The present invention provides compounds of the formula (I):

wherein ring A is a phenyl or pyridyl ring; X represents a linker selected from the group consisting of :

RI represents hydroxy, Ci-6alkyl, fluoroCl-6alkyl, C2-6alkenyl, <BR> <BR> <BR> <BR> C3-7cycloalkyl, C3-7cycloalkylCi-4alkyl, Cl-6alkoxy, fluoroCi-6alkoxy,<BR> <BR> <BR> <BR> <BR> <BR> <BR> Ci-6alkoxyCi-4alkyl, Ci-6alkoxyCi-4alkoxy, fluoroCi-6alkoxyCi-4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, phenoxy, cyano, halogen, NRaRb, SRa, SORa, SO2Ra, OS02Ra, NRaCORc, CORa, CO2Ra or CONRaRb where Ra and Rb each independently represent hydrogen, C1-4alkyl, C3-5cycloa lkyl, fluoroCi-4alkyl or CH2CO2Ci-4alkyl, and Rt represents Ci-6alkyl, Ci-6alkoxy, fluoroCi-6alkyl or phenyl; R2 represents hydrogen, halogen, Cl 6alkyl or C1 6alkoxy ; or when R2 is adjacent to R1, they may be joined together such that there is formed a 5-or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen and sulphur, which ring is optionally substituted by a group selected from Ci-4alkyl, CFs, =0 or =S; R3 represents hydrogen, halogen, C1-yalkyl, fluoroC1-6alkyl, C1-6alkoxy, fluroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, cyano, SRa, SORa, SO2Ra, NRaRb, NRaCOR14, CORa, CO2R2, CONRaRb or C1-4alkyl substituted by cyano, CO2Ra or CONRaRb where Ra and Rb are as previously defined ; or R3 represents a 5-or 6-membered aromatic heterocyclic group containing 1,2,3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur,

which group is optionally substituted by one or two groups selected from C1-6alkyl, C1-6alkyoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, trifluoromethyl, OCF3, NO2, CN, SRa, SORa, S02Ra, CORa, CO2Ra, phenyl, -(CH2)rNRaR5, -(CH2)rNRaCORb, -(CH2)rCONRaRb, or CH2C (O) Ra, where Ra and Rb are as previously defined and r is zero, 1 or 2; R4 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, fluoroCl-6alkyl, fluoroCi-6alkoxy, hydroxy, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or Cl 4alkyl substituted by Cl 4alkoxy, wherein Ra and Rb are as previously defined ; R5 is hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or Cl 6alkoxy substituted by C1-4alkoxy ; R6 represents hydrogen, hydroxy or a Cl 4alkyl group optionally substituted by a hydroxy group; R7 represents hydrogen, hydroxy,-(CH2) nNR8R9,-(CH2) nCO2R carbocyclyl, C-linked heterocyclyl or heteroaryl; or R6 and R7 together represent =O, =CHC02Ra or-O (CH2) O- ; R8 and R9 each independently represent hydrogen, C1-6alkyl, C2-6alkenyl, hydroxyC1-6alkyl, (CH2)qC3-7cycloalkyl, (CH2) qaryl, (CH2) qheterocyclyl, CHO, C (O) C1-6alkyl, C (O) (CH2) qC3-7cycloalkyl, C (O) (CH2) qaryl, C (O) (CH2) qheterocyclyl, C (O) (CH2) pNRaRb, (CH2) qCO2C1-6alkyl, CO2(CH2)qC3-7cycloalkyl, CO2(CH2) qaryl, CO2 (CH2) qheterocyclyl, CO2 (CH2) PNRaRb, (CH2) pNRaCORb, (CH2) pNRaCO2R6, (CH2) qCONRaaryl or (CH2) qCONRaheterocyclyl where Ra and Rb are as previously defined ; or R8 and R9, together with the nitrogen atom to which they are attached, represent a heteroaliphatic ring selected from the group consisting of :

RIO and Reach independently represent hydrogen, halogen, hydroxy, <BR> <BR> <BR> <BR> Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyCi-6alkyl, fluoroCi-6alkyl, Ci-6alkoxy, (CH2) qC3-7cycloalkyl, (CH2) qaryl, (C2-6alkenyl) aryl, (C2-6alkynyl) aryl, (CH2) qheterocyclyl, (CH2) qNRaRb, O (CH2) qC3-7cycloalkyl, O (CH2) qaryl, O (CH2) qheterocyclyl, O (CH2) pNRaRb, OC (O) C1-6alkyl, C (O) C1-6alkyl, C (O) (CH2) qaryl, C (O) (CH2) qheterocyclyl, C (O) (CH2) qNRaRb, C02H, CO2C1-6alkyl, CO2 (CH2) qC3-7cycloalkyl, C02 (CH2) qaryl, CO2 (CH2) qheterocyclyl or C02 (CH2) pNRaRb, where Ra and Rb are as previously defined ; or, when they are attached to the same carbon atom, Ri and R"may together represent =O, =CHCO2Ra, -O (CH2) mO--CH20 (CH2) s-,-CH20CH2C (O)-, -CH20CH2CH (OH)-,-CH20CH2C (CH3) 2-,-CH20C (CH3) 2CH2-, -C (CH3) 20CH2CH2-,-CH2C (O) OCH2-,-OC (O) CH2CH2-,-C (O) OCH2CH2-, -C (O) OC (CH3) 2CH2-,-C (O) OCH2C (CH3)2-, -OCH2(CH2)s-, -OC(CH3)2CH2CH2-, -OCH2C (CH3) 2CH2-,-OCH2CH2C (CH3) 2-,-OCH2CH=CHCH2-, -OCH2CH (OH) CH2CH2-,-OCH2CH2CH (OH) CH2-,-OCH2C (O) CH2CH2-, -OCH2CH2C (O) CH2-, or a group of the formula or, where they are attached to adjacent carbon atoms, RIO and Rll may together represent-OCH2CH2-or-OCH2CH (OH)-, or Rl° and Rll may together form a fused benzene ring;

or, RIO and Rll together form a Ci-2alkylene bridge across the pyrrolidine, piperidine or hexamethyleneimine ring to which they are attached; R12 represents hydrogen, C1-6alkyl, (CH2) qC3-7cycloalkyl, (CH2) qaryl, (CH2) qheterocyclyl, CHO, C (O) C1-6alkyl, C (O) (CH2) qC3-7cycloalkyl, C (O) (CH2) qaryl, C (O) (CH2) qheterocyclyl, CO2Cl-6alkyl, CO2 (CH2) qC3-7cycloalkyl, CO2(CH2)qaryl, CO2 (CH2) qheterocyclyl or CO2 (CH2) pNRaRb, where Ra and Rb are as previously defined; or, where they are attached to adjacent carbon atoms, R12 and R18 may together form a fused imidazolyl or triazolyl ring; Ri3 represents hydrogen, Ci-alkyl or C (O) C16alkyl ; R'4, R15, R16, R17, R18 and R19 each independently represent hydrogen, hydroxy, Ci-6alkyl, Ci-6alkenyl, hydroxyCl. 6alkyl, Ci-4alkoxyCi-4alkyl, (CH2) pNRaRb, CHO, C (O) C1-6alkyl or CO2C1-6alkyl ; or, R14 and R15 together represent -CH2CH2-; or, R16 and R17 together represent-CH2CH2- ; or, R'8 and R'9 together represent-CH2CH2-; R20 represents hydrogen, halogen, hydroxy, Cl-4alkyl, hydroxyCi-4alkyl or fluoroCl-4alkyl ; R21a represents hydrogen, halogen or hydroxy and R2lb represents hydrogen; or R2la and R2lb both represent fluorine or together represent oxo (=O) ; R22 and R23 each independently represent hydrogen, halogen, hydroxy, Cl 6alkyl or oxo (=O) ; n is zero, 1 or 2; m is 1 or 2 ; pis 1,2,3 or 4; q is zero, 1,2,3 or 4; and s is 1, 2 or 3 ; and pharmaceutically acceptable salts and N-oxides thereof.

According to an alternative embodiment, the present invention also provides compounds of the formula (I') :

wherein R6 represents hydrogen or a Ci-4alkyl group optionally substituted by a hydroxy group; R7 represents hydrogen, hydroxy,-(CH2) nNR8R9,-(CH2) nCO2Ra, carbocyclyl or heteroaryl; or R6 and R7 together represent =0, =CHC02Ra or-O (CH2) mO~ ; R8 and R9 each independently represent hydrogen, C1-6alkyl, C2-6alkenyl, (CH2) qC3-7cycloalkyl, (CH2) qaryl, (CH2) qheterocyclyl, CHO, C (O) C1-6alkyl, C (O) (CH2) qC3-7cycloalkyl, C (O) (CH2) qaryl, C (O) (CH2) qheterocyclyl, C (O) (CH2) pNRaRb, (CH2) qC02Ci-6alkyl, CO2 (CH2) qC3-7cycloalkyl, CO2 (CH2) qaryl, C02 (CH2) qheterocyclyl, C02 (CH2) pNRaRb, (CH2) pNRaCORb or (CH2) pNRaCO2Rb, where Ra and Rb are as previously defined ; or R8 and R9, together with the nitrogen atom to which they are attached, represent a heteroaliphatic ring selected from the group consisting of :

RIO and Reach independently represent hydrogen, halogen, hydroxy, Ci-6alkyl, Cz-6alkenyl, C2-6alkynyl, hydroxyCi-6alkyl, Ci-6alkoxy, (CH2) qC3-7cycloalkyl, (CH2) qaryl, (C2-6alkenyl) aryl, (C2-6alkynyl)aryl, (CH2) qheterocyclyl, (CH2) qNRaRb, O (CH2) qC3-7cycloalkyl, 0 (CH2) qaryl, O (CH2) qheterocyclyl, O (CH2) pNRaRb, OC (O) C1-6alkyl, C (O) C1-6alkyl, C (O) (CH2) qaryl, C (O) (CH2) qheterocyclyl, C (O) (CH2) qNRaRb, C02H, CO2C1-6alkyl, C02 (CH2) qC3-7cycloalkyl, C02 (CH2) qaryl, C02 (CH2) qheterocyclyl or C02 (CH2) pNRaRb, where Ra and Rb are as previously defined; or, when they are attached to the same carbon atom, RIO and Rll together represent =0, =CHC02Ra,-O (CH2) m0-,-OCH2CH2CHz-,-CH20CH2CH2-or -CH20CH2C (O)- ; or, where they are attached to adjacent carbon atoms, Rl° and Rll together form a fused benzene ring; or, R10 and R11 together form a C1-2alylene bridge across the pyrrolidine, piperidine or hexamethyleneimine ring to which they are attached; pi2 represents hydrogen, C1-6alkyl, (CH2) qC3-7cycloalkyl, (CH2) qaryl, (CH2) qheterocyclyl, CHO, C (O) C1-6alkyl, C (O) (CH2) qC3-7cycloalkyl, C (O) (CH2) qaryl, C (O) (CH2) qheterocyclyl, CO2Cl-6alkyl, CO2 (CH2) qC3-7cycloalkyl, CO2 (CH2) qaryl, C02 (CH2) qheterocyclyl or C02 (CH2) pNRaRb, where Ra and Rb are as previously defined ;

R14, R15, R16, R17, R18 and Rl9 each independently represent hydrogen, hydroxy, Cl-6alkyl, Ci-6alkenyl, hydroxyCl- 6alkyl, (CHz) pNRaRb, CHO, C (O) Cl 6alkyl or CO2Cl 6alkyl ; and X, Rl, R2, R3, R4, R5, R13, n, m, p and q are as defined in relation to formula (I); and pharmaceutically acceptable salts thereof.

A preferred class of compound of formula (1) is that wherein Rl is hydroxy, Cl-6alkyl, fluoroC1-6alkyl, C2-6alkenyl, C1-6alkoxy, fluoroC1-6alkoxy, C2-6alkenyloxy, C3-7cycloalkoxy, Cs-7cycloalkylCz-4alkoxy, cyano, NRaRb, SRa, OSO2Ra, or RI together with the group R2 form a 5-membered saturated ring containing one oxygen atom.

A particularly preferred class of compound of formula (I) is that wherein RI is Ci-salkyl, fluoroCi-6alkyl, Ci-6alkoxy, fluoroCi-6alkoxy, Cs-7cycloalkoxy or C3-7cycloalkoxyCl-4alkyl, especially methyl, trifluoromethyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, cyclopropoxy or cyclopropylmethoxy.

Another preferred class of compound of formula (I) is that wherein R2 is a hydrogen, fluorine or chlorine atom, especially a hydrogen atom.

A further preferred class of compound of formula (I) is that wherein R3 is hydrogen, halogen, fluoroCi-6alkyl, fluoroCi-6alkoxy, cyano, NRaRb, NRaCORd (where Rd is methyl, methoxy, trifluoromethyl or phenyl), or a 5-membered aromatic heterocyclic group as previously defined.

Also preferred is the class of compound of formula (I) in which R3 is Ci-salkyl, fluoroCi-6alkyl, fluoroCi-6alkoxy or a 5-membered aromatic heterocyclic group as previously defined, especially methyl, trifluoromethyl, trifluoromethoxy or 5-trifluoromethyl-1, 2,3,4-tetrazol-1-yl.

Certain particularly apt compounds of the present invention include those wherein R3 is a group selected from pyrrole, furan, thiene, pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, triazine, and tetrazole, each heteroaryl group being optionally substituted as previously defined.

Preferred compounds of the present invention are those wherein R3 is a group selected from furan, pyridine, pyrazole, imidazole, oxazole, isoxazole,

pyrazine, pyrimidine, thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1, 3,4-oxadiazole and tetrazole, each heteroaryl group being optionally substituted as previously defined.

Particularly preferred compounds of the present invention are those wherein R3 is a group selected from furan, pyridine, pyrimidine, 1,2,3-triazole, 1,2,4-triazole and tetrazole, each heteroaryl group being optionally substituted as previously defined.

An especially preferred class of compound of formula (I) is that wherein R3 is the group where R20 is hydrogen, halogen, Ci-6alkyl, Ci-6alkoxy, CFs, OCFs, N02, CN, SRa, SORT, SO2Ra, CORa, CO2Ra, (CH2) rCONRaRb, (CH2) rNRaRb or (CH2) rNRaCORbX where Ra, Rb and r are as previously defined.

R20 is preferably hydrogen, Ci-4alkyl, especially methyl, CF3, (CH2) rCONRaRb, SORa or SO2Ra where Ra and Rb are preferably hydrogen, C1-4alkyl or fluoroCi-4alkyl and r is as previously defined. Most especially, R20 is CF3.

Preferably Rl and R3 are in the 3 and 5 positions of the phenyl ring.

More preferably Rl is 3-fluoro or 3-CF3.

More preferably R3 is 5-fluoro or 5-CF3.

More preferably R2 is hydrogen.

Most preferably R1 is 3-CF3, R2 is hydrogen and R3 is 5-CF3.

Another preferred class of compounds of formula (I) is that wherein R and R3 are in the 2-and 5-positions of the phenyl ring.

In this sub-class of compounds of formula (I), R1 is preferably Cl 6alkoxy or Cs ? cycloalkoxy, especially methoxy or cyclopropoxy.

Also in this sub-class of compounds of formula (I), R2 is preferably hydrogen.

Also, in this sub-class of compounds of formula (I) R3 is preferably hydrogen, Ci-6alkoxy, fluoroCi-6alkoxy or a 5-membered aromatic heterocyclic group as previously defined. Most especially, R3 is hydrogen, methoxy or trifluoromethoxy.

A further preferred class of compound of formula (I) is that wherein R4 is hydrogen.

Another preferred class of compounds of formula (I) is that wherein R5 is hydrogen, fluorine, chlorine or CF3, especially hydrogen or fluorine.

Preferably R4 is hydrogen and R5 is hydrogen or 4-fluoro.

Another further preferred class of compounds of formula (I) is that wherein R6 is hydrogen.

A further preferred class of compounds of formula (I) is that wherein R7 is hydroxy,-(CH2) nNR8R9, a C-linked heterocyclyl group or R6 and R7 together represent =0,-O (CH2) mO- or -CH2OCH2C(O)-, Another preferred class of compounds of formula (I) is that wherein R7 is hydroxy or- (CH2) nNR8R9, or R6 and R7 together represent =0,-O (CH2) mO- or -CH20CH2C (O)-.

A further preferred class of compounds of formula (I) is that wherein R8 represents hydrogen, Ci-6alkyl, C2-6alkenyl, hydroxyCi-salkyl, (CH2) qC3-7cycloalkyl, (CH2) qaryl, (CH2) qheterocyclyl, C (O) C1-6alkyl, C (O) (CH2) qaryl, C (O) (CH2) qheterocyclyl, C (O) (CH2) pNRaRb, (CH2) qCO2C1-6alkyl, (CH2) pNRaCO2Rb or (CH2) qCONRaaryl ; and R9 represents hydrogen, C1-6alkyl, (CH2) qC3-7cycloalkyl or COzCl-6alkyl ; or R8 and R9 together with the nitrogen atom to which they are attached represent a heteroaliphatic ring selected from the group consisting of

A yet further preferred class of compounds of formula (I) is that wherein R8 represents hydrogen, C1-6alkyl, C2-6alkenyl, (CH2) qC3-7cycloalkyl, (CH2) qaryl, (CH2) qheterocyclyl, C (O) Cl. 6alkyl, C (O) (CH2) qaryl, C (O) (CH2) qheterocyclyl, C (O) (CH2) pNRaRb, (CH2) qC02Ci-6alkyl or (CH2) pNRaCO2Rb ; and R9 represents hydrogen, C1-6alkyl, (CH2) qC3-7cycloalkyl or CO2C1-6alkyl; or R8 and R9 together with the nitrogen atom to which they are attached represent a heteroaliphatic ring selected from the group consisting of

A further preferred class of compounds of formula (I) is that wherein RIO represents hydrogen, hydroxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyCi-6alkyl, fluoroCi-6alkyl, (C2-6alkynyl) aryl, (CHz) qaryl, (CH2) qheterocyclyl, (CH2) qNRaRb, OC (O) C1-6alkyl, C (O) (CH2) qNRaRb, COzH or CO2Ci-6alkyl ; and Rll represents hydrogen, halogen, hydroxy, Cl 6alkyl or (CH2) q NRaRb ; or when they are attached to the same carbon atom, RIO and Rll may together represent =0,-O (CH2) mO-,-CH20 (CH2)s-, -CH2OCH2C(O)-, -CH2OCH2CH (OH)-,-CH20CH2C (CH3) 2-,-CH20C (CH3) 2CH2-, -C (CH3) 20CH2CH2-,-CH2C (O) OCH2-,-OC (O) CH2CH2-,-C (O) OCH2CH2-, -C (O) OC (CH3) 2CH2-,-C (O) OCH2C (CH3) 2-,-OCH2 (CH2) s--OC (CH3) 2CH2CH2-, -OCH2CH=CHCH2-,-OCH2CH (OH) CH2CH2-,-OCH2CH2CH (OH) CH2-, -OCH2C (O) CH2CH2-, or a group of the formula or, when they are attached to adjacent carbon atoms, RIO and R"may together represent-OCH2CH2-or-OCH2CH (OH)-, or RIO and R"may together form a fused benzene ring; or RIO and R11 together form a Ci-2alkylene bridge across the pyrrolidine or piperidine ring to which they are attached.

Another preferred class of compounds of formula (I) is that wherein RIO represents hydrogen, hydroxy, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyCl-6alkyl, (C2-6alkynyl) aryl, (CH2) qaryl, (CH2) qheterocyclyl, (CH2) qNRaRb, OC (O) C1-6alkyl, C (O) (CH2) qNRaRb, CO2H or CO2C1-6alkyl ; and R"represents hydrogen, halogen, hydroxy, C1-6alkyl or (CH2) qNRaRb ; or when they are attached to the same carbon atom, Ri and Rll together represent =O or-O (CH2) mO-;

or, when they are attached to adjacent carbon atoms, Rl° and Together form a fused benzene ring; or RIO and Rlt together form a Cl-2alkylene bridge across the pyrrolidine or piperidine ring to which they are attached.

A further preferred class of compounds of formula (1) is that wherein R12 represents hydrogen, Ci-salkyl, (CH2) qC3-7cycloalkyl, (CH2) qaryl, (CH2) qheterocyclyl, CHO, C (O) C1-6alkyl, C (O) C3-7cycloalkyl, C (O) (CH2) qaryl or C02Ci-6alkyl.

A yet further prefered class of compounds of formula (I) is that wherein R9 represents hydrogen, C1-6alkyl, (CH2) qC3-7cycloalkyl or C02Ci-6alkyl.

A particularly preferred class of compounds of formula (I) is that wherein R8 represents hydrogen, Ci-6alkyl, C2-4alkenyl, C3acycloalkyl, CHzCs-7cycloalkyl, (CH2) qphenyl, (CH2) qfuryl, (CH2) qpyridyl, (CH2) qtriazolinone, C (O) Cl 4alkyl, C (O) (CH2) qphenyl, C (O) (CH2) qimidazolyl, C (O) (CH2) qtetrazolyl, C (O) (CH2) pyrrolidinyl, C (O) (CH2) pNRaRb, CH2C (O) Ci-4alkyl or (CH2) pNRaCO2C1-4alkyl ; and R9 represents hydrogen, C1-6alkyl, CH2C3-5cycloalkyl or CO2Ci-4alkyl ; or R8 and R9 together with the nitrogen atom to which they are attached represent a heteroaliphatic ring selected from the group consisting of :

A further particularly preferred class of compounds of formula (I) is that wherein: RIO represents hydrogen, hydroxy, methyl, allyl, acetylene, hydroxyCi-4alkyl,-C=C (phenyl), phenyl, 4-fluorophenyl, CH2phenyl, CH2CH2phenyl, heterocyclyl (wherein said heterocyclyl is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and hexamethyleneimine, wherein each ring is optionally substituted by one or two groups selected from methyl, hydroxymethyl, cyclohexyl, dimethylamino and benzisothiazole or there is optionally a benzene ring fused to the ring, or there is optionally present a-CH2CH2-bridge across the ring), NRaRb, OC (O) CH3, C (O) NRaRb, C02H or CO2Ci-4alkyl ; and R1l represents hydrogen, fluorine, hydroxy, methyl or dimethylamino; or, when they are attached to the same carbon atom, RIO and R"together represent =O or-OCH2CH20- ; or, when they are attached to adjacent carbon atoms, RIO and Rll together form a fused benzene ring; or, RIO and Together form a-CH2CH2-bridge across the pyrrolidine or piperidine ring to which they are attached.

A yet further particularly preferred class of compounds of formula (I) is that wherein R12 represents hydrogen, Cl6alkyl, Cs-6cycloalkyl, CH2C3-6cycloalkyl (especially CH2cyclopropyl or CH2cyclohexyl), phenyl, CH2phenyl, CH2CH2phenyl (wherein each of said phenyl groups are optionally substituted by one or two substituents selected from fluorine, CF3 or methoxy), CH2heterocyclyl (wherein said heterocyclyl is selected from the group consisting of 2-, 3-or 4-pyridine, 2-or 3-thiophene, 2-or 3-furan, thiazole, and benzisothiazole), CHO, C (O) Ci-4alkyl, C (O) C3-6cycloalkyl (especially C (O) cyclopropyl or C (O) cyclohexyl), C (O) CH2cycloalkyl (especially C (O) CH2cyclopropyl or C (O) CH2cyclohexyl),

C (O) CH2CH2C3-6cycloalkyl (especially C (O) CH2CH2cyclohexyl), C (O) phenyl or CO2C1-4alkyl.

Yet another particularly preferred class of compounds of formula (I) is that wherein R9 represents hydrogen, Ci-6alkyl, CH2Cs-scycloalkyl or C02Ci-4alkyl.

Another preferred class of compound of formula (I) is that wherein the ring A is a phenyl ring.

Particularly preferred compounds of formula (I) are those wherein R7 represents a group selected from:

wherein R30 represents 4-pyridyl, phenyl, phenyl mono-substituted by fluorine, chlorine, methyl, methoxy or CO2methoxy, or phenyl disubstituted by methyl; R31 represents C2-4alkyl or (CH2) qC3-7cycloalkyl, especially tert-butyl, cyclopropylmethyl or cyclohexyl; R32 represents Cl 6aIkyl, tetrahydropyranyl or benzyl; R33 and R34, which may be attached to the same or different carbon atoms, each independently represent hydrogen or methyl; R35 represents hydroxy or methoxy; R36 represents hydroxyCi-4alkyl (especially hydroxymethyl), C1-4alkoxy (especially methoxy) or hydroxy ; R37 represents methoxy C2-4alkyl (especially methoxymethyl) or C2-4alkyl ; R33 represents hydrogen, oxo (=O), hydroxy, trifluoromethyl, Cl 3alkyl (especially isopropyl) or hydroxyCi-salkyl (especially hydroxymethyl or hydroxyethyl); R39 represents a ring-forming moiety selected from -OCH2CH2O-, -CH2OCH2Ch2-, -CH2OCH2CH2CH2-, -CH2OCH2C (O)-,-CH20CH2CH (OH)-, -CH2OC (CH3) 2CH2-,-C (CH3) 20CH2CH2-,-CH2C (O) OCH2-,-C (O) OCH2CH2-, -C (O) OC (CH3) 2CH2-,-OCH2CH2CH2-,-OCH2CH2CH2CH2-,-OC (CH3) 2CHzCH2, -OCH2CH=CHCH2-,-OCH2CH (OH) CH2CH2-,-OCH2CH2CH (OH) CH2-, -OCH2C (O) CH2CH2-and a group of the formula

R40 is hydrogen or hydroxy, especially hydrogen; R41 is C1-3alkyl, especially isopropyl ; and n is zero, 1 or 2, especially zero.

Further preferred compounds of formula (I) are those wherein R7 represents a group selected from:

wherein R25 represents hydrogen, methyl or hydroxymethyl ; R26 represents hydrogen, methyl, hydroxy, methylamino, dimethylamino, cyclopropylamino, phenyl, or phenyl substituted by fluorine; and R27 represents hydrogen, methyl, hydroxy, methylamino, dimethylamino or cyclopropylamino.

Another preferred class of compounds of formula (1) is that wherein R2'a represents hydrogen, fluorine or hydroxy and R2lb is hydrogen, or R2la and R2lb both represent fluorine or together represent oxo (=O). In particular, R2la is preferably hydrogen, fluorine or hydroxy and R2lb is hydrogen. Most especially, R21a and R21b are preferably both hydrogen.

Another preferred class of compounds of formula (I) is that wherein X represents a linker selected from:

Another preferred class of compounds of formula (1) is that wherein R13 represents hydrogen, methyl or acetyl. In particular, R13 represents hydrogen.

A further preferred class of compounds of formula (I) is that wherein one of the groups Rl4, Rl5, Rie and Rl7 represents hydrogen, hydroxy, Cl 6alkyl, hydroxyC1-6alkyl, (CH2)pNRaRb, CHO, C (O) Ci-alkyl or C02Cl-6alkyl, and the other (s) of the groups R14, Ri5, R16 and Rl7 each represent hydrogen.

A particularly preferred class of compounds of formula (I) is that wherein one of the groups R14, Rl5, R16 and R17 represents methyl or hydroxymethyl, and the other (s) of groups R14, R15, Rl6 and R17 each represent hydrogen.

A further preferred class of compounds of formula (1) is that wherein RIB and Rl9 each independently represent hydrogen or methyl.

Most especially, a preferred class of compounds of formula (I) is that wherein X represents a linker selected from:

Another preferred class of compounds of formula (I) is that wherein n is zero.

A further preferred class of compounds of formula (I) is that wherein m is 2.

Another preferred class of compounds of formula (I) is that wherein p is 1, 2 or 3, particularly 1 or 2, and especially 1.

A further preferred class of compounds of formula (I) is that wherein q is zero, 1 or 2, particularly zero or 1.

One favoured group of compounds of the present invention are of the formula (Ia) and pharmaceutically acceptable salts thereof :

wherein Ai is fluorine or CF3 ; A2 is fluorine or CF3 ; A3 is fluorine or hydrogen; R6 and R7 are as defined in relation to formula (I) ; and X is a linker selected from: When any variable occurs more than one time in formula (I) or formula (Ia) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.

As used herein, the term"alkyl"or"alkoxy"as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

As used herein, the term"hydroxyCl-6alkyl"means a Cl 6alkyl group in which one or more (in particular 1 to 3, and especially 1) hydrogen atoms have

been replaced by hydroxy groups. Particularly preferred are hydroxyCi-salkyl groups, for example, CH20H, CH2CH2OH, CH (CH3) OH or C (CH3) 20H, and most especially CH20H.

As used herein, the terms"fluoroCl. 6alkyl"and fluoroCl 6alkoxy"means a Ci-alkyl or Cl 6alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroC-salkyl and fluoroCi-3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCH2CF3.

The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable (CH2) qC3 7cycloalkyl group where q is 1 may be, for example, cyclopropylmethyl or cyclohexylmethyl.

Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.

As used herein, the terms"alkenyl"and"alkynyl"as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is acetylene or propargyl.

When used herein the term"halogen"means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.

As used herein, the term"aryl"as a group or part of a group means an aromatic radical such as phenyl, biphenyl or naphthyl, wherein said phenyl, biphenyl or naphthyl group may be optionally substituted by one, two or three groups independently selected from halogen, Ci-6alkyl, Cl-6alkoxy, fluoroCi-6alkyl, fluoroCi-6alkoxy, NO2, cyano, SRa, SORa, SO2Ra, CORa, C02Ra, CONRaRb, C2-6alkenyl, Cz-6alkynyl, CmalkoxyCi-4alkyl or-O (CHz) mO-. Preferably said phenyl, biphenyl or naphthyl group is optionally substituted by one or two substituents, especially none or one. Particularly preferred substituents include fluorine, chlorine, bromine, Ci-4alkyl (especially methyl), Ci-4alkoxy (especially methoxy), trifluoromethyl, trifluormethoxy or vinyl.

As used herein, the term"heterocyclyl"as a group or part of a group means a saturated, partially saturated or unsaturated heteroatom-containing ring-shaped radical, where the heteroatoms may be selected from nitrogen,

oxygen and sulfur. Examples of saturated heterocyclyl radicals include N-linked saturated 3 to 6-membered heteromonocyclic groups containing 1 to 3 nitrogen atoms and optionally 1 oxygen or sulfur atom (for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or piperazinyl substituted on the nitrogen atom by a Ci-4alkyl group or a C2 4alkyl group substituted by hydroxy or C1 2alkoxy). Examples of saturated heterocyclyl radicals also include C-linked saturated 3 to 6-membered heteromonocyclic groups containing, for example, one oxygen atom (for instance, tetrahydrofuranyl or tetrahydropyranyl). Examples of partially saturated heterocyclyl radicals include N-linked partially saturated 3 to 6-membered heteromonocyclic groups containing 1 to 3 nitrogen atoms (for example, 3-pyrroline). Examples of unsaturated heterocyclyl radicals include heteroaromatic rings selected from pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indolyl, benzofuranyl, benzthiophenyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl or benzisothiazolyl.

Said saturated and partially saturated heterocyclyl radicals may be optionally substituted by one, two or three groups independently selected from halogen, Ci-6alkyl, Ci-6alkoxy, fluoroCi-6alkyl, fluoroCi-6alkoxy, NO, cyano, oxo (=0), NRaRb, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb, C2 6alkenyl, C2 6alkynyl, Ci-4alkoxyCi-4alkyl,-O (GH2) O-,-OCH2CH2CH2-,-CH20CH2CH2-or -CH20CH2C (O)-. Preferably said saturated or partially saturated heterocyclyl radical is optionally substituted by one or two substituents, especially none or one. Particularly preferred substituents include fluorine, chlorine, bromine, Cl-4alkyl (especially methyl), Ci-4alkoxy (especially methoxy), trifluoromethyl, trifluoromethoxy, oxo, vinyl, Ci-4alkylamino (especially methylamino) or di (Ci-4alkyl) amino (especially dimethylamino).

Said unsaturated heterocyclyl radicals may be optionally substituted by one, two or three groups independently selected from halogen, Cl-6alkyl, Ci-6alkoxy, fluoroCi-6alkyl, fluoroCi-6alkoxy, NO2, cyano, NRaRb, SRa, SORa, SO2Ra, CORa, C02Ra, CONRaRb, Ca-salkenyl, C2-6alkynyl, Cl-4alkoxyC1-4alkyl or -O (CH2) mO-. Preferably said unsaturated heterocyclyl is optionally substituted by one or two substituents, especially none or one. Particularly preferred

substituents include fluorine, chlorine, bromine, C1-4alkyl (especially methyl), Ci-4alkoxy (especially methoxy), trifluoromethyl, trifluoromethoxy or vinyl.

As used herein, the term"carbocyclyl"as a group or part of a group means a 3 to 7-membered cycloalkyl radical such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein said cycloalkyl radical may be optionally substituted by one, two or three groups independently selected from halogen, C1-6alkyl, C1-6alkoxy, hydroxyCl-6alkyl, fluoroGi-6alkyl, fluoroCi-6alkoxy, NOz, cyano, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl, Ci-4alkoxyCi-4alkyl or-O (CH2) mO-. Preferably said cycloalkyl radical is substituted by one or two substituents, especially one. Particularly preferred substituents include fluorine, chlorine, bromine, Ci-4alkyl (especially methyl), methoxy, hydroxyCi-4alkyl (especially C (CH3) 2OH), trifluoromethyl, trifluoromethoxy or vinyl.

Specific compounds within the scope of this invention include: cis- (RS)-4-methanesulfonyloxy-N- {1- [3, 5-bis (trifluoromethyl) phenyllethyl}-1- phenylcyclohexanecarboxamide; (RS)-1-{1-[(1,4-dioxa-8-phenylspiro[4.5] decan-8-yl) methoxy] ethyl]}-3,5- bis (trifluoromethyl) benzene; (RS)-1-{1-[(4-oxo-1-phenylcyclohesyl) methoxy] ethyl}-3, 5- bis (trifluoromethyl) benzene; (RS)-ß-[(1, 4-dioxa-8-phenylsp*o [4.5] decan-8-yl) methoxy]-3, 5- bis (trifluoromethyl) benzeneethanol; (RS)-ß- [(4-oxo-1-phenylcyclohexyl)methoxy]-3, 5- bis (trifluoromethyl) benzeneethanol; (RS)-4-oxo-1-phenyl-N- {1- [3, 5- bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide ; (RS)-1- (8-phenyl-1, 4-dioxaspiro [4.5] decan-8-yl)-3- [3, 5- bis (trifluoromethyl) phenyl] propan-2-yl ethanoate; (RS)-1-(8-phenyl-1,4-dioxaspiro [4.5] decan-8-yl)-3- [3, 5- bis (trifluoromethyl) phenyl] propan-1-yl ethanoate; (RS)-1- (8-phenyl-1, 4-dioxaspiro [4.5] decan-8-yl)-3- [3, 5- bis (trifluoromethyl) phenyl] propan-2-ol ; RS)-4- {2-hydroxy-3- [3,5-bis (trifluoromethyl) phenyl] propyl}-4- phenylcyclohexanone;

trans- (RS)-1- ( {4- [4- (4-fluorophenyl) piperidin-1-yl]-oc-methyl-l- phenylcyclohexanemethoxy} methyl)-3, 5-bis (trifluoromethyl) benzene; cis- (RS)-1- ( {a-ethenyl-4- [4- (4-fluorophenyl) piperidin-1-yl]-1- phenylcyclohexanemethoxy} methyl)-3, 5-bis (trifluoromethyl) benzene; trans- (RS)-1- ( {a-ethenyl-4- [4- (4-fluorophenyl) piperidin-1-yl]-1- phenylcyclohexanemethoxy} methyl)-3, 5-bis (trifluoromethyl) benzene; trans- (RS)-4- [4- (4-fluorophenyl) piperidin-1-yl]-1-phenyl-a- [3, 5- bis (trifluoromethyl) phenylmethoxy] cyclohexaneethanol ; trans- (RS)-1- ( {a-ethyl-4- [4- (4-fluorophenyl) piperidin-1-yl]-1- phenylcyclohexanemethoxy} methyl)-3, 5-bis (trifluoromethyl) benzene; trans-1-[([4-[4-(4-fluorophenyl)piperidin-1-yl]-1- phenylcyclohexyl} methoxy) methyl]-2-methoxybenzene ; trans-1-[([4-[4-(4-fluorophenyl)piperidin-1-yl]-1- penylcyclohexyl}methoxy)methyl]-2-(cyclopropoxy)-5-(trifluor omethoxy) benzene; cis-(RS)-1- [1-({4- [4-(4-fluorophenyl) piperidin-1-yl]-1- phenylcyclohexyl} methosy) ethyl]-3, 5-bis (trifluoromethyl) benzene ; trans- (RS)-1- [l- ( {4- [4- (4-fluorophenyl) piperidin-1-yl]-1- phenylcyclohexyl} methoxy) ethyl]-3, 5-bis (trifluoromethyl) benzene; trans-(RS)-ß-[(4-hydroxy-1-phenylcyclohexyl)methyoxy]-3, 5- bis (trifluoromethyl) benzeneethanol ; cis-(RS)-ß-[(4-hydroxy-1-phenylcyclohexyl)methyoxy]-3, 5- bis (trifluoromethyl) benzeneethanol ; cis-(RS)-ß-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylc yclohexyl}methoxy)-3, 5- bis (trifluoromethyl) benzeneethanol; trans-(RS)-ß-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1-pheny lcyclohexyl}methoxy)- 3,5-bis (trifluoromethyl) benzeneethanol; cis- and trans-(RS)-ß-{[1-phenyl-4-(phenylmethylamino)cyclohexyl]met hoxy}-3, 5- bis (trifluoromethyl) benzeneethanol; cis- and trans-(RS)-ß-[(1-phenyl-4-(piperidin-1-yl)cyclohexyl)methox y]-3, 5- bis (trifluoromethyl) benzeneethanol; trans-(RS)-ß-{ [1-phenyl-4-(phenylmethylamino) cyclohexyl] methoxy}-3,5- bis (trifluoromethyl) benzeneethanol;

cis-(RS)-ß-{[1-phenyl-4-(phenylmethylamino)cyclohexyl]metho xy}-3, 5- bis (trifluoromethyl) benzeneethanol; trans-(RS)-ß-[(4-amino-1-phenylcyclohexyl)methoxy]-3, 5- bis (trifluoromethyl) benzeneethanol; cis-(RS)-ß-[(4-amino-1-phenylcyclohexyl)methoxy]-3, 5- bis (trifluoromethyl) benzeneethanol; trans-(RS)-ß-({4-[N-methyl(phenylmethyl)amino]-1-phenylcycl ohexyl}methoxy)- 3,5-bis (trifluoromethyl) benzeneethanol ; trans-(RS)-ß-[(4-methylamino-1-phenylcyclohexyl)methoxy]-3, 5- bis (trifluoromethyl) benzeneethanol; trans-(RS)-ß-[(4-{N-[2-(dimethylamino)acetyl]amino}-1- phenylcyclohexyl) methoxy]-3, 5-bis (trifluoromethyl) benzeneethanol; trans- (RS, S)-N- (l- { [a-hydroxymethyl-3, 5-bis (trifluoromethyl) phenylmethoxy] methyl}-l-phenylcyclohexyl)-2-pyrrolidinecarboxamide ; cis-and trans- (RS)-P- [ (l-phenyl-4-dimethylaminocyclohexyl) methoxy]-3, 5- bis (trifluoromethyl) benzeneethanol ; trans- (RS)-P- [ (4-cyclopropylmethylamino-1-phenylcyclohexyl) methoxy]-3, 5- bis (trifluoromethyl) benzeneethanol ; 1, 2-dihydro-5-{[N-(1-{[α-hydroxymethyl-3, 5-bis (trifluoromethyl) phenylmethoxy] methyl}-1-phenylcyclohex-4-yl) methylamino] methyl}-3H-1, 2,4-triazol-3-one; cis-(RS)-methyl l-(l-{[a-hydrogymethyl-3,5-bis (trifluoromethyl) phenylmethoxy] methyl}-l-phenylcyclohex-4-yl) piperidine-4-carboxylate ; trans-(RS)-methyl 1-(1-{[a-hydroxymethyl-3,5- bis (trifluoromethyl) phenylmethoxy] methyl}-l-phenylcyclohex-4-yl) piperidine-4- carboxylate; trans- (RS)-1- (1- { [a-hydroxymethyl-3,5-bis (trifluoromethyl) phenylmethoxy] methyl}-1-phenylcyclohex-4-yl) piperidine-4-methanol ; trans-(RS)-1-(1-{[α-hydroxymethyl-3, 5-bis (trifluoromethyl) phenylmethoxy] methyl}-1-phenylcyclohex-4-yl) piperidine-4-carboxylic acid ; trans- (RS)-l- (l- { [a-hydroxymethyl-3, 5-bis (trifluoromethyl) phenylmethoxy] methyl}-1-phenylcyclohex-4-yl)-a, a-dimethylpiperidine-4-methanol ; trans-(RS)-1-(1-{[α-hydroxymethyl-3 5-bis (trifluoromethyl) phenylmethoxy] methyl}-1-phenylcyclohex-4-yl)-N, N-dimethylpiperidine-4-carboxamide ;

RS)-methyl (1-(1-{[3035-hydroxymethyl-3, 5-bis (trifluoromethyl) phenylmethoxy] methyl}-l-phenylcyclohex-4-ylidene) acetate ; cis-and trans-(RS)-methyl (1-(1-{[α-hydroxymethyl-3 5- bis (trifluoromethyl) phenylmethoxy] methyl3-1-phenylcyclohex-4-yl) acetate; cis-(RS)-1-[2-(1-(1-{[α-hydroxymethyl-3, 5-bis (trifluoromethyl) phenylmethoxy] methyl}-1-phenylcyclohex-4-yl) ethyl] pyrrolidine ; trans-(RS)-1-[2-(1-(1-{[α-hydroxymethyl-3, 5-bis (trifluoromethyl) phenylmethoxy] methyl}-l-phenylcyclohex-4-yl) ethyl] pyrrolidine ; trans-(RS)-methyl α-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1- phenylcyclohexyl} methoxy)-3, 5-bis (trifluoromethyl) benzeneacetate; trans-3, 5-bis (trifluoromethyl) phenylmethyl 4- [4- (4-fluorophenyl) piperidin-1-yl]-1- phenylcyclohexanecarboxylate; trans-(RS)-1-[3, 5-bis (trifluoromethyl) phenyl] ethyl 4- [4- (4-fluorophenyl) piperidin- 1-yl]-1-phenylcyclohexanecarboxylate ; trans- (RS)-2-hydroxy-2- [3, 5-bis (trifluoromethyl) phenyl] ethyl 4- [4- (4- fluorophenyl) piperidin-1-yl]-1-phenylcyclohexanecarboxylate ; trans- (RS)-a- (hydroxymethyl)- [3, 5-bis (trifluoromethyl) phenyl] methyl 4- [4- (4- fluorophenyl) piperidin-1-yl]-1-(phenyl) cyclohexanecarboxylate ; trans- (RS)-methyl a- ( {4- [4- (4-fluorophenyl) piperidin-1-yl]-1- phenylcyclohexyl}carbonyloxy)-3, 5-bis (trifluoromethyl) benzeneacetate ; cis- {4- [4- (4-fluorophenyl) piperidin-1-yl]-1-phenylcyclohexyl} methyl 3,5- bis (trifluoromethyl) benzoate ; trans- {4- [4- (4-fluorophenyl) piperidin-1-yl]-1-phenylcyclohexyl} methyl 3,5- bis (trifluoromethyl) benzoate; cis-1-phenyl-4- (4-phenylpiperidin-1-yl)-N- { [3,5-bis (trifluoromethyl)phenyl] methyl} cyclohexanecarboxamide ; trans-1-phenyl-4- (4-phenylpiperidin- 1-yl)-N-1 [3, 5-bis (trifluoromethyl) phenyl] methyl} cyclohexanecarboxamide ; trans-4- [4-(4-fluorophenyl) piperidin-1-yl]-N-{ [3-(methoxy) phenyl] methyl}-1- phenylcyclohexanecarboxamide ; trans- (RS)-4- [4- (4-fluorophenyl) piperidin-1-yl]-N- {1- [3, 5- bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide ;

trans- (R)-4- [4- (4-fluorophenyl) piperidin-1-yl]-N- 1- [3,5- bis (trifluoromethyl) phenyl] ethyl}-l-phenylcyclohexanecarboxamide ; trans- (S)-4- [4- (4-fluorophenyl) piperidin-1-yl]-N- {1- [3, 5- bis (trifluoromethyl) phenyl] ethyl}-l-phenylcyclohexanecarboxamide ; cis-(RS)-4- [4-(4-fluorophenyl) piperidin-1-yl]-N-{1-[3,5- bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide ; trans-N-methyl-1-phenyl-4-(4-phenylpiperidin-1-yl)-N-{[3, 5- bis (trifluoromethyl) phenyl] methyl} cyclohexanecarboxamide ; trans- (RS)-4- [4- (4-fluorophenyl) piperidin-1-yl]-N-methyl- {1- [3, 5- bis (trifluoromethyl) phenyl] ethyl}-l-phenylcyclohexanecarboxamide ; trans- (RS)-4- [4- (4-fluorophenyl) piperidin-1-yl]-1-phenyl-N- {2-hydroxy-1- [3, 5- bis (trifluoromethyl)phenyl]}ethyl}cyclohexanecarboxamide ; trans- (RS)-4- (1, 4-dioxa-8-azaspiro [4.5] decane-8-yl)-l-phenyl-N- {l- [3, 5- bis (trifluoromethyl) phenyl]ethyl}cyclohexanecarboxamide ; trans-(RS)-4-(4-oxopiperidin-1-yl)-1-phenyl-N-{1-[3, 5- bis (trifluoromethyl) phenyl] ethyl}cyclohexanecarboxamide ; trans- (RS)-4- (4-hydroxypiperidin-1-yl)-l-phenyl-N-11- [3, 5- bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide ; trans-(RS)-4-(but-3-enylamino)-1-phenyl-N-{1-[3, 5- bis (trifluoromethyl) phenyl]ethyl}cyclohexanecarboxamide ; trans-(RS)-4-(4-hydroxy-4-phenylpiperidin-1-yl)-1-phenyl-N-{ 1-[3, 5- bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide ; trans-(RS)-4-(1, 2,3,6-tetrahydro-4-phenylpyridin-l-yl)-l-phenyl-N- {l- [3,5- bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide ; trans- (RS)-4- (1, 2,3, 6-tetrahydro-4-methylpyridin-1-yl)-1-phenyl-N-{1-[3, 5- bis (trifluoromethyl) phenyl]ethyl}cyclohexanecarboxamide ; trans- (RS)-4- (4-hydroxy-4- (phenylethyl) piperidin-1-yl)-l-phenyl-N-11- [3,5- bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide ; trans-(RS)-4- [(phenylmethyl) amino]-N-{1- [3,5-bis (trifluoromethyl) phenyl] ethyl}- 1-phenylcyclohexanecarboxamide ; cis-(RS)-4-[(phenylmethyl)amino]-N-{1-[3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide ;

trans- (RS)-4- [N-methyl (phenylmethyl) amino]-N- {1- [3, 5- bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide ; trans-(RS)-4-methylamino-N-{1-[3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide; trans- (RS)-4-amino-N-11- [3, 5-bis (trifluoromethyl) phenyl] ethyl)-1- phenylcyclohexanecarboxamide; trans- (RS)-4- (dimethylamino)-N-1 1- [3,5-bis (trifluoromethyl)phenyl]ethyl}-1- phenylcyclohexanecarboxamide ; trans-(RS)-4-[4-(phenylbutyl)amino]-N-{1-[3, 5-bis (trifluoromethyl) phenyl] ethyl}- 1-phenylcyclohexanecarboxamide ; trans-(RS)-4-[N-methyl-4-(phenylbutyl)amino]-N-{1-[3, 5- bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide ; trans- (RS)-4-acetylamino-N- {1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide ; trans-(RS)-4-[(C1-oxo-4-phenylbutyl)amino]-N-{1-[3, 5-bis (trifluoromethyl) phenyl] ethyl}-l-phenylcyclohexanecarboxamide ; cis-and trans- (RS)-1, 1-dimethylethyl 4- [1-({1-[3, 5-bis (trifluoromethyl) phenyl] ethylamino} carbonyl)-l-phenylcyclohex-4-yl]-l-piperazinecarboxylate ; trans- (RS)-4- [4- (phenylmethyl) piperazin-1-yl]-N- {1- [3, 5- bis (trifluoromethyl) phenyl]ethyl}-1-phenylcyclohexanecarboxamide ; trans- (RS)-4- (piperazin-1-yl)-N- {1- [3, 5-bis (trifluoromethyl) phenyl]ethyl}-1- phenylcyclohexanecarboxamide ; trans- (RS)-4- (4-methylpiperazin-1-yl)-N-11- [3, 5-bis (trifluoromethyl) phenyl]ethyl}- 1-phenylcyclohexanecarboxamide ; trans- (RS)-4- (4-acetylpiperazin-1-yl)-N-11- [3, 5-bis (trifluoromethyl) phenyl] ethyl}- 1-phenylcyclohexanecarboxamide ; trans-(RS)-4-(aminomethyl)-N-{1-[3, 5-bis (trifluoromethyl) phenyllethyl}-l- phenylcyclohexanecarboxamide ; trnas-(RS)-4-(N,N-dimethylaminomethyl)-N-{1-[3, 5- bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide ; trans- (RS)-4- [ (piperidin-1-yl) methyl]-N- 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}- 1-phenylcyclohexanecarboxamide ;

trans- (RS)-4- [ (morpholin-4-yl) methyl]-N- 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-l-phenylcyclohexanecarboxamide ; trans-(RS)-4-({N- [2-(dimethylamino) acetyl]} aminomethyl)-N-{1- [3,5- bis (trifluorome. thyl) phenyl] ethyl}-l-phenylcyclohexanecarboxamide ; trans- (RS)-4- (lH-1, 2,3-triazol-1-yl)-N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl}-l- phenylcyclohexanecarboxamide ; trans-N-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclo hexyl}methyl)-3, 5- bis (trifluoromethyl) benzenecarboxamide ; trans-N-({4- [4-(4-fluorophenyl) piperidin-1-yl]-1-phenylcyclohexyl} methyl)-2- (methoxy) benzenemethanamine; trans-N- ( {4- [4- (4-fluorophenyl) piperidin-1-yl]-1-phenylcyclohexyl} methyl)-3, 5- bis (trifluoromethyl) benzenemethanamine ; cis-N-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohe xyl}methyl)-3, 5- bis (trifluoromethyl)benzenemethanamine- trans-N-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclo hexyl}methyl)-N- methyl-3, 5-bis (trifluoromethyl) benzenemethanamine ; cis-and trans-N-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1- phenylcyclohexyl}methyl)-N-{ [3,5-bis (trifluoromethyl) phenyl] methyl} acetamide ; <BR> <BR> <BR> <BR> trans-(RS)-N-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenyl cyclohexyl}methyl)-α- methyl-3, 5-bis (trifluoromethyl) benzenemethanamine ; trans-(RS)-α-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1- phenylcyclohexyl} methylamino)-3, 5-bis (trifluoromethyl)benzeneethanol ; trans- (RS)-a- ( {4- [4- (4-fluorophenyl) piperidin-1-yl]-1- phenylcyclohexyl} methylamino)-3, 5-bis (trifluoromethyl) benzeneethanamine ; cis-and trans- (E)-4- (4-fluorophenyl)-1- (4-phenyl-4- {3- [3, 5- bis (trifluoromethyl) phenyl] prop-l-enyl} cyclohexyl) piperidine ; cis-and trans- (E)-4- (4-fluorophenyl)-1- (4-phenyl-4- {3- [3, 5- bis (trifluoromethyl) phenyl] propyl} cyclohexyl) piperidine; cis-and trans- (RS)-4- (4-fluorophenyl)-1- (4- {2-hydroxy-3- [3, 5- bis (trifluoromethyl) phenyl] propyl}-4-phenylcyclohexyl) piperidine; cis-and trans- (RS)-4- (4-fluorophenyl)-1- (4- {2-oxo-3- [3, 5- bis (trifluoromethyl) phenyl] propyl}-4-phenylcyclohexyl) piperidine;

1- { [ (1, 4-dioxa-8-phenylspiro [4.5] decan-8-yl) methoxy] methyl}-3, 5- bis (trifluoromethyl) benzene; <BR> <BR> <BR> <BR> 1-({[4-oxo-1-phenylcyclohexyl] methoxy} methyl)-3,5-bis (trifluoromethyl) benzene;<BR> <BR> <BR> <BR> <BR> cis-1-({4-14-(4-fluorophenyl) piperidin-1-yl]-1-phenylcyclohexanemethoxy} methyl)- 3,5-bis (trifluoromethyl) benzene; trans-1- ( {4- [4- (4-fluorophenyl) piperidin-1-yl]-1- phenylcyclohexanemethoxy} methyl)-3, 5-bis (trifluoromethyl) benzene; (RS)-4-methylene-1-phenyl-N- 1- [3,5-bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide; cis- (RS)-4- (hydroxymethyl)-N- 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide ; trans- (RS)-4- (hydroxymethyl)-N-11- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-l- phenylcyclohexanecarboxamide ; and pharmaceutically acceptable salts thereof.

In a further aspect of the present invention, the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.

For use in medicine, the salts of the compounds of formula (I) will be non- toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e. g. sodium or potassium salts; and alkaline earth metal salts, e. g. calcium or magnesium salts.

The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate

acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.

The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in"Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the"parent drug"or"parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.

The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention have one or more asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers.

It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

The preferred compounds of the formula (I) and (Ia) will have the stereochemistry of the 1-and 4-positions as shown in formula (Ib)

It will be appreciated that the preferred definitions of the various substituents recited herein may be taken alone or in combination and, unless otherwise stated, apply to the generic formula for compounds of the present invention as well as to the preferred classes of compound represented by formula (Ia) and formula (Ib).

The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.

Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.

A more detailed description of pharmaceutical compositions that are suitable for the formulation of compounds of the present invention is disclosed in US patent No. 6,071,927, the content of which is incorporated herein by reference (see in particular, column 8, line 50 to column 10, line 4).

The present invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises bringing a compound of formula (I) into association with a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity. A comprehensive listing of clinical conditions, uses and methods of treatment for which the compounds of the present invention will be useful is disclosed in US patent No. 6,071,927, the content of which is incorporated herein by reference (see, in particular, column 10, line 14 to column 22, line 18).

In particular, the compounds of the present invention are useful in the treatment of a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder,

bipolar II disorder and cyclothymic disorder; and anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders.

The compounds of the present invention are also particularly useful in the treatment of nociception and pain. Diseases and conditions in which pain predominates, include soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, migraine, episiotomy pain, and burns.

The compounds of the present invention are also particularly useful in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; in the treatment of inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; and in the treatment of allergic disorders such as eczema and rhinitis.

The compounds of the present invention are also particularly useful in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as ulcerative colitis, Crohn's disease and irritable bowel syndrome.

The compounds of the present invention are also particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure.

Most especially, the compounds of formula (I) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy; by radiation including radiation therapy such as in the treatment of cancer; and in the treatment of post-operative nausea and vomiting.

The excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimising the risk of unwanted side effects.

In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.

For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

In the treatment of emesis, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

In the treatment of psychiatric disorders, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.

According to a general process (A), compounds of formula (I), in which X is -C (O) N (Rl3) CRl4Rl5-, may be prepared by the reaction of a compound of formula (II) with a compound of formula (III)

in the presence of a base and a coupling reagent.

Suitable bases of use in the reaction include tertiary amines, for example, triethylamine.

Suitable coupling reagents include any of the coupling reagents commonly used in peptide synthesis. A preferred coupling reagent is 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). Preferably the coupling reaction is effected in the presence of 1-hydroxybenzotriazole hydrate (HOBT).

The reaction is conveniently effected in a suitable organic solvent such as, for example, dimethylformamide.

According to an alternative general process (B), compounds of formula (I), in which X is-C (O) N (Rl3) CRl4Rl5-, may be prepared by the reaction of an amine of formula (III) with an activated carboxylic acid derivative of formula (IV) where L is a leaving group.

Suitable activated carboxylic acid derivatives represented in formula (IV) include acyl halides (e. g. acid chlorides) and acid anhydrides including mixed anhydrides (e. g. acid formic anhydride). These activated derivatives may be formed from the corresponding acid of formula (II) by well known procedures.

For example, acid chlorides may be prepared by reaction with phosphorus pentachloride, thionyl chloride or oxalyl chloride and acid anhydrides may be prepared by reaction with an appropriate acid anhydride (e. g. trifluoroacetic anhydride), an acid chloride (e. g. acetyl chloride), an alkyl or aralkyl haloformate (e. g. ethyl or benzyl chloroformate) or methanesulphonyl chloride.

A particularly preferred reagent for activating the carboxylic acid group is bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl).

Activated carboxylic acid derivatives of formula (IV) may also be prepared in situ by reaction of the corresponding acids of formula (II), with a coupling reagent such as carbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphorylazide.

The conditions under which the activated carboxylic acid derivatives of formula (IV) are formed and subsequently reacted with the amines of formula (III) will depend upon the nature of the activated derivative. However, in general the reaction between the compounds (III) and (IV) may be carried out in a non-aqueous medium such as, for example, dimethylformamide, tetrahydrofuran, acetonitrile or a halogenated hydrocarbon such as dichloromethane at a temperature within the range-25°C to +150°C. The reaction may optionally be carried out in the presence of a base such as triethylamine or pyridine and the base may also be used as the solvent for reaction.

Where acid chlorides are used, the reaction may be carried out using the Schotten-Baumann technique in the presence of a suitable base, for example, aqueous sodium hydroxide, conveniently at a temperature between 0°C and 100°C, for example, room temperature.

According to another general process (C), compounds of formula (I), in which X is-CRl4Rl5N (Rl3) C (O)-, may be prepared by the reaction of a compound of formula (V) with a compound of formula (VI) or an activated derivative thereof

using the methods described in processes (A) and (B), above.

According to another general process (D), compounds of formula (I), in which X is -CR14R15N (R13) CR16R17-, may be prepared by the reaction of a compound of formula (VII) with a compound of formula (VIII)

(wherein R30 is-CRl4Rl5NH2 and R31 is CHO, or R30 is CHO and R3'is -CRl6Rl7NH2) in the presence of a reducing agent.

Suitable reducing agents for use in this reaction include, for example, sodium cyanoborohydride or sodium triacetoxyborohydride.

The reaction is conveniently effected in a suitable solvent such as a halogenated hydrocarbon, for example, 1,2-dichloroethane, an alcohol, for example, methanol, acetic acid or a mixture thereof.

According to another general process (E), compounds of formula (I), in which X is-C (O) OCR14R15-, may be prepared by the reaction of an activated carboxylic acid derivative (IV) with a compound of formula (IX)

in the presence of a base.

Suitable bases of use in the reaction include aromatic amines such as pyridine or 4- (dimethylamino) pyridine (DMAP).

The reaction is conveniently effected in a suitable aprotic solvent such as, for example, dimethylformamide, or a halogenated hydrocarbon, for example, dichloromethane, or a mixture thereof.

According to another general process (F), compounds of formula (I), in which X is-CRl4Rl50C (O)-, may be prepared by the reaction of a compound of formula (X) with a compound of formula (XI)

(provided that R2la is not hydroxy) using a method described in process (E) above.

According to another general process (G), compounds of formula (I), in which X is-CRl4Rl50CRl6Rl7-, may be prepared by reacting a compound of formula (X) with a compound of formula (XII)

(wherein Hal is a halogen atom such as chlorine, iodine or, preferably, bromine), in the presence of a base such as sodium hydride.

The reaction is conveniently effected in a suitable aprotic solvent such as, for example, dimethylformamide.

According to another general process (H), compounds of formula (I), in which X is-CH=CHCRl8Rl9-, may be prepared by the reaction of a compound of formula (VII) where R30 is CHO with a compound of formula (XIII) in the presence of lithium hexamethyldisilazide.

The reaction is conveniently effected in a suitable aprotic solvent such as an ether, for example, tetrahydrofuran, at a reduced temperature, for example, at about-78°C.

According to another general process (J), compounds of formula (I), in which X is-CRl4Rl5CH=CH-, may be prepared by the reaction of a compound of formula (VIII) wherein R3'is CHO with a compound of formula (XIV)

using the method described in process (H), above.

It will be appreciated that compounds of formula (I) may also be prepared from other compounds of formula (I) by a variety of interconversion processes.

Thus, according to general process (K. 1), compounds of formula (I) in which X is-CRl4Rl5N (Rl3) CRl6Rl7-, may be prepared by the interconversion of a compound of formula (I) in which X is either-C (O) N (R13) CR14R'5- or -CR14Rl5N (Ri3) C (O)-, by reaction with a reducing agent.

Suitable reducing agents for use in this reaction include sodium borohydride or borane. tetrahydrofuran complex.

The reaction is conveniently effected in a solvent such as an ether, for example, tetrahydrofuran.

According to another general process (K. 2), compounds of formula (I) in which X is-CRl4Rl5OCH (CH3)- or -CH(CH3)OCR14R15-, may be prepared by interconversion of a compound of formula (I) in which X is-CRl4Rl50C (O)- or -C (O) OCR14Rl5-, respectively, by reaction with dimethyltitanocene in toluene followed by reduction using, for instance, catalytic hydrogenation conditions, for example, hydrogenation in the presence of palladium hydroxide on carbon, in a suitable solvent such as an ester, for example, ethyl acetate.

According to another general process (K. 3), compounds of formula (I) in which X is -CR14R15OCH (CHzOH)-or-CH (CHzOH) OCRl4Rl5-, may be prepared by interconversion of a compound of formula (I) in which X is -CR14R15OC (O)- or -C (O) OCR14R15-, respectively, by reaction with dimethyltitanocene in toluene followed by reduction using, for instance, a reducing agent such as

borane. tetrahydrofuran complex, followed by treatment with hydrogen peroxide in the presence of a base such as sodium hydroxide.

According to another general process (K. 4), compounds of formula (I) in which X is-CRl4Rl5CRl6Rl7CRl8Rl9-, may be prepared by interconversion of a compound of formula (I) in which X is -CR14=CR16CR18R19- or -CR14R15CR16=CR18-, by reduction using, for instance, catalytic hydrogenation conditions, for example, hydrogenation in the presence of palladium hydroxide on carbon, in a suitable solvent such as an alcohol, for example, methanol.

According to another general process (K. 5), compounds of formula (I) in which R7 is-(CH2) nNR8R9 (where n is zero) may be prepared by interconversion of a compound of formula (I) in which R6 and R7 together represent =0, by reaction with an appropriate amine, R8R9NH, in the presence of sodium cyanoborohydride and a Lewis acid, for example, zinc chloride, in a solvent such as an alcohol, for example, methanol, or in the presence of sodium triacetoxyborohydride in a solvent such as a halogenated hydrocarbon, for example, 1,2-dichloroethane.

Yet further interconversion reactions that may be effected using conventional procedures are shown in the following Scheme 1. The methods depicted in Scheme 1 are not exhaustive and illustrate just some of the possible routes to further compounds of formula (I).

Scheme 1 X HNC/O zu R3 Oh O Han N 0 NaCNBH3, NaCNBH3, ZnCl2, ME nCl2, MeOH R4 R R1 RUZ 5 v X _ 5 v X _ R s R2 R s R2 R R N N N 0 0 ph 0 o"ot ph HCl, Ph acetone | H2, Pd-C R4 . 4 Ri R1 R1 R1 Ra R2 Rs R2 FUT N Ç tN) Scheme 1 (continued) Scheme 1 (continued) It will be appreciated that reference to R, R'and R"in Scheme 1 refers to suitable substituents within the scope of the definitions of formula (I), insofar as said substituents are compatible with the reaction conditions described in Scheme 1.

Preferably, where R2la is halogen or hydroxy, or R2la and R2lb both represent fluorine or together represent oxo (=0), such substituents are introduced at a late stage by conventional methodology. It will be appreciated, however, that where such substituents are compatible with the reactions

described above, then such groups may be present, even if not depicted in the above formulae.

Further details of suitable procedures for the preparation of compounds of formula (I) will be found in the accompanying Examples.

Compounds of formula (II) may be prepared by conventional methods.

Thus for example, a compound of formula (II) wherein R6 and R7 together represent =O may be prepared according to the following two-step procedure or by methods analogous thereto: In step (i), methyl phenyl acetate is treated with a base such as sodium hydride and reacted with methyl acrylate. The reaction is conveniently effected in a solvent such as dimethylformamide at a temperature between 0°C and room temperature. In step (ii), selective decarboxylation is effected using, for example, lithium hydroxide. The reaction is conveniently effected in a solvent or mixture of solvents such as an alcohol, for example, methanol, an ether, for example, tetrahydrofuran, and water. The desired carboxylic acid is obtained by acid hydrolysis of the ester using, for example, a mineral acid such as hydrochloric acid.

Compounds of formula (III) are either known compounds or may be prepared by conventional methods. Examples of suitable methods include, but are not limited to, the methods shown in Scheme 2.

Scheme 2

0 s R1 NH40Ac, NaCNBH3, ß R1 0 R2 3A sieves, MeOH H2N 3 3 Compounds of formula (V) in which R14 and R15 are both hydrogen may be prepared from the corresponding carbonitrile compound of formula (XV)

by treatment with a reducing agent such as lithium aluminium hydride. The reaction is conveniently effected at room temperature in a solvent such as an ether, for example, diethyl ether.

Similarly, compounds of formula (VII) in which R30 is CHO may be prepared, for example, by reduction of the corresponding carbonitrile of formula (XV) using a suitable reducing agent such as diisobutylaluminium hydride (DIBAL-H). The reaction is conveniently effected in a solvent such as a halogenated hydrocarbon, for example, dichloromethane, or a hydrocarbon, for example, hexane, or a mixture thereof.

Compounds of formula (IX) are either known compounds or may be prepared by conventional methods, for instance, reduction of the corresponding carboxylic acid using, for example, lithium aluminium hydride at room temperature in a solvent such as as ether, for example, diethyl ether.

Similarly, compounds of formula (X) may be prepared by reduction of the corresponding carboxylic acid or, more preferably, the corresponding aldehyde of formula (VII) in which R30 is CHO. Suitable reducing agents include diisobutylaluminium hydride, lithium aluminium hydride or, more preferably, sodium borohydride. The reaction is conveniently effected in a solvent such as an ether, for example, diethyl ether, a halogenated hydrocarbon, for example dichloromethane, or a hydrocarbon, for example, hexane, or a mixture thereof.

Compounds of formula (XI) may be prepared from the corresponding carboxylic acid of formula (VI) using methods analogous to those described herein for the synthesis of compounds of formula (IV).

Compounds of formulae (XIII) and (XTV) may be prepared by conventional methods, in particular by the reaction of a compound of formula (XVI) or (XVII), respectively

(provided that R2la is not hydroxy) with 2,2'-dithiobis (benzothiazole) in the presence of tributylphosphine to afford the ethylthiobenzothiazole which is subsequently oxidised using, for example, oxone. The benzothiazole step is conveniently effected in an aprotic solvent such as an ether, for example, tetrahydrofuran, whilst the oxidation step is conveniently effected in a solvent such as a halogenated hydrocarbon, for example, chloroform.

Compounds of formulae (VI), (XII), (XV) and (XVI) are either known compounds or may be prepared by conventional methods, for instance, by methods analogous to those described herein.

Compounds of formula (I) in which the ring A is a pyridyl ring may be prepared in an analogous manner to the methods described above, replacing the phenyl ring depicted in the above formulae as appropriate.

It will be appreciated that the general methodology described above may be adapted, using methods that are readily apparent to one of ordinary skill in the art, in order to prepare further compounds of the present invention.

During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W.

McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01165.

The compounds were found to be active with ICso at the NKi receptor of less than lOOnM on said test method.

The following non-limiting Examples serve to illustrate the preparation of compounds of the present invention:

DESCRIPTION 1 Dimethyl 4-Oxo-l-phenyl-1, 3-cyclohexanedicarboxylate Sodium hydride (60% in mineral oil, 35.8 g, 1.49 mol) was washed with hexane to remove the mineral oil, suspended in dimethylformamide (400 mL) and cooled to 0 °C. Methyl phenyl acetate (42 mL, 0.3 mol) was added slowly with stirring. Methyl acrylate (59 mL, 0.65 mol) was added dropwise over 2 hours at 0 °C and the mixture was stirred at room temperature overnight. Aqueous ammonium chloride (saturated) was added and the mixture was extracted with dichloromethane (2 x 700 mL). The combined organic fractions were washed with water (5 x 500 mL), dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtO (80: 20) and the residue was triturated with isohexane/Et20 (50: 50). The solid was collected and dried in vacuo to give the title compound as colorless crystals (30 g, 35%).

'HNMR (400MHz, CDC13) õ 12.11 (1H, s), 7.36-7.25 (5H, m), 3.81 (3H, s), 3.64 (3H, s), 3.08 (1H, d, J 16.1 Hz), 2. 73 (1H, d, J 16.1 Hz), 2.26-2.37 (2H, m), and 2.22-2.17 (2H, m).

DESCRIPTION 2 4-Oxo-1-phenylcvclohexanecarboxylic Acid Lithium hydroxide monohydrate (11.08 g, 264 mmol) was added to a suspension of dimethyl 4-oxo-1-phenyl-1, 3-cyclohexanedicarboxylate (Description 1,25.5 g, 87.9 mmol) in methanol (250 mL), water (83 mL) and tetrahydrofuran (83 mL) and the mixture was heated under reflux for 3 days. The mixture was cooled and the tetrahydrofuran and methanol were evaporated under reduced pressure. The pH was adjusted to 1 with hydrochloric acid (SM) and the mixture was extracted with dichloromethane. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a light yellow solid (19 g, 99%).'H NMR (400MHz, CDC13) 8 7.50-7.29 (SH, m), 2.29-2.73 (2H, m), 2.62-2.55 (2H, m), 2.47-2.41 (2H, m), and 2.35-2.27 (2H, m).

DESCRIPTION 3 (RS)-1-F3 5-Bis (trifluoromethyl) phenyl-1 2-ethanediol Osmium tetroxide (2.5 wt% solution in 2-methyl-2-propanol, 1 mL) was added to a mixture of l-ethenyl-3, 5-bis (trifluoromethyl) benzene (1.85 g, 7. 74 mmol) and N-methylmorpholine-N- oxide (1.13 g, 9.67 mmol) in tetrahydrofuran (35 mL) and water (15 mL) and the mixture was stirred at room temperature for 18 hours. Aqueous sodium bisulfite (saturated, 30 mL) was added and the tetrahydrofuran was evaporated under reduced pressure. The mixture was extracted with ethyl acetate (2 x 100 mL) and the combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound

(2.09 g, 98%).'H NMR (400MHz, CDC13) 8 7.86 (2H, s), 7.82 (1H, s), 4.97 (1H, dd, J 8.0, 4.0 Hz), 3.87 (1H, dd, J 11. 0,4.0 Hz), and 3.66 (1H, dd, J 8. 0,11.0 Hz).

DESCRIPTION 4 (RS)-1-f3. 5-Bis (trifluoromethvl)-a-{ [2-(trimethylsilvl ! ethoxylmethoxymethvl} benzenemethanol N-Ethyl-N, N-diisopropylamine (465 pi, 2.67 mmol) was added over 2 minutes, to a solution of (RS)-1-[3, 5-bis (trifluoromethyl) phenyl-1, 2-ethanediol (Description 3,488 mg, 1.78 mmol) and [2- (chloromethoxy) ethyl] trimethylsilane (315 il, 1.78 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 4 hours, then at 50 °C for 1 hour. The mixture was cooled and dichloromethane (20 mL) and water (20 mL) were added. The layers were separated and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90: 10) to give the title compound (352 mg, 49%).'H NMR (400MHz, CDC13) 8 7.86 (2H, s), 7.79 (1H, s), 4.96 (1H, m), 4.73 (2H, s), 3.87 (1H, dd, J 11.1,3.0 Hz), 3.73 (1H, br s), 3.61 (3H, m), 0.93 (2H, t, J 8.5 Hz), and 0.02 (9H, s).

DESCRIPTION 5 (RS)-oc-Methyl-3, 5-bis (trifluoromethyl) benzenemethanamine O-Methylhydroxylamine hydrochloride (19.57 g, 234 mmol) was added to a solution of 1- [3,5-bis (trifluoromethyl) phenyl] ethanone (50 g, 195 mmol), and sodium acetate (31.9 g, 234 mmol) in ethanol (450 mL) and water (150 mL) and the mixture was heated under reflux for 18 hours. The mixture was cooled, water (1000 mL) was added and the mixture was extracted with diethyl ether. The combined organic fractions were dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL), cooled to 0 °C and borane-tetrahydrofuran complex (1M in tetrahydrofuran, 730 mL) was added. The mixture was heated under reflux for 18 hours, cooled and hydrochloric acid (5M, 500 mL) was added slowly. The tetrahydrofuran was evaporated under reduced pressure and the mixture was basified with aqueous sodium hydroxide (4M). The mixture was extracted with ether and the combined organic fractions were washed with aqueous sodium hydroxide (4M) and dried (MgSO4). and ethereal hydrogen chloride (400 mL, 400 mmol) was added. The solid was collected, washing with diethyl ether, and dried in vacuo to give (RS)-c-methyl-3, 5-bis (trifluoromethyl) benzenemethanamine hydrochloride as a

colorless solid (48. 2 g, 100%).'H NMR (400MHz, CD30D) 8 8.13 (2H, s), 8. 07 (1H, s), 4.73 (1H, q, J 6.8 Hz), 3.31 (2H, d, J 1. 4 Hz), and 1.69 (3H, d, J 6.8 Hz). m/z (ES+) 258 (M+1).

A sample was suspended in aqueous sodium hydroxide (4M) and extracted with ether. The combined organic fractions were washed with aqueous sodium hydroxide (4M), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil.'H NMR (400MHz, CDC13) õ 7.85 (2H, s), 7.76 (1H, s), 4.30 (1H, q, J 6.6 Hz), 1.74 (2H, br s), and 1.42 (3H, d, J 6. 6 h). m/z (ES+) 258 (M+1).

DESCRIPTION 6 (RS)-2-Methoxy-a-methylbenzenemethanamine Hydrochloride Sodium cyanoborohydride (2.46 g, 39.1 mmol) was added to a mixture of 1- (2- methoxyphenyl) ethanone (5.87 g, 39.1 mmol), ammonium acetate (30 g, 391 mmol) and 3A molecular sieves (20 g) in methanol (200 mL) and the mixture was stirred at room temperature for 3 days. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in aqueous sodium hydroxide (1M) and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water, dried (MgSO), and the solvent was evaporated under reduced pressure. The residue was dissolved in diethyl ether and ethereal hydrogen chloride (1M, 50 mL) was added. The solid was collected, washing with diethyl ether, and dried in vacuo to give the title compound as a colorless solid (6.82 g, 93%). m/z (ES+) 135 (M+1-NH3).

DESCRIPTION 7 (RS)-a-Ethvl-3, 5-bis strifluoromethyl) benzenemethanamine Hvdrochloride Prepared from 1- [3, 5-bis (trifluoromethyl) phenyl] propanone according to the method of Description 6. m/z (ES+) 272 (M+1), 255 (M+1-NH,).

DESCRIPTION 8 Methyl 3, 5-Bis (trifluoromethyl) benzeneacetate Sulfuric acid (conc., 1 mL) was added to a solution of 3,5-bis (trifluoromethyl) benzeneacetic acid (50.0 g, 0.18 mol) in methanol (400 mL) and the mixture was stirred at room temperature for 1 week. The solvent was evaporated and ethyl acetate (100 mL) and aqueous sodium hydrogen carbonate (saturated, 600 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 300 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (49.0 g, 93%).'H NMR (400MHz, CDC13) 7.80 (1H, s), 7.75 (2H, s), 3.77 (2H, s), and 3.75 (3H, s).

DESCRIPTION 9 Methyl a, cc-Dimethyl-3, 5-bis (trifluoromethyl) benzeneacetate Sodium hydride (60 % in mineral oil, 2.1 g, 52.5 mmol) was added in portions to a solution of methyl 3,5-bis (trifluoromethyl) benzeneacetate (Description 8,5 g, 17.5 mmol) in dimethylformamide (100 mL) and the mixture was stirred for 10 minutes. Iodomethane (5.45 mL, 87.5 mmol) was added and the mixture was stirred at room temperature overnight.

Aqueous ammonium chloride (saturated) was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (100: 0 increasing to 90: 10) to give the title compound as a colorless oil (5.34 g, 97%).'H NMR (400MHz, CDC13) 8 7. 78 (3H, s), 3.69 (3H, s), and 1.65 (6H, s).

DESCRIPTION 10 ana-Dimethyl-3, 5-bis (trifluoromethyl) benzeneacetic Acid Lithium hydroxide monohydrate (2.13 g, 50.6 mmol) was added to a suspension of methyl a, a-dimethyl-3, 5-bis (trifluoromethyl) benzeneacetate (Description 9,5.3 g, 16.88 mmol) in methanol (60 mL), water (20 mL) and tetrahydrofuran (20 mL) and the mixture was degassed and stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure and the residue was suspended in hydrochloric acid (1M). The mixture was extracted with ethyl acetate and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (5.05 g, 100%).'H NMR (400MHz, CDCI3) 8 7.84 (2H, s), 7.80 (1H, s), and 1.68 (6H, s).

DESCRIPTION 11 a. a-Dimethyl-3, 5-bis (trifluoromethvl) benzenemethanamine Hydrochloride Diphenylphosphoryl azide (0.43 mL, 2 mmol) was added to asolution of a, a-dimethyl-3, 5- bis (trifluoromethyl) benzeneacetic acid (Description 10,0.5 g, 1.67 mmol) and triethylamine (0.6 mL, 4.2 mmol) in toluene (20 mL) and the mixture was stirred at 90 °C for 18 hours. The mixture was cooled, diluted with ethyl acetate and washed with aqueous sodium carbonate (saturated), dried (MgS04) and the solvent was evaporated under reduced pressure.

Hydrochloric acid (5M, 15 mL) was added and the mixture was heated under reflux for 18 hours. The mixture was cooled, basified with aqueous sodium hydroxide (4M) and extracted with ethyl acetate. The combined organic fractions were washed with water, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was dissolved in diethyl

ether and ethereal hydrogen chloride (1M) was added. The solid was collected, washing with diethyl ether, and dried in vacuo to give the title compound as a colorless solid (100 mg, 20%). m/z (ES+) 272 (M+1), 255 (M+1-NH3).

DESCRIPTION 12 (RS)-Methyl a-Amino-3, 5-bis (trifluoromethyrlZbenzeneacetate Hvdrochloride Palladium on carbon (5%, 220 mg) was added to a solution of methyl a-diazo-3, 5- bis (trifluoromethyl) benzeneacetate (WO 9521819,1.22 g, 3.91 mmol) in methanol/acetic acid (3: 1,33 mL) and the mixture was shaken under an atmosphere of hydrogen (40 psi) for 18 hours. The mixture was filtered through a glass fibre pad and the solvent was evaporated under reduced pressure. Ethyl acetate (100 mL) and aqueous sodium carbonate (10%, 100 mL) were added and the layers were separated. The aqueous fraction was extracted with ethyl acetate (50 mL) and the combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and ethereal hydrogen chloride (1M, 5 mL) was added. The solid was collected, washing with ethyl acetate and ether, and dried in vacuo to give the title compound (432 mg, 33%). m/z (ES+) 302 (M+1).

DESCRIPTION 13 2- (Cyclopropyloxy)-5- (trifluoromethoxy) phenylmethvl Methanesulfonate Methanesulfonyl chloride (0.31 mL, 0.46 g, 4.0 mmol) was added dropwise to a stirred, cooled (-10 °C) solution of 2- (cyclopropyloxy)-5- (trifluoromethoxy) benzenemethanol (W09900368,0.5 g, 2.0 mmol) and triethylamine (0.56 mL, 0.40 g, 4.0 mmol) in dichloromethane (10 mL) and the mixture was stirred at 0 °C for 30 minutes, then at room temperature for 2 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic fractions were washed with aqueous citric acid (10%, 20 mL), aqueous sodium hydrogen carbonate (saturated, 50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound.'H NMR (400MHz, CDC1,) 8 7.28-7.22 (3H, m), 5.20 (2H, s), 3.80-3.77 (1H, m), 3.01 (3H, s), and 0.85-0.79 (4H, m).

DESCRIPTION 14 4- (4-Fluorophenyl) pyridine A mixture of 4-fluorobenzeneboronic acid (38.7 g, 276 mmol), 4-bromopyridine hydrochloride (48.9 g, 250 mmol), [1, 4-butanediylbis (diphenylphosphine-kP)] dichloropalladium (Organometallics 1998,17,661; 1.52 g, 2.5 mmol), 1,2-dimethoxyethane

(500 mL) and sodium carbonate solution (2M, 440 mL) was degassed with bubbling nitrogen and stirred at 80 °C for 24 hours. The mixture was cooled and extracted with ethyl acetate.

The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the crude title compound as a brown solid (50.87 g) which was used without further purification.'H NMR (360MHz, CDC13) 8 8.65 (2H, m), 7.61 (2H, m), 7.49 (2H, dd, J 1.6,4.6 Hz), and 7.09 (2H, m).

DESCRIPTION 15 4- (4-Fluorophenyl)-1. 2, 3, 6-tetrahydro-1- (phenylmethyl)rridine Benzyl bromide (52.4 mL, 441 mmol) was added to a solution of 4- (4-fluorophenyl) pyridine (Description 14,50.87 g, 294 mmol) in acetone (500 mL) and the mixture was heated under reflux for 3 days. The mixture was cooled to room temperature and the solid was collected, washed with acetone and diethyl ether and dried in vacuo. The solid was dissolved in methanol (400 mL) and water (100 mL), cooled to 0 °C and sodium borohydride (20.6 g, 542 mmol) was added in portions. The mixture was stirred at room temperature for 1 hour, then heated to reflux for 18 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. Dichloromethane (300 mL) and water (200 mL) were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a light brown oil (61.5 g, 78%). m/z (ES+) 268 (M+1).

DESCRIPTION 16 4-(4-Fluorophenyl) piperidine Palladium hydroxide on carbon (20%, 5 g) was added to a solution of 4- (4-fluorophenyl)- 1, 2,3,6-tetrahydro-l- (phenylmethyl) pyridine (Description 15,60 g, 225 mmol) in methanol (500 mL) and the mixture was shaken under an atmosphere of hydrogen (50 psi) for 48 hours.

The mixture was filtered through a glass fibre pad, washing with methanol, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and ethereal hydrogen chloride (1M, 300 mL) was added. The solid was collected and recrystallised from 2-propanol to give 4- (4 fluorophenyl) piperidine hydrochloride as a colorless solid (30.5 g, 63%).'H NMR (400MHz, CD30D) 8 7.31-7.27 (2H, m), 7.09-7.03 (2H, m), 3.48 (2H, m), 3.30 (2H, td, J 3.0,13.1 Hz), 2.91 (1H, m), 2.05 (2H, m), and 1.87 (2H, m). m/z (ES+) 180 (M+1).

A sample (1 g, 4.64 mmol) was suspended in ethyl acetate and washed with saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (825 mg, 99%).'H NMR

(400MHz, CDOD) 8 7.25-7.21 (2H, m), 7.02-6.97 (2H, m), 3.14 (2H, m), 2.78-2.64 (3H, m), 1.80 (2H, m), and 1.63 (2H, m). m/z (ES+) 180 (M+1).

DESCRIPTION 17 Benzenebutanal 1, 1, 1-Tris (acetyloxy)-l, 1-dihydro-1, 2-benziodoxol-3 (1H)-one (1.7 g, 4.0 mmol) was added to a solution of benzenebutanol (0.5 g, 3.3 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through a plug of silica gel, washing with dichloromethane, and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (466 mg, 95%).'H NMR (400MHz, CDC13) 8 9.76 (1H, m), 7.31-27 (2H, m), 7.22-7.16 (3H, m), 2.66 (2H, t, J 7.3 Hz), 2.45 (2H, t, J 7.3 Hz), 1.97 (2H, quin, J 7. 3 Hz).

DESCRIPTION 18 Methyl 4-Oxo-1-phenylcyclohexanecarboxylate Acetyl chloride (0.46 mL, 0.50 g, 6.4 mmol) was added to a solution of 4-oxo-1- phenylcyclohexanecarboxylic acid (Description 2,0.94 g, 4.3 mmol) in methanol (5 mL) and the mixture was heated under reflux for 20 hours. The mixture was cooled, poured into aqueous sodium hydrogen carbonate (saturated, 100 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic fractions were dried (Na2SO) and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL), acetic acid (6 mL) and water (2 mL) were added and the mixture was stirred at 45 °C for 2 hours. The mixture was cooled, the solvent was evaporated under reduced pressure and aqueous sodium hydrogen carbonate (saturated, 100 mL) was added. The mixture was extracted with ethyl acetate (2 x 50 mL), the combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (0.98 g, 98%).'H NMR (250MHz, CDC13) 8 7.45-7.26 (5H, m), 3.72 (3H, s), 2.77 (2H, m), 2.61-2.38 (4H, m), and 2.25 (2H, m).

DESCRIPTION 19 Cis-Methyl 4-r4- (4-Fluorophenvl)niperidin-1-yll-1-phenylcvclohexanecarboxyla te, Cis-4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexane carboxylic Acid and Trans-Methvl 4-r4-(4-Fluorophenv1) piperidin-1-vll-1-phenvlcyclohexanecarboxvlate A solution of sodium cyanoborohydride (0.93 g, 14.9 mmol) and zinc chloride (1.01 g, 7.45 mmol) in methanol (30 mL) was added to a solution of methyl 4-oxo-1- phenylcyclohexanecarboxylate (Description 18,3.45 g, 14.9 mmol) and 4- (4-

fluorophenyl) piperidine (Description 16,3.2 g, 17.9 mmol) in methanol (50 mL) and the mixture was stirred at room temperature for 24 hours. The mixture was poured into water and extracted with ethyl acetate and the combined organic fractions were dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was recrystallised from ethanol to give cis-methyl 4-[4-(4-fluorophenyl) piperidin-1-yl]-1-phenylcyclohexanecarboxylate (0.9 g, 15%) as a colorless solid.'H NMR (400MHz, CD30D) 8 7.38-7.36 (2H, m), 7.33-7.29 (2H, m), 7.26-7.20 (3H, m), 7.02-6.98 (2H, m), 3.66 (3H, s), 3.10 (2H, m), 2.71 (2H, m), 2.56-2.52 (1H, m), 2.43-2.32 (3H, m), 2.05 (2H, m), 1.84 (2H, m), 1.78-1.62 (4H, m), and 1.54-1.48 (2H, m). m/z (ES+) 396 (M+1).

The mother liquors from the recrystallisation were collected and the solvent was evaporated under reduced pressure. Methanol (20 mL) and hydrochloric acid (6M, 200 mL) were added and the mixture was heated under reflux for 3 days. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (100 mL) and acetyl chloride (0.77 mL, 10.8 mmol) was added slowly. The mixture was heated under reflux for 6 hours, cooled and the solvent was evaporated under reduced pressure. Ethyl acetate and aqueous sodium carbonate (saturated) were added and the layers were separated. The solid which formed in the organic layer was collected and dried in vacuo to give cis-methyl 4- (4- (4- fluorophenyl) piperidin-1-ylj-1-phenylcyclohexanecarboxylic acid as a colorless solid (1.2 g, 21%). m/z (ES+) 382 (M+1).

The mother liquors from the recrystallisation were dried (MgSO4) and the solvent was evaporated under reduced pressure to give trans-methyl 4- (4- (4 fluorophenyl) piperidin-1-ylj- I-phenylcyclohexanecarboxylate as a colorless solid, (1.6 g, 27%).

'H NMR (400MHz, CD30D) 8 7.51-7.48 (2H, m), 7.38-7.34 (2H, m), 7.24-7.17 (3H, m), 6.98-6.94 (2H, m), 3.56 (3H, s), 3.00 (2H, m), 2.79 (2H, m), 2.48-2.41 (2H, m), 2.24-2.17 (2H, m), 1.96-1.86 (4H, m), 1.75 (2H, m), 1.70-1.63 (2H, m), and 1.43-1.37 (2H, m). m/z (ES+) 396 (M+1).

DESCRIPTION 20 Trans-4-f4- (4-Fluorophenyl) piperidin-1-yl 1-1-phenylcyclohexanecarboxylic Acid Hydrochloride Hydrochloric acid (6M, 100 mL) was added to a suspension of trans-methyl 4- [4- (4- fluorophenyl) piperidin-1-yl]-1-phenylcyclohexanecarboxylate (Description 19,1.6 g, 4.05 mmol) in methanol (10 mL) and the mixture was heated under reflux for 48 hours. The mixture was cooled and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (1.5 g, 89%). m/z (BS+) 382 (M+1).

DESCRIPTION 21 Trarzs-4-r4- (4-Fluorophenyl) piperidin-1-ylphenylcyclohexanemethanol Diisobutylaluminium hydride (1M in hexanes, 1.95 mL, 1.95 mmol) was added slowly to a cooled (-78 °C) solution of traiis-methyl 4- [4- (4-fluorophenyl) piperidin-1-yll-l- phenylcyclohexanecarboxylate (Description 19,235 mg, 0.59 mmol) in dichloromethane (10 mL) and hexane (10 mL). The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was poured into aqueous ammonium chloride (saturated) and extracted with dichloromethane. The combined organic fractions were dried (MgS04) and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow foam (230 mg, 100%). m/z (ES+) 368 (m+1).

DESCRIPTION 22 (RS)-a-Methyl-8-phenvl-1, 4-dioxaspirof4. 51decane-8-methanol A solution of 8-phenyl-1, 4-dioxaspiro [4.5] decane-8-carboxaldehyde (J. Med. Chem. 1975,18, 593-599; 4 g, 16.2 mmol) in tetrahydrofuran (100 mL) was added dropwise to a solution of methyl magnesium bromide (3.0M in ether, 8. 1 mL, 24.3 mmol) in tetrahydrofuran (50 mL) at 0 °C. The mixture was allowed to warm to room temperature over 4 hours, then aqueous ammonium chloride (saturated, 75 mL), water (75 mL) and ethyl acetate (100 mL) were added. The layers were separated and the organic fraction was dried (MgS04) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (4.03 g, 96%).'H NMR (360MHz, CDCL) 5 0.96 (3H, d, J 6.5 Hz), 1.12 (1H, br s), 1.40-1.66 (4H, m), 1.76-1.86 (2H, m), 2.24-2.28 (1H, m), 2.46-2.51 (1H, m), 3.61-3.64 (1H, m), 3.85-3.96 (4H, m), and 7.21-7.38 (SH, m).

DESCRIPTION 23 (RS)-oc-Ethenyl-8-phenyl-1 4-dioxaspirof4. 51decane-8-methanol Prepared from 8-phenyl-1, 4-dioxaspiro [4.5] decane-8-carboxaldehyde (J. Med. Chem. 1975,18, 593-599) and vinylmagnesium bromide according to the method of Description 22.'H NMR (400MHz, CDCI3) 8 1.31 (1H, br s), 1.42-1.69 (4H, m), 1.76-1.89 (2H, m), 2.23-2.28 (1H, m), 2.45-2.51 (1H, m), 3.85-3.96 (SH, m), 5.09-5.14 (2H, m), 5.55-5.63 (1H, m), and 7.21-7.39 (SH, m).

DESCRIPTION 24 Trans-4- (4-Oxopiperidin-1-yl)-1-phenvlcyclohexanecarboxvlic Acid Hydrochloride Sodium acetoxyborohydride (7.0 g, 32.9 mmol) was added to a degassed solution of 4-oxo-1- phenylcyclohexanecarboxylic acid (Description 2,5.98 g, 27.4 mmol) and 1,4-dioxa-8- azaspiro [4.5] decane (4.32 g, 30.2 mmol) in dichloroethane (125 mL) and the mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure, methanol (120 mL) was added and the mixture was stirred at room temperature for 1 hour.

The mixture was filtered and cooled to 0 °C. Acetyl chloride (10 mL) was added slowly and the mixture was heated under reflux for 20 hours. The mixture was cooled, filtered and the solvent was evaporated under reduced pressure. Aqueous sodium carbonate (saturated, 200 mL) was added and the mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. Hydrochloric acid (5M, 300 mL) was added and the mixture was heated under reflux for 20 hours. The mixture was cooled and the solvent was evaporated under reduced pressure to give the title compound (3.36 g, 36%). m/z (ES+) 302 (M+1).

DESCRIPTION 25 Trans-4-f4- (Phenylmethyl) piperazin-1-yll-1-phenylcyclohexanecarboxylic Acid Hydrochloride Prepared from 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 2) and 1- (phenylmethyl) piperazine according to the method of Description 24. m/z (ES+) 379 (M+1).

DESCRIPTION 26 Cis-(R$)-4-Hvdroxy-1-phenvl-N-t 3=5-bis (trifluoromethvl ! phenyllethYl} cyclohexanecarboxamide Sodium borohydride (0.31 g, 8.3 mmol) in ethanol (10 mL) was added dropwise over 10 minutes to a stirred, cooled (0 °C) solution of (RS)-4-oxo-l-phenyl-N-1 1- [3, 5- bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 18,1.90 g, 4.1 mmol) in ethanol (60 mL). The mixture was stirred at 0 °C for 30 minutes, then hydrochloric acid (2M, 20 mL) was added. The mixture was stirred at room temperature for 10 minutes, then the pH was adjusted to 7.0 with aqueous potassium carbonate (saturated) and the ethanol was evaporated under reduced pressure. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with aqueous sodium hydrogen carbonate (saturated, 2 x 50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was crystallized from EtOH/H2O (50: 50,30 mL) and the solid was collected and dried in vacuo at 40 °C to give the title

compound (1.37 g, 72%).'HNMR (400MHz, CD30D) õ 7.76 (1H, s), 7.69 (2H, s), 7.32-7.17 (5H, m), 5.16 (1H, q, J 7.1 Hz), 3.60 (1H, m), 2.62 (2H, m), 1.97-1.47 (6H, m), and 1.43 (3H, d, J 7. 1 Hz).

DESCRIPTION 27 Cis- (RS)-4-Methanesulfonyloxv-N- {1- [3 5-bis (trifluoromethvl) phenvll ethyl}-1- phenylcyclohexanecarboxamide Methanesulfonyl chloride (0.9 mL, 11.6 mmol) was added to a stirred, cooled (0 °C) solution of cis- (RS)-4-hydroxy-1-phenyl-N- { 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Description 26,1.33 g, 2.9 mmol) and pyridine (0.94 mL, 11.6 mmol) in dichloromethane (100 mL) and the mixture was stirred at room temperature for 24 hours. The mixture was washed with aqueous citric acid (10%) and aqueous sodium hydroxide (1M), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give the title compound as a colorless foam (1.44 g, 95%).'H NMR (400MHz, CDCI3) 8 7.72 (1H, s), 7.44 (2H, s), 7.42-7.38 (2H, m), 7.35-7.31 (3H, m), 5.41 (1H, d, J6. 9 Hz), 5.07 (1H, m), 4.78 (1H, m), 3.03 (3H, s), 2.60-2.40 (2H, m), 2.14-1.87 (6H, m), and 1.35 (3H, d, J 7. 0 Hz).

DESCRIPTION 28 Trans- (RS)-4-Azido-N- (1-f3, 5-bis (trifluoromethyl) phenyllethyl}-1- phenylcyclohexanecarboxamide Sodium azide (621 mg, 9.55 mmol) was added to a solution of cis- (RS)-4- methanesulfonyloxy-N- {1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide (Description 27,1.0 g, 1.91 mmol) in dimethylformamide (15 mL) and the mixture was then stirred at 90 °C for 24 hours. The mixture was cooled, poured into aqueous ammonium chloride (saturated) and extracted with ethyl acetate. The combined organic fractions were washed with aqueous ammonium chloride (saturated) and water, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give the title compound as a yellow solid (920 mg, 100%).'H NMR (400MHz, CDCI3) 8 7.72 (1H, s), 7.45-7.31 (7H, m), 5.34 (1H, d, J 7.0 Hz), 5.03 (1H, m), 3.63 (1H, m), 2.41-2.37 (1H, m), 2.23-2.12 (3H, m), 1.99-1.93 (2H, m), 1.67-1.47 (2H, m), and 1.30 (3H, d, J 7. 0 Hz).

DESCRIPTION 29 Trans-(RS)-4-Cyano-N-{1-[3,5-bis(trifluoromethyl)phenyl]ethy l}-1- phenylcyclohexanecarboxamide Tetrabutylammonium cyanide (153 mg, 0. 57 mmol) was dried azeotropically by evaporating toluene under reduced pressure, then a solution of cis- (RS)-4-methanesulfonyloxy-N- { 1- [3, 5- bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide (Description 27, 100 mg, 0.19 mmol) in toluene (10 mL) was added and the mixture was stirred at 70 °C for 9 hours. Further tetrabutylammonium cyanide (153 mg, 0.57 mmol) was added and the mixture was stirred at 70 °C for 24 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic fractions were washed with water (50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (80: 20), to give the title compound (50 mg, 56%).'H NMR (360MHz, CD 30D) 8 7.76 (1H, s), 7.66 (2H, s), 7.36-7.22 (5H, m), 5.12 (1H, q, J7. 0 Hz), 3.00-2.96 (1H, m), 2.48-2.39 (2H, m), 2.29-2.21 (1H, m), 2.04-1.79 (5H, m), and 1.41 (3H, d, J 7. 0 Hz).

DESCRIPTION 30 Cis-and Trans-4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexa necarbonitrile Prepared as a mixture of cis-and trans-isomers from 4-oxo-1-phenylcyclohexanecarbonitrile and 4- (4-fluorophenyl) piperidine (Description 16) according to the method of Example 55. m/z (ES+) 363 (M+1).

DESCRIPTION 31 Trans-4-r4- (4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexanecarbonitr ile Prepared from the mixture of isomers of Description 30 by flash column chromatography on silica gel, eluting with OELCL/MeOH/NIL (Aq.) (98: 2: 0.2). m/z (ES+) 363 (M+1).

DESCRIPTION 32 rmn-4-f4-f4-Fluorophenvl) piperidin-l-vl1-l-phenylcyclohexanemethanamine Lithium aluminium hydride (1M in ether, 0.69 mL, 0.69 mmol) was added to a solution of trans-4- [4- (4-fluorophenyl) piperidin-1-ylj-1-phenylcyclohexanecarbonitrile (Description 31, 250 mg, 0.69 mmol) in ether (10 mL) and the mixture was stirred at room temperature for 1 hour. Water (0.5 mL), aqueous sodium hydroxide (1M, 1 mL) and water (1.5 mL) were added and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered, washing with ether, and the layers were separated. The organic layer was washed

with brine (10 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (243 mg, 96%). m/z (ES+) 367 (M+1).

DESCRIPTION 33 2-(f (2-r3. 5-Bis (trifluoromethyl) phenyllethyl thio) benzothiazole Tributylphosphine (3.46 mL, 2.81 g, 13.9 mmol) was added over 30 minutes to a mixture of 3,5-bis (trifluoromethyl) benzeneethanol (3.26 g, 12.6 mmol) and 2,2'-dithiobis (benzothiazole) (4.20 g, 12.6 mmol) in tetrahydrofuran (120 mL) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and water (150 mL) was added. The mixture was extracted with ether (2 x 150 mL) and the combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure.

The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90: 10) to give the title compound (3.87 g, 75%). m/z (ES') 408 (M+1).

DESCRIPTION 34 2-({(2-[3,5-Bis(trifluoromethyl)phenyl]ethyl}sulfonyl)benzot hiazole Oxone (8.58 g, 14.0 mmol) was added to a mixture of 2- ( { (2- [3, 5- bis (trifluoromethyl) phenyl] ethyl} thio) benzothiazole (Description 33,2.47 g, 6.1 mmol) and wet alumina (7 g) in chloroform (100 mL) and the mixture was heated under reflux for 1 hour.

The mixture was cooled, filtered and the solvent was evaporated under reduced pressure to give the title compound (2.62 g, 99%). m/z (ES+) 440 (M+1).

DESCRIPTION 35 (E)-8-Phenyl-8- {3-f3. 5-bis (trifluoromethvl) phenyllprop-1-envl}-1. 4-dioxaspirof4. 51decane Lithium hexamethyldisilazide (1M in tetrahydrofuran, 7.0 mL, 7.0 mmol) was added over 10 minutes to a cooled (-78 °C) solution of 8-phenyl-1, 4-dioxaspiro [4.5] decane-8- carboxaldehyde (J. Med. Chem. 1975,18,593-599,1.68 g, 6.8 mmol) and 2- ( { (2- [3, 5- bis (trifluoromethyl) phenyl] ethyl} sulfonyl) benzothiazole (Description 34,2.99 g, 6.8 mmol) in tetrahydrofuran (15 mL) and the mixture was stirred at-78 °C for 1 hour, then allowed to warm to room temperature. Aqueous ammonium chloride (saturated, 10 mL) was added and the mixture was stirred at room temperature for 30 minutes. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic fractions were washed with brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90: 10) to give the title compound as a pale yellow oil (2.43 g, 92%).

'HNMR (400MHz, CDCL) 8 7.70 (1H, s), 7.56 (2H, s), 7.36-7.18 (5H, m), 5.65 (1H, d, J

15.3 Hz), 5.41 (1H, dt, Jd 15.3, Jt 7.0 Hz), 3.94 (4H, m), 3.45 (2H, d, J 7.0 Hz), 2.22 (2H, m), 1.99 (2H, m), and 1.75-1.61 (4H, m).

DESCRIPTION 36 Trans- (RS)-4-Methyl-3-piperidinol Hydrochloride A slurry of palladium on carbon (10%, 600 mg) in ethanol (10 mL) was added to a solution of trans-(RS)-4-methyl-1-(phenylmethyl)-3-piperidinol (Tetrahedron 1970,26,5519-5527,6 g, 29.2 mmol) and hydrochloric acid (2M, 10 mL) in ethanol (100 mL) and the mixture was shaken under hydrogen (50 psi) for 42 hours. The mixture was filtered through Celiez and the solvent was evaporated under reduced pressure. Toluene (50 mL) was added and evaporated under reduced pressure to give the title compound as a colorless solid (4.4 g, 99%). m/z (ES+) 115 (M+1).

DESCRIPTION 37 Trans- (RS)-1, 1-Dimethylethyl 3-Hydroxv-4-methylpiperidinecarboxlate Di-tert-butyl dicarbonate (4.32 g, 20 mmol) was added to a solution of trans- (RS)-4-methyl-3- piperidinol hydrochloride (Description 36,2.93 g, 19.4 mmol) and triethylamine (4.1 mL, 29 mmol) in dichloromethane (150 mL) and the mixture was stirred at room temperature for 16 hours. N, N-Dimethylethylenediamine (506 pL) was added and the mixture was stirred at room temperature for 16 hours. The mixture was washed with aqueous citric acid (10%, 100 mL), dried (MgS04), and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (4.0 g, 96%). m/z (ES+) 159 (M+1).

DESCRIPTION 38 (RS)-1. 1-Dimethylethyl 4-Methyl-3-oxopiperidinecarboxylate 1, 1, 1-Tris (acetyloxy)-l, l-dihydro-1, 2-benziodoxol-3 (1H)-one (4. 17 g, 0.13 mmol) was added to a solution of trans-(RS)-1, 1-dimethylethyl 3-hydroxy-4-methylpiperidinecarboxylate (Description 37,2 g, 9.3 mmol) in dichloromethane (60 mL) and the mixture was stirred at room temperature for 60 minutes. Aqueous sodium bisulfite (10%, 50 mL) was added) and the mixture was stirred at room temperature for 5 minutes. Saturated aqueous sodium hydrogen carbonate (50 mL) was added and the layers were separated. The organic fraction was dried (MGSO) and the solvent was evaporated under reduced pressure to give the title compound (1.96 g, 99%). m/z (ES+) 157 (M+1).

DESCRIPTION 39 (RS)-3,3-Difluoro-4-methylpiperidine Hydrochloride Diethylaminosulphur trifluoride (1.18 mL, 8.97 mmol) was added to a stirred, cooled (0 °C) solution of (RS)-1, 1-dimethylethyl 4-methyl-3-oxopiperidinecarboxylate (Description 38, 500 mg, 2.24 mmol) in dichloromethane and the mixture was stirred at room temperature for 16 hours. Ice (5 g) and water (5 mL) were added and the mixture was stirred at room temperature for 20 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic fractions were washed with brine (50 mL), dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was suspended in diethyl ether (50 mL) and treated with methanolic hydrogen chloride (1M, 3 mL). The mixture was stirred at room temperature for 30 minutes, then the solvent was evaporated under reduced pressure to give the title compound as a solid (303 mg, 78%). m/z (ES+) 136 (M+1).

DESCRIPTION 40 1-(11-Dim thylethyl) 4-Ethvl 4-(2-Propenvl)-1*4-piperidinedicarboxylate A solution of 1- (1, 1-dimethylethyl) 4-ethyl 1,4-piperidinedicarboxylate (25.0 g, 97 mmol) in tetrahydrofuran (100 mL) was added slowly to a stirred, cooled (-78 °C) solution of potassium hexamethyldisilazide (29.0 g, 145 mmol) in tetrahydrofuran (150 mL), maintaining the internal temperature below-65 °C. The mixture was stirred at-78 °C for 30 minutes, then 3-bromopropene (12.6 mL, 145 mmol) was added dropwise over 10 minutes. The mixture was stirred at-78 °C for 1 hour, then saturated aqueous ammonium chloride (400 mL) and water (100 mL) were added and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate (3 x 400 mL) and the combined organic fractions were washed with aqueous citric acid (10%, 2 x 250 mL), saturated aqueous sodium hydrogen carbonate (400 mL) and brine (200 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (29.3 g, 100%).'H NMR (400MHz, CDCI,) 8 5.75-5.60 (1H, m), 5.10-5.00 (2H, m), 4.16 (2H, q, J 7 Hz), 3.92-3.78 (2H, m), 2.90 (2H, br t, J 14 Hz), 2.26 (2H, d, J 7 Hz), 2.08 (2H, br d, J 14 Hz), 1.45 (9H, s), 1.45-1.30 (2H, m), and 1.26 (3H, t, 77ho).

DESCRIPTION 41 1 1-Dimethylethyl 1-Oxo-2-oxa-8-azaspiroF4. 5ldecane-8-carboxylate 1- (1, 1-Dimethylethyl) 4-ethyl 4- (2-propenyl)-1, 4-piperidinedicarboxylate (Description 40, 20.0 g, 67.2 mmol) was dissolved in methanol (300 mL) and dichloromethane (300 mL) and cooled to-78 °C. Oxygen was bubbled through the solution for 10 minutes, then ozone for

75 minutes, to give a persistant blue coloration. Oxygen was bubbled through the solution for 10 minutes, then nitrogen for 10 minutes. Sodium borohydride (5.1 g, 135 mmol) was added and the mixture was stirred at-78 °C for 1 hour. Further sodium borohydride (5.1 g, 135 mmol) was added and the mixture was stirred at room temperature for 16 hours. Acetone (75 mL) was added and the mixture was stirred at room temperature for 10 minutes. Water (50 mL) was added and the organic solvent was evaporated under reduced pressure. Saturated aqueous ammonium chloride (500 mL) was added and the mixture was extracted with ethyl acetate (2 x 500 mL). The combined organic fractions were washed with aqueous citric acid (10%, 500 mL), saturated aqueous sodium hydrogen carbonate (500 mL) and brine (200 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (15.0 g, 88%).'H NMR (400MHz, CDC13) 6 4.31 (2H, t, J 7 Hz), 3.97-3.87 (2H, m), 3.17-3.07 (2H, m), 2.20 (2H, t, J 7 Hz), 1.92-1.82 (2H, m), 1.60-1.45 (2H, m), and 1.45 (9H, s).

DESCRIPTION 42 1 1-Dimethylethyl 4- (2-Hydroxyethyl)-4- (hydroxymethyl)-1-piperidinecarboxylate Diisobutylaluminium hydride (1. OM in dichloromethane, 3.60 mL, 3.60 mmol) was added over 10 minutes to a stirred, cooled (-78 °C) solution of 1, 1-dimethylethyl l-oxo-2-oxa-8- azaspiro [4.5] decane-8-carboxylate (Description 41,400 mg, 1.57 mmol) in dichloromethane (4 mL) and the mixture stirred at-78 °C for 3 hours, then at 0 °C for 2 hours. Water (1.6 mL) was added very slowly at 0 °C and the mixture was warmed to room temperature and stirred overnight. The mixture was filtered through Hyflo>, washing with dichloromethane, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate, to give the title compound (255 mg, 63%). m/z (ES+) 260 (M+1).

DESCRIPTION 43 1. l-Dimethylethyl 2-Oxa-8-azaspirof4. 51decane-8-carboxylate Diethyl azodicarboxylate (183, ul, 1.16 mmol) in tetrahydrofuran (0.5 mL) was added dropwise to a stirred, cooled (0 °C) solution of 1,1-dimethylethyl 4- (2-hydroxyethyl)-4- (hydroxymethyl)-1-piperidinecarboxylate (Description 42,250 mg, 0.96 mmol) and triphenylphosphine (303 mg, 1.16 mmol) in tetrahydrofuran (10 mL) and the mixture was stirred at 0 °C for 90 minutes then at room temperature overnight. The mixture was cooled to 0 °C and further triphenylphosphine (126 mg, 0.48 mmol) and diethyl azodicarboxylate (76 1ll, 0.48 mmol) were added. The mixture was stirred at room temperature for 2.5 hours, then the solvent was evaporated under reduced pressure and the residue was purified by flash

column chromatography on silica gel, eluting with isohexane/EtOAc (80: 20), to give the title compound as a colorless oil (150 mg, 65%). m/z (ES+) 186 (M+l-C4Hg).

DESCRIPTION 44 2-Oxa-8-azaspirof4. 51decane Methanolic hydrogen chloride (3M, 3 mL) was added to a stirred, cooled (0 °C) solution of 1, 1-dimethylethyl 2-oxa-8-azaspiro [4.5] decane-8-carboxylate (Description 43,150 mg, 0.62 mmol) in methanol and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol and passed through Amberlyst 26 ion exchange resin, eluting with methanol. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane, dried (Na, SO,) and the solvent was evaporated under reduced pressure to give the title compound (77 mg, 88%). m/z (ES+) 142 (M+1).

EXAMPLE 1 1-{[(1,4-Dioxa-8-phenylspiro[4,5]decan-8-yl)methoxy]methyl}- 2-methoxybenzene Sodium hydride (60% dispersion in mineral oil, 720 mg, 30.0 mmol) was added to a solution of 8-phenyl-1, 4-dioxaspiro [4.5] decane-8-methanol (J. Org. Cliem. 1974,39,2311-2313,1.5 g, 6.0 mmol) in dimethylformamide (20 mL) and the mixture was stirred at room temperature for 1 hour. 1-(Chloromethyl)-2-methoxybenzene (816 mg, 6.0 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was cooled, poured into water (50 mL) and extracted with ether (2 x 50 mL). The combined organic fractions were washed with water (3 x 50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90: 10), to give the title compound as a colorless solid (930 mg, 42%).'H NMR (400MHz, CDC13) 8 7.43-7.40 (2H, m), 7.33-7.29 (2H, m), 7.21-7.13 (3H, m), 6.86 (1H, td, J 0.6,7.4 Hz), 6.78 (1H, d, J 8. 2 Hz), 4.41 (2H, s), 3.95-3.86 (4H, m), 3.74 (3H, m), 3.41 (2H, s), 2.26 (2H, dd, J 3. 2,15.0 Hz), 1.98 (2H, dd, J 3. 6,13.0 Hz), and 1.68-1.53 (4H, m).

EXAMPLE 2 1-( {r4-0xo-l-phenylcyclohexyl1methoxy} methyl)-2-methoxybenzene Prepared from 1- { [(1, 4-dioxa-8-phenylspiro [4.5] decan-8-yl) methoxy] methyl}-2- methoxybenzene (Example 1) according to the method of Example 10.'H NMR (400MHz, CDCL) 8 7.50-7.47 (2H, m), 7.41-7.37 (2H, m), 7.30-7.15 (3H, m), 6.89 (1H, td, J0. 7,

7.4 Hz), 6.81 (1H, d, J 8.2 Hz), 4.44 (2H, s), 3.76 (3H, s), 3.46 (2H, s), 2.56-2.51 (2H, m), and 2.34-2.17 (6H, m).

EXAMPLE 3 1-{[(1,4-Dioxa-8-phenylspiro[4,5]decan-8-yl)methyoxy]methyl} -2-(cyclopropoxy)-5- (trifluoromethoxv) benzene Prepared from 8-phenyl-1, 4-dioxaspiro [4.5] decane-8-methanol (J. Org. Chelem. 1974,39,2311- 2313) and 2-(cyclopropyloxy)-5-(trifluoromethoxy) phenylmethyl methanesulfonate (Description 13) according to the method of Example 1.'H NMR (400MHz, CDCl3) 87. 42 (2H, dd, J 8.0,1.0 Hz), 7.32 (2H, t, J 8. 0 Hz), 7.23-7.18 (1H, m), 7.12-7.09 (1H, m), 7.03-7.01 (2H, m), 4.31 (2H, s), 3.97-3.88 (4H, m), 3.68-3.63 (1H, m), 3.40 (2H, s), 2.29 (2H, d, J 14.0 Hz), 1.94 (2H, dt, Jd 4-0, Jt 14.0 Hz), 1.67-1.53 (4H, m), and 0.77-0.66 (4H, m).

EXAMPLE 4 l- (ff4-0xo-l-phenylcyclohexyl1methoxy} methyl)-2- (cyclopropoxv)-5- (trifluoromethoxy) benzene Prepared from 1- { [(1, 4-dioxa-8-phenylspiro [4.5] decan-8-yl) methoxy] methyl}-2- (cyclopropoxy)-5- (trifluoromethoxy) benzene (Example 3) according to the method of Example 10.'H NMR (400MHz, CDC13) 8 7.49 (2H, d, J 7.6 Hz), 7.41 (2H, t, J 7.6 Hz), 7.29 (1H, t, J 7.6 Hz), 7.13 (1H, d, J 8. 8 Hz), 7.06-7.00 (2H, m), 4.34 (2H, s), 3.69-3.65 (1H, m), 3.45 (2H, s), 2.61-2.56 (2H, m), 2.38-2.32 (4H, m), 2.17-2.09 (2H, m), and 0.79-0.66 (4H, m).

EXAMPLE 5 (RS)-l-f (oc-Methyl-8-phenyl-1, 4-dioxaspirof4. 51decane-8-methoxy) methyll-3, 5- bis (trifluoromethyl) benzene Sodium hydride (60% suspension in mineral oil, 700 mg, 30 mmol) was added in portions to a solution of (RS)-a-methyl-8-phenyl-1, 4-dioxaspiro [4.5] decane-8-methanol (Description 22, 4 g, 15.3 mmol) in dimethylformamide (30 mL) and the mixture was stirred at room temperature for 1 hour. 1- (Bromomethyl)-3, 5-bis (trifluoromethyl) benzene (2.8 mL, 15.3 mmol) was added and the mixture was stirred at 95 °C for 2.5 hours. The mixture was cooled, poured into water (500 mL) and extracted with diethyl ether (2 x 500 mL). The combined organic fractions were dried (MgSO,) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90: 10) to give the title compound as a pale oil (4.1 g, 55%).'H NMR (360MHz, CDC13) 8 0.98 (3H, d, J 6.5 Hz), 1.48-1.65 (4H, m), 1.87-1.97 (2H, m),

2.24-2.28 (1H, m), 2.43-2.50 (1H, m), 3. 43 (1H, q, J 6.1 Hz), 3.86-3.96 (4H, m), 4.33 (1H, d, J 12.6 Hz), 4.61 (1H, d, J 12.6 Hz), 7.19-7.41 (5H, m), 7.69 (2H, s), and 7.75 (1H, s).

EXAMPLE 6 (RS)-1-f (a-Methyl-4-oxo-1-phenylcyclohexanemethoxy) methyll-3, 5- bis(trifluoromethyl) benzene Prepared from (R [ (a-methyl-8-phenyl-1, 4-dioxaspiro [4.5] decane-8-methoxy) methyl]- 3,5-bis (trifluoromethyl) benzene (Example 5) according to the method of Example 10.'H NMR (360MHz, CDCI3) 8 1.03 (3H, d, J 6.5 Hz), 1.98-2.15 (2H, m), 2.23-2.33 (4H, m), 2.53-2.58 (1H, m), 2.70-2.78 (1H, m), 3.50 (1H, q, J 6. 1 Hz), 4.34 (1H, d, J 12.6 Hz), 4.63 (1H, d, J 12.6 Hz), 7.28-7.49 (5H, m), 7.67 (2H, s), and 7.77 (1H, s).

EXAMPLE 7 (R S)-l-f (a-Ethenyl-8-phenyl-1 z4-dioxaspirof4. 51decane-8-methoxv ! methvll-3. 5- bis (trifluoromethyl) benzene Prepared from (RS)-α-ethenyl-8-phenyl-1, 4-dioxaspiro [4.5] decane-8-methanol (Description 23) and 1- (bromomethyl)-3, 5-bis (trifluoromethyl) benzene according to the method of Example 5.'H NMR (360MHz, CDCl3) # 1. 46-1.62 (4H, m), 1.76-1.90 (2H, m), 2.26-2.32 (1H, m), 2.45-2.54 (1H, m), 3.58 (1H, d, J 8.3 Hz), 3.85-3.95 (4H, m), 4.24 (1H, d, J 12. 6 Hz), 4.53 (1H, d, J 12.6 Hz), 5.12-5.29 (2H, m), 5.40-5.50 (1H, m), 7.20-7.40 (5H, m), 7.61 (2H, s), and 7.73 (1H, s).

EXAMPLE 8 (RS-l-f (a-Ethenyl-4-oxo-1-phenylcyclohexanemethoxy) methyll-3, 5- bis (trifluoromethyl) benzene Prepared from (RS)-1-[(α-ethenyl-8-phenyl-1, 4-dioxaspiro [4.5] decane-8-methoxy) methyl]- 3,5-bis (trifluoromethyl) benzene (Example 7) according to the method of Example 10.'H NMR (360MHz, CDC13) õ 1.92-2.04 (2H, m), 2.22-2.41 (4H, m), 2.58-2.65 (1H, m), 2.77-2.83 (1H, m), 3.63 (1H, d, J 8.4 Hz), 4.26 (2H, d, J 12.8 Hz), 4.56 (1H, d, J 12.8 Hz), 5.17 (1H, d, J 17.2 Hz), 5.29-5.34 (1H, m), 5.45-5.54 (1H, m), 7.29-7.49 (5H, m), 7.59 (2H, s), and 7.75 (1H, s).

EXAMPLE 9 (1,4-Dioxa-8-phenylspirof4 Sldecan-8-vl) methyl 3, 5-Bis (trifluoromethbenzoate 3,5-Bis (trifluoromethyl) benzoyl chloride (115 gel, 0.64 mmol) was added to a solution of 8- phenyl-1, 4-dioxaspiro [4.5] decane-8-methanol (J. Org. Chem. 1974,39,2311-2313,150 mg, 0.6 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 16 hours. Triethylamine (83 jil, 0.6 mmol) and 4-dimethylamino pyridine (1 crystal) were added and the mixture was stirred at room temperature for 1 hour. 3,5- Bis (trifluoromethyl) benzoyl chloride (57 ul, 0.32 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (5: 1), to give the title compound as a colorless oil (231 mg, 78%) contaminated with about 10% of (4-oxo-1-phenylcyclohexyl} methyl 3,5- bis (trifluoromethyl) benzoate.'H NMR (360MHz, CD13) õ 1.55-1.73 (SH, m), 1.97 (2H, dt, J 3.7,13.7 Hz), 2.39 (2H, m), 3.89-3.98 (4H, m), 7.23-7.27 (1H, m), 7.35-7.7.39 (2H, m), 7.45-7.47 (2H, m), 8.02 (1H, s), and 8.31 (2H, s).

EXAMPLE 10 (4-Oxo-l-phenylcvclohexyl} methvl 3. 5-Bis (trifluoromethyl) benzoate Hydrochloric acid (2M, 2 mL, 4 mmol) was added to a solution of (1, 4-dioxa-8- phenylspiro [4.5] decan-8-yl) methyl 3,5-bis (trifluoromethyl) benzoate (Example 9,220 mg, 0.45 mmol) in acetone and the mixture was heated under reflux for 30 minutes. The mixture was cooled and the solvent was evaporated under reduced pressure. Aqueous sodium carbonate (saturated) was added and the mixture was extracted with ethyl acetate (3 x 20 mL).

The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (190 mg, 95%).'H NMR (360MHz, CDC13) 8 2.04-2.13 (2H, m), 2. 37-2.42 (4H, m), 2.66-2.76 (2H, m), 4.37 (2H, s), 7.34 (1H, t, J 7. 3 Hz), 7.46 (2H, t, J 7. 7 Hz), 7.53-7.56 (2H, m), 8.04 (1H, s), and 8.32 (2H, s).

EXAMPLE 11 1-{1-[(1,4-Dioxa-8-phenylspiro[4,5]decan-8-yl)methoxy]etheny l]}-3,5- bis (trifluoromethyl) benzene A solution of (1, 4-dioxa-8-phenylspiro [4.5] decan-8-yl) methyl 3,5- bis (trifluoromethyl) benzoate (Example 9,500 mg, 1.0 mmol) in toluene (10 mL) was

degassed with a stream of nitrogen for 15 minutes. Dimethyltitanocene (0.2M in toluene, 10 mL, 2 mmol) was added and the mixture was degassed for a further 10 minutes. The mixture was heated at 90 °C in the dark for 12 hours, cooled, degassed for 10 minutes, and further dimethyltitanocene (0.2M in toluene, 5 mL, 1 mmol) was added. The mixture was heated at 90 °C in the dark for 15 hours, cooled, and sodium bicarbonate (3.1 g), methanol (50 mL) and water (1.9 mL) were added. The mixture was stirred at 40 °C for 2 hours, cooled, filtered through a bed of Celiez and the solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2 x 50 mL). The combined organic fractions were washed with brine, dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Clz/isohexane (50: 50), to give the title compound as a colorless gum (272 mg, 55%). 1H NMR (360MHz, CDCl3) 8 1.59-1.72 (4H, m), 1.96-2.04 (2H, m), 2.41 (2H, br s, J 13. 7 Hz), 3.77 (2H, s), 3.89-3.98 (4H, m), 4.27 (1H, d, J 3.3 Hz), 4.69 (1H, d, J 3.3 Hz), 7.23-7.27 (1H, m), 7.36-7.40 (2H, m), 7.47-7.50 (2H, m), 7.75 (1H, s), and 7.85 (2H, s).

EXAMPLE 12 (RS)-1-{1-r (1. 4-Dioxa-8-phenvlspirof4. 5ldecan-8-el) methoxYlethyll}-3*5- bis (trifluoromethyl) benzene Palladium on carbon (5%, 20 mg) was carefully added as an aqueous slurry to a solution of 1- {1-[(1, 4-dioxa-8-phenylspiro [4. 5] decan-8-yl) methoxy] ethenyl]}-3, 5- bis (trifluoromethyl) benzene (Description34,265 mg, 0. 5 mmol) in ethanol (20 mL) and ethyl acetate (2 mL) and the mixture was shaken under an atmosphere of hydrogen (50 psi) for 3 hours. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound as a colorless gum (225 mg, 85%).'H NMR (360MHz, CDC13) 8 1.30 (3H, d, J 6. 5 Hz) 1.54-1.64 (4H, m), 1.86-1.97 (2H, m), 2.21-2.30 (2H, m), 3.19 (1H, d, J 8.7 Hz), 3.27 (1H, d, J 8.7 Hz), 3.87-3.97 (4H, m), 4.24 (1H, q, J 6.5 Hz), 7.19-7.37 (5H, m), 7.50 (2H, s), and 7.71 (1H, s).

EXAMPLE 13 (RS)-1-f 1-[(4-Oxo-1-phenvlcyclohexyl) methoxvlethyl}-3. 5-bis (trifluoromethyl) benzene Prepared from (RS)-1-{1-[(1, 4-dioxa-8-phenylspiro [4.5] decan-8-yl) methoxy] ethyl]}-3, 5- bis (trifluoromethyl) benzene (Example 12) according to the method of Example 10.'H NMR (360MHz, CDCL) 8 1.34 (3H, d, J 6. 5 Hz) 2.03-2.15 (2H, m), 2.29-2.36 (4H, m), 2.51-2.60 (2H, m), 3.23 (1H, d, J 9.0 Hz), 3.31 (1H, d, J 9. 0 Hz), 4.29 (1H, q, J 6.5 Hz), 7.27-7.31 (1H, m), 7.37-7.45 (4H, m), 7.51 (2H, s), and 7.73 (1H, s).

EXAMPLE 14 (RS)-ß-ff14-Dioxa-8-phenylSpiror4. 51decan-8-vl) methoxyl-35-bis (trifluoromethYl) benzeneethanol Borane tetrahydrofuran complex (1M in THF, 1.2 mL, 1.2 mmol) was added to a cooled (0 C) solution of 1-fl- [ (1, 4-dioxa-8-phenylspiro [4.5] decan-8-yl) methoxy] ethenyl]}-3, 5- bis (trifluoromethyl) benzene (Description34, 280 mg, 0.6 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 48 hours. Aqueous sodium hydroxide (4M, 2 mL) followed by aqueous hydrogen peroxide (30%, 2 mL) were added and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added and the mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the crude title compound as a colorless gum (263 mg), which was used without further purification.

EXAMPLE 15 (Rm--r (4-Oxo-l-phenylcyclohexyl) methoxvl-3, 5-bis (trifluoromethyl) benzeneethanol Prepared from (RS)-P- [ (1, 4-dioxa-8-phenylspiro [4.5] decan-8-yl) methoxy]-3, 5- bis (trifluoromethyl) benzeneethanol (Example 14) according to the method of Example 10.'H NMR (360MHz, CDCI,) 8 1.75-1.79 (1H, m), 2.01-2.09 (2H, m), 2.32-2.37 (4H, m), 2.56-2.69 (2H, m), 3.37 (1H, d, J 8. 8 Hz), 3.41 (1H, d, J 8.8 Hz), 3.53-3.57 (2H, m), 4.30-4.33 (1H, m), 7.31-7.35 (1H, m), 7.41-7.48 (4H, m), 7.52 (2H, s), and 7.79 (1H, s).

EXAMPLE 16 3, 5-Bis (trifluoromethyl) phenylmethvl4-Oxo-l-phenylcyclohexanecarboxylate Oxalyl chloride (4.8 mL, 55 mmol) was added to a solution of 4-oxo-1- phenylcyclohexanecarboxylic acid (Description 2,6 g, 27 mmol) and dimethylformamide (1 drop) in toluene (150 mL) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and toluene was added. The solvent was evaporated under reduced pressure and the residue was dissolved in toluene (100 mL). 3,5- Bis (trifluoromethyl) benzenemethanol (6.25 g, 26 mmol) and 4-dimethylaminopyridine (3.62 g, 30 mmol) were added and the mixture was heated under reflux for 24 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and hydrochloric acid (2M, 100 mL). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexanelCH2Cl2 (60: 40 increasing to

50: 50) to give the title compound (4.5 g, 40%).'H NMR (360MHz, CDC13) õ 2.33-2.53 (6H, m), 2.72-2.77 (2H, m), 5.23 (2H, s), 7.28-7.41 (5H, m), 7.51 (2H, s), and 7.77 (1H, s).

EXAMPLE 17 4-Oxo-1-phenyl-N-{ [3. 5-bis (trifluoromethyl) phenyllmethyl} cyclohexanecarboxamide Prepared from 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 2) and 3,5-bis (trifluoromethyl) benzylamine according to the method of Example 177. m/z (ES+) 444 (M+1).

EXAMPLE 18 (RS)-4-Oxo-l-phenyl-N-1 1-f3, 5-bis (trifluoromeLhyl) phenyllethyll cyclohexanecarboxamide Bis (2-oxo-3-oxazolidinyl) phosphinic chloride (2.18 g, 8.6 mmol) was added to a cooled (0 °C) solution of 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 2,1.33 g, 6.1 mmol) and triethylamine (2.55 mL, 1.85 g, 18.3 mmol) in dichloromethane (20 mL) and the mixture was stirred at room temperature for 20 minutes (RS)-a-methyl-3, 5- bis (trifluoromethyl) benzenemethanamine (Description 5,1.57 g, 6.1 mmol) in dichloromethane (10 mL) was added and the mixture was stirred at room temperature for 26 hours. The solvent was evaporated under reduced pressure and hydrochloric acid (2M, 50 mL) was added. The mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organic fractions were washed with hydrochloric acid (2M, 2 x 50 mL), aqueous sodium hydrogen carbonate (saturated, 2 x 50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (65: 35), to give the title compound as a colorless foam (1.96 g, 70%). m/z (ES+) 458 (M+1).

EXAMPLE 19 N-r (8-Phenyl-1. 4-dioxaspiror4. 51decan-8-yl) methyll-3, 5-bis (trifluoromethyl) benzenemethanamine Sodium triacetoxyborohydride (4.77 g, 22. 5 mmol) was added to a solution of 8-phenyl-1, 4- dioxaspiro [4.5] decane-8-carboxaldehyde (J. Med. Chem. 1975,18,593-599). (1.1 g, 4.5 mmol) and 3,5-bis (trifluoromethyl) benzenemethanamine (1.1 g, 4.5 mmol) in dichloroethane (50 mL) and the mixture was stirred at room temperature overnight. The mixture was poured into saturated aqueous sodium hydrogen carbonate (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic fractions were washed with brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash

column chromatography on silica gel, eluting with isohexane/EtOAc (75: 25), to give the title compound as a yellow oil (1.0 g, 47%). m/z (ES+) 473 (M+1).

EXAMPLE 20 N-f (8-Phenvl-1 4-dioxaspirof. 51decan-8-yl) methyll-N-f f. 5-bis (trifluoromethvl) phenyll methylt acetamide Acetic anhydride (2 mL) was added to a solution of N- [ (8-phenyl-1, 4-dioxaspiro [4.5] decan-8- yl) methyl]-3,5-bis (trifluoromethyl) benzenemethanamine (Example 19,291 mg, 0.61 mmol) in pyridine (5 mL) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (25 mL).

The mixture was washed with aqueous copper sulphate (5%, 2 x 25 mL) and brine (25 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (316 mg, 100%). m/z (ES+) 516 (M+1).

EXAMPLE 21 N-f(4-Oxo-1-phenylcyclohexvDmethyII-N- {f3. 5-bis (trifluoromethyDphenyl1methyl} acetamide Prepared from N- [ (8-phenyl-1, 4-dioxaspiro [4.5] decan-8-yl) methyl]-N- {t3, 5- bis (trifluoromethyl) phenyl] methyl} acetamide (Example 20) according to the method of Example 10.'H NMR (400MHz, CDC13) mixture of two rotamers; major rotamer 8 7.76 (1H, s), 7.50-7.39 (5H, m), 7.20 (2H, s), 3.71 (2H, s), 3.56 (2H, s), 2.75-2.10 (8H, m), and 2.07 (3H, s); minor rotamer 8 7.72 (1H, s), 7.50-7.39 (5H, m), 7.31 (2H, s), 4.24 (2H, s), 3.43 (2H, s), 2.75-2.10 (8H, m), and 1.83 (3H, s).

EXAMPLE 22 (E)-4-Phenyl-4-{3-[3 5-bis (trifluoromethyl) phenyl]prop-1-enyl}cyclohexanone Prepared from 8-phenyl-8- {3- [3, 5-bis (trifluoromethyl) phenyl] prop-1-enyl} 1, 4- dioxaspiro [4.5] decane (Description 35) according to the method of Example 10.'H NMR (400MHz, CDC13) õ 7.71 (1H, s), 7.62 (2H, s), 7.46-7.28 (5H, m), 5.75 (1H, d, J 15. 4 Hz), 5.49 (1H, dt, J, 15.4, Ja 7.1 Hz), 3.49 (2H, d, J 7. 1 Hz), 2.46 (6H, m), and 2.20 (2H, m).

EXAMPLE 23 (RSl-l- (8-Phenyl-1,4-dioxaspiro[4,5]decan-8-yl)-3-[3 5-bis (trifluoromethylßphenyll propan-2- yl Ethanoate and (RS)-1-(8-Phenyl-1,4-dioxaspiro[4,5]decan-8-yl]-3-[3, 5-bis (trifluoromethyl) phenyll propan-l- yl Ethanoate Borane-tetrahydrofuran complex (1. OM in tetrahydrofuran, 12 mL, 12 mmol) was added over 10 minutes to a solution of (Z-8-phenyl-8- {3- [3, 5-bis (trifluoromethyl) phenyl] prop-1- enyl} 1, 4-dioxaspiro [4.5] decane (Description 35,1.88 g, 4 mmol) and the mixture was stirred at room temperature for 4.5 hours. Water (2 mL) then aqueous sodium hydroxide (4M, 20 mL) and aqueous hydrogen peroxide (30 w/v%, 20 mL) were added and the mixture was stirred at room temperature for 30 minutes. Water (150 mL) was added and the mixture was extracted with ether (2 x 150 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in pyridine (10 mL) and 4-dimethylaminopyridine (10 mg) and acetic anhydride (5 mL) were added. The mixture was stirred at room temperature for 4 hours, then water (150 mL) was added. The mixture was extracted with ethyl acetate (2 x 150 mL) and the combined organic fractions were washed with water (2 x 150 mL) and aqueous copper sulfate (5%, 2 x 100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CHzCl2/EtOAc (99: 1 increasing to 95: 5), to give: <BR> <BR> <BR> <BR> (RS)-1-(8-phenyl-1, 4-dioxaspiro [4. 5] decan-8-yl)-3-f3, 5-bis (trifluoromethyl) phenyl] propan- 2-yl etlzanoate (803 mg, 38%) ;'H NMR (360MHz, CDC13) õ 7.67 (1H, s), 7.36 (2H, s), 7.28-7.13 (5H, m), 4.87 (1H, m), 3.90 (4H, m), 2.68 (1H, dd, J 13. 7,6.7 Hz), 2.45 (1H, dd, J 13.7,6.2 Hz), 2.23 (2H, m), 1.96 (1H, dd, J 14.7,7.4 Hz), 1.80-1.45 (7H, m), and 1.72 (3H, m) ; and (RS)-1-(8-Phenyl-1,4-dioxaspiro[4,5]decan-8-yl]-3-[3,5-bis(t rifluoromethyl)phenyl] propan- 1-yl ethanoate (425 mg, 20%);'H NMR (360MHz, CDCl3) 8 7.66 (1H, s), 7.44 (2H, s), 7.35-7.20 (5H, m), 4.98 (1H, dd, J 10.1,2.1 Hz), 3.89 (4H, m), 2.51 (2H, m), 2.24 (2H, m), 2.06 (3H, s), and 1.95-1.40 (8H, m).

EXAMPLE 24 <BR> <BR> <BR> <BR> <BR> (RS)-1-(8-Phenyl-1. 4-dioxaspiror4. sldecan-8-yl)-3-r3*5-bis (trifluoromethyl) phenyll propan-2- ol Potassium carbonate (2.5 g) was added to a solution of (rus)-1- (8-phenyl-1, 4- dioxaspiro [4.5] decan-8-yl)-3- [3, 5-bis (trifluoromethyl) phenyl] propan-2-yl ethanoate (Example 23,700 mg, 1.3 mmol) in methanol (20 mL) and water (3 mL) and the mixture was stirred at

room temperature for 4 days. The methanol was evaporated under reduced pressure, water (50 mL) was added and the mixture was extracted with ethyl acetate (3 x 75 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (626 mg, 97%).'H NMR (400MHz, CDC1,) 8 7.68 (1H, s), 7.49 (2H, s), 7.34 (4H, m), 7.22 (1H, m), 3.91 (4H, m), 3.75 (1H, m), 2.66 (1H, dd, J 13.8,8.2 Hz), 2.56 (1H, dd, J 13. 8,4.5 Hz), 2.33 (4H, m), and 1.89- 1.49 (4H, m).

EXAMPLE 25 (RS)-4-2-Hydroxv-3-r3, 5-bis (trifluoromethyl) phenyllpropyl}-4-phenylcyclohexanone Prepared from (RS)-l- (8-phenyl-1, 4-dioxaspiro [4.5] decan-8-yl)-3- [3, 5- bis (trifluoromethyl) phenyl] propan-2-ol (Example 24) according to the method of Example 10.'H NMR (400MHz, CDCl3) # 7.70 (1H, s), 7.48 (2H, s), 7.42 (3H, m), 7.29 (2H, m), 3.72 (1H, m), 2.76-2.56 (4H, m), 2.33 (4H, m), and 2.03-1.77 (4H, m).

EXAMPLE 26 Trans-(RS)-1-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-α-methy l-1- phenylcyclohexanemethoxY} methyl)-3, 5-bis (trifluoromethvl) benzene Prepared from (RS)-1-[(α-methyl-4-oxo-1-phenylcyclohexanemethoxy) methyl]-3,5- bis (trifluoromethyl) benzene (Example 6) and 4- (4-fluorophenyl) piperidine (Description 16) according to the method of Example 55. The product was purified by preparative thin layer chromatography on silica gel, eluting with CH2Cl2/MeOH/Et3N (Aq.) (95: 5: 1). m/z (ES+) 608 (M+1).

EXAMPLE 27 <BR> <BR> <BR> <BR> Cis-(RS)-1-({α-Ethenyl-4-[4-(4-fluorophenyl)piperidin-1-yl] -1-<BR> <BR> <BR> <BR> phenylcyclohexanemethoxy} methyl)-3, 5-bisftrifluoromethyl) benzeneand<BR> <BR> <BR> <BR> Trans-(RS)-1-({α-Ethenyl-4-[4-(4-fluorophenyl)piperidin-1-y l]-1- phenylcyclohexanemethoxy methyl-3. 5-bis (trifluoromethyl) benzene Prepared from (RS)-1-[(α-ethenyl-4-oxo-1-phenylcyclohexanemethoxy) methyl]-3,5- bis (trifluoromethyl) benzene (Example 8) and 4- (4-fluorophenyl) piperidine (Description 16) according to the method of Example 55. The product was purified by preparative thin layer chromatography on silica gel, eluting with CHZCLs/MeOH/NH3 (Aq.) (95: 5: 1): trans- (RS)-I- ( (4- (4- (4-fluorophenyl) piperidin-1-ylJ-a ethenyl-l- phenylcyclohexanemethoxyJmethyl)-3, 5-bis (trifluoromethyl) benzene ;'H NMR (400MHz,

CDC1,) 8 1.21-1.41 (2H, m), 1.50-1.90 (8H, m), 2.20-2.26 (2H, m), 2.35-2.45 (3H, m), 2.63-2.68 (1H, m), 2.90-2.93 (2H, m), 3.37 (1H, d, J 8.4 Hz), 4.23 (1H, d, J 12. 6 Hz), 4.53 (1H, d, J 12. 6 Hz), 5.17 (1H, d, J 18. 8 Hz), 5.25-5.29 (1H, m), 5.42-5.51 (1H, m), 6.91-6.99 (2H, m), 7.10-7.42 (7H, m), 7.61 (2H, s), and 7.74 (1H, s); m/z (ES+) 620 (M+1) ; cis-(RS)-1-({4-[4-(4-fluorophenyl)piperidin-1-yl]-α-ethenyl -1- phenylcyclohexanemethoxyJmethyl)-3, 5-bis (trifluoromethyl) benzene ;'H NMR (400MHz, CDCI3) 8 1.44-1.68 (IOH, m), 2.10-2.31 (4H, m), 2.42-2.50 (1H, m), 2.75-2.83 (1H, m), 3.05-3.15 (2H, m), 4.07-4.11 (1H, m), 4.38 (1H, d, J 13. 2 Hz), 4.61 (1H, d, J 13.2 Hz), 5.18-5.28 (3H, m), 6.95-6.99 (2H, m), 7.16-7.44 (7H, m), 7.74 (2H, s), and 7.76 (1H, s); m/z (ES+) 620 (M+1).

EXAMPLE 28 <BR> <BR> <BR> <BR> <BR> Trans-(RS)-4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenyl-α- [3,5-bis(trifluoromethyl)<BR> <BR> <BR> <BR> <BR> <BR> phenylmethoxyl cyclohexaneethanol Ozone was bubbled through a stirred, cooled (-78 °C) solution of trans- (RS)-l- (14- [4- (4- fluorophenyl) piperidin-l-yl]-a-ethenyl-l-phenylcyclohexanemethoxy} methyl)-3, 5- bis (trifluoromethyl) benzene (Example 27,240 mg, 0.39 mmol) in dichloromethane (50 mL) and methanol (20 mL) for 5 minutes. Sodium borohydride (140 mg, 3.9 mmol) and methanol (50 mL) were added and the mixture was allowed to warm to room temperature. The solvent was evaporated under reduced pressure and ethyl acetate (50 mL) and aqueous sodium bicarbonate (saturated, 50 mL) were added. The layers were separated and the organic fraction was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/MeOH (90: 10) to give the title compound (52 mg, 21%). m/z (ES+) 624 (M+1).

EXAMPLE 29 <BR> <BR> <BR> <BR> <BR> Trans-(RS)-1-({α-Ethyl-4-[4-(4-fluorophenyl)piperidin-1-yl] -1-<BR> <BR> <BR> <BR> <BR> <BR> phenylcvclohexanemethoxy Tmethyl !-3. 5-bis (trifluoromethyl) benzene A slurry of palladium on carbon (10%, 20 mg) in methanol (10 mL) was added to a solution of trans- (RS)-I- (I (x-ethenyl-4- [4- (4-fluorophenyl) piperidin-1-yl]-l- phenylcyclohexanemethoxy} methyl)-3, 5-bis (trifluoromethyl) benzene (Example 27,90 mg, 0.14 mmol) in methanol (15 mL) and the mixture was shaken under an atmosphere of hydrogen (50 psi) for 16 hours. The mixture was filtered through Celiez and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (88 mg, 98%). m/z (ES+) 622 (M+1).

EXAMPLE 30 Trans-1-r ( {4-r4- (4-FIuorophenyI) piperidin-1-yH-1-phenylcyclohexyl t methoxy) methyl1-2- methoxybenzene A solution of sodium cyanoborohydride (83 mg, 1.3 mmol) and zinc chloride (90 mg, 0.66 mmol) in methanol (10 mL) and added to a solution of 1-({[4-oxo-1- phenylcyclohexyl] methoxy} methyl)-2-methoxybenzene (Example 2,400 mg, 1.3 mmol) and 4- (4-fluorophenyl) piperidine (Description 16,256 mg, 1.43 mmol) in methanol (10 mL) and the mixture was stirred at room temperature for 24 hours. The mixture was poured into saturated aqueous sodium hydrogen carbonate (20 rnL) and extracted with ethyl acetate (2 x 20 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel, eluting with CHzCI2/MeOH/NH3 (Aq.) (98: 2: 0.2), to give the title compound. m/z (ES+) 488 (M+1).

EXAMPLE 31 Trans-1-[({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcycl ohexyl}methoxy)methyl]-2- (cyclopropoxy)-5- (trifluoromethoxy) benzene Prepared from 1-({ [4-oxo-1-phenylcyclohexyl] methoxy} methyl)-2-(cyclopropoxy)-5- (trifluoromethoxy) benzene (Example 4) and 4- (4-fluorophenyl) piperidine (Description 16) according to the method of Example 55. m/z (ES+) 598 (M+1).

EXAMPLE 32 Cis-(RS)-1-[1-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-pheny lcyclohexyl}methoxy) ethyl]- 35-bis (trifluoromethyl) benzene and Trans-(RS)-1-[1-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phe nylcyclohexyl}methoxy) ethyl1-3. 5-bis (trifluoromethyl) benzene Prepared from (RS)-1-{1-[(4-oxo-1-phenylcyclohexyl) methoxy] ethyl}-3, 5- bis (trifluoromethyl) benzene (Example 13) and 4- (4-fluorophenyl) piperidine (Description 16) according to the method of Example 55: Cis- (RS)1-[1-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcycl ohexyl}methoxy) ethyl]- 3,5-bis(trifluoromethyl)benzene- 1H NMR (400MHz, CDCl3) # 1.32 (3H, d, J 6. 5 Hz), 1.43-1.90 (10h, m), 2.20-2.40 (4H, m), 2.44-2.50 (2H, m), 3.07-3.09 (2H, m), 3.45 (1H, d, J 9.2 Hz), 3.58 (1H, d, J 9.2 Hz), 4.28 (1H, q, J 6.5 Hz), 6.95-7.00 (2H, m), 7.16-7.30 (4H, m), 7.31-7.38 (3H, m), 7.51 (2H, s), and 7.72 (1H, s); m/z (ES+) 608 (M+1) ;

Trans-(RS)-1-[1-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phe nylcyclohexyl}methoxy) enthyl]- 3, 5-bis (trifluoromethyl) benzene ;'H NMR (360MHz, CDC13) 8 1.32 (3H, d, J 6.5 Hz), 1.42- 1.83 (10H, m), 2.10-2.20 (2H, m), 2.32-2.44 (4H, m), 2.90-3.00 (2H, m), 3.10 (1H, d, J 8.9 Hz), 3.16 (1H, d, J 8. 9 Hz), 4.23 (1H, q, J6. 5Hz), 6.93 (2H, t, J 8. 6 Hz), 7.10-7.22 (2H, m), 7.25-7.36 (5H, m), 7.52 (2H, s), and 7.72 (1H, s); m/z (ES+) 608 (M+1).

The following compounds were prepared as mixtures of cis-and trans-isomers from (RS)-1- {1-[(4-oxo-l-phenylcyclohexyl) methoxy] ethyl}-3, 5-bis (trifluoromethyl) benzene (Example 13) according to the method of Example 55, substituting a suitable amine for piperidine. P jX cF3 I/ NRz 2, 0 CF3 Cis-(RS)-& Trans-(RS)- mlz Ex.-NR, Formula M. W. (ES+) (M+1). 33 C28H33F6NO 513 514 34/-\ C28H33F6N02 529 530 zou 35/\ C31H37F6N03 585 586 -M)-COEt 36/-\ C27H31F6NO2 515 516 - 37 _ C27H3 lF6NO 499 500 H V 38/C25H29F6NO 473 474

The following trans-isomers were prepared from the compounds of Examples 33,34,37 and 38 by preparative thin layer chromatography on silica gel, eluting with CHCI/MeOH/EtN (95: 5: 1). Pi5-q CF3 -CF3 NEZ Trans-(RS)- mlz Ex.-NR2 Formula M. W. (ES+) (M+1). 39 < C28H33F6NO 513 514 40 C28H33F6NO2 529 530 r t-oH zou 41 V C27H3lF6NO 499 500 42/C25H29F6NO 473 474 -

EXAMPLE 43 Cis-(RS)-ß-[(4-Hydroxy-1-phenylcyclohexyl)methoxy]-3, 5-bis (trifluoromethyl) benzeneethanol and Trans-(RS)-ß-[(4-Hydroxy-1-phenylcyclohexyl)methoxy]-3,5-bi s(trifluoromethyl) benzeneethanol Sodium borohydride (25 mg, 0.65 mmol) was added to a solution of (RS)-ß-[(4-oxo-1- phenylcyclohexyl) methoxy]-3,5-bis (trifluoromethyl) benzeneethanol (Example 15,75 mg, 0.16 mmol) in ethanol (5 mL) and the mixture was stirred at room temperature for 25 minutes.

The solvent was evaporated under reduced pressure and ethyl acetate (50 mL) and hydrochloric acid (2M, 50 mL) were added. The layers were separated and the organic fraction was washed with brine (50 mL), dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC column chromatography on silica gel, eluting with CI4, CI/EtOAc (80: 20) to give: trans-(RS)-ß-[(4-hydroxy-1-phenylcyclohexyl)methoxy]-3,5-bi s(trifluoromethyl) benzeneethanol (34 mg, 46%) ;'H NMR (400MHz, CD30D) 8 1.21-1.35 (2H, m), 1.62-1.82

(4H, m), 2.31-2.35 (1H, m), 2.47-2.51 (1H, m), 3.24 (1H, d, J 8.8 Hz), 3.36 (1H, d, J 8.8 Hz), 3.49-3.65 (3H, m), 4. 31 (1H, t, J 5.4 Hz), 7.16-7.20 (1H, m), 7.28-7.32 (2H, m), 7.40-7. 42 (2H, m), 7.64 (2H, s), and 7.80 (1H, s); and cis-(RS)-ß-[(4-hydroxy-1-phenylcyclohexyl)methoxy]-3,5-bis( trifluoromethyl) benzeneethanol (10 mg, 14%) ;'HNMR (400MHz, CD30D) 8 1.49-1.70 (4H, m), 1.80-1.85 (1H, m), 1.91-1.95 (1H, m), 2.07-2.14 (1H, m), 2.20-2.26 (1H, m), 3.37 (1H, d, J 8. 8 Hz), 3.49-3.61 (3H, m), 3.69-3.71 (1H, m), 4.34 (1H, t, J 5.6 Hz), 7.15-7.19 (1H, m), 7.26-7.29 (2H, m), 7.38-7.40 (2H, m), 7.65 (2H, s), and 7.80 (1H, s).

EXAMPLE 44 Cis-(RS)-ß-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylc yclohexyl}methoxy)-3,5- bis (trifluoromethyl) benzeneethanol and Trans-(RS)-ß-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-pheny lcyclohexyl}methoxy)-3,5- bis (trifluoromethyl) benzeneethanol Prepared from (RS)-ß-[(4-oxo-1-phenylcyclohexyl) methoxy]-3,5-bis (trifluoromethyl) benzeneethanol (Example 15) and 4- (4-fluorophenyl) piperidine (Description 16) according to the method of Example 55: Cis-(RS)-ß-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylc yclohexyl} methoxy)-3,5- bis (trifluoromethyl) benzeneethanol ;'H NMR (360MHz, CDC13) 8 1.46-1.78 (6H, m), 1.80-2.06 (6H, m), 2.20-58 (6H, m), 3.04-3.30 (1H, m), 3.42-3.64 (3H, m), 3.68-3.76 (1H, m), 6.97 (2H, t, J 8. 7 Hz), 7.17-7.21 (3H, m), 7.32-7.39 (4H, m), 7.57 (2H, s), and 7.79 (1H, s); m/z (ES+) 624 (M+1) ; Trans-(RS)-ß-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1-pheny lcyclohexyl} methoxy)-3,5- bis (trifluoromethyl) benzefzeetlzanol ;'H NMR (360MHz, CDC13) 8 1.21-1.98 (13H, m), 2.21-2.58 (4H, m), 2.58-2.68 (1H, m), 2.97-3.12 (1H, m), 3.22 (1H, d, J 8. 7 Hz), 3.28 (1H, d, J 8.7 Hz), 3.51 (1H, m), 4.24-4.30 (1H, m), 6.95 (2H, t, J 8.7 Hz), 7.10-7.15 (2H, m), 7.25 (1H, s), 7.37-7.38 (4H, m), 7.53 (2H, s), and 7.78 (1H, s); m/z (ES) 624 (M+l).

EXAMPLE 45 Cis-and Trans-(RS)-ß-{r 1-Phenyl-4-(phenylmethylamino) cvclohexyllmethoxy}-35- bis (trifluoromethyl) benzeneethanol Sodium triacetoxyborohydride (98 mg, 0.46 mmol) and glacial acetic acid (19 mg, 0.33 mmol) were added to a solution of (RS)--[(4-oxo-1-phenylcyclohexyl) methoxy]-3, 5- bis (trifluoromethyl) benzeneethanol (Example 15, 156 mg, 0.33 mmol) and benzylamine (35 mg, 0.33 mmol) in dichloroethane (3 mL) and the mixture was stirred at room temperature

overnight. Aqueous sodium hydrogen carbonate (saturated, 3 mL) and dichloromethane (5 mL) were added and the layers were separated. The organic fraction was poured onto an SCX cartridge (Varian Bond Elut ; 10 mL/500 mg) and the cartridge was washed with methanol (4 x 2 mL), then eluted with methanolic ammonia (2M, 2 x 2 mL). The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (151 mg, 83%).'H NMR and analytical HPLC showed this to be a 1 : 1 mixture of trans : cis isomers. m/z (ES+) 552 (M+1).

The following compounds were prepared as mixtures of cis-and trans-isomers from (RS)-ß- [ (4-oxo-l-phenylcyclohexyl) methoxy]-3,5-bis (trifluoromethyl) benzeneethanol (Example 15) according to the method of Example 45, substituting a suitable amine for benzylamine. OH Q Y P >CF3 CAF3 NRz Cis-(RS)-& Trans-(RS)- mlz Ex.-NRz Formula M. W. (ES+) (M+1). 46 C27H3lF6NO3 531 532 zip 47 Ph C31H33F6N02 565 566 H 48 W Ph C32H35F6NO2 579 580 H 49 NX C27H31F6NO2 515 516 H V 50 _ N', Ph C33H37F6N02 593 594 H 51 C29H30F6N202 552 553 -H I/ 52 _% C29H30F6N202 552 553 -H I/ 53 _% C29H30F6N202 552 553 H OH P>+CF3 CAF3 NRz" Cis-(RS)-& Trans-(RS)- m/z Ex.-NR, Formula M. W. (ES+) (M+1). 54 C28H29F6N03 541 542 "TEL/

EXAMPLE 55 Cis- and Trans-(RS)-ß-[(1-Phenyl-4-(piperidin-1-yl)cyclohexyl)methox y]-3,5- bis (trifluoromethyl) benzeneethanol A mixture of sodium cyanoborohydride (6.8 mg, 0.11 mmol) and zinc chloride (7.3 mg, 0.05 mmol) in methanol (2 mL) was added to a solution of (RS)-ß-[(4-oxo-1- phenylcyclohexyl) methoxy]-3,5-bis (trifluoromethyl) benzeneethanol (Example 15,25 mg, 0.05 mmol) and piperidine (16) il, 0.05 mmol) in methanol (2 mL) and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and aqueous sodium hydrogen carbonate (saturated, 3 mL) and dichloromethane (5 mL) were added. The layers were separated and the organic fraction was poured onto an SCX cartridge (Varian Bond Elut ; 10 mL/500 mg). The cartridge was washed with methanol (4 x 2 mL), then eluted with methanolic ammonia (2M, 2 x 2 mL). The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (20 mg, 70%).'H NMR and analytical HPLC showed this to be a 1: 1 mixture of trans : cis isomers. m/z (ES+) 530 (M+1).

The following compounds were prepared as mixtures of cis-and trans-isomers from (RS)-ß- [ (4-oxo-l-phenylcyclohexyl) methoxy]-3, 5-bis (trifluoromethyl) benzeneethanol (Example 15) according to the method of Example 55, substituting a suitable amine for piperidine. OH OH p CF3 NR2 CF3 NRz Cs-(RS)-& Trczns-(RS)- mlz Ex.-NR2 Formula M. W. (ES+) (M+1). 56- C28H33F6N03 545 546 OH U cO2Et C31H37F6NO4 601 602 u 58 OH C28H33F6NO3 545 546 59 Ph C31H33F6N02 565 566 60 _% C31H34F6N202 580 581 Et 61 F C33H35F7N202 624 625 62 C27H3lF6N02 515 516 _D 63 C24H27F6N02 475 476 H 64 \ C30H38F6N202 572 573 -N)-MMez 65/\ C29H35F6NO2 543 544 _ ? 66 C32H33F6N02 577 578 - (b OH P >+CF3 NR2 CF3 NRz Cis-(RS)-& Trans-(RS)- rn/z Ex.-NR, Formula M. W. (ES+) (M+l) 67/\ C29H35F6NO2 543 544 68 C34H35F6N302S 663 664 I u 69 C29H35F6N02 543 544 70 C28H33F6N02 529 530 - 71 C27H31F6N02S 547 548 72 C29H35F6N02 543 544 73 C29H33F6N02 541 542 - 74C02Me C26H29F6N04 533 534 75 _Co C33H42F6N202 612 613 76/\ C30H37F6NO2 557 558 S C29H35F6N03 559 560 OH OH P CF3 NR2 CF3 NRZ Cis- (RS)- & Trans- (RS)- m/z Ex.-NR, Formula M. W. (ES+) (M+1). 78/C29H35F6NO3 559 560 -1-- 79 C26H29F6NO2 501 502 H The following isomers were prepared from the compounds of Examples 55,56 and 46 by MPLC chromatography on silica gel, eluting with CH2Cl2/MeOH/Et3N (95: 5: 0.2). rn/z Ex.-NR2 Stereochemistry Formula M. W. (ES+) (M+1). 80 < Cis-(RS)-C28H33F6NO2 529 530 81 < Trans-(RS)-C28H33F6NO2 529 530 _W 82 Cis- (RS)- C28H33F6NO3 545 546 rvoH 83 g Trans-(RS)-C28H33F6NO3 545 546 OH 84/5 Tråns-(RS)-C27H3 lF6NO3 531 532 -2

EXAMPLE 85 Trans-(RS)-ß-{[1-Phenyl-4-(phenylmethylamino)cyclohexyl]met hoxy}-3,5- bis (trifluoromethyl) benzeneethanol Hydrochloride and Cis-(RS)-ß-{[1-Phenyl-4-(phenylmethylamino)cyclohexyl]metho xy}-3,5- bis (trifluoromethyl) benzeneethanol Hydrochloride Benzylamine (1.07 mL, 9.8 mmol) was added to a mixture of (RS)-P- [ (4-oxo-l- phenylcyclohexyl) methoxy]-3,5-bis (trifluoromethyl) benzeneethanol (Example 15,1.5 g, 3.2 mmol) and dry alumina (1 g) in ethanol (35 mL) and the mixture was heated under reflux overnight. The mixture was cooled, filtered and cooled to-78 °C. Sodium borohydride (1.23 g, 32.6 mmol) was added in portions over 2 hours, then aqueous sodium hydrogen carbonate (saturated, 20 mL) was added and the mixture was warmed to room temperature.

The solvent was evaporated under reduced pressure and ethyl acetate (50 mL) and water (50 mL) were added. The layers were separated and the organic fraction was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2CI2/MeOH/Et3N (98: 2: 1) to give a 5: 1 mixture of trans : cis isomers (1.48 g), which was dissolved in ethyl acetate: hexane (3: 1, 13 mL) and treated with ethereal hydrogen chloride (1M, 2.7 mL). The solid was collected and dried in vacuo to give: trans-(RS)-ß-{[1-phenyl-4-(phenylmethylamino)cyclohexyl]met hoxy}-3,5- bis (trifluoromethyl) benzeneethanol hydrochloride (1.3 g, 72%). lH NMR (400MHz, CD30D) 8 1.43-1.54 (2H, m), 1.73-1.82 (2H, m), 2.05-2.18 (2H, m), 2.50-2.58 (1H, m), 2.67-2.71 (1H, m), 2.82-2.88 (1H, m), 3.24 (1H, d, J 8.6 Hz), 3.37 (1H, d, J 8.6 Hz), 3.53-3.64 (2H, m), 4.13 (2H, s), 4.34 (1H, t, J 5.0 Hz), 7.20-7.24 (1H, m), 7.33-7.45 (9H, m), 7.65 (2H, s), and 7.81 (1H, s). m/z (ES+) 552 (M+1).

The mother liquors from the recrystallisation were collected and the solvent was evaporated under reduced pressure. The residue was crystallised from ethanol/water (70: 30) and the solid was collected and dried in vacuo to give: cis- (RS)-/3- (l phenyl4- (phenylmethylamino) cyclohexylJmethoxyj-3, 5- bis (trifluoromethyl) benzeneethanol hydrochloride (50 mg, 3%).'H NMR (400MHz, CD30D) 8 1.39-1.70 (4H, m), 1.81-1.90 (2H, m), 2.15-2.18 (1H, m), 2.36-2.39 (1H, m), 2.56-2.60 (1H, m), 3.48-3.61 (3H, m), 3.84 (1H, d, J 8.6 Hz), 3.77 (2H, s), 4.37 (1H, t, J 5. 0 Hz), 7.18-7.48 (10H, m), 7.64 (2H, s), and 7.80 (1H, s). m/z (ES') 552 (M+1).

EXAMPLE 86 Trans- (RS)-- f 1-Phenyl-4- (phenylmethylamino) cyclohexyllmethoxy}-3, 5- bis (trifluoromethyl) benzeneethanol A sample of trans-(RS)-ß-{[1-phenyl-4-(phenylmethylamino) cyclohexyl] methoxy}-3, 5- bis (trifluoromethyl) benzeneethanol hydrochloride (Example 85) was suspended in aqueous sodium hydrogen carbonate (saturated) and the mixture was extracted with ethyl acetate (3 x).

The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound.'H NMR (400MHz, CD30D) 8 1.17-1.29 (2H, m), 1.58-1.68 (2H, m), 1.83-1.89 (2H, m), 2.36-2.40 (1H, m), 2.53-2.65 (2H, m), 3.21 (1H, d, J 8.0 Hz), 3.33 (1H, d, J 8.0 Hz), 3.51 (1H, dd, J 10. 8,4.8 Hz), 3.61 (1H, dd, J 10.8,5.6 Hz), 3.72 (2H, s), 4.30 (1H, t, J 5. 2 Hz), 7.15-7.30 (8H, m), 7.40-7.42 (2H, m), 7.63 (2H, s), and 7.79 (1H, s).

EXAMPLE 87 Trans-(RS)-ß-[(4-Amino-1-phenylcyclohexyl)methoxy]-3, 5-bis (trifluoromethyl) benzeneethanol A slurry of palladium on carbon (5%, 20 mg) in methanol (10 mL) was added to a solution of trans-(RS)-ß- { [1-phenyl-4-(phenylmethylamino) cyclohexyl] methoxy}-3,5- bis (trifluoromethyl) benzeneethanol hydrochloride (Example 85,79 mg, 0.13 mmol) in ethanol (4 mL) and the mixture was shaken under an atmosphere of hydrogen (50 psi) for 16 hours.

The mixture was filtered through Celte, washing with ethanol, and the solvent was evaporated under reduced pressure. The residue was crystallised from EtO/EtOAc (2: 1, 1 mL) and the solid was collected and dried in vacuo to give the title compound as a colorless solid (25 mg, 37%). m/z (ES+) 462 (M+1).

EXAMPLE 88 <BR> <BR> <BR> <BR> <BR> <BR> Cis-(RS)-ß-r (4-Amino-1-phenvlcyclohexyl) methoxyl-3.5-bis (trifluoromethyl) benzeneethanol Prepared from cis-(RS)-ß- { [1-phenyl-4-(phenylmethylamino) cyclohexyl] methoxy}-3, 5- bis (trifluoromethyl) benzeneethanol hydrochloride (Example 85) according to the method of Example 87. m/z (ES+) 462 (M+1).

EXAMPLE 89 Trans-(RS)-ß-({4-[N-Methyl(phenylmethyl)amino]-1-phenylcycl ohexyl}methoxy)-3,5- bis(trifluoromethyl) benzeneethanol Prepared from trans-(RS)-ß- { [1-phenyl-4-(phenylmethylamino) cyclohexyl] methoxy}-3, 5- bis (trifluoromethyl) benzeneethanol (Example 86) according to the method of Example 212. m/z (ES+) 566 (M+1).

EXAMPLE 90 Trans-(RS)-ß-r (4-Methylarnino-1-phenvlcvclohexyl) methoxyl-3,5-bis(trifluoromethyl) benzeneethanol Prepared from trans-(RS)-ß-({4-[N-methyl (phenylmethyl) amino]-l-phenylcyclohexyl} methoxy)-3,5-bis (trifluoromethyl) benzeneethanol (Example 89) according to the method of Example 87. m/z (ES+) 476 (M+1).

EXAMPLE 91 Trans- (RS)-3-f (4- {N-f2- (Dimethylamino) acetyllamino} 1-phenylcyclohexyl) methoxyl-3, 5- bis (trifluoromethyl ! benzeneethanol Triethylamine (25 p. L, 0.18 mmol) was added to a mixture of trans-(RS)-ß-[(4-amino-1- phenylcyclohexyl) methoxy]-3,5-bis (trifluoromethyl) benzeneethanol (Example 87,30 mg, 0.06 mmol), N, N-dimethylglycine (18 mg, 0.15 mmol), 1-hydroxybenzotriazole (8 mg, 0.06 mmol) and 1- (dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15 mg, 0.08 mmol) in dry dichloromethane (3 mL) and the mixture was stirred at room temperature overnight. Aqueous sodium hydroxide (0. 05M, 3 mL) and dichloromethane (5 mL) were added and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 3 mL) and the combined organic fractions were poured onto an SCX cartridge (Varian Bond ElutTM ; 10 mL/500 mg). The cartridge was washed with methanol (4 x 2 mL), then eluted with methanolic ammonia (2M, 2 x 2 mL) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on a short column of silica gel, eluting with CH2Cl2/MeOH/Et3N (100: 0: 1 increasing to 90: 10: 1), to give the title compound as a colorless solid (12 mg, 36%). m/z (ES+) 547 (M+1).

The following compounds were prepared from trans-(RS)-ß-[(4-amino-1- phenylcyclohexyl) methoxy]-3,5-bis (trifluoromethyl) benzeneethanol (Example 87) or trans- (RS)-ß-[(4-methylamino-1-phenylcyclohexyl) methoxy]-3, 5-bis (trifluoromethyl) benzeneethanol (Example 90) according to the method of Example 91, substituting a suitable acid for N, N-dimethylglycine. OH CF3 P trr,, zu CF3 NRZ Trans- (RS)- mlz Ex.-NR, Formula M. W. (ES+) (M+1). 20M-H C26H27F6N503H572 H H po C30H34F6N603 640 641 -NRz H 94 2 C3lH38F6N203 600 601 H 0 95 P C29H36P6N203 574 575 w NMe2 H 96 P C27H27F6N303 555 556 -H f/H 97'C29H34F6N203 572 573 H H 98 R p2tU C33H40F6N205 658 659 V H v 99 0 C25H27F6N03 503 504 -Wi H 100 oh C27H29F6N503 585 586 t4 N 101 R C32H40F6N203 614 615 OH CF3 -NR2 CF3 cl3 CE3 NRZ Traszs- (RS- m/z Ex.-NR2 Formula M. W. (ES+) (M+1). 102 P C28H29F6N303 569 570 tNH fuzz 103 $, C30H36F6N203 586 587

'1-Pyrrolidineacetic acid: WO 9519344.

EXAMPLE 104 <BR> <BR> <BR> <BR> <BR> <BR> Trans-(RS,S)-N-(1-{[α-Hydroxymethyl-3,5-bis(trifluoromethyl )phenylmethoxy]methyl}-1-<BR> <BR> <BR> <BR> <BR> <BR> <BR> phenvlcyclohexyD-2-pyrrolidinecarboxamide Trifluoroacetic acid (4 drops) was added to a solution of trans-(RS,S)-1,1-dimethylethyl 2-[(1- { [ c-hydroxymethyl-3, 5-bis (trifluoromethyl) phenylmethoxy] methyl}-1-phenyl cyclohexylamino) carbonyl]-1-pyrrolidinecarboxylate (Example 98,5 mg, 8 umol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 5 minutes.

Aqueous sodium hydrogen carbonate (saturated, 3 mL) and dichloromethane (5 mL) were added and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 3 mL) and the combined organic fractions were poured onto an SCX cartridge (Varian Bond Elut ; 10 mL/500 mg). The cartridge was washed with methanol (4 x 2 mL), then eluted with methanolic ammonia (2M, 2 x 2 mL) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (3 mg, 70%). m/z (ES+) 559 (M+1).

EXAMPLE 105 Cis-and Trans-(RS)-ß-[(1-Phenyl-4-dimethylaminocyclohexyl)methoxy]- 3,5- bis (trifluoromethyl) benzeneethanol A slurry of palladium on carbon (5%, 20 mg) in methanol (10 mL) was added to a solution of (RS)-ß-{ [l-phenyl-4-(phenylmethylamino) cyclohexyl] methoxy}-3, 5-

bis (trifluoromethyl) benzeneethanol (1: 1 mixture of cis-and trans-isomers, Example 45, 140 mg, 0,25 mmol) in methanol (4 mL) and the mixture was shaken under an atmosphere of hydrogen (50 psi) for 16 hours. The mixture was filtered through Celiez and a slurry of palladium hydroxide (20%, 50 mg) in methanol (10 mL), aqueous formaldehyde (37%, 2 mL) and acetic acid (35 mg) were added. The mixture was shaken under an atmosphere of hydrogen (50 psi) for 16 hours, filtered through Celite, washing with methanol, and the solvent was evaporated under reduced pressure to give the title compound as an oil (90 mg, 72%).'H NMR and analytical HPLC showed this to be a 1: 2 mixture of trans-and cis- isomers. m/z (ES+) 490 (M+1).

EXAMPLE 106 Trans-(RS)-ß-[(4-Cyclopropylmethylamino-1-phenylcyclohexyl) methoxy]-3, 5- bis (trifluoromethyl) benzeneethanol Hydrochloride Prepared from trans-(RS)-ß-[(4-amino-1-phenylcyclohexyl) methoxy]-3,5- bis (trifluoromethyl) benzeneethanol (Example 87) and cyclopropane carboxaldehyde according to the method of Example 55. m/z (ES+) 516 (M+1).

EXAMPLE 107 1, 2-Dihydro-5- { [N-(1-{ra-Hvdroxymethyl-3. 5-bis (trifluoromethphenylmethoxyl methyl}- 1-phenylcvclohex-4-yl) methylaminolmethyl}-3H-1, 2, 4-triazol-3-one Methyl 2- (2-chloro-l-iminoethyl) hydrazinecarboxylic acid (J. Med. Chem. 1996,39,2907- 2914; 8 mg, 0.05 mmol) was added to a mixture of trans- (RS)-P- [ (4-methylamino-l- phenylcyclohexyl) methoxy]-3,5-bis (trifluoromethyl) benzeneethanol (Example 90,23 mg, 0.04 mmol) and potassium carbonate (30 mg, 0.22 mmol) in dimethylformamide (1 mL) and the mixture was stirred at room temperature for 72 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in toluene (10 mL) and the mixture was stirred under reflux for 16 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/Et3N (100: 0: 1 increasing to 90: 10: 1), to give the title compound as a colorless oil (8 mg, 32%). m/z (ES+) 573 (M+1).

EXAMPLE 108 <BR> <BR> <BR> <BR> <BR> Cis- (RS)-Methyl 1- (1- fa-Hydroxymethyl-3, 5-bis (trifluoromethyl) phenvlmethoxyl methyl}- 1-phenylcyclohex-4-yl) piperidine-4-carboxylate and Trans- (RS-Methyl 1- (1- ( fa-Hydroxymethyl-3, 5-bis (trifluoromethphenvlmethoxvl methyl}-l-phenylcyclohex-4-yl) piperidine-4-carboxylate A mixture of sodium cyanoborohydride (83 mg, 1.3 mmol) and zinc chloride (90 mg, 0.65 mmol) in methanol (2 mL) was added to a solution of (RS)-ß-[(4-oxo-1- phenylcyclohexyl) methoxy]-3, 5-bis (trifluoromethyl) benzeneethanol (Example 15,300 mg, 0.65 mmol) and ethyl 4-piperidinecarboxylate (307 mg, 1.96 mmol) in methanol (30 mL) and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and aqueous sodium hydrogen carbonate (saturated, 3 mL) and dichloromethane (3 mL) were added. The layers were separated and the organic fraction was poured onto an SCX cartridge (Varian Bond Eluf ; 10 mL/500 mg). The cartridge was washed with methanol (4 x 2 mL), then eluted with methanolic ammonia (2M, 2 x 2 mL) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (5 mL) and sodium (catalytic) was added. The mixture was stirred at room temperature for 1 hour, then the solvent was evaporated under reduced pressure and ethyl acetate (50 mL) and water (50 mL) were added. The layers were separated and the organic fraction was dried (MGSO) and and the solvent was evaporated under reduced pressure. The residue was purified by MPLC chromatography on silica gel, eluting with CH2Cl2/MeOH/Et3N (95: 5: 0.2) to give: <BR> <BR> <BR> <BR> cis-(RS)-methyl 1-(1-{[α-hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethox y]methyl}-1- phenyl cyclohex-4-yl) piperidine-4-carboxylate as a colorless solid (130 mg, 33%) ;'H NMR (360MHz, CD30D) 8 1.45-1.94 (1OH, m), 2.16-2.36 (6H, m), 2.90-2.95 (2H, m), 3.47 (3H, s), 3.42-3.53 (3H, m), 3.69 (1H, d, J 8. 8 Hz), 4.30-4.32 (1H, m), 7.22-7.26 (1H, m), 7.32-7.39 (4H, m), 7.56 (2H, s), and 7.78 (1H, s); m/z (ES+) 588 (M+1) ; and <BR> <BR> <BR> <BR> trans-(RS)-methyl 1-(1-{[α-hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethox y]methyl}-1- phenyl cyclohex-4-yl) piperidine-4-carboxylate as a colorless solid (97 mg, 25%) ;'H NMR (360MHz, CD30D) 8 1.27-1.33 (2H, m), 1.60-1.68 (4H, m), 1.77-1.83 (4H, m), 2.12-216 (2H, m), 2.24-2.27 (1H, m), 2.39-2.44 (2H, m), 2.56-2.61 (1H, m), 2.78-2.82 (2H, m), 3.21 (1H, d, J 8.8 Hz), 3.33 (1H, d, J 8.8 Hz), 3.52 (1H, dd, J 11.5,5.0 Hz), 3.61 (3H, s), 3.58-3. 63 (1H, m), 4.31 (1H, t, J5. 8 Hz), 7.16-7. 20 (1H, m), 7.28-7.33 (2H, m), 7.39-7.41 (2H, m), 7.64 (2H, s), and 7.80 (1H, s); rn/z (ES+) 588 (M+1).

EXAMPLE 109 <BR> <BR> <BR> <BR> Trans-(RS)-1-(1-f ra-HvdroxymethYI-3.5-bis (trifluoromethyl) phenylmethoxylmethyl}-1-<BR> <BR> <BR> <BR> <BR> phenylcyclohex-4-yl) piperidine-4-methanol A solution of diisobutylaluminium hydride (1. OM in toluene, 0.35 mL, 0.35 mmol) was added to a cooled (0 °C) solution of trans-(RS)-methyl 1-(1-{ [a-hydroxymethyl-3, 5- bis (trifluoromethyl) phenylmethoxy] methyl}-1-phenyl cyclohex-4-yl) piperidine-4-carboxylate (Example 108,50 mg, 0.08 mmol) in toluene (5 mL). The solution was allowed to warm to room temperature and stirred for 16 hours. Methanol (2 mL), then water (2 mL) and ethyl acetate (5 mL) were added and the layers were separated. The organic fraction was dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (40 mg, 84%). m/z (ES+) 560 (M+1).

EXAMPLE 110 Trans-(RS)-1-(1-{[α-Hydroxymethyl-3, 5-bis (trifluoromethYI) phenylmethoxYlmethyl}-1- phenylcyclohex-4-yl) piperidine-4-carboxylic Acid Potassium hydroxide (38 mg, 0.68 mmol) was added to a solution of trans-(R$-methyl 1-(1- { [a-hydroxymethyl-3, 5-bis (trifluoromethyl) phenylmethoxy] methyl}-l-phenyl cyclohex-4- yl) piperidine-4-carboxylate (Example 108, 50 mg, 0.08 mmol) in methanol (5 mL) and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and water (2 mL) was added. The mixture was neutralised with hydrochloric acid (2M) and extracted with ethyl acetate (2 x 5 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (28 mg, 56%). m/z (ES+) 574 (M+1).

EXAMPLE 111 Trans-(RS)-1-(1-{[α-Hydroxymethyl-3,5-bis(trifluoromethyl)p henylmethoxy]methyl}-1- phenylcyclohex-4-yl)-α, a-dimethylpiperidine-4-methanol A solution of trans-(RS)-methyl 1-(1-{ [a-hydroxymethyl-3, 5- bis (trifluoromethyl) phenylmethoxy] methyl}-1-phenylcyclohex-4-yl) piperidine-4-carboxylate (Example 108,21 mg, 0.04 mmol) in tetrahydrofuran (5 mL) was added dropwise to a cooled (0 °C) solution of methyl magnesium bromide (3.0M in ether, 0.05 mL, 0.15 mmol) in tetrahydrofuran (5 mL). The solution was allowed to warm to room temperature and stirred for 4 hours. Aqueous ammonium chloride (saturated, 7 mL), then water (7 mL) and ethyl acetate (10 mL) were added and the layers were separated. The organic fraction was dried

(MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (13 mg, 62%). m/z (ES+) 588 (M+1).

EXAMPLE 112 Trans-(RS)-1-(1-{[α-Hydroxymethyl-3, 5-bis (trifluoromethyl) phenylmethoxylmethyl}-1- phenylcyclohex-4-yl)-N, N-dimethylpiperidine-4-carboxamide Prepared from trans-(RS)-l-(l-f [a-hydroxymethyl-3, 5- bis (trifluoromethyl) phenylmethoxy] methyl}-1-phenyl cyclohex-4-yl) piperidine-4-carboxylic acid (Example 110) and dimethylamine hydrochloride according to the method of Example 182. m/z (ES+) 601 (M+1).

EXAMPLE 113 <BR> <BR> <BR> <BR> <BR> (RS)-Methyl (l- (l-fa-Hrdroxymethyl-3, 5-bis (trifluoromethyl) phenylmethoxylmethyl}-1- phenylcyclohex-4-ylidene) acetate Methyl (triphenylphosphoranylidene) acetate (261 mg, 0.78 mmol) was added to a solution of (RS)-ß-[(4-oxo-1-phenylcyclohexyl) methoxy]-3, 5-bis (trifluoromethyl) benzeneethanol (Example 15,300 mg, 0.65 mmol) in dichloromethane (5 mL) and the mixture was stirred at 40 °C for 16 hours. Additional methyl (triphenylphosphoranylidene) acetate (217 mg, 0.65 mmol) was added and the mixture was stirred at 40 °C for 16 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (80: 20), to give the title compound as a colorless oil (290 mg, 86%).'H NMR (360MHz, CDC13) 8 1.72-1.86 (3H, m), 2.18-2.29 (3H, m), 2.33-2.56 (2H, m), 3.21 (1H, d, J 8. 8 Hz), 3.36 (1H, d, J 8. 8 Hz), 3.49-3.52 (3H, m), 3.67 (3H, s), 4.25-4.32 (1H, m), 5.62 (1H, s), 7.26-7.27 (1H, m), 7.38-7.41 (4H, m), 7.53 (2H, s), and 7.77 (1H, s).

EXAMPLE 114 Cis-and Trans-(RS)-M ethyl (1-(1-{[α-Hydroxymethyl-3,5-bis(trifluoromethyl) phenylmethoxylmethyl}-1-phenylcyclohex-4-yl) acetate A slurry of palladium on carbon (5%, 10 mg) in methanol (1 mL) was added to a solution of (RS)-methyl (1- (1- { [a-hydroxymethyl-3,5-bis (trifluoromethyl) phenylmethoxy] methyl}-1- phenyl cyclohex-4-ylidene) acetate (Example 113,100 mg, 0.19 mmol) in methanol (5 mL) and the mixture was shaken under an atmosphere of hydrogen (40 psi) for 1 hour. The mixture was filtered through Celiez and the solvent was evaporated under reduced pressure to give the title compound as an oil (87 mg, 87%).'H NMR and analytical HPLC showed this to be a

1: 1 mixture of trans-and cis-isomers.'H NMR (400MHz, CDC13) 8 1.04-1.35 (2H, m), 1.54-1.87 (6H, m), 2.07-2.50 (3H, m), 3.20-3.29 (2H, m), 3.43-3.51 (2H, m), 3.62 and 3.68 (Total 3H, each s), 4.24-4.32 (1H, m), 7.22-7.43 (5H, m), 7.54 (2H, m), and 7.78 (1H, m).

EXAMPLE 115 Cis- (7 ! y)-l-r2- (l- (l-fra-Hydroxymethyl-3. 5-bis (trifluoromethvl) phenylmethoxy1methvl}-l- <BR> <BR> <BR> <BR> phenylcyclohex-4-yl) ethyllpyrrolidine and<BR> <BR> <BR> <BR> <BR> <BR> Trans-(RS)-1-[2-(1-(1-{[α-Hydroxymethyl-3,5-bis(trifluorome thyl)phenylmethoxy] methyl}-<BR> <BR> <BR> <BR> <BR> <BR> 1-phenylcyclohex-4-yl)ethyllpyrrolidine A solution of diisobutylaluminium hydride (1. OM in hexane, 0.33 mL, 0.33 mmol) was added dropwise to a cooled (-78 °C) solution of (RS)-methyl (1- (1-1 [ (X-hydroxymethyl-3, 5- bis (trifluoromethyl) phenylmethoxy]methyl}-1-phenyl cyclohex-4-yl) acetate (Example 114, 1: 1 mixture of trans-and cis-isomers, 87 mg, 0.17 mmol) in isohexane/dichloromethane (3: 1, 12 mL). The mixture was stirred at-78 °C for 4 hours, then methanol (2 mL), water (2 mL) and ethyl acetate (5 mL) were added. The layers were separated and the organic fraction was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (3 mL) and pyrrolidine (0.14 mL, 1.7 mmol) and a mixture of sodium cyanoborohydride (42 mg, 0.66 mmol) and zinc chloride (46 mg, 0.33 mmol) in methanol (5 mL) were added. The mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. Aqueous sodium hydrogen carbonate (saturated, 3 mL) and dichloromethane (3 mL) were added and the layers were separated. The organic fraction was poured onto an SCX cartridge (Varian Bond Elut ; 10 mL/500 mg) and the cartridge was washed with methanol (4 x 2 mL), then eluted with methanolic ammonia (2M, 2 x 2 mL). The solvent was evaporated under reduced pressure. The residue was purified by MPLC column chromatography on silica gel, eluting with CH, CyMeOH/EtjN (98: 2: 0.2) to give: cis(RS)-1-[2-(1-(1-{[α-hydroxymethyl-3,5-bis(trifluoromethy l)phenylmethoxy]methyl]-1- phenyl cyclohex 4-yl)ethyl]pyrrolidine (13 mg, 14%) as a colorless solid ; 1H NMR (360MHz, CD30D) 8 1.23-1.45 (3H, m), 1.57-1.74 (6H, m), 2.00-2.08 (4H, m), 2.14-2.20 (1H, m), 2.31-2.35 (1H, m), 3.00-3.22 (6H, m), 3.44-3.60 (3H, m), 3.76 (1H, d, J 8.8 Hz), 4.37 (1H, t, J 5. 6 Hz), 7.14-7.18 (1H, m), 7.24-7.28 (2H, m), 7.37-7.39 (2H, m), 7.65 (2H, s), and 7.81 (1H, s); m/z (ES+) 544 (M+1) ; and <BR> <BR> <BR> <BR> trans-(RS)-1-[2-(1-(1-{[α-hydroxymethyl-3,5-bis(trifluorome thyl)phenylmethoxy] methyl}-1- phenyl cyclohex4-yl) ethyljpyrrolidine (10 mg, 11%) as a colorless solid ; 1H NMR (360MHz, CD30D) 8 1.01-1.11 (2H, m), 1.46-1.50 (3H, m), 1.60-1.71 (4H, m), 2.01-2.09 (4H, m),

2.36-2.41 (1H, m), 2.51-2.56 (1H, m), 3.03-3.35 (7H, m), 3.35 (1H, d, J 8.8 Hz), 3.47 (1H, dd, J 10. 8,7.2 Hz), 3.51 (1H, dd, J 7.2,4.3 Hz), 4.31 (1H, t, J 5.8 Hz), 7.16-7.20 (1H, m), 7.24-7.31 (2H, m), 7.37-7.40 (2H, m), 7.64 (2H, s), 7.80 (1H, s); m/z (ES+) 544 (M+1).

EXAMPLE 116 <BR> <BR> <BR> <BR> <BR> Trans-(RS)-Methyl α-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl } methoxy)- 3, 5-bis (trifluoromethyl) benzeneacetate Methyl a-diazo-3, 5-bis (trifluoromethyl) benzeneacetate (WO 95/21819, 97 mg, 0.31 mmol) in dichloromethane (1 mL) was added over 15 minutes to a mixture of trans-4- [4- (4- fluorophenyl) piperidin-1-yl]-1-phenylcyclohexanemethanol (Description 21,98 mg, 0.27 mmol) and rhodium acetate dimer (1 mg) in dichloromethane (1 mL) and the mixture was stirred at room temperature for 1 hour, then at 40 °C for 1 hour. The mixture was cooled and further methyl a-diazo-3, 5-bis (trifluoromethyl) benzeneacetate (110 mg, 0.35 mmol) in dichloromethane (1 mL) was added. The mixture was stirred at room temperature for 0.5 hour, then at 40 °C for 0.5 hour. The mixture was cooled, divided into four portions and poured onto four SCX cartridges (Varian Bond E1ut ; 10 mL/500 mg). Each cartridge was washed with methanol (4 x 1 mL), then eluted with methanolic ammonia (2M, 4 x 1 mL). The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3 (Aq.) (97.5: 2.5: 0.25) to give the title compound (61 mg, 35%). m/z (ES+) 652 (M+1).

EXAMPLE 117 Trans-3, 5-Bis (trifluoromethyl) phenylmethyl4-f4- (4-Fluorophenyl) piperidin-1-yll-1- phenylcyclohexanecarboxylate Prepared from 3,5-bis (trifluoromethyl) phenylmethyl 4-oxo-1-phenylcyclohexanecarboxylate (Example 16) and 4- (4-fluorophenyl) piperidine (Description 16) according to the method of Example 55. The product was purified by preparative thin layer chromatography on silica gel, eluting with CH2Cl/MeOHEt3N (Aq.) (95: 5: 1). m/z (ES+) 608 (M+1).

EXAMPLE 118 <BR> <BR> <BR> <BR> Trans- (RS-1-f3 5-Bis (trifluoromethvl) phen l1yl 4-r4- (4-Fluorophenpiperidin-1- l phenylcyclohexanecarboxylate Oxalyl chloride (31 ul, 0.36 mmol) was added to a mixture of trans-4- [4- (4- fluorophenyl) piperidin-1-yl]-1-phenylcyclohexanecarboxylic acid hydrochloride (Description 20,50 mg, 0.12 mmol) and dimethylformamide (1 drop) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under

reduced pressure and the residue was dissolved in dichloroethane (2 mL). (RS)-a-Methyl-3, 5- bis (trifluoromethyl) benzenemethanol (93 mg, 0.36 mmol), triethylamine (59 gel, 0.42 mmol) and 4-dimethylaminopyridine (1 mg) were added and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and aqueous sodium carbonate (10%, 25 mL) and ethyl acetate (25 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (25 mL). The combined organic fractions were washed with brine (25 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90: 10 increasing to 0: 100), to give the title compound (39 mg, 52%). m/z (ES+) 622 (M+1).

EXAMPLE 119 Trans-(RS)-2-Hydroxy-2-[3, 5-bis (trifluoromethvl) phenyl1ethyl4-r4- (4- Fluorophenyl) piperidin-1-yll-1-phenvlcvclohexanecarboxylate Oxalyl chloride (50 il) was added to a mixture of trans-4- [4- (4-fluorophenyl) piperidin-1-yl]- 1-phenylcyclohexanecarboxylic acid hydrochloride (Description 20,63 mg, 0.15 mmol) and dimethylformamide (I drop) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloroethane (4 mL). Triethylamine (100 1ll, 0.72 mmol), (RS)-1-[3, 5- bis (trifluoromethyl) phenyl]-1, 2-ethanediol (Description 3,110 mg, 0.40 mmol) and 4- dimethylaminopyridine (1 mg) were added and the mixture was stirred at room temperature for 2 hours. Dichloromethane (20 mL) and aqueous sodium carbonate (10%, 20 mL) were added and the layers were separated. The aqueous fraction was extracted with dichloromethane (10 mL), then with ethyl acetate (10 mL). The combined organic layers were dried (Na, SO,) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NEl3 (Aq.) (95: 5: 0.5 increasing to 90: 10: 1) to give the title compound. m/z (ES+) 638 (M+1).

EXAMPLE 120 Trans-(RS)-α-({[2-(Trimethylsilyl)ethoxy]methoxy}methyl)-[3 ,5- bis (trifluoromethyl) phenyl]methyl 4-[4-(4-Fluorophenyl)piperidin-1-yl]-1- phenylcyclohexanecarboxylate Prepared from trans-4- [4- (4-fluorophenyl) piperidin-1-yl]-l-phenylcyclohexanecarboxylic acid hydrochloride (Description 20) and (RS)-1- [3, 5-bis (trifluoromethyl)-a-{[2- (trimethylsilyl) ethoxy] methoxymethyl} benzenemethanol (Description 4) according to the method of Example 119. m/z (ES+) 768 (M+1).

EXAMPLE 121 Trans- (RS)-a- (Hydroxymethyl)-f3, 5-bis (trifluoromethyl)phenyl]methyl 4-[4-(4- FluorophenyDpiperidin-l-yl1-l- (phenyt) cyclohexanecarboxylate Trifluoroacetic acid (0.5 mL) was added to a solution of trans-(RS)-ot-({[2- (trimethylsilyl) ethoxy] methoxy} methyl)- [3, 5-bis (trifluoromethyl) phenyl] methyl 4- [4- (4- fluorophenyl)piperidin-1-yl]-1-(phenyl)cyclohexanecarboxylat e (Example 120,37 mg, 48 jmiol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3 (Aq.) (95: 5: 0.5) to give the title compound (19 mg, 62%). m/z (ES+) 638 (M+1).

EXAMPLE 122 Trans-(RS)-Methyl α-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1- phenylcyclohexyl}carbonyloxy)-3,5-bis(trifluoromethyl)benzen eacetate Methyl a-diazo-3, 5-bis (trifluoromethyl) benzeneacetate (WO 95/21819,200 mg, 0.64 mmol) in dichloromethane (2 mL) was added to a mixture of tratis-4- [4- (4-fluorophenyl) piperidin-l- yl]-1-phenylcyclohexanecarboxylic acid hydrochloride (Description 20,103 mg, 0.25 mmol) and rhodium acetate dimer (4 mg) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 1 hour. Further methyl a-diazo-3, 5-bis (trifluoromethyl) benzeneacetate (100 mg, 0.32 mmol) in dichloromethane (1 mL) was added and the mixture was stirred at room temperature for 1 hour. Further methyl Oc-diazo-3, 5-bis (trifluoromethyl) benzeneacetate (50 mg, 0.16 mmol) in dichloromethane (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CHCI/MeOH (97.5: 2.5) to give the title compound (18 mg, 11%). m/z (ES+) 666 (M+I).

EXAMPLE 123 Cis-{4-f4- (4-Fluorophenvl) iperidin-1-ylphenylcyclohexyl methyl 3 5- Bis (trifluoromethyl) benzoate and Trans-{4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohex yl}methyl 3,5- Bis (trifluoromethyl) benzoate Sodium triacetoxyborohydride (420 mg, 2 mmol) was added to a mixture of (4-oxo-1- phenylcyclohexyl) methyl 3,5-bis (trifluoromethyl) benzoate (Example 10,180 mg, 0.4 mmol), 4- (4-fluorophenyl) piperidine (Description 16,72 mg, 0.4 mmol), and acetic acid (114 1,

2 mmol) in 1,2-dichloroethane and the mixture was stirred at room temperature for 70 hours.

Saturated aqueous sodium hydrogen carbonate (30 mL) was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were washed with brine, dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography, eluting with isohexane/EtOAc (50: 50) to give: cis-{4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl }methyl 3,5- bis (trifluoromethyl) benzoate (7.8 mg, 3%) ;'HNMR (360MHz, CDC1,) 8 1.69-1.93 (1OH, m), 2.24-2.60 (6H, m), 3.15 (2H, br d, J 10. 6 Hz), 4.60 (2H, s), 6.98 (2H, t, J 8. 7 Hz), 7.16-7.26 (3H, m), 7.34-7.38 (2H, m), 7.43-7.45 (2H, m), 8.00 (1H, s), and 8.23 (2H, s); m/z (ES+) 608 (M+1) ; and trans-{4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohex yl}methyl 3,5- bis (trifluoromethyl) benzoate (9 mg, 4%);'H NMR (360MHz, CDCI,) 5 1.34-1.44 (2H, m), 1.60-178 (6H, m), 1.86-1.88 (2H, m), 2.14-2.20 (2H, m), 2.36-2.52 (2H, m), 2.58 (2H, br d, J 12.4 Hz), 2.95 (2H, d, J 11.4 Hz), 4.23 (2H, s), 6.94 (2H, t, J 8.7 Hz), 7.11-7.15 (2H, m), 7.22-7.26 (1H, m), 7.36-7.40 (2H, m), 7.45-7.47 (2H, m), 8.03 (1H, s), and 8.32 (2H, s); m/z (ES+) 608 (M+1).

EXAMPLE 124 CM-1-Phenyl-4- (4-phenylpipendin-1-yD-N-f f3. 5-bis (trifluoromethyl) phenyllmethyl} cyclohexanecarboxamide and Trans-1-Phenyl-4-(4-phenylpiperidin-1-yl)-N-{[3,5-bis(triflu oromethyl)phenyl]methyl} cyclohexanecarboxamide Prepared as a mixture of cis-and trans-isomers from 4-oxo-1-phenyl-N-{ [3,5- bis (trifluoromethyl) phenyl] methyl} cyclohexanecarboxamide (Example 17) and 4- phenylpiperidine according to the method of Example 45. The isomers were separated by HPLC purification [YMC R&D CR isohexane/EtOH (60: 40)]: cis-l-phenyl4- (4-phenylpiperidin-1-yl)-N f [3, 5-bis (trifluoromethyl) phenylJmethylj cyclohexanecarboxamide ;'H NMR (360MHz, CD30D) 8 7.79 (1H, s) 7.69 (2H, s), 7.38-7.18 (10H, m), 4.47 (2H, s), 3.15 (2H, m), 3.05-2.40 (6H, m), 2.06 (2H, m), and 1.97-1.78 (9H, m) ; m/z (ES+) 589 (M+1) ; trans-1-phenyl-4-(4-phenylpiperidin-1-yl)-N-{[3,5-bis(triflu oromethyl)phenyl]methyl} cyclohexanecarboxamide ;'H NMR (360MHz, CD30D) 8 7.74 (1H, s) 7.55 (2H, s), 7.53-7.14 (1OH, m), 4.39 (2H, s), 3.06 (2H, m), 2.80 (2H, m), 2.53 (2H, m), 2.32 (2H, m), and 1.99-1. 29 (11H, m) ; m/z (ES+) 589 (M+1).

The following compounds were prepared as mixtures of cis-and trans-isomers from (RS)-4- oxo-1-phenyl-N- {1-[3 5-bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 18) according to the method of Example 55, substituting a suitable amine for piperidine. P $<CF3 H I Q"V NRZ CF3 NR Cis- (RS) &Trans- (RS) m/z Ex.-Nd ; Formula M. W. (ES+) (M+1). 125 C24H26F6N20 472 473 H 126 C27H30F6N20 512 513 -V 127 OH C28H32F6N202 542 543 128 _ > C27H30F6N20 512 513 H 129 _oo Et C31H36F6N203 598 599 130 Ac C30H34F6N203 584 585 131 _ % C3lH33P6N30 577 578 Et 132 C27H30F6N202 528 529 - 133 < C28H32F6N20 526 527 134 Ph C35H38F6N202 632 633 -0 OCH p t H I NRZ CF3 Cis-(RS) &Trans- (RS) mlz Ex.-NR ; Formula M. W. (ES+) (M+1). 135 _@0 C33H41F6N30 609 610 1 136 A C28H31F6N302 555 556 CHO U 137 F C33H34F7N30 621 622 138-,/-' C30H37F6N30 569 570 -NMe2 U 139/» C29H34F6N20 540 541 140/\ C32H32F6N20 574 575 -cob 141 C29H34F6N20 540 541 142 _@t C34H34F6N40S 660 661 I U 143 C29H34F6N20 540 541 144 C28H32F6N20 526 527 Y 145/^\ C27H30F6N20S 544 545 -NDs 146 C29H34F6N20 540 541 p) NR2 CF3 0""r Cis- (RS &Trans- (RS lTI/Z Ex.-NR, Formula M. W. (ES+) (M+1). 147 _oZMe C26H28F6N203 530 531 148 \/\ C33H41F6N30 609 610 149 C30H36F6N20 554 555 _W 150 C29H34F6N202 556 557 OH 151/C29H34F6N202 556 557 152 C26H28F6N20 498 499 H The following compounds were prepared from trans-4-[4-(4-fluorophenyl)piperidin-1-yl]-1- phenylcyclohexanecarboxylic acid hydrochloride (Description 20) according to the method of Example 177, substituting a suitable amine for (RS)-a-methyl-3, 5- bis (trifluoromethyl) benzenemethanamine hydrochloride. P =CtHKR H Trans- F ----- rn/z Ex.-R Formula M. W. (ES+) (M+1 153 Me C32H37FN202 500 501 6 154'Me C33H39FN202 514 515 ()- 1552 C35H37F7N20 634 635 +rCF3 CF3

(RS)-2-Methoxy-oc-methylbenzenemethanamine Hydrochloride : Description 6.

2 (RS)-a-Ethyl-3, 5- bis (trifluoromethyl) benzenemethanamine Hydrochloride: Description 7.

The following compounds were prepared from trans-4- [4- (4-fluorophenyl) piperidin-1-yl]-1- phenylcyclohexanecarboxylic acid hydrochloride (Description 20) according to the method of Example 158, substituting a suitable amine for 3- (methoxy) benzenemethanamine. Pt oNR H /Trans- F mlz Ex.-R Formula M. W. (ES+) (M+1). 156'C35H37F7N20 634 635 o CF3 CF3 1572 2NIe C35H35F7N203 664 665 CF3 ()-I

'a, oc-Dimethyl-3, 5- bis (trifluoromethyl) benzenemethanamine Hydrochloride: Description 11.

2 (RS)-Methyl a-Amino-3, 5- bis (trifluoromethyl) benzeneacetate Hydrochloride: Description 12.

EXAMPLE 158 Trans-4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-yl]-N-{[3-(meth oxy)phenyl]metyhyl}-1- phenvlcyclohexanecarboxamide Bis (2-oxo-3-oxazolidinyl) phosphinic chloride (40 mg, 0.16 mmol) was added to a solution of trans-4- [4- (4-fluorophenyl) piperidin-1-yl]-1-phenylcyclohexanecarboxylic acid hydrochloride (Description 20,50 mg, 0.13 mmol) and triethylamine (91 ttl, 0.65 mmol) in dichloromethane

(5 mL) and the mixture was stirred at room temperature for 10 minutes. 3- (Methoxy) benzenemethanamine (18 µl, 0.14 mmol) was added and the mixture was stirred at room temperature overnight. Aqueous sodium carbonate (10%, 20 mL) and ethyl acetate (20 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 20 mL) and the combined organic fractions were washed with brine (20 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (0.5 mL) and poured onto an SCX cartridge (Varian Bond Elut ; 10 mL/500 mg). The cartridge was washed with methanol (2 x 5 mL), then eluted with methanolic ammonia (2M, 5 mL). The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3 (Aq.) (96: 4: 0.4), to give the title compound (38 mg, 58%). m/z (ES+) 501 (M+1).

The following compounds were prepared from trans-4- [4- (4-fluorophenyl) piperidin-1-yl]-1- phenylcyclohexanecarboxylic acid (Description 20) according to the method of Example 158, substituting a suitable amine for 3- (methoxy) benzenemethanamine. prtt p /Trans- k--, mlz Ex.-X-Formula M. W. (ES+) <BR> <BR> (M+1).<BR> <P>159 2-C1 C31H34C1FN20 504 505 506 507 160 3-C1 C31H34C1FN20 504 505 506 507 161 2,3-Cl, C31H33C12FN20 538 539 540 541 542 543 P prte 43 Trans- k-11 mlz Ex.-X-Formula M. W. (ES+) (M+1).

162 2,4-Cl2 C31H33Cl2FN2O 538 539 <BR> <BR> <BR> 540 541<BR> <BR> <BR> <BR> <BR> 542 543 163 3-CI-4-F C31h33ClF2N2O 522 522 524 525 164 2, 4-F2, C3lH33F3N20 506 507 165 2, 6-F2 C3lH33F3N20 506 507 166 3, 5-F2 C3lH33F3N20 506 507 167 2,3-Me, C33H39FN20 498 499 168 2-CF3 C32H34F4N20 538 539 169 3-CF3 C32H34F4N20 538 539 170 4-CF3 C32H34F4N20 538 539 171 2, 4-(OMe)2 C33H39FN203 530 531 172 3, 5-(OMe)2 C33H39FN203 530 531 173 2,4, 6-(OMe)3 C34H41FN204 560 561 174 2, 6-(OMe)2 C33H39FN203 530 531 175 3, 4-(OMe)2 C33H39FN203 530 531 176 2, 5-(OMe)2 C33H39FN203 530 531

EXAMPLE 177 Trans-(RS)-4-[4-(4-Fluorophenyl)piperidin-1-yl]-N-{1-[3,5- bis (trifluoromethyl) phenyl]ethyl}-1-phenylcyclohexanecarboxamide Triethylamine (0.13 mL, 0.96 mmol) was added to a mixture of trans-4- [4- (4- fluorophenyl) piperidin-1-yl]-1-phenylcyclohexanecarboxylic acid hydrochloride (Description 20,100 mg, 0.24 mmol), (RS)-cc-methyl-3, 5-bis (trifluoromethyl) benzenemethanamine hydrochloride (Description 5,125 mg, 0.43 mmol) and 1-hydroxy benzotriazole (129 mg, 0.96 mmol) in dimethylformamide (10 mL) and the mixture was stirred at room temperature for 10 minutes. 1-(Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (184 mg, 0.96 mmol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic fractions were washed with aqueous sodium carbonate (saturated), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CHCl,/MeOH/Nl- (Aq.) (90 : 10: 1) to give the title compound as a colorless solid (145 mg, 97%). m/z (ES+) 621 (M+1).

EXAMPLE 178 Trans-(R)-4-[4-(4-Fluorophenyl)piperidin-1-yl]-N-{1-[3,5-bis (trifluoromethyl)phenyl] ethyl}- 1-phenyyclohexanecarboxamide and Trans-(S)-4-[4-(4-Fluorophenyl)piperidin-1-yl]-N-{1-[3,5-bis (trifluoromethyl)phenyl] ethyl}- 1-phenylcyclohexanecarboxamide The mixture of enantiomers of Example 177 was separated by chiral HPLC (Chirobiotic V; MeOH/E% N/AcOH ; 100: 0.1: 0.1; 1 mL/min ; 260 nm) to give: trans-(R)-4-[4-(4-fluorophenyl)piperidin-1-yl]-N-{1-[3,5-bis (trifluoromethyl)phenyl] ethyl}-1- phenylcyclohexanecarboxamide ; m/z (ES+) 621 (M+1) ; and trans-(S)-4-[4-(4-fluorophenyl)piperidin-1-yl]-N-{1-[3,5-bis (trifluoromethyl)phenyl] ethyl}-1- phenylcyclohexanecarboxamide ; m/z (ES+) 621 (M+1).

EXAMPLE 179 Cis-(RS)-4-[4-(4-Fluorophenyl)piperidin-1-yl]-N-{1-[3,5-bis( trifluoromethyl)phenyl] ethyl}- 1-phenvlcyclohexanecarboxamide Hydrochloride Prepared from cis-4- [4- (4-fluorophenyl) piperidin-1-yl]-l-phenylcyclohexanecarboxylic acid (Description 19) and (RS)- (X-methyl-3, 5-bis (trifluoromethyl) benzenemethanamine hydrochloride (Description 5) according to the method of Example 177. m/z (ES+) 621 (M+1).

EXAMPLE 180 Trans-N-Methyl-1-phenyl-4-(4-phenylpiperidin-1-yl)-1N-{[3, 5- bis (trifluoromethvlOphenvllmethvl lcvclohexanecarboxamide Prepared from 1-phenyl-4- (4-phenylpiperidin-1-yl)-N- { [3,5-bis (trifluoromethyl) phenyl] methyl cyclohexanecarboxamide (Mixture of cis-and trans-isomers, Example 124) according to the method of Example 156, followed by HPLC purification [YMC R&D CR isohexane/EtOH (60: 40)]. m/z (ES+) 603 (M+1).

EXAMPLE 181 Trans-(RS)-4-[4-(4-Fluorophenyl)piperidin-1-yl]-N-methyl-{1- [3,5- bis (trifluoromethyl) phenyllethylJ-1-phenylcyclohexanecarboxamide Sodium hydride (60% in mineral oil, 6.5 mg, 0.16 mmol) was added to a solution of trans- (RS)-4-[4-(4-fluorophenyl)piperidin-1-yl]-N-{1- [3,5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide (Example 177,50 mg, 0.08 mmol) in dimethylformamide (5 mL) and the mixture was stirred at room temperature for 30 minutes. Iodomethane (15 ul, 0.24 mmol) was added and the mixture was stirred for 1 hour. Aqueous ammonium chloride (saturated) was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (Hichrom RPB; 250 x 20 mm; 65%MeCN in 0.1%TFA-HZO; 20 mL/min ; 210 nm) to give the title compound as a colorless solid, (20 mg, 39%). m/z (ES+) 635 (M+1).

EXAMPLE 182 Trans-(RS)-4-f4-(4-Fluorophenvl) piperidin-l-vll-l-phenvl-N-T 2-hvdroxv-1-f35- bis (trifluoromethyl) phenyl ethyl} cyclohexanecarboxamide Lithium borohydride (12 mg, 0.55 mmol) was added to a solution of tran-(RS)-methyl α-({4- [4- (4-fluorophenyl) piperidin-1-yl]-1-phenylcyclohexyl} carbonylamino)-3, 5- bis (trifluoromethyl) benzeneacetate (Example 157,100 mg, 0.15 mmol) in tetrahydrofuran (4 mL) and the mixture was stirred at room temperature for 1.5 hours. Hydrochloric acid (2M, 1 mL) was added and the mixture was stirred at room temperature for 10 minutes. Potassium carbonate (500 mg) was added and the mixture was extracted with ethyl acetate (2 x 30 mL).

The combined organic fractions were washed with aqueous sodium carbonate (10%, 20 mL) and brine (20 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure.

The residue was purified by flash column chromatography on silica gel, eluting with CHICL/MeOH/NH3 (Aq.) (95: 5: 0.5) to give the title compound (41 mg, 43%). m/z (ES+) 637 (M+1).

EXAMPLE 183 Trans- (RS)-4-(1,4-Dioxa-8-azaspiro[4,5]decane-8-yl)-1-phenyl-N-{1- [3, 5- bis (trifluoromethyl ! phenyllethyl lcyclohexanecarboxamide Sodium triacetoxyborohydride (303 mg, 1.4 mmol) was added to a degassed solution of 4- oxo-1-phenylcyclohexanecarboxylic acid (Description 2,260 mg, 1.2 mmol) and 1,4-dioxa-8- azaspiro [4.5] decane (0.15 mL, 168 mg, 1.2 mmol) in dichloroethane (5 mL) and the mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure and the residue was suspended in dichloromethane. Triethylamine (0.83 mL, 0.60 g, 6 mmol) and bis (2-oxo-3-oxazolidinyl) phosphonic chloride (460 mg, 1.8 mmol) were added.

The mixture was stirred at room temperature for 10 minutes, then (RS)-ac-methyl-3, 5- bis (trifluoromethyl) benzenemethanamine hydrochloride (Description 5,420 mg, 1.4 mmol) was added and the mixture was stirred at room temperature for 20 hours. Aqueous sodium carbonate was added and the mixture was extracted with dichloromethane. The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure.

The residue was purified by flash column chromatography on silica gel, eluting with CHCI,/MeOH/NH, (Aq.) (96: 4: 0.4) to give the title compound (120 mg, 17%). m/z (ES+) 585 (M+1).

EXAMPLE 184 Trans- (RS-4- (4-Oxopiperidin-1-Z-l-phenyl-N- {1-f3, 5-bis (trifluoromethyl) phenyll ethyl}cyclohexanecarboxamide Prepared from trans-4- (4-oxopiperidin-1-yl)-l-phenylcyclohexanecarboxylic acid hydrochloride (Description 24) and (RS)-a-methyl-3, 5-bis (trifluoromethyl) benzenemethanamine hydrochloride (Description 5) according to the method of Example 158. m/z (ES+) 541 (M+1).

EXAMPLE 185 Trans-(RS)-4-(4-Hydroxypiperidin-1-yl)-1-phenyl-N-{1-[3,5-bi s(trifluoromethyl)phenyl] ethyl} cyclohexanecarboxamide Sodium borohydride (22.5 mg, 0.59 mmol) was added to a solution of trans-(RS)-4-(4- oxopiperidin-1-yl)-1-phenyl-N- {1- [3, 5-bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 184, 319 mg, 0.59 mmol) in ethanol (3 mL) and the mixture was stirred at room temperature for 1 hour. Aqueous ammonium chloride (saturated, 1 mL) and aqueous sodium carbonate (saturated, 10 mL) were added and the mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic fractions were dried (Na2SO4)

and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (95: 5: 0.5 increasing to 85 : 15: 1.5) to give the title compound (250 mg, 78%). m/z (ES+) 543 (M+1).

EXAMPLE 186 Trans-(RS)-4-(But-3-enylamino)-1-phenvI-N-f l-r3.5-bis (trifluoromethyl) phenyllethvl T cyclohexanecarboxamide (N-Ethylethanaminato) trifluorosulfur (45 ul, 59 mg, 0.36 mmol) was added dropwise to a cooled (-60 °C) solution of trans- (RS)-4- (4-hydroxypiperidin-1-yl)-l-phenyl-N-1 1- [3, 5- bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 185,90 mg, 0.16 mmol) in ethyl acetate (5 mL) and the mixture was stirred at-60 °C for 1 hour, then allowed to warm to room temperature. Aqueous sodium hydrogen carbonate (saturated, 10 mL) was added and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic fractions were washed with aqueous sodium carbonate (saturated, 20 mL) and brine (20 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC chromatography on silica gel, eluting with EtOAc/MeOH (85: 15) to give the title compound (45 mg, 53%). m/z (ES+) 513 (M+1).

EXAMPLE 187 Trans-(RS)-4-(4-Hydroxy-4-phenylpiperidin-1-yl)-1-phenyl-N-{ 1-[3 5- bis (trifluoromethyl) phenyllethyl Scyclohexanecarboxamide Phenylmagnesium bromide (1M in tetrahydrofuran, 0.3 mL, 0.3 mmol) was added dropwise to a cooled (0 °C) solution of trans- (RS-4- (4-oxopiperidin-1-yl)-1-phenyl-N- { 1- [3, 5- bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 184,53 mg, 0.1 mmol) in tetrahydrofuran (2 mL) and the mixture was stirred at 0 °C for 10 minutes, then at room temperature for 1 hour. Aqueous ammonium chloride (saturated, 0.3 mL) and aqueous sodium carbonate (saturated, 10 mL) were added and the mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic fractions were dried (NaS04) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (1 mL) and poured onto an SCX cartridge (Varian Bond ElutT ; 10 moi./500 mg). The cartridge was washed with methanol (4 x 1 mL), then eluted with methanolic ammonia (2M, 4 x 1 mL). The solvent was evaporated under reduced pressure to give the title compound (45 mg, 75%). m/z (ES+) 619 (M+1).

The following compounds were prepared from trans- (RS)-4- (4-oxopiperidin-1-yl)-l-phenyl- N- {1- [3, 5-bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 184) according to the method of Example 187, substituting a suitable Grignard reagent for phenylmagnesium bromide. CF3 P j H cl3 = CFa NRZ Trans-(RS) l m/z Ex.-NR, Formula M. W. (ES+) (M+1). 188/)/C29H34F6N202 556 557 uOH 189 OH C30H32F6N202 566 567 190--Ph C35H38F6N202 632 633 OH 191/-\, wOH C31H36F6N202 582 583 -hX 192 H C36H36F6N202 642 643 Ph

EXAMPLE 193 Trans- (RS)-4-(1,2,3,6-Tetrahydro-4-phenylpyridin-1-yl)-1-phenyl-N- {1-[3,5- bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide p-Toluenesulfonic acid hydrate (10 mg, 0.05 mmol) was added to a solution of trans- (RS)-4- (4-hydroxy-4-phenylpiperidin-1-yl)-1-phenyl-N- {1- [3, 5- bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 187,26 mg, 0.04 mmol) in toluene (8 mL) and the mixture was heated under reflux for 8 hours. The mixture was cooled and aqueous sodium carbonate (saturated, 20 mL) was added. The mixture was extracted with ethyl acetate (2 x 20 mL) and the combined organic fractions were dried (Na, SO,) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (1 mL) and poured onto an SCX cartridge (Varian Bond Elut ; 10 mL/500 mg).

The cartridge was washed with methanol (4 x 1 mL), then eluted with methanolic ammonia

(2M, 4 x 1 mL). The solvent was evaporated under reduced pressure to give the title compound (24 mg, 94%). m/z (ES+) 601 (M+1).

EXAMPLE 194 Trans-(RS)-4-(1,2,3,6-Tetrahydro-4-methylpyridin-1-yl)-1-phe nyl-N-{1-[3,5- bis (trifluoromethyl) phenyllethyl Tcyclohexanecarboxamide Prepared from trarzs- (RS-4- (4-hydroxy-4-methylpiperidin-1-yl)-l-phenyl-N- { 1- [3, 5- bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 188) according to the method of Example 193. m/z (ES+) 539 (M+1).

EXAMPLE 195 Trans-(RS)-4-(4-Hydroxy-4-(phenylethyl)piperidin-1-yl)-1-phe nyl-N-{1-[3,5- bis(trifluoromethyl)phenyl]ethyl}cyclohexanecarboxamide Palladium on carbon (5%, 5 mg) was added to a solution of trans- (RS)-4- (4-hydroxy-4- (phenylethynyl) piperidin-l-yl)-l-phenyl-N- {l- [3, 5-bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 192,23 mg, 0.036 mmol) in ethanol (10 mL) and hydrochloric acid (2M, 1 mL) and the mixture was shaken under an atmosphere of hydrogen (50 psi) for 24 hours. The mixture was filtered through Celiez and the solvent was evaporated under reduced pressure. Ethyl acetate (10 mL) and aqueous sodium carbonate (10%, 10 mL) were added and the layers were separated. The aqueous fraction was extracted with ethyl acetate (10 mL) and the combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (1 mL) and poured onto an SCX cartridge (Varian Bond Elut ; 10 mL/500 mg). The cartridge was washed with methanol (4 x 1 mL), then eluted with methanolic ammonia (2M, 4 x 1 mL). The solvent was evaporated under reduced pressure to give the title compound (20 mg, 86%). m/z (ES+) 647 (M+1).

The following compounds were prepared from trans- (RS)-4- (4-oxopiperidin-1-yl)-1-phenyl- N- {1- [3, 5-bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 184) according to the method of Example 55, substituting a suitable amine for piperidine. P tir#,, H il CF3 NR2 CF3 Trans-(RS) mlz Ex.-NR, Formula M. W. (ES+) (M+1). 196 C35H46F6N40 652 653 197 _, S, C34H43F6N30 623 624 198 C37H4lF6N30 657 658 199 » C34H43F6N30 623 624 200 _093 C39H43F6NSOS 743 744 U 201 _ C34H43F6N30 623 624 202/\ A C33H41F6N30 609 610 203 _grCs C32H39F6N30S 627 628 204 C34H41F6N30 621 622 205 _9N02Me C31H37F6N303 613 614 v 206-) 00 C38H50F6N40 692 693 207 C35H45F6N30 637 638 208 C34H43F6N302 639 640 OH oH P -NR2 CF3 0"T cl3 CF3 NR2 Trans-(RS) miz Ex.-NR2 Formula M. W. (ES+) (M+1). 209 4 C34H43F6N302 639 640 0-ka 210 A C31H37F6N30 581 582 H

EXAMPLE 211 Cis- (RS)-4-r (Phenylmethvl) aminol-N-l-f3, 5-bis (trifluoromethyl) phenvllethyl}-1- phenylcyclohexanecarboxamide and Trans-(RS)-4-[(Phenylmethyl)amino]-N-{1-[3,5-bis(trifluorome thyl)phenyl]ethyl}-1- phenylcyclohexanecarboxamide Prepared from (RS)-4-oxo-1-phenyl-N-{1-[3, 5-bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 18) and benzylamine according to the method of Example 45: Cis-(RS)-4-[(phenylmethyl)amino]-N-{1-[3,5-bis(trifluorometh yl)phenyl]ethyl}-1- phenylcyclohexanecarboxamide ;'H NMR (400MHz, CDCl3) 8 7.70 (1H, s), 7.46 (2H, s), 7.33-7.24 (10H, m), 5.09 (1H, q, J 7. 0 Hz), 3.83 (2H, s), 2.58-2.55 (2H, m), 2.43 (1H, br d, J 15.2 Hz), 2.04 (1H, br d, J 11. 4 Hz), 1.95-1.87 (2H, m), 1.64-1.42 (3H, m), and 1.37 (3H, d, J 7.0 Hz); m/z (ES+) 549 (M+1) ; Trans-(RS)-4-[(phenylmethyl)amino]-N-{1-[3,5-bis(trifluorome thyl)phenyl]ethyl}-1- pherzylcyclohexanecarboxamide ;'H NMR (400MHz, CDC13) 8 7.70 (s, 1H), 7.50-7.42 (6H, m), 7.34-7.21 (6H, m), 5.00 (1H, q, J7. 0 Hz), 3.75 (2H, s), 2.72-2.67 (1H, m), 2.48 (1H, br d, J 14. 3 Hz), 2.37 (1H, br d, J 14. 2 Hz), 2.17-2. 06 (2H, m), 1.92-1.88 (2H, m), 1.39-1. 16 (2H, m), and 1.27 (3H, d, J 7.0 Hz); m/z (ES+) 549 (M+l).

EXAMPLE 212 <BR> <BR> <BR> <BR> Trans-(RS)-4-[N-Methvl (pheny1methvl) amunol-N-f l-f35-bis (trifluoromethvl) phenyll ethvl}- 1-phenylcyclohexanecarboxamide Sodium cyanoborohydride (275 mg, 4.38 mmol) was added to a solution of trans- (RS)-4- [ (phenyImethyl) amino]-N- {l- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide (Example 211,1.2 g, 2.19 mmol) and aqueous formaldehyde (37%, 820 gel, 10.94 mmol) in acetonitrile (20 mL) and the mixture was stirred at room temperature for 15 minutes. Acetic acid was added until the pH was neutral. The mixture was stirred at room temperature for 45 minutes, adding further acetic acid to maintain neutral pH.

The solvent was evaporated under reduced pressure and aqueous sodium hydroxide (1M, 20 mL) and dichloromethane (20 mL) were added. The layers were separated and the aqueous layer was extracted dichloromethane (2 x 20 mL). The combined organic fractions were washed with brine (40 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (1.26 g, 100%). m/z (ES+) 563 (M+1).

EXAMPLE 213 Trans-(RS)-4-Methylamino-N-{3,5-bis(trifluoromethyl)phenyl]e thyl}-1- phenylcyclohexanecarboxamide Prepared from trans- (RS)-4- [N-methyl (phenylmethyl) amino]-N- { 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide (Example 212) according to the method of Example 229. m/z (ES+) 473 (M+1).

EXAMPLE 214 Trans-(RS)-4-Amino-N-{1-[3,5-bis(trifluoromethyl)phenyl]ethy l}-1- phenylcyclohexanecarboxamide Triphenylphosphine (1.0 g, 3.82 mmol) was added to a solution of trans-(RS)-4-azido-N-{1- [3,5-bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide (Description 28, 920 mg, 1.90 mmol) in tetrahydrofuran (10 mL) and water (1 mL) and the mixture was heated under reflux for 24 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3 (Aq.) (80: 20: 2), to give the title compound as a colorless solid (670 mg, 87%). m/z (ES+) 459 (M+1), 442 (M+1-NEI3).

EXAMPLE 215 Trans-(RS)-4-(Dimethvlamino)-N- {l-f3.5-bis (trifluoromethyl) phenyllethyl}-1- phenylcyclohexanecarboxamide Palladium hydroxide (50 mg) was added to a solution of trans- (RS)-4-amino-N- { 1- [3, 5- bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide (Example 214,50 mg, 0.11 mmol) and aqueous formaldehyde (37%, 2 mL) in methanol (10 mL) and the mixture was shaken under an atmosphere of hydrogen (50 psi) for 18 hours. The mixture was filtered through a glass fibre pad, washing with methanol, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with aqueous sodium carbonate (saturated), dried (MgSO4) and the solvent was evaporated under reduced pressure.

The residue was dissolved in ethanol and ethereal hydrogen chloride (1M) was added. The solvent was evaporated under reduced pressure and the residue was crystallised from EtOAc/Et2O (50: 50) to give the title compound as a colorless solid (20 mg, 35%). m/z (ES+) 487 (M+1).

EXAMPLE 216 Trans-(RS)-4-[4-(Phenylbutyl)amino]-N-{1-[3,5-bis(trifluorom ethyl)phenyl]ethyl}-1- phenylcyclohexanecarboxamide Hydrochloride Prepared from trans- (RS)-4-amino-N-1 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide (Example 214) and benzenebutanal (Description 17) according to the method of Example 55. m/z (ES+) 591 (M+1).

The following compounds were prepared from trans-(RS)-4-amino-N-{1-[3, 5- bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide (Example 214) according to the method of Example 45, substituting a suitable aldehyde or ketone for benzylamine. PIT*"CF3 CF3 H IN NR2 CF3 Trans-(RS) mlz Ex.-NR, Formula M. W. (ES+) (M+1). P T tu#" w \ H I CF3 Nu2 NR2 Trans-(RS) mlz Ex.-NR2 Formula M. W. (ES+) (M+1). 217 | C26H30F6N20 500 501 H H 218 C28H32F6N20 526 527 H H 219 C29H34F6N20 540 541 H H 220 C3lH36F6N20 566 567 3 221 C37H48F6N20 650 651 './ u 222 C29H36F6N20 542 543 - 223 NPh C30H30F6N20 548 549 H

EXAMPLE 224 Trans-(RS)-4-[N-Methyl-4-(phenylbutyl)amino]-N-{1-[3,5-bis(t rifluoromethyl)phenyl] ethyU-1-phenylcvclohexanecarboxamide Prepared from trans- (RS)-4- [4- (phenylbutyl) amino]-N- { 1- [3, 5- bis (trifluoromethyl) phenyl] ethyl}-l-phenylcyclohexanecarboxamide Hydrochloride (Example 216) according to the method of Example 215. m/z (ES+) 605 (M+1).

EXAMPLE 225 Trans-RS)-4-Acetylamino-N-{l-r3,5-bis (trifluoromethyl) phenyllethyl}-1- phenylcyclohexanecarboxamide Acetic anhydride (0.1 mL, 1. 1 mmol) was added to a solution of trans-(RS)-4-amino-N-{1- [3,5-bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide (Example 214, 50 mg, 0.11 mmol) in dichloromethane (5 mL) and the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (50 mL) and washed with aqueous sodium carbonate (saturated) and water, dried (MgSO4), and the solvent was evaporated under reduced pressure to give the title compound as a colorless foam, (54 mg, 98%). m/z (ES+) 501 (M+1).

EXAMPLE 226 Trans-(RS)-4-[(1-Oxo-4-phenylbutyl)amino]-N-{1-[3, 5-bis (trifluoromethyl) phenyll ethyl}- !- phenylcyclohexanecarboxamide Prepared from trans- (RS)-4-amino-N- { 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide (Example 214) and benzenebutanoic acid (27 mg, 0.16 mmol) according to the method of Example 158. m/z (ES+) 605 (M+1).

EXAMPLE 227 Cis-and Trans-(RS)-1,1-Dimethylethyl 4-[1-({1-[3,5-Bis(trifluoromethyl)phenyl] ethvlamino} carbonvl)-1-phenylcyclohex-4-yll-1-piperazinecarbox Prepared as a mixture of cis-and trans-isomers from (7 ? y)-4-oxo-l-phenyl-N- { 1- [3, 5- bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 18) and 1,1- dimethylethyl 1-piperazinecarboxylate according to the method of Example 45. m/z (ES+) 628 (M+1).

EXAMPLE 228 Trans-(RS)-4-[4-(Phenylmethyl)piperazin-1-yl]-N-{1-[3,5-bis( trifluoromethyl)phenyl] ethyl}- 1-phenylcyclohexanecarboxamide Bis (2-oxo-3-oxazolidinyl) phosphinic chloride (1.56 g, 6.12 mmol) was added to a mixture of <BR> <BR> <BR> trans-4- [4- (phenylmethyl) piperazin-1-yl]-1-phenylcyclohexanecarboxylic acid hydrochloride (Description 25,1.92 g, 5.1 mmol) and triethylamine (3.55 mL, 25.5 mmol) in dichloromethane (200 mL) and the mixture was stirred at room temperature for 15 minutes.

(RS)-ot-Methyl-3, 5-bis (trifluoromethyl) benzenemethanamine hydrochloride (Description 5, 1.64 g, 5.6 mmol) was added and the mixture was stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure and aqueous sodium carbonate (10%, 100 mL)

and ethyl acetate (100 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic fractions were washed with aqueous sodium carbonate (10%, 100 mL) and brine (20 mL), dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and ethereal hydrogen chloride (1M, 10.2 mL) was added. The solid was collected and aqueous sodium carbonate (10%, 100 mL) and ethyl acetate (100 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic fractions were washed with aqueous sodium carbonate (10%, 100 mL) and brine (20 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (1.7 g, 54%). m/z (ES+) 618 (M+1).

EXAMPLE 229 Trans-(RS)-4-(Piperazin-l-yl)-N-{l-f3.5-bis (trifluoromethyl) phenynethyl}-1- phenylcyclohexanecarboxamide Palladium hydroxide on carbon (20%, 20 mg) was added to a mixture of trans- (RS)-4- [4- (phenylmethyl) piperazin-1-yl]-N-1 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide (Example 228,700 mg, 1.3 mmol), hydrochloric acid (1M, 2.6 mI :) and acetic acid (5 mL) in ethyl acetate (50 mL) and the mixture was shaken under an atmosphere of hydrogen (50psi) for 20 hours. The mixture was filtered through a glass fibre pad, washing with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and washed with aqueous sodium carbonate (10%, 20 mL) and brine (20 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOEVNH3 (Aq.) (90: 10: 1), to give the title compound. m/z (ES+) 528 (M+1).

The following compounds were prepared from trans-(RS)-4-(piperazin-1-yl)-N-{1-[3, 5- bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide (Example 229) according to the method of Example 45, substituting a suitable aldehyde or ketone for (RS)-ß- [ (4-oxo-l-phenylcyclohexyl) methoxy]-3, 5-bis (trifluoromethyl) benzeneethanol. PC CF3 H I/ CF3 cl R Trans-(RS) rn/z Ex.-R Formula M. W. (ES+) (M+1). 230 C32H35F6N302 607 608 231 A C31H37F6N30 581 582 232 C30H37F6N30 569 570 233 4 C32H39F6N30 595 596 234 ICF3 C36H35F12N30 753 754 Me 235 C35H39F6N302 647 648 x, W 236 C34H43F6N30 623 624 237 C33H43F6N30 611 612 238 j C31H39F6N30 583 584 P *, CE3 H UtCF3 Caf3 R Trans-(RS) mlz Ex.-R Formula M. W. (ES+) (M+1). 239 w C32H35F6N30S 623 624 240 > C32H35F6N30S 623 624 S 241""Ph C35H39F6N30 631 632 242 w C3lH34F6N40S 624 625 243 < C33H36F6N40 618 619 244 < C33H36F6N40 618 619 u 245 C33H36F6N40 618 619

EXAMPLE 246 Trans-(RS)-4-(4-Methylpiperazin-1-yl)-N-{1-[3, 5-bis (trifluoromethyl) phenyl]ethyl}-1- phenylcyclohexanecarboxamide Prepared from trans- (RS)-4- (piperazin-1-yl)-N- { 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide (Example 229) according to the method of Example 215. m/z (ES+) 542 (M+1).

EXAMPLE 247 Trans-(RS)-4-(4-Acetylpiperazin-1-yl)-N-{1-[3,5-bis(trifluor omethyl)phenyl]ethyl}-1- phenylcyclohexanecarboxamide Acetyl chloride (100 µl) was added to a solution of trans- (RS)-4- (piperazin-1-yl)-N-1 1- [3, 5- bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide (Example 229,25 mg, 0.05 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 20 minutes. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (20 mL). The mixture was washed with aqueous sodium carbonate (10%, 20 mL) and brine (20 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (27 mg, 95%). m/z (ES+) 570 (M+1).

The following compounds were prepared from trans- (R)-4- (piperazin-1-yl)-N- { 1- [3, 5- bis (trifluoromethyl) phenyllethyl}-1-phenylcyclohexanecarboxamide (Example 229) according to the method of Example 247, substituting a suitable acid chloride for acetyl chloride. P jU XCF3 H I CF3 CL R Trans-(RS mlz Ex.-R Formula M. W. (ES+) (M+1). 248 < C30H35F6N302 583 584 0 249 C3lH37F6N302 597 598 0 O 250 Y Ph C34H35F6N302 631 632 0 251 > C34H41F6N302 637 638 o 0 P tXCF3 H (/ CF3 = CFs R Trans-(RS) mlz Ex.-R Formula M. W. (ES+) (M+1). 252 C31H35F6N302 595 596 0 253 rPh C35H37F6N302 645 646 o O

The following compounds were prepared from trans- (RS)-4- (piperazin-1-yl)-N-1 1- [3, 5- bis (trifluoromethyl) phenyl]ethyl}-1-phenylcyclohexanecarboxamide (Example 229) according to the method of Example 158, substituting a suitable acid for trans-4- [4- (4- fluorophenyl) piperidin-1-yl]-1-phenylcyclohexanecarboxylic acid hydrochloride. P '. CF3 H I CF3 R Trans- (RS) mlz Ex.-R Formula M. W. (ES+) (M+1). 254 C3lH37F6N302 597 598 0 255 C36H45F6N302 665 666 0 p t CF3 H CF3 3 R Trans- (RS) mlz Ex.-R Formula M. W. (ES+) (M+1). 256 C35H43F6N302 651 652 o 257 rV C32H37F6N302 609 610 o

EXAMPLE 258 Trans-(RS)-4-(Aminomethvl)-N- {1-r3.5-bis (trifluoromethyl) phenYll ethyl}-1- phenylcyclohexanecarboxamide Raney nickel (10 mg) was added to a solution of trans- (RS)-4-cyano-N- { 1- [3, 5- bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide (Description 29,50 mg, 0.11 mmol) in methanolic ammonia (2M, 50 mL) and the mixture was shaken under an atmosphere of hydrogen (45 psi) for 4 hours. Further Raney nickel (10 mg) was added and the mixture was shaken under an atmosphere of hydrogen (45 psi) for 2 hours. The mixture was filtered through a glass fibre pad, washing with methanol, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/N (Aq.) (95: 5: 0.5), to give the title compound. m/z (ES+) 473 (M+1).

EXAMPLE 259 Trans-(RS)-4-(N,N-Dimethylaminomethyl)-N-{1-[3,5-bis(trifluo romethyl)phenyl]ethyl}-1- phenylcyclohexanecarboxamide Prepared from trans- (RS)-4- (aminomethyl)-N-1 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide (Example 258) according to the method of Example 214. m/z (ES) 501 (M+1).

EXAMPLE 260 Trans-(RS)-4-[(Piperidin-1-yl)methyl]-N-{1-[3,5-bis(trifluor omethyl)phenyl]ethyl}-1- phenylcyclohexanecarboxamide 1,5-Dibromopentane (14 µl, 0.106 mmol) was added to a mixture of trans- (RS)-4- (aminomethyl)-N- {1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide (Example 258,50 mg, 0.106 mmol), potassium carbonate (23 mg, 0.212 mmol) and sodium iodide (8 mg, 0.053 mmol) in dimethylformamide (10 mL) and the mixture was stirred at 100 °C for 5 h, then at room temperature overnight. Ether (25 mL) and water (25 mL) were added and the layers were separated. The aqueous layer was extracted with ether (25 mL) and the combined organic fractions were washed with water (25 mL) and brine (25 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOWNH3 (Aq.) (95: 5: 0.5), and the residue was dissolved in methanol (0.5 mL) and poured onto an SCX cartridge (Varian Bond Elut ; 10 mL/500 mg). The cartridge was washed with methanol (2 x 5 mL), then eluted with methanolic ammonia (2M, 5 mL). The solvent was evaporated under reduced pressure to give the title compound (20 mg, 35%). m/z (ES+) 541 (M+1).

EXAMPLE 261 Trans- (RS)-4-r (Morpholin-4-yl) methyll-(l-r3, 5-bis (trifluoromethyl) phenyllethYl}-1- phenylcyclohexanecarboxamide Prepared from trans- (RS)-4- (aminomethyl)-N-f 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1- phenylcyclohexanecarboxamide (Example 258) according to the method of Example 260, substituting bis (2-bromoethyl) ether for 1,5-dibromopentane. m/z (ES+) 543 (M+1).

EXAMPLE 262 Trans-(RS)-4-({N-[2-(Dimethylamino)acetyl]}aminomethyl)-N-{1 -[3,5- bis(trifluoromethyl)phenyl]ethyl}-1-phenylcyclohexanecarboxa mide 1- (Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.138 mmol) was added to a mixture of N, N-dimethylglycine (13 mg, 0.127 mmol), triethylamine (44 µl, 0.318 mmol) and 1-hydroxybenzotriazole (14 mg, 0.106 mmol) in dichloromethane (5 mL) and the mixture was stirred at room temperature for 10 minutes. A solution of trans-(RS)-4- (aminomethyl)-N- {1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-l- phenylcyclohexanecarboxamide (Example 258, 50 mg, 0.106 mmol) in dichloromethane (6 mL) was added and the mixture was stirred at room temperature overnight. Water (25 mL) was added and the mixture was extracted with ethyl acetate (2 x 25 mL). The combined

organic fractions were washed with brine (25 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CIiCl2/MeOH/NH3 (Aq.) (95: 5: 0.5) to give the title compound (50 mg, 85%). m/z (ES+) 558 (M+1).

EXAMPLE 263 Trans-(RS)-4-(1H-1,23,-Triazol-1-yl)-N-{1-[3,5-bis(trifluoro methyl)phenyl]ethyl}-1- phenylcyclohexanecarboxamide (Trimethylsilyl) acetylene (0.3 mL, 2.0 mmol) was added to a solution of trans- (RS)-4-azido- N- {1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}-1-phenylcyclohexanecarboxamide (Description 28, 50 mg, 0. 1 mmol) in toluene and the mixture was stirred at 80 °C for 48 hours. The mixture was cooled, the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (60: 40).

The residue was dissolved in tetrahydrofuran (5 mL) and acetic acid (68 µl, 1.16 mmol) and tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 0.35 mL, 0.35 mmol) were added. The mixture was stirred at room temperature for 3 days and the solvent was evaporated under reduced pressure. Ethyl acetate and aqueous sodium carbonate (saturated) were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (50: 50), to give the title compound as a colourless foam (30 mg, 59%). m/z (ES+) 511 (M+1), 442 (M+1-C2H3N3).

EXAMPLE 264 Trans-N-({4-F4-(4-Fluorophenvl) piperidin-l-vll-1-phenvlcyclohexvl} methel)-3, 5- bis (trifluoromethyl) benzenecarboxamide 3,5-Bis (trifluoromethyl) benzoyl chloride (54 gel, 0.3 mmol) was added dropwise to a solution of trans-4- [4- (4-fluorophenyl) piperidin-1-yl]-1-phenylcyclohexanemethanamine (Description 32,100 mg, 0.27 mmol) in dichloromethane (5 mL) and the mixture was stirred at room temperature for 90 minutes. Water (5 mL) and saturated aqueous sodium hydrogen carbonate (2 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic fractions were washed with brine (10 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (0.5 mL) and poured onto an SCX cartridge (Varian Bond Elut ; 10 mIJ500 mg). The cartridge was washed with methanol (2 x 5 mL), then eluted with methanolic ammonia (2M, 5 mL). The solvent was evaporated under reduced pressure to give the title compound (105 mg, 64%). m/z (ES') 607 (M+1).

EXAMPLE 265 Trans-N-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclo hexyl}methyl)-2- (methoxy) benzenemethanamine Sodium triacetoxyborohydride (286 mg, 1. 35 mmol) was added to a solution of trans-4- [4- (4- fluorophenyl) piperidin-1-yl]-1-phenylcyclohexanemethanamine (Description 32,100 mg, 0.27 mmol) and 2-methoxybenzaldehyde (33 µl, 0.27 mmol) in dichloroethane (10 mL) and the mixture was stirred at room temperature for 24 hours. Water (10 mL) and saturated aqueous sodium hydrogen carbonate (20 mL) were added and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic fractions were washed with brine (10 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (0.5 mL) and poured onto an SCX cartridge (Varian Bond E1ut ; 10 mL/500 mg). The cartridge was washed with methanol (2 x 5 mL), then eluted with methanolic ammonia (2M, 5 mL). The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (95: 5: 0.5), to give the title compound (25 mg, 19%). m/z (ES+) 487 (M+1).

EXAMPLE 266 Cis-N- {4-f4-(4-Fluorophenyl ! piperidin-l-yll-l-phenylcyclohexyl} methyl)-3*5- bis (trifluoromethyl) benzenemethanamine and Trans-N- ( {4-f4- (4-Fluorophenyl) piperidin-l-yl1-l-phenylcyclohexyl} methvl)-3. 5- bis (trifluoromethyl) benzenemethanamine Palladium on activated carbon (5%) was added to a solution of 4- [4- (4- fluorophenyl) piperidin-1-yl]-1-phenylcyclohexanecarbonitrile (mixture of cis-and trans- isomers, Description 30,180 mg, 0.5 mmol) and hydrochloric acid (conc., 5 mL) in methanol (15 mL) and the mixture was shaken under an atmosphere of hydrogen (50 psi) for 65 hours.

Additional palladium on activated carbon (5%) was added and the mixture was shaken under an atmosphere of hydrogen (50 psi) for 24 hours. The mixture was filtered through a glass fibre pad, washing with methanol, and the solvent was evaporated under reduced pressure.

The residue was dissolved in ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL) was added. The mixture was filtered and the layers were separated. The organic layer was washed with brine (10 mL), dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (10 mL) and 3,5- bis (trifluoromethyl) benzaldehyde (42 mg, 0. 17 mmol) and a mixture of sodium cyanoborohydride (11 mg, 0.17 mmol) and zinc chloride (12 mg, 0.085 mmol) in methanol

(10 mL) were added. The mixture was stirred at room temperature overnight, poured into saturated aqueous sodium hydrogen carbonate (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic fractions were washed with brine (10 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (ABZ+; 250 x 10.0 mm id; 34% MeCN in 0.1% TFA-O; 5 ml/min ; 210 nm) to give: cis-N- ( (4- (4- (4 fluorophenyl) piperidin-1-yl]-1-phenyl cyclohexylJniethyl)-3, 5- bis (trifluorornethyl) berazenemethanamine ;'H NMR (400MHz, CDC13) 8 7.73 (1H, s), 7.70 (2H, s), 7.38-7.33 (4H, m), 7.25-7.16 (3H, m), 6.97 (2H, t, J 8.7 Hz), 3.77 (2H, s), 3.08-3.00 (2H, m), 2.79 (2H, s), 2.52-2.41 (1H, m), 2.36 (2H, d, J 12. 8 Hz), 2.30-2.17 (2H, m), 1.89-1.38 (8H, m), and 0.90-0.81 (2H, m) ; m/z (ES+) 593 (M+1) ; trans-N-({4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenyl cyclohexyl}methyl)-3,5- bis (trif uoromethylAbenzenemethanamine ;'H NMR (400MHz, CDCI3) õ 7.71 (1H, s), 7.65 (2H, s), 7.39-7.34 (4H, m), 7.24-7.19 (1H, m), 7.15-7.11 (2H, m), 6.96-6.92 (2H, m), 3.71 (2H, m), 2.93 (2H, br d, J 11.5 Hz), 2.58 (2H, br d, J 12.4 Hz), 2.51 (2H, s), 2.40-2.35 (2H, m), 2.18-2.12 (2H, m), 1.81-1.74 (4H, m), 1.69-1.59 (2H, m), 1.48-1.40 (2H, m), and 1.35-1.26 (2H, m). m/z (ES+) 593 (M+1).

EXAMPLE 267 Trans-N-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclo hexyl}methyl)-N-methyl-3,5- bis (trifluoromethyl) benzenemethanamine Formaldehyde (37% w/v in water, 2 mL), palladium hydroxide on carbon (20%, 10 mg) and acetic acid (24 p. l, 0.42 mmol) were added to a solution of trans-N- (14- [4- (4- fluorophenyl) piperidin-1-yl]-1-phenylcyclohexyl} methyl)-3, 5-bis (trifluoromethyl) benzenemethanamine (Example 266,102 mg, 0.17 mmol) in methanol (10 mL) and the mixture was shaken under an atmosphere of hydrogen (50 psi) for 2.5 hours. Additional palladium hydroxide on carbon (20%, 10 mg) was added and and the mixture was shaken under an atmosphere of hydrogen (50 psi) for 1 hour. The mixture was filtered through a glass fibre pad, washing with methanol, and the solvent was evaporated under reduced pressure.

The residue was dissolved in methanol (0.5 mL) and poured onto an SCX cartridge (Varian Bond Elut ; 10 mL/500 mg). The cartridge was washed with methanol (2 x 5 mL), then eluted with methanolic ammonia (2M, 5 mL). The solvent was evaporated under reduced pressure to give the title compound. m/z (ES+) 607 (M+1).

EXAMPLE 268 Cis- and Trans-N-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclo hexyl}methyl)-N- f f3, 5-bis (trifluoromethyl) phenvllmethvl} acetamide Prepared as a mixture of cis-and traris-isomers from N- [ (4-oxo-l-phenylcyclohexyl) methyl]- N-{[3, 5-bis (trifluoromethyl) phenyl] methyl} acetamide (Example 21) and 4- (4- fluorophenyl) piperidine (Description 16) according to the method of Example 55. m/z (ES+) 635 (M+1).

EXAMPLE 269 <BR> <BR> <BR> <BR> <BR> <BR> Trans-(RS)-N-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenyl cyclohexyl}methyl)-α-methyl- 3, 5-bis (trifluoromethyl) benzenemethanamine Borane-tetrahydrofuran complex (1M in tetrahydrofuran, 0.2 mL) was added to a solution of trans- (RS)-4- [4- (4-fluorophenyl) piperidin-1-yl]-N- 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl}- 1-phenylcyclohexanecarboxamide (Example 177,20 mg, 0.032 mmol) in tetrahydrofuran (5 mL) and the mixture was heated under reflux for 24 hours. The mixture was cooled and methanol (10 mL) was added. The mixture was heated under reflux for 1 hour, cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water, aqueous sodium carbonate (saturated) and water, dried (MgS04), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with CtCliMeOH/NH3 (Aq.) (95: 5: 0.5). The residue was dissolved in diethyl ether and ethereal hydrogen chloride (1M) was added. The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (20 mg, 97%). m/z (ES+) 607 (M+1).

EXAMPLE 270 <BR> <BR> <BR> <BR> <BR> <BR> Trans-(RS)-α-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-pheny lcyclohexyl} methylamino)- 3. 5-bis (trifluoromethyl) benzeneethanol and <BR> <BR> <BR> <BR> Trans-(RS)-α-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-pheny lcyclohexyl} methylamino)- 3, 5-bis (trifluoromethyl) benzeneethanamine A solution of trans- (RS)-methyl a- (14- [4- (4-fluorophenyl) piperidin-1-yll-l- phenylcyclohexyl} carbonylamino)-3, 5-bis (trifluoromethyl) benzeneacetate (Example 157, 0.25 mmol) in methanol (1.5 mL) was poured onto an SCX cartridge (Varian Bond Elut ; 10 mL/500 mg). The cartridge was washed with methanol (4 x 1 mL), then eluted with methanolic ammonia (2M, 4 x 1 mL). The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (4 mL) and toluene (2 mL) and lithium borohydride (10 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for

30 minutes, then at 50 °C for 30 minutes. The mixture was cooled and hydrochloric acid (2M) and ethyl acetate were added. The layers were separated, the organic fraction was dried (Na, SO,) and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL) and borane-tetrahydrofuran complex (1M in tetrahydrofuran, 1 mL) was added. The mixture was stirred at 60 °C for 1 hour, then further borane-tetrahydrofuran complex (1M in tetrahydrofuran, 1 mL) was added and the mixture was stirred at 60 °C for 1 hour. The mixture was cooled and aqueous sodium carbonate (10%, 20 mL) and ethyl acetate (20 mL) were added. The layers were separated and the aqueous fraction was extracted with ethyl acetate (10 mL). The combined organic fractions were dried (Na, SO,) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (3 mL) and heated under reflux for 3 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, filtered and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel, eluting with CH2CI2/MeOH/NH3 (Aq.) (95: 5: 0.5) to give: <BR> <BR> <BR> <BR> trans- (RS)-c ( [4- (4- (4 fluorophenyl) piperidin-1-ylJ-1-phenylcyclohexyljmethylamino)-3, 5- bis (trifluoromethyl) benzeneethanol (25 mg, 16%) ;'H NMR (400MHz, CDCI) 8 7.75 (1H, s), 7.52 (2H, s), 7.40-7.30 (4H, m), 7.27-7.17 (1H, m), 7.20-7.10 (2H, m), 6.95 (2H, t, J 8.0 Hz), 3.65 (1H, dd, J 8.2,4.2 Hz), 3.57 (1H, dd, J 10.7,4.2 Hz), 3.31 (1H, dd, J 10.7,8.2 Hz), 2.95 (2H, br d, J 11.0 Hz), 2.55 (2H, br d, J 11. 0 Hz), 2.50-2.30 (2H, m), 2.46 (1H, d, J 11. 0 Hz), 2.36 (1H, d, J 11.0 Hz), 2.20 (2H, br t, J 11.0 Hz), 2.10-1.60 (6H, m), and 1.55-1.20 (4H, m) ; m/z (ES+) 623 (M+1) ; and <BR> <BR> <BR> <BR> trans- (RS)-ce ( (4-j4- (4-fluorophenyl) piperidin-1-yl)-1-phenylcyclohexyljmethylamino)-3, 5- bis (trifluoromethyl)benzeneethanamine ;'H NMR (360MHz, CDC13) 8 7.74 (1H, s), 7.60 (2H, s), 7.40-7.30 (4H, m), 7.27-7.17 (1H, m), 7.18-7.08 (2H, m), 6.94 (2H, t, J 8.0 Hz), 3.45 (1H, dd, J 7. 6,4.8 Hz), 2.96 (2H, br d, J 10 Hz), 2.77 (1H, dd, J 12.0,4.8 Hz), 2.57 (1H, dd, J 12. 0, 7.6 Hz), and 2.55-1.40 (20H, m). m/z (ES+) 622 (M+1).

EXAMPLE 271 Cis-and Trans-(E)-4-(4-Fluorophenyl)-1-(4-phenyl-4-{3-[3,5- bis (trifluoromethyl) phenyllprop-l-enyl} cyclohexyl) piperidine Prepared as a mixture of cis-and trans-isomers from (E)-4-phenyl-4- {3- [3, 5- bis (trifluoromethyl) phenyl] prop-1-enyl} cyclohexanone Example 22) and 4- (4- fluorophenyl) piperidine (Description 16) according to the method of Example 45. m/z (ES+) 590 (M+1).

EXAMPLE 272 Cis-and Trans-(E)-4-(4-Fluorophenyl)-4-(4-phenyl-4-{3-[3,5- bis(trifluoromethyl)phenyl]propyl}cyclohexyl)piperidine Prepared as a mixture of cis-and trans-isomers from (E)-4-(4-fluorophenyl)-4-(4-phenyl-4- {3- [3, 5-bis (trifluoromethyl) phenyl] prop-1-enyl} cyclohexyl) piperidine (mixture of cis-and trans-isomers, Example 271) according to the method of Description 16. m/z (ES+) 592 (M+1).

EXAMPLE 273 Cis-and Trans-(RS)-4-(4-Fluorophenyl)-1-(4-{2-hydroxy-3-[3, 5- bis (trifluoromethyl) phenyllpropyl}-4-phenvlcyclohexyl) piperidine Prepared as a mixture of cis-and trans-isomers from (RS)-4-{2-hydroxy-3-[3, 5- bis (trifluoromethyl) phenyl] propyl}-4-phenylcyclohexanone (Example 25) and 4- (4- fluorophenyl) piperidine (Description 16) according to the method of Example 45. m/z (ES+) 608 (M+1).

EXAMPLE 274 Cis-and Trans- (RS)-4- (4-Fluorophenyl)-1- (4- 2-oxo-3- 3, 5-bis (trifluoromethyl) phenyl1 propyrl4-phenylcyclohexyllpiperidine Prepared as a mixture of cis-and trans-isomers from (RS)-4-(4-fluorophenyol)-1-(4-{2- hydroxy-3- 3, 5-bis (trifluoromethyl) phenyl] propyl}-4-phenylcyclohexyl) piperidine (mixture of cis-and trans-isomers, Example 273) according to the method of Description 17. m/z (ES+) 606 (M+1).

EXAMPLE 275 l- (1,4-Dioxa-8-phenylspiro[4,5]decan-8-yl)methoxylmethyl}-3,5- bis(trifluoromethyl) benzene Prepared from 8-phenyl-1, 4-dioxaspiro [4.5] decane-8-methanol (J. Org. Chem. 1974,39,2311- 2313) and 1- (bromomethyl)-3, 5-bis (trifluoromethyl) benzene according to the method of Example 1.'H NMR (360MHz, CDC13) 8 1.53-1.65 (4H, m), 1.88-1.96 (2H, m), 2.28-2.32 (2H, m), 3.42 (2H, s), 3.88-3.97 (4H, m), 4.42 (2H, s), 7.20-7.42 (5H, m), 7.55 (2H, s), and 7.72 (1H, s).

CuIF603 requires C, 60.76, H, 5.09; found C, 61.15, H, 5.07.

EXAMPLE 276 1-({[4-Oxo-1-phenylcyclohexyl]methoxy}methyl)-3,5-bis(triflu oromethyl)benzene Pyridiniump-toluenesulfonate (100 mg, 0.4 mmol) was added to a solution of 1-1 [ (1, 4-dioxa- 8-phepylspiro [4.5] decan-8-yl) methoxy] methyl}-3, 5-bis (trifluoromethyl) benzene (Example 275,5 g, 1 mmol) in acetone-water (8: 1,9 mL) and the mixture was heated under reflux for 3 days. The mixture was cooled and the solvent was evaporated under reduced pressure.

Aqueous sodium hydrogen carbonate (saturated) and ethyl acetate were added and the layers were separated. The organic fraction was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (70: 30), to give the title compound as a colorless oil (350 mg, 83%).'H NMR (360MHz, CDCI,) 8 2.06-2.10 (2H, m), 2.27-2.38 (4H, m), 2.58-2.65 (2H, m), 3.47 (2H, s), 4.44 (2H, s), 7.29-7.50 (5H, m), 7.56 (2H, s), and 7.75 (1H, s).

C22H2X602 requires C, 61.39, H, 4.68; found C, 60.92, H 4.51.

EXAMPLE 277 Cis-1-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohe xanemethoxy}methyl)-3,5- bis (trifluoromethyl) benzene and <BR> <BR> <BR> Trans-1- (4-f4- (4-Fluorophenyl) piperidin-l-rll-1-phenylcyclohexanemethoxy} methyl)-3, 5- bis (trifluoromethyl) benzene Prepared from 1-({[4-oxo-1-phenylcyclohexyl] methoxy} methyl)-3, 5- bis (trifluoromethyl) benzene (Example 276) and 4- (4-fluorophenyl) piperidine (Description 16) according to the method of Example 45: cis-1-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohe xanemethoxy}methyl)-3,5- bis (trifluoromethyl) benzene ;'H NMR (400MHz, CDC1,) 8 7.73 (1H, s), 7.55 (2H, s), 7.42-7.17 (7H, m), 7.00-6.95 (2H, m), 4.45 (2H, s), 3.70 (2H, s), 3.10 (2H, m), 2.47 (1H, m), 2.36-2.20 (6H, m), and 1.87-1.54 (9H, m). m/z (ES+) 594 (M+1) ; trans-1-({4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclo hexanemethoxy}methyl)-3,5- bis (trifluoromethyl) benzene ;'H NMR (400MHz, CDC13) 8 7.74 (1H, s), 7.57 (2H, s), 7.39 (4H, m), 7.24 (1H, m), 7.15 (2H, dd, J 8. 6,5.4 Hz), 6.95 (2H, t, J 8. 6 Hz), 4.42 (2H, s), 3.33 (2H, s), 3.04 (2H, m), 2.75-1.62 (14H, m), and 1.39 (2H, m). m/z (ES+) 594 (M+1).

EXAMPLE 278 (RS)-4-Methvlene-1-phenlI-f3, 5-bis (trifIuoromethyl) phenvnethvl} cyclohexanecarboxamide Methyltriphenylphosphonium bromide (1.71 g, 4.8 mmol) was dried azeotropically by evaporating toluene (3 x 20 mL) under reduced pressure, suspended in tetrahydrofuran

(20 mL) and cooled in ice. Butyllithium (1.6M in hexanes, 3.0 mL, 4.8 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was cooled in ice and (RS)-4-oxo-l-phenyl-N-f 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 18,0.91 g, 2.0 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred at room temperature for 1 hour, then heated under reflux for 3 hours. The mixture was cooled, poured into water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with water (3 x 50 mL) and brine (50 mL), dried (MgS04) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2CI2, to give the title compound as a colorless solid (0.67 g, 73%);'H NMR (400MHz, CD. OD) 5 7.76 (1H, s), 7.69 (2H, s), 7.34-7.20 (5H, m), 5.14 (1H, q, J 7. 1 Hz), 4.64 (2H, s), 2.53 (2H, m), 2.27 (4H, m), 1.99 (1H, m), 1.77 (1H, m), and 1.42 (3H, d, J 7.1 Hz).

EXAMPLE 279 Cis- (RS)-4- (Hydroxymethyl)-N- { l-f3, 5-bis (trifluoromethyl)phenyl]ethyl}-1- phenylcyclohexanecarboxamide and Trans-(RS)-4-(Hydroxymethyl)- N-{1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-1- phenylcyclohexanecarboxamide 9-Borabicyclo [3.3.1] nonane (0. 5M in tetrahydrofuran, 1.0 mL, 0.5 mmol) was added to a solution of (RS)-4-methylene-1-phenyl-N- 1- [3, 5-bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 278,182 mg, 0.4 mmol) in tetrahydrofuran (2 mL) and the mixture was stirred at room temperature for 2 hours. Ethanol (0.5 mL), aqueous sodium hydroxide (4M, 0.2 mL) and aqueous hydrogen peroxide (35%, 0.2 mL) were added and the mixture was stirred at 50 °C for 1 hour. The mixture was cooled, poured into aqueous sodium hydrogen carbonate (saturated, 20 mL) and water (10 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic fractions were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by MPLC chromatography on silica gel, eluting with isohexane/EtOAc (70: 30 increasing to 50: 50), to give: cis- (RS)-4- (hydroxymethyl)-N- f I- (3, 5-bis (trif luoromethyl) phenyl) ethyl)-1- phenylcyclohexanecarboxamide (113 mg, 60%),'H NMR (400MHz, CD30D) 8 7.76 (1H, s), 7.71 (2H, s), 7.31 (2H, d, J7. 5Hz), 7.25 (2H, t, J7. 5Hz), 7.20 (1H, t, J 7.5 Hz), 5.14 (1H, q, J 7. 1 Hz), 3.32 (2H, m), 2.67 (2H, m), 1.89-1.48 (5H, m), 1.43 (3H, d, J 7.1 Hz), and 1.24-1.09 (2H, m); and trans- (RS)-4- (hydroxymethyl)-N-(1- (3, 5-bis (trifluoromethyl) phenylJethylj-1- phenylcyclohexanecarboxamide (34 mg, 18%),'H NMR (400MHz, CD30D) 8 7.73 (1H, s), 7.61 (2H, s), 7.44 (2H, d, J 7.5 Hz), 7.34 (2H, t, J 7. 5 Hz), 7.23 (1H, t, J 7. 5 Hz), 5.03 (1H, q,

J7. 0Hz), 3.29 (2H, d, J 6.6 Hz), 2.68 (1H, m), 2.54 (1H, m), 1.90 (2H, m), 1.72 (2H, m), 1.56 (1H, m), 1.39 (3H, d, J 7. 0 Hz), 1.20 (1H, m), and 1.07 (1H, m).

The following compound was prepared from trans- (RS)-P- [ (4-methylamino-1- phenylcyclohexyl) methoxy]-3, 5-bis (trifluoromethyl) benzeneethanol (Example 90) and lH-imidazole-4-acetic acid according to the method of Example 91. mlz Ex. A B-NR Stereochemistry Formula M. W. (ES+) (M+1). 280 CH2O H HH Trans-(RS)-Cz9H3lF6N303 583 584 H-I-I-

The following compounds were prepared according to the method of Example 45, substituting a suitable ketone for (RS)-ß-[(4-oxo-1-phenylc yclohexyl)methoxy]-3, 5- bis (trifluoromethyl) benzeneethanol, and a suitable amine for benzylamine, followed by separation of diastereoisomers by chromatography on silica gel. m/z Ex. A B-NR Stereochemistry Formula M. W. (ES+) (M+1). 81HH \, C- (-CNO, T 281 H H Cis- (RS)- C3,, AFNO, 555 556 0 282 H H Trans- (RS ?- C30-'35 6N02 555 556 0 283 Me H F Trans- (RS- Cz9H33F8N0 563 564

mlz Ex. A B-NR Stereochemistry Formula M. W. (ES+) (M+1). 284 Me H @ Cis-(R$-C3lH37F6NO2 569 570 0 285 Me H/-\. rM- (- C,, HF, NO, 569 570 o 286 Me H F_ (0 Trans-(RS)-C27H30F6N2°2 528 529 NH DU 287 Me H Trans- (RS)- C,, IlFN20, 604 605 420 288 CI H _NOOO CM- (- CF, NO, 585 586 po 289 CH20 H _, \ Trans-(RS)-C3lH37F6NO3 585 586 H The following compounds were prepared from trans-(RS)-4-(4-oxopiperidin-1-yl)-1-phenyl- N- {1- [3, 5-bis (trifluoromethyl) phenyl] ethyl} cyclohexanecarboxamide (Example 184) according to the method of Example 187, substituting a suitable Grignard reagent for phenylmagnesium bromide. rn/z Ex. A B-NR Stereochemistry Formula M. W. (ES+) (M+1). 290 Me H"Trans- (RS- C32H, F6NZO2 598 599 mlz Ex. A B-NR Stereochemistry Formula M. W. (ES+) (M+1). 291 Me H H Trans- (RS- C3, H8F6NZO2 584 585 - 292 Me H H Trans- (RS- C32H.F6Nz0, 598 599 293 Me H/-\ PH Trans-(RS)-C30H36F6N202 570 571 EXAMPLE 294 Cis-(RS)-and Trans-(RS)-1-(4-{2-hydroxy-3-[3, 5-bis (trifluoromethyl)phenyl]propyl}-4- phenylcyclohexyl) piperidine Prepared as a 1 : 1 mixture of diastereoisomers from (RS)-4- {2-hydroxy-3- [3, 5- bis (trifluoromethyl) phenyl] propyl}-4-phenylcyclohexanone (Example 25) and piperidine according to the method of Example 45.'H NMR (400MHz, CDC13) 8 7.68 (1H, s), 7.50 and 7.48 (Total 2H, each s), 7.4-7.25 (4H, m), 7.25-7.15 (1H, m), 3.80-3.70 and 3.70-3.60 (Total 1H, each m), and 2.75-1.20 (23H, m). m/z (ES+) 514 (M+1).

EXAMPLE 295 (RS)-1-(8-Phenyl-1. 4-dioxaspiror4. 51decan-8-el)-3-r3. 5-bis (trifluoromethyl) phenyl r-1- ol Potassium carbonate (1.75 g, 12.7 mmol) was added to a solution of (RS)-1- (8-phenyl-1, 4- dioxaspiro [4.5] decan-8-yl)-3- [3, 5-bis (trifluoromethyl) phenyl] propan-1-yl ethanoate (Example 23,410 mg, 0.773 mmol) in methanol (15 mL) and water (2 mL) and the mixture was stirred at room temperature for 48 hours, then at 50 °C for 24 hours. The mixture was cooled and the methanol was evaporated under reduced pressure. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic fractions were dried (Na, SO,) and the solvent was evaporated under reduced pressure to give the title compound (334 mg, 88%).'H NMR (400MHz, CDCl3) 8 7.68 (1H, s), 7.53 (2H, s), 7.4-7.3 (4H, m),

7.3-7.2 (1H, m), 3.95-3.8 (4H, m), 3.36 (1H, br d, J 9 Hz), 2.91 (1H, ddd, J 14,10,5 Hz), 2.64 (1H, ddd, J 16, 9,7.5 Hz), 2.5-2.4 (1H, m), 2.3-2.2 (1H, m), 1.9-1.7 (3H, m), and 1.65-1. 20 (6H, m).

EXAMPLE 296 (RS)-4-{1-Hydroxy-3-[3,5-bis(trifluoromethyl)phenyl]propyl}- 4-phenylcyclohexanone Prepared from (RS)-1-(8-phenyl-1,4-dioxaspiro [4.5] decan-8-yl)-3- [3, 5- bis (trifluoromethyl) phenyl] propan-1-ol (Example 295) according to the method of Example 10.'H NMR (400MHz, CDC13) 8 7.69 (1H, s), 7.51 (2H, s), 7.5-7.4 (4H, m), 7.35-7.25 (1H, m), 3.44 (1H, br d, J 11 Hz), 2.93 (1H, ddd, J 14,10,5 Hz), 2.8-2.7 (1H, m), 2.7-2.6 (1H, m), 2.6-2.5 (1H, m), 2.4-2.2 (4H, m), 2.05-1.9 (2H, m), 1.85-1.75 (1H, m), and 1.45-1.3 (2H, m).

EXAMPLE 297 Trans-(RS)-1-(4-{1-hydroxy-3-[3, 5-bis (trifluoromethyl) phenyl]propyl}-4- phenylcyclohexyl) piperidine Prepared from (RS)-4- 1-hydroxy-3- [3, 5-bis (trifluoromethyl) phenyl] propyl}-4- phenylcyclohexanone (Example 296) and piperidine according to the method of Example 45, followed by separation of diastereoisomers by chromatography on silica gel.'H NMR (400MHz, CDC1,) 8 7.67 (1H, s), 7.51 (2H, s), 7. 4-7.3 (4H, m), 7.3-7.2 (1H, m), 3.30 (1H, br d, J 11 Hz), 2.90 (1H, ddd, J 14,10,5 Hz), 2.7-2.55 (2H, m), 2.45-2.3 (8H, m), 1.85-1.75 (3H, m), and 1.7-1.2 (10H, m). m/z (ES+) 514 (M+1).

EXAMPLE 298 Cis-(RS)-4-(4-Fluorophenyl)-1-(4-{1-hydroxy-3-[3, 5-bis (trifluoromethyl) phenyllpropyl}-4- phenylcyclohexyl) piperidine ; and Trans- (RS-4- (4-Fluorophenv1)-1- (4-{1-hydroxy-3-f3, 5-bis (trifluoromethyl)phenyl]propyl}-4- phenylcyclohexyl) piperidine Prepared from (R. S')-4- { l-hydroxy-3- [3, 5-bis (trifluoromethyl) phenyl] propyl}-4- phenylcyclohexanone (Example 296) and 4- (4-fluorophenyl) piperidine (Description 16) according to the method of Example 45, followed by separation by flash column chromatography on silica gel, eluting with CH2CliMeOH/NH3 (Aq.) (97.5: 2.5: 0.25 increasing to 95: 5: 0.5), to give cis-(rs)-4-(4-fluorophenyl)-1-(4-{1-hydroxy-3-[3,5- bis (trifluoromethyl) phenyl] propylj-4-phenylcyclohexyl) piperidine ;'H NMR (400MHz, CDC13) 8 7.68 (1H, s), 7.58 (2H, s), 7.4-7.3 (4H, m), 7.3-7.25 (1H, m), 7.25-7.15 (2H, m), 6.99 (2H, t, J9 Hz), 3.85 (1H, br d, J 10 Hz), 3.25-3.05 (2H, m), 2.95-2.85 (1H, m), 2.78-2.62

(2H, m), 2.50 (1H, quin, J7 Hz), 2.45-2. 15 (4H, m), 1.9-1.4 (12H, m), and 1.2-1.08 (1H, m); m/z (ES+) 608 (M+1) ; and. trans-(RS)-4-(4-fluorophenyl)-1-(4-{1-hydroxy-3-[3,5- bis (trifluoromethyl) pherrylJpropyl f-4-phenylcyclohexyl) piperidine ;'H NMR (400MHz, CDCI3) 8 7.67 (1H, s), 7.52 (2H, s), 7.4-7.3 (4H, m), 7.3-7.2 (1H, m), 7.13 (2H, dd, J 8. 7, 5.5 Hz), 6.94 (2H, t, J 8.7 Hz), 3.31 (1H, br d, J 10.5 Hz), 3.0-2.85 (3H, m), 2.69-2.58 (2H, m), 2.55-2.35 (3H, m), 2.3-2.1 (2H, m), 1.9-1.5 (9H, m), and 1.4-1.2 (4H, m); m/z (ES+) 608 (M+1).

EXAMPLE 299 Trans-4-(4-Fluorophenyl)-1-(4-{1-oxo-3-[3,5-bis(trifluoromet hyl)phenyl]propyl}-4- phenylcyclohenyl) piperidine 1, 1, 1-Tris (acetyloxy)-1, 1-dihydro-1, 2-benziodoxol-3 (lH)-one (28 mg, 0.066 mmol) was added to a solution of trans- (RS)-4- (4-fluorophenyl)-l- (4-1 1-hydroxy-3- [3, 5- bis (trifluoromethyl) phenyl] propyl}-4-phenylcyclohexyl) piperidine (Example 298,14 mg, 0.023 mmol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bisufite (1 mL) and aqueous sodium hydrogen carbonate (5%, 15 mL) were added and the mixture was stirred at room temperature for 20 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (2 mL). The combined organic fractions were poured onto an SCX cartridge (Varian Bond Elutrm ; 10 mol/500 mg). The cartridge was washed with methanol (4 x 2 mL), then eluted with methanolic ammonia (2M, 2 x 2 mL). The solvent was evaporated under reduced pressure to give the title compound (13.1 mg, 94%).'H NMR (400MHz, CDCl3) 8 7.61 (1H, s), 7.35 (2H, s), 7.28-7.08 (7H, m), 6.95 (2H, t, J 9 Hz), 2.95 (2H, br d, J 11 Hz), 2.80 (2H, t, J 7 Hz), 2.6-2.5 (2H, m), 2.54 (2H, t, J 7 Hz), 2.45-2.30 (2H, m), 2.15 (2H, t, J 11 Hz), 1.9-1.5 (8H, m), and 1.5-1.35 (2H, m). m/z (ES+) 606 (M+1).

EXAMPLE 300 (RS)-1-(4-Oxo-1-phenylcyclohexyl)-3-[3,5-bis(trifluoromethyl )phenyl]propan-2-yl Ethanoate Prepared from (RS)-l- (8-phenyl-1, 4-dioxaspiro [4.5] decan-8-yl)-3- [3, 5- bis (trifluoromethyl) phenyl] propan-2-yl ethanoate (Example 23) according to the method of Example 10.'H NMR (400MHz, CDC13) 8 7.69 (1H, s), 7.38 (2H, s), 7.36-7.20 (5H, m), 4.95-4.85 (1H, m), 2.73 (1H, dd, J 14, 7 Hz), 2.62-2.47 (2H, m), 2.46 (1H, dd, J 14, 6 Hz), 2.35-2.20 (4H, m), 2.02 (1H, dd, J 14, 7 Hz), 1.95-1.80 (2H, m), 1.77 (1H, dd, J 14,3 Hz), and 1.75 (3H, m).

EXAMPLE 301 Trans-(RS)-1-{4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylc yclohexyl}-3-[3,5- bis (trifluoromethyl) phenyl] propan-2-yl Ethanoate Prepared from (RS)-1-(4-oxo-1-phenylcyclohexyl)-3-[3, 5-bis (trifluoromethyl) phenyl] propan- 2-yl ethanoate (Example 300) and 4- (4-fluorophenyl) piperidine (Description 16) according to the method of Example 45, followed by separation of diastereoisomers by flash column chromatography on silica gel, eluting with CH2CI2/MeOH (95: 5).'H NMR (400MHz, CDCl3) 8 7.68 (1H, s), 7.36 (2H, s), 7.32-7.10 (7H, m), 6.92 (2H, t, J 9 Hz), 4.92-4.82 (1H, m), 3.01 (2H, br d, J 9 Hz), 2.66 (1H, dd, J 14, 7 Hz), 2.6-2.2 (6H, m), 2.40 (1H, dd, J 14, 6 Hz), 2.10-1.70 (7H, m), 1.74 (3H, s), 1.64 (1H, dd, J 14,3 Hz), and 1.55-1.22 (4H, m). m/z (ES+) 650 (M+1).