2,6-Dichloro-4-trifluoromethyl-benzenesulfonyl)- 1.08 piperidine-2-carboxylic acid ethyl ester 28 1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidine- 0.48 3-carboxylic acid ethyl ester 29 2-(5-Methyl-[1, 2,4] oxadiazol-3-yl)-l- (4-trifluoromethyl- benzenesulfonyl)-piperidine 30 1-(2-Methyl-4-trifluoromethyl-benzenesulfonyl)-piperidine-0. 33 2-carboxylic acid ethyl ester 31 (2S)-1-(4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 0.32 carboxylic acid tert-butyl ester 32 (3R)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-3- carboxylic acid ethyl ester 33 1- 41 carboxylic acid tert-butyl ester 34 2- (5-Ethyl-oxazol-2-yl)-1- (4-trifluoromethyl- benzenesulfonyl)-pipendine 35 (2S)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- carboxylic acid tert-butylamide 36 (2S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)- 0.25 piperidine-2-carboxylic acid ethyl ester 37 (2S)-1-(4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 0.44 carboxylic acid benzyl ester 38 (2S)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- carboxylic acid ethylamide 39 (2S)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- carboxylic acid benzylamide 40 (2S)-1-(4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 6.89 carboxylic acid cyclopropylamide 41 (3R)-1-(4-Trifluoromethyl-benzenesulfonyl)-piperidine-3- carboxylic acid tert-butyl ester 42 (2S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)- 0.37 piperidine-2-carboxylic acid tert-butyl ester 43 (3R)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-0. 61 piperidine-3-carboxylic acid ethyl ester 44 (3R)-1-(2-Bromo-4-trifluoromethyl-benzenesulfonyl)- 0.38 piperidine-3-carboxylic acid ethyl ester 45 (3R)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)- 0.51 piperidine-3-carboxylic acid tert-butyl ester 46 (3R)-l- (2-Bromo-4-trifluoromethyl-benzenesulfonyl)- piperidine-3-carboxylic acid tert-butyl ester 47 2- (5-Methyl-oxazol-2-yl)-l- (4-trifluoromethyl- 0. 57 benzenesulfonyl)-piperidine 48 (2S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2-(5-0 08 methyl-oxazol-2-yl)-piperidine 49 (2S)-1- (2-Bromo-4-trifluoromethyl-benzenesulfonyl)- piperidine-2-carboxylic acid ethyl ester 50 (2S)-1-(2-Bromo-4-trifluoromethyl-benzenesulfonyl)-0 35 piperidine-2-carboxylic acid tert-butyl ester 51 (2S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2-(5-O. 07 ethyl-oxazol-2-yl)-piperidine 52 (2S)-2- (5-Ethyl-oxazol-2-yl)-1- (4-trifluoromethyl- benzenesulfonyl)-piperidine. 1 53 (2S)-1- [1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)- piperidin-2-yl]-butan-1-one 54 1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-piperidine-7. 46 2-carboxylic acid dimethylamide 55 (S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2-(5-0 98 ethyl-thiazol-2-yl)-piperidine 56 (S)-1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 3. 31 carboxylic acid methyl ester (S)-1- (4-Difluoromethyl-benzenesulfonyl)-2- (5-ethyl- 1. 28 thiazol-2-yl)-piperidine 58 (S)-l- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2- (5- 0. 69 methyl-thiazol-2-yl)-piperidine 59 (S)-2-(5-Methyl-oxazol-2-yl)-1-(4-trifluoromethyl-0 benzenesulfonyl)-piperidine 60 (R)-l- (4-Triiluoromethyl-benzenesulfbnyl)-piperidme-2- carboxylic acid tert-butylamide (R)-l- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- carboxylic acid tert-butyl ester 62 (R)-2- (5-Methyl-oxazol-2-yl)-l- (4-trifluorometliyl- 1. 99 benzenesulfonyl)-piperidine 63 (S)-l- (4-Difluoromethyl-benzenesulfonyl)-2- (5-methyl- 1. 45 oxazol-2-yl)-piperidine 64 (S)-2- (5-Methyl-thiazol-2-yl)-1- (4-trifluoromethyl- 1. 56 benzenesulfonyl)-piperidine 65 (S)-1-(4-Difluoromethyl-benzenesulfonyl)-2-(5-methyl-1 71 thiazol-2-yl)-piperidine 66 (S)-2-(5-tert-Butyl-oxazol-2-yl)-1-(4-trifluoromethyl-0 29 benzenesulfonyl)-piperidine 67 (S)-2-(5-tert-Butyl-oxazol-2-yl)-1-(2-chloro-4- trifluoromethyl-benzenesulfonyl)-piperidine 68 (S)-2- (5-Methyl- [1, 3, 4] tbiadiazol-2-yl)-l- (4-trifluoromethyl- 5. 64 benzenesulfonyl)-piperidine 69 (S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2-(5-1 33 methyl- [1, 3, 4] thiadiazol-2-yl)-piperidine 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 2, 4 carboxylic acid (2-thiophen-2-yl-ethyl)-amide 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-2, 1 carboxylic acid (5-methyl-furan-2-ylmethyl)-amide 72 Piperidin-1-yl- [l- (4-trifluoromethyl-benzenesulfonyl)- g, 12 iperidin-2-yl]-methanone 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 3. 29 carboxylic acid sec-butylamide 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 1. 17 carboxylic acid cyclopentylamide 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 3. 12 carboxylic acid isopropylamide 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 9. 60 carboxylic acid cyclopropylamide 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- , 19 carboxylic acid (3-methyl-butyl)-amide 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- carboxylic acid ethylamide 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 6. 38 carboxylic acid propylamide 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 3. 64 carboxylic acid butylamide 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- carboxylic acid (3, 3-dimethyl-butyl)-amide 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- carboxylic acid isobutyl-amide 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- carboxylic acid (1, 2-dimethyl-propyl)-amide 84 1- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 3. 29 carboxylic acid (1-ethyl-propyl)-amide gs (1, 3-Dihydro-isoindol-2-yl)- [l- (4-trifluoromethyl- 3. 59 benzenesulfonyl)-piperidin-2-yl]-methanone 86 (S)-l- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)- 0. 49 piperidine-2-carboxylic acid tert-butylamide 87 (S)-1-(4-Difluoromethyi-benzenesulfonyl)-piperidine-2-3 96 carboxylic acid tert-butylamide gag (S)-2- (5-tert-Butyl-oxazol-2-yl)-1- (4-difluoromethyl- 0. 30 benzenesulfonyl)-piperidine 89 (S)-1-(2-Chloro-4-difluoromethyl-benzenesulfonyl)- piperidine-2-carboxylic acid methyl ester (S)-2- (5-tert-Butyl-thiazol-2-yl)-1- (4-trifluoromethyl- 2. 40 benzenesulfonyl)-piperidine 91 (S)-2- (5-tert-Butyl-thiazol-2-yl)-l- (2-chloro-4- trifluoromethyl-benzenesulfonyl)-piperidine (S)-2- (5-tert-Butyl-thiazol-2-yl)-1- (4-difluoromethyl- benzenesulfonyl)-piperidine 93 (S)-1-(2-Chloro-4-difluoromethyl-benzenesulfonyl)-0. 86 pipelidine-2-carboxylic acid ethyl ester (S)-l- (2-Chloro-4-difluoromethyl-benzenesulfonyl)- piperidine-2-carboxylic acid tert-butylamide 95 (S)-l- (4-Trifluoromethyl-benzenesulfonyl)-piperidine-2- 3. 15 carboxylic acid (2, 2-dimethyl-propyl)-amide 96 (S)-1-(4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-5 32 carboxylic acid isopropylamide (S)-1- (4-Difluoromethyl-benzenesulfonyl)-piperidine-2- 11. 81 carboxylic acid isopropylamide 98 (S)-l- (4-Difluoromethyl-benzenesulfonyl)-piperidine-2- 3. 65 carboxylic acid (2, 2-dimethyl-propyl)-amide (S)-2- (5-tert-Butyl- [1, 3, 4] oxadiazol-2-yl)-l- (2-chloro-4- trifluoromethyl-benzenesulfonyl)-piperidine 100 (S)-1-(2-Chloro-4-difluoromethyl-benzenesulfonyl)-2-(5-3 03 methyl- [1, 3, 4] thiadiazol-2-yl)-piperidine 101 (R)-1-(4-Difluoromethyl-benzenesulfonyl)-piperidine-2-22 40 carboxylic acid isopropylamide 102 (R)-1-(4-Difluoromethyl-benzenesulfonyl)-piperidine-2-5. 70 carboxylic acid tert-butylainide 103 (R)-1-(4-Difluoromethyl-benzenesulfonyl)-piperidine-2-3 69 carboxylic acid (2, 2-dimethyl-propyl)-amide 104 (R)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-1. 72 piperidine-2-carboxylic acid isopropylamide 105 l (R)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-1. 34 piperidine-2-carboxylic acid tert-butylamide 106 (R)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-1. 05 piperidine-2-carboxylic acid (2, 2-dimethyl-propyl)-amide 107 (R)-1-(4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-9 38 carboxylic acid isopropylamide 108 (R)-1-(4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-3 29 carboxylic acid (2, 2-dimethyl-propyl)-amide 109 (S)-2- (5-tert-Butyl- [1, 3, 4] oxadiazol-2-yl)-1-(4-0. 56 trifluoromethyl-benzenesulfonyl)-piperidine (S)-l- (2-Chloro-4-trifluoromethyl-benzenesulibnyl)-2- (5- trifluoromethyl- [1, 3, 4] oxadiazol-2-yl)-piperidine (S)-l- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)- piperidine-2-carboxylic acid (2, 2-dimethyl-propyl)-amide 0. 96 112 (S)-1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)- piperidine-2-carboxylic acid isopropylamide 113 (S)-[1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-8 66 piperidin-2-ylmethyl]-dimethyl-amine 114 (S)-[1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-1. 45 piperidin-2-ylmethyl]-cyclopropyl-amine 115 (S)-tert-Butyl-[l-(2-chloro-4-trifluoromethyl-9 22 benzenesulfonyl)-piperidin-2-ylmethyl]-amine 116 (S)-2- (5-tert-Butyl- [1, 3, 4] thiadiazol-2-yl)-1-(2-chloro-4- trifluoromethyl-benzenesulfonyl)-piperidine (S)-2- (5-tert-Butyl- [ 1, 3, 4] thiadiazol-2-yl)-l- (4- 2. 34 tnfluoromethyl-benzenesulfonyl)-iperidine 118 (S)-2- (5-tert-Butyl- [1, 3, 4] thiadiazol-2-yl)-1-(4- difluoromethyl-benzenesulfonyl)-piperidine 119 (2-Chloro-4-triiluoromethyl-benzenesulfbnyl)-l, 2, 3, 4, 5, 6- 0. 86 hexahydro- [2, 3'] bipyridinyl 120 1- (4-Trifluoromethyl-benzenesulfonyl)-1, 2, 3, 4, 5, 6- 2. 11 hexahydro- [2, 3'] bipyridinyl 121 (S)-tert-Butyl- [l- (4-difluoromethyl-benzenesulfonyl)- 27, 54 piperidin-2-ylmethyl]-amine (S)- [1- (4-Difluoromethyl-benzenesulfonyl)-piperidin-2- 30. 00 ylmethyl]-dimethyl-amine 123 (S)-2- [l- (4-Difluoromethyl-benzenesulfonyl)-piperidin-2- 2. 61 yl]-benzooxazole 124 (R)-2- (5-tert-Butyl- [1, 3, 4] oxadiazol-2-yl)-1-(2-chloro-4- trifluoromethyl-benzenesulfonyl)-piperidine 125 (5-tert-Butyl- [l, 3, 4] oxadiazol-2-yl)-l- (2-chloro-4- trifluoromethyl-benzenesulfonyl)-piperidine 126 (S)-2-(5-tert-Butyl-lH-imidazol-2-yl)-1-(2-chloro-4-1 09 trifluoromethyl-benzenesulfonyl)-piperidine 127 (R)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2-(5-2. 02 methyl- [1, 3, 4] thiadiazol-2-yl)-piperidine 128 (S)-2- (5-tert-Butyl-lH-imidazol-2-yl)-1- (4-trifluoromethyl- 1, 10 benzenesulfonyl)-piperidine 129 (S)-1-(2-Chloro-4-trifluoromethyl-benzerlesutfonyl)-2-(5-0. 44 methyl- [1, 3, 4] oxadiazol-2-yl)-piperidine 1- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2- (5- methoxymethyl- [1, 3, 4] thiadiazol-2-yl)-piperidine 131 (S)- [l- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)- 1. 55 piperidin-2-yl]- [1, 3, 4] thiadiazol-2-yl}-methanol 133 (S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2-(5-0. 42 methoxymethyl- [1, 3, 4] oxadiazol-2-yl)-piperidine 134 (R)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonylj-3-(5-1 73 methyl- [1, 3, 4] thiadiazol-2-yl)-piperidine (S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-4, 4- 135 difluoro-2- (5-methoxymethyl- [1, 3, 4] thiadiazol-2-yl)- 1. 39 _ piperidine 4- (5-tert-Butyl- [ 1, 3, 4] oxadiazol-2-yl)-l- (2-chloro-4- tnfluoromethyl-benzenesulfonyl)-piperidine. 2 137 2-l- (2-Chloro-4-trifluoromethyl-benzenesulfonyl)- 1. 12 piperidin-3-yl]-benzooxazole 138 4- (5-tert-Butyl- [1, 3, 4] oxadiazol-2-yl)-1-(4-trifluoromethyl-2. 30 benzenesulfonyl)-piperidine 139 (S)-2- (5-tert-Butyl- [1, 2, 4] oxadiazol-3-yl)-1-(2-chloro-4-1. 69 trifluoromethyl-benzenesulfonyl)-piperidine 140 (S)-1-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-2-(5-0. 34 methyl- [1, 2, 4] oxadiazol-3-yl)-piperidine