0001 This invention relates to a class of gem-disubstituted cyclohexane derivatives which are useful as tachykinin antagonists. More particularly, the compounds of the invention are useful as neurokinin 1 (NK-1) receptor antagonists. 0002 The present invention provides compounds of the formula (I): 3

0003 wherein 0004 ring A is a phenyl or pyridyl ring; 0005 X represents a linker selected from the group consisting of: 4

0006 R1 represents hydroxy, C1-6alkyl, fluoroC1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C1-6alkoxyC1-4alkyl, C1-6alkoxyC1-4alkoxy, fluoroC1-6alkoxyC1-4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, phenoxy, cyano, halogen, NRaRb, SRa, SORa, SO2Ra, OSO2Ra, NRaCORa, COR2Ra, CO2Ra or CONRaRb where Ra and Rb each independently represent hydrogen, C1-4alkyl, C3-5cycloalkyl, fluoroC1-4alkyl or CH2CO2C1-4alkyl, and Rc represents C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl or phenyl; 0007 R2 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; 0008 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 C1-4alkyl, CF3, O or S; 0009 R3 represents hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, cyano, SRa, SORa, SO2Ra, NRaRb, NRaCOR14, CORa, CO2Ra, CONRaRb or C1-4alkyl substituted by cyano, CO2Ra or CONRaRb where Ra and Rb are as previously defined; 0010 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, C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, trifluoromethyl, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, phenyl, (CH2)rNRaRb, (CH2)rNRaCORb, (CH2)rCONRaRb, or CH2C(O)Ra, where Ra and Rb are as previously defined and r is zero, 1 or 2; 0011 R4 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, hydroxy, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb are as previously defined; 0012 R5 is hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or C1-6alkoxy substituted by C1-4alkoxy; 0013 R6 represents hydrogen, hydroxy or a C1-4alkyl group optionally substituted by a hydroxy group; 0014 R7 represents hydrogen, hydroxy, (CH2)nNR8R9, (CH2)nCO2Ra, carbocyclyl, C-linked heterocyclyl or heteroaryl; 0015 or R6 and R7 together represent O, CHCO2Ra or O(CH2)mO; 0016 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)pNRaCO2Rb, (CH2)qCONRaaryl or (CH2)qCONRaheterocyclyl where Ra and Rb are as previously defined; 0017 or R8 and R9, together with the nitrogen atom to which they are attached, represent a heteroaliphatic ring selected from the group consisting of: 6

0018 R10 and R11 each independently represent hydrogen, halogen, hydroxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyC1-6alkyl, fluoroC1-6alkyl, C1-6alkoxy, (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, CO2H, CO2C1-6alkyl, CO2(CH2)qC3-7cycloalkyl, CO2(CH2)qaryl, CO2(CH2)qheterocyclyl or CO2(CH2)pNRaRb, where Ra and Rb are as previously defined; 0019 or, when they are attached to the same carbon atom, R10 and R11 may together represent O, CHCO2Ra, O(CH2)mO, CH2O(CH2)s, CH2OCH2C(O), CH2OCH2CH(OH), CH2OCH2C(CH3)2, CH2OC(CH3)2CH2, C(CH3)2OCH2CH2, 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, OCH2CHCHCH2, OCH2CH(OH)CH2CH2, OCH2CH2CH(OH)CH2, OCH2C(O)CH2CH2, OCH2CH2C(O)CH2, or a group of the formula 7

0020 or, where they are attached to adjacent carbon atoms, R10 and R11 may together represent OCH2CH2 or OCH2CH(OH), or R10 and R11 may together form a fused benzene ring; 0021 or, R10 and R11 together form a C1-2alkylene bridge across the pyrrolidine, piperidine or hexamethyleneimine ring to which they are attached; 0022 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, CO2C1-6alkyl, CO2(CH2)qC3-7cycloalkyl, CO2(CH2)qaryl, CO2(CH2)qheterocyclyl or CO2(CH2)pNRaRb, where Ra and Rb are as previously defined; 0023 or, where they are attached to adjacent carbon atoms, R12 and R18 may together form a fused imidazolyl or triazolyl ring; 0024 R13 represents hydrogen, C1-6alkyl or C(O)C1-6alkyl; 0025 R14, R15, R16, R17, R18 and R19 each independently represent hydrogen, hydroxy, C1-6alkyl, C1-6alkenyl, hydroxyC1-6alkyl, C1-4alkoxyC1-4alkyl, (CH2)pNRaRb, CHO, C(O)C1-6alkyl or CO2C1-6alkyl; 0026 or, R14 and R15 together represent CH2CH2; 0027 or, R16 and R17 together represent CH2CH2; 0028 or, R18 and R19 together represent CH2CH2; 0029 R20 represents hydrogen, halogen, hydroxy, C1-4alkyl, hydroxyC1-4alkyl or fluoroC1-4alkyl; 0030 R21a represents hydrogen, halogen or hydroxy and R21b represents hydrogen; 0031 or R21a and R21b both represent fluorine or together represent oxo (O); 0032 R22 and R23 each independently represent hydrogen, halogen, hydroxy, C1-6alkyl or oxo (O); 0033 n is zero, 1 or 2; 0034 m is 1 or 2; 0035 p is 1, 2,3 or 4; 0036 q is zero, 1, 2, 3 or 4; and 0037 s is 1, 2 or 3; 0038 and pharmaceutically acceptable salts and N-oxides thereof. 0039 According to an alternative embodiment, the present invention also provides compounds of the formula (I): 8

0040 wherein 0041 R6 represents hydrogen or a C1-4alkyl group optionally substituted by a hydroxy group; 0042 R7 represents hydrogen, hydroxy, (CH2)nNR8R9, (CH2)nCO2Ra, carbocyclyl or heteroaryl; 0043 or R6 and R7 together represent O, CHCO2Ra or O(CH2)mO; 0044 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)qCO2C1-6alkyl, CO2(CH2)qC3-7cycloalkyl, CO2(CH2)qaryl, CO2(CH2)qheterocyclyl, CO2(CH2)pNRaRb, (CH2)pNRaCORb or (CH2)pNRaCO2Rb, where Ra and Rb are as previously defined; 0045 or R8 and R9, together with the nitrogen atom to which they are attached, represent a heteroaliphatic ring selected from the group consisting of: 9

0046 R10 and R11 each independently represent hydrogen, halogen, hydroxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyC1-6alkyl, C1-6alkoxy, (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, CO2H, CO2C1-6alkyl, CO2(CH2)qC3-7cycloalkyl, CO2(CH2)qaryl, CO2(CH2)qheterocyclyl or CO2(CH2)pNRaRb, where Ra and Rb are as previously defined; 0047 or, when they are attached to the same carbon atom, R10 and R11 together represent O, CHCO2Ra, O(CH2)mO, OCH2CH2CH2, CH2OCH2CH2 or CH2OCH2C(O); 0048 or, where they are attached to adjacent carbon atoms, R10 and R11 together form a fused benzene ring; 0049 or, R10 and R11 together form a C1-2alkylene bridge across the pyrrolidine, piperidine or hexamethyleneimine ring to which they are attached; 0050 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, CO2C1-6alkyl, CO2(CH2)qC3-7cycloalkyl, CO2(CH2)qaryl, CO2(CH2)qheterocyclyl or CO2(CH2)pNRaRb, where Ra and Rb are as previously defined; 0051 R14, R15, R16, R17, R18 and R19 each independently represent hydrogen, hydroxy, C1-6alkyl, C1-6alkenyl, hydroxyC1-6alkyl, (CH2)pNRaRb, CHO, C(O)C1-6alkyl or CO2C1-6alkyl; 0052 and X, R1, R2, R3, R4, R5, R13, n, m, p and q are as defined in relation to formula (I); 0053 and pharmaceutically acceptable salts thereof. 0054 A preferred class of compound of formula (I) is that wherein R1 is hydroxy, C1-6alkyl, fluoroC1-6alkyl, C2-6alkenyl, C1-6alkoxy, fluoroC1-6alkoxy, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, cyano, NRaRb, SRa, OSO2Ra, or R1 together with the group R2 form a 5-membered saturated ring containing one oxygen atom. 0055 A particularly preferred class of compound of formula (I) is that wherein R1 is C1-6alkyl, fluoroC1-6alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C3-7cycloalkoxy or C3-7cycloalkoxyC1-4alkyl, especially methyl, trifluoromethyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, cyclopropoxy or cyclopropylmethoxy. 0056 Another preferred class of compound of formula (I) is that wherein R2 is a hydrogen, fluorine or chlorine atom, especially a hydrogen atom. 0057 A further preferred class of compound of formula (I) is that wherein R3 is hydrogen, halogen, fluoroC1-6alkyl, fluoroC1-6alkoxy, cyano, NRaRb, NRaCORd (where Rd is methyl, methoxy, trifluoromethyl or phenyl), or a 5-membered aromatic heterocyclic group as previously defined. 0058 Also preferred is the class of compound of formula (I) in which R3 is C1-6alkyl, fluoroC1-6alkyl, fluoroC1-6alkoxy or a 5-membered aromatic heterocyclic group as previously defined, especially methyl, trifluoromethyl, trifluoromethoxy or 5-trifluoromethyl-1,2,3,4tetrazol-1-yl. 0059 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. 0060 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. 0061 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. 0062 An especially preferred class of compound of formula (I) is that wherein R3 is the group 10

0063 where R20 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, (CH2)rCONRaRb, (CH2)rNRaRb or (CH2)rNRaCORb, where Ra, Rb and r are as previously defined. 0064 R20 is preferably hydrogen, C1-4alkyl, especially methyl, CF3, (CH2)rCONRaRb, SORa or SO2Ra where Ra and Rb are preferably hydrogen, C1-4alkyl or fluoroC1-4alkyl and r is as previously defined. Most especially, R20 is CF3. 0065 Preferably R1 and R3 are in the 3 and 5 positions of the phenyl ring. 0066 More preferably R1 is 3-fluoro or 3-CF3. 0067 More preferably R3 is 5-fluoro or 5-CF3. 0068 More preferably R2 is hydrogen. 0069 Most preferably R1 is 3-CF3, R2 is hydrogen and R3 is 5-CF3. 0070 Another preferred class of compounds of formula (I) is that wherein R1 and R3 are in the 2- and 5-positions of the phenyl ring. 0071 In this sub-class of compounds of formula (I), R1 is preferably C1-6alkoxy or C3-7cycloalkoxy, especially methoxy or cyclopropoxy. 0072 Also in this sub-class of compounds of formula (I), R2 is preferably hydrogen. 0073 Also, in this sub-class of compounds of formula (I) R3 is preferably hydrogen, C1-6alkoxy, fluoroC1-6alkoxy or a 5-membered aromatic heterocyclic group as previously defined. Most especially, R3 is hydrogen, methoxy or trifluoromethoxy. 0074 A further preferred class of compound of formula (I) is that wherein R4 is hydrogen. 0075 Another preferred class of compounds of formula (I) is that wherein R5 is hydrogen, fluorine, chlorine or CF3, especially hydrogen or fluorine. 0076 Preferably R4 is hydrogen and R5 is hydrogen or 4fluoro. 0077 Another further preferred class of compounds of formula (I) is that wherein R6 is hydrogen. 0078 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 O, O(CH2)mO or CH2OCH2C(O). 0079 Another preferred class of compounds of formula (I) is that wherein R7 is hydroxy or (CH2)nNR8R9, or R6 and R7 together represent O, O(CH2)mO or CH2OCH2C(O). 0080 A further preferred class of compounds of formula (I) is that wherein R8 represents hydrogen, C1-6alkyl, C2-6alkenyl, hydroxyC1-6alkyl, (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; 0081 and R9 represents hydrogen, C1-6alkyl, (CH2)qC3-7cycloaklyl or CO2C1-6alkyl; 0082 or R8 and R9 together with the nitrogen atom to which they are attached represent a heteroaliphatic ring selected from the group consisting of 11

0083 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)C1-6alkyl, C(O)(CH2)qaryl, C(O)(CH2)qheterocyclyl, C(O)(CH2)pNRaRb, (CH2)qCO2C1-6alkyl or (CH2)pNRaCO2Rb; 0084 and R9 represents hydrogen, C1-6alkyl, (CH2)qC3-7cycloalkyl or CO2C1-6alkyl; 0085 or R8 and R9 together with the nitrogen atom to which they are attached represent a heteroaliphatic ring selected from the group consisting of 12

0086 A further preferred class of compounds of formula (I) is that wherein R10 represents hydrogen, hydroxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyC1-6alkyl, fluoroC1-6alkyl, (C2-6alkynyl)aryl, (CH2)qaryl, (CH2)qheterocyclyl, (CH2)qNRaRb, OC(O)C1-6alkyl, C(O)(CH2)qNRaRb, CO2H or CO2C1-6alkyl; 0087 and R11 represents hydrogen, halogen, hydroxy, C1-6alkyl or (CH2)qNRaRb; 0088 or when they are attached to the same carbon atom, R10 and R11 may together represent O, O(CH2)mO, CH2O(CH2)s, CH2OCH2C(O), CH2OCH2CH(OH), CH2OCH2C(CH3)2, CH2OC(CH3)2CH2, C(CH3)2OCH2CH2, 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, OCH2CHCHCH2, OCH2CH(OH)CH2CH2, OCH2CH2CH(OH)CH2, OCH2C(O)CH2CH2, or a group of the formula 13

0089 or, when they are attached to adjacent carbon atoms, R10 and R11 may together represent OCH2CH2 or OCH2CH(OH), or R10 and R11 may together form a fused benzene ring; 0090 or R10 and R11 together form a C1-2alkylene bridge across the pyrrolidine or piperidine ring to which they are attached. 0091 Another preferred class of compounds of formula (I) is that wherein R10 represents hydrogen, hydroxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyC1-6alkyl, (C2-6alkynyl)aryl, (CH2)qaryl, (CH2)qheterocyclyl, (CH2)qNRaRb, OC(O)C1-6alkyl, C(O)(CH2)qNRaRb, CO2H or CO2C1-6alkyl; 0092 and R11 represents hydrogen, halogen, hydroxy, C1-6alkyl or (CH2)qNRaRb; 0093 or when they are attached to the same carbon atom, R10 and R11 together represent O or O(CH2)mO; 0094 or, when they are attached to adjacent carbon atoms, R10 and R11 together form a fused benzene ring, 0095 or R10 and R11 together form a C1-2alkylene bridge across the pyrrolidine or piperidine ring to which they are attached. 0096 A further preferred class of compounds of formula (I) is that wherein R12 represents hydrogen, C1-6alkyl, (CH2)qC3-7cycloalkyl, (CH2)qaryl, (CH2)qheterocyclyl, CHO, C(O)C1-6alkyl, C(O)C3-7cycloalkyl, C(O)(CH2)qaryl or CO2C1-6alkyl. 0097 A yet further prefered class of compounds of formula (I) is that wherein R9 represents hydrogen, C1-6alkyl, (CH2)qC3-7cycloalkyl or CO2C1-6alkyl. 0098 A particularly preferred class of compounds of formula (I) is that wherein R8 represents hydrogen, C1-6alkyl, C2-4alkenyl, C3-7cycloalkyl, CH2C3-7cycloalkyl, (CH2)qphenyl, (CH2)qfuryl, (CH2)qpyridyl, (CH2)qtriazolinone, C(O)C1-4alkyl, C(O)(CH2)qphenyl, C(O)(CH2)qimidazolyl, C(O)(CH2)qtetrazolyl, C(O)(CH2)pyrrolidinyl, C(O)(CH2)pNRaRb, CH2C(O)C1-4alkyl or (CH2)pNRaCO2C1-4alkyl; 0099 and R9 represents hydrogen, C1-6alkyl, CH2C3-5cycloalkyl or CO2C1-4alkyl; 0100 or R8 and R9 together with the nitrogen atom to which they are attached represent a heteroaliphatic ring selected from the group consisting of: 14

0101 A further particularly preferred class of compounds of formula (I) is that wherein: 0102 R10 represents hydrogen, hydroxy, methyl, allyl, acetylene, hydroxyC1-4alkyl, CC(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, CO2H or CO2C1-4alkyl; and 0103 R11 represents hydrogen, fluorine, hydroxy, methyl or dimethylamino; 0104 or, when they are attached to the same carbon atom, R10 and R11 together represent O or OCH2CH2O; 0105 or, when they are attached to adjacent carbon atoms, R10 and R11 together form a fused benzene ring; 0106 or, R10 and R11 together form a CH2CH2 bridge across the pyrrolidine or piperidine ring to which they are attached. 0107 A yet further particularly preferred class of compounds of formula (I) is that wherein R12 represents hydrogen, C1-6alkyl, C3-6cycloalkyl, 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)C1-4alkyl, 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. 0108 Yet another particularly preferred class of compounds of formula (I) is that wherein R9 represents hydrogen, C1-6alkyl, CH2C3-5cycloalkyl or CO2C1-4alkyl. 0109 Another preferred class of compound of formula (I) is that wherein the ring A is a phenyl ring. 0110 Particularly preferred compounds of formula (I) are those wherein R7 represents a group selected from: 15

0111 wherein 0112 R30 represents 4-pyridyl, phenyl, phenyl mono-substituted by fluorine, chlorine, methyl, methoxy or CO2methoxy, or phenyl disubstituted by methyl; 0113 R31 represents C2-4alkyl or (CH2)qC3-7cycloalkyl, especially tert-butyl, cyclopropylmethyl or cyclohexyl; 0114 R32 represents C1-6alkyl, tetrahydropyranyl or benzyl; 0115 R33 and R34, which may be attached to the same or different carbon atoms, each independently represent hydrogen or methyl; 0116 R35 represents hydroxy or methoxy; 0117 R36 represents hydroxyC1-4alkyl (especially hydroxymethyl), C1-4alkoxy (especially methoxy) or hydroxy; 0118 R37 represents methoxy C2-4alkyl (especially methoxymethyl) or C2-4alkyl; 0119 R38 represents hydrogen, oxo (O), hydroxy, trifluoromethyl, C1-3alkyl (especially isopropyl) or hydroxyC1-3alkyl (especially hydroxymethyl or hydroxyethyl); 0120 R39 represents a ring-forming moiety selected from OCH2CH2O, CH2OCH2CH2, CH2OCH2CH2CH2, CH2OCH2C(O), CH2OCH2CH(OH), CH2OC(CH3)2CH2, C(CH3)2OCH2CH, CH2C(O)OCH2, C(O)OCH2CH2, C(O)OC(CH3)2CH2, OCH2CH2CH2, OCH2CH2CH2CH2, OC(CH3)2CH2CH2, OCH2CHCHCH2, OCH2CH(OH)CH2CH2, OCH2CH2CH(OH)CH2, OCH2C(O)CH2CH2 and a group of the formula 16

0121 R40 is hydrogen or hydroxy, especially hydrogen; 0122 R41 is C1-3alkyl, especially isopropyl; and 0123 n is zero, 1 or 2, especially zero. 0124 Further preferred compounds of formula (I) are those wherein R7 represents a group selected from: 17

0125 wherein 0126 R25 represents hydrogen, methyl or hydroxymethyl; 0127 R26 represents hydrogen, methyl, hydroxy, methylamino, dimethylamino, cyclopropylamino, phenyl, or phenyl substituted by fluorine; and 0128 R27 represents hydrogen, methyl, hydroxy, methylamirno, dimethylamino or cyclopropylamino. 0129 Another preferred class of compounds of formula (I) is that wherein R21a represents hydrogen, fluorine or hydroxy and R21b is hydrogen, or R21a and R21b both represent fluorine or together represent oxo (O). In particular, R21a is preferably hydrogen, fluorine or hydroxy and R21b is hydrogen. Most especially, R21a and R21b are preferably both hydrogen. 0130 Another preferred class of compounds of formula (I) is that wherein X represents a linker selected from: 18

0131 Another preferred class of compounds of formula (I) is that wherein R13 represents hydrogen, methyl or acetyl. In particular, R13 represents hydrogen. 0132 A further preferred class of compounds of formula (I) is that wherein one of the groups R14, R15, R16 and R17 represents hydrogen, hydroxy, C1-6alkyl, hydroxyC1-6alkyl, (CH2)pNRaRb, CHO, C(O)C1-6alkyl or CO2C1-6alkyl, and the other(s) of the groups R14, R15, R16 and R17 each represent hydrogen. 0133 A particularly preferred class of compounds of formula (I) is that wherein one of the groups R14, R15, R16 and R17 represents methyl or hydroxymethyl, and the other(s) of groups R14, R15, R16 and R17 each represent hydrogen. 0134 A further preferred class of compounds of formula (I) is that wherein R18 and R19 each independently represent hydrogen or methyl. 0135 Most especially, a preferred class of compounds of formula (I) is that wherein X represents a linker selected from: 19

0136 Another preferred class of compounds of formula (I) is that wherein n is zero. 0137 A further preferred class of compounds of formula (I) is that wherein m is 2. 0138 Another preferred class of compounds of formula (I) is that wherein p is 1, 2 or 3, particularly 1 or 2, and especially 1. 0139 A further preferred class of compounds of formula (I) is that wherein q is zero, 1 or 2, particularly zero or 1. 0140 One favoured group of compounds of the present invention are of the formula (Ia) and pharmaceutically acceptable salts thereof: 20

0141 wherein 0142 A1 is fluorine or CF3; 0143 A2 is fluorine or CF3; 0144 A3 is fluorine or hydrogen; 0145 R6 and R7 are as defined in relation to formula (I); and 0146 X is a linker selected from: 21

0147 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. 0148 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. 0149 As used herein, the term hydroxyC1-6alkyl means a C1-6alkyl 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 hydroxyC1-3alkyl groups, for example, CH2OH, CH2CH2OH, CH(CH3)OH or C(CH3)2OH, and most especially CH2OH. 0150 As used herein, the terms fluoroC1-6alkyl and fluoroC1-6alkoxy means a C1-6alkyl or C1-6alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroC1-3alkyl and fluoroC1-3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCH2CF3. 0151 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. 0152 Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy. 0153 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. 0154 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. 0155 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, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, NO2, cyano, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl, C1-4alkoxyC1-4alkyl or O(CH2)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, C1-4alkyl (especially methyl), C1-4alkoxy (especially methoxy), trifluoromethyl, trifluormethoxy or vinyl. 0156 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 C1-4alkyl 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. 0157 Said saturated and partially saturated heterocyclyl radicals may be optionally substituted by one, two or three groups independently selected from halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, NO2, cyano, oxo (O), NRaRb, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl, C1-4alkoxyC1-4alkyl, O(CH2)mO, OCH2CH2CH2, CH2OCH2CH2 or CH2OCH2C(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, C1-4alkyl (especially methyl), C1-4alkoxy (especially methoxy), trifluoromethyl, trifluoromethoxy, oxo, vinyl, C1-4alkylamino (especially methylamino) or di(C1-4alkyl)amino (especially dimethylamino). 0158 Said unsaturated heterocyclyl radicals may be optionally substituted by one, two or three groups independently selected from halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, NO2, cyano, NRaRb, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl, C1-4alkoxyC1-4alkyl 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), C1-4alkoxy (especially methoxy), trifluoromethyl, trifluoromethoxy or vinyl. 0159 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, hydroxyC1-6alkyl, fluoroC1-6alkyl, fluoroC1-6alkoxy, NO2, cyano, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl, C1-4alkoxyC1-4alkyl or O(CH2)mO. Preferably said cycloalkyl radical is substituted by one or two substituents, especially one. Particularly preferred substituents include fluorine, chlorine, bromine, C1-4alkyl (especially methyl), methoxy, hydroxyC1-4alkyl (especially C(CH3)2OH), trifluoromethyl, trifluoromethoxy or vinyl. 0160 Specific compounds within the scope of this invention include: 0161 cis-(RS)-4-methanesulfonyloxy-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0162 (RS)-1-1-(1,4-dioxa-8-phenylspiro4.5decan-8-yl)methoxyethyl-3,5-bis(trifluoromethyl)benzene; 0163 (RS)-1-1-(4-oxo-1-phenylcyclohexyl)methoxyethyl-3,5-bis(trifuoromethyl)benzene; 0164 (RS)--(1,4-dioxa-8-phenylspiro4.5decan-8-yl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol; 0165 (RS)--(4oxo-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol; 0166 (RS)-4-oxo-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide; 0167 (RS)-1-(8-phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-2-yl ethanoate; 0168 (RS)-1-(8-phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-1-yl ethanoate; 0169 (RS)-1-(8-phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-2-ol; 0170 RS)-4-2-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexanone; 0171 trans-(RS)-1-(4-4-(4-fluorophenyl)piperidin-1-yl--methyl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene; 0172 cis-(RS)-1-(-ethenyl-4-4(4-fluorophenyl)piperid-1-yl--1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene; 0173 trans-(RS)-1-(-ethenyl-4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene; 0174 trans-(RS)-4-4-(4fluorophenyl)piperidin-1-yl-1-phenyl--3,5-bis(trifluoromethyl)phenylmethoxycyclohexaneethanol; 0175 trans-(RS)-1-(-ethyl-4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene; 0176 trans-1-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)methyl-2-methoxybenzene; 0177 trans-1-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)methyl-2-(cyclopropoxy)-5-(trifluoromethoxy)benzene; 0178 cis-(RS)-1-1-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)ethyl-3,5-bis(trifluoromethyl)benzene; 0179 trans-(RS)-1-1-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)ethyl-3,5-bis(trifluoromethyl)benzene; 0180 trans-(RS)--(4-hydroxy-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol; 0181 cis-(RS)--(4-hydroxy-1-phenylcyclohexyl)methoxyl-3,5-bis(trifluoromethyl)benzeneethanol; 0182 cis-(RS)--(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)-3,5-bis(trifluoromethyl)benzeneethanol; 0183 trans-(RS)--(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)-3,5-bis(trifluoromethyl)benzeneethanol; 0184 cis- and trans-(RS)--1-phenyl-4-(phenylmethylamino)cyclohexylmethoxy-3,5-bis(trifluoromethyl)benzeneethanol; 0185 cis- and trans-(RS)--(1-phenyl-4-(piperidin-1-yl)cyclohexyl)methoxy-3,5-bis(trifiuoromethyl)benzeneethanol; 0186 trans-(RS)--1-phenyl-4-(phenylmethylamino)cyclohexylmethoxy-3,5-bis(trifluoromethyl)benzeneethanol; 0187 cis-(RS)--1-phenyl-4-(phenylmethylamino)cyclohexylmethoxy-3,5-bis(trifluoromethyl)benzeneethanol; 0188 trans-(RS)--(4-amino-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol; 0189 cis-(RS)--(4-amino-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol; 0190 trans-(RS)--(4-N-methyl(phenylmethyl)amino-1-phenylcyclohexylmethoxy)-3,5-bis(trifluoromethyl)benzeneethanol; 0191 trans-(RS)--(4-methylamino-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol; 0192 trans-(RS)--(4-N-2-(dimethylamino)acetylamino-1-phenylcyclohexyl)methoxyl-3,5-bis(trifluoromethyl)benzeneethanol; 0193 trans-(RS,S)-N-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohexyl)-2-pyrrolidinecarboxamide; 0194 cis- and trans-(RS)--(1-phenyl-4-dimethylaminocyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol; 0195 trans-(RS)--(4-cyclopropylmethylamino-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol; 0196 1,2-dihydro-5-N-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)methylaminomethyl-3H-1,2,4-triazol-3-one; 0197 cis-(RS)-methyl 1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)piperidine-4-carboxylate; 0198 trans-(RS)-methyl 1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4yl)piperidine-4-carboxylate; 0199 trans-(RS)-1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)piperidine-4-methanol; 0200 trans-(RS)-1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)piperidine-4-carboxylic acid; 0201 trans-(RS)-1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4yl)-,-dimethylpiperidine-4-methanol; 0202 trans-(RS)-1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)-N,N-dimethylpiperidine-4-carboxamide; 0203 RS)-methyl (1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-ylidene)acetate; 0204 cis- and trans-(RS)-methyl(1-(1--hydroxmethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)acetate; 0205 cis-(RS)-1-2-(1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4yl)ethylpyrrolidine; 0206 trans-(RS)-1-2-(1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)ethylpyrrolidine; 0207 trans-(RS)-methyl -(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)-3,5-bis(trifluoromethyl)benzeneacetate; 0208 trans-3,5-bis(trifluoromethyl)phenylmethyl 4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylate; 0209 trans-(RS)-1-3,5-bis(trifluoromethyl)phenylethyl 4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylate; 0210 trans-(RS)-2-hydroxy-2-3,5-bis(trifluoromethyl)phenylethyl 4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylate; 0211 trans-(RS)--(hydroxymethyl)-3,5-bis(trifluoromethyl)phenylmethyl 4-4-(4-fluorophenyl)piperidin-1-yl-1-(phenyl)cyclohexanecarboxylate; 0212 trans-(RS)-methyl -(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylcarbonyloxy)-3,5-bis(trifluoromethyl)benzeneacetate; 0213 cis-4-4-(4fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl 3,5-bis(trifluoromethyl)benzoate; 0214 trans-4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl 3,5-bis(trifluoromethyl)benzoate; 0215 cis-1-phenyl-4-(4-phenylpiperidin-1-yl)-N-3,5-bis(trifuoromethyl)phenylmethylcyclohexanecarboxamide; 0216 trans-1-phenyl-4-(4-phenylpiperidin-1-yl)-N-3,5-bis(trifiuoromethyl)phenylmethylcyclohexanecarboxamide; 0217 trans-4-4-(4-fluorophenyl)piperidin-1-yl-N-3-(methoxy)phenylmethyl-1-phenylcyclohexanecarboxamide; 0218 trans-(RS)-4-4-(4-fluorophenyl)piperidin-1-yl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarbomide; 0219 trans-(R)-4-4-(4-fluorophenyl)piperidin-1-yl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0220 trans-(S)-4-4-(4-fluorophenyl)piperidin-1-yl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0221 cis-(RS)-4-4-(4-fluorophenyl)piperidin-1-yl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0222 trans-N-methyl-1-phenyl-4-(4-phenylpiperidin-1-yl)-N-3,5-bis(trifluoromethyl)phenylmethylcyclohexanecarboxamide; 0223 trans-(RS)-4-4-(4-fluorophenyl)piperidin-1-yl-N-methyl-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0224 trans-(RS)-4-4-(4-fluorophenyl)piperidin-1-yl-1-phenyl-N-2-hydroxy-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide; 0225 trans-(RS)-4-(1,4-dioxa-8-azaspiro4.5decane-8-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide; 0226 trans-(RS)-4-(4oxopiperidin-1-yl)-1-phenyl-N-4-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide; 0227 trans-(RS)-4-(4hydroxypiperidin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide; 0228 trans-(RS)-4-(but-3-enylamino)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide; 0229 trans-(RS)-4-(4-hydroxy-4-phenylpiperidin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide; 0230 trans-(RS)-4-(1,2,3,6-tetrahydro-4-phenylpyridin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide; 0231 trans-(RS)-4-(1,2,3,6-tetrahydro-4-methylpyridin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide; 0232 trans-(RS)-4-(4-hydroxy-4-(phenylethyl)piperidin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide; 0233 trans-(RS)-4-(phenyhmethyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0234 cis-(RS)-4-(phenylmethyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0235 trans-(RS)-4-N-methyl(phenylmethyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0236 trans-(RS)-4-methylamino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0237 trans-(RS)-4-amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0238 trans-(RS)-4-(dimethylamino)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0239 trans-(RS)-4-4-(phenylbutyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0240 trans-(RS)-4-N-methyl-4-(phenylbutyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0241 trans-(RS)-4-acetylamino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0242 trans-(RS)-4-(1-oxo-4-phenylbutyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0243 cis- and trans-(RS)-1,1-dimethylethyl 4-1-(1-3,5-bis(trifluoromethyl)phenylethylaminocarbonyl)-1-phenylcyclohex-4-yl-1-piperazinecarboxylate; 0244 trans-(RS)-4-4-(phenylmethyl)piperazin-1-yl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0245 trans-(RS)-4-(piperazin-1-yl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarbomide; 0246 trans-(RS)-4-(4-methylpiperazin-1-yl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0247 trans-(RS)-4-(4-acetylpiperazin-1-yl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0248 trans-(RS)-4-(aminomethyl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0249 trans-(RS)-4-(N,N-dimethylaminomethyl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0250 trans-(RS)-4-(piperidin-1-yl)methyl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0251 trans-(RS)-4-(morpholin-4-yl)methyl-N-(1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0252 trans-(RS)-4-(N-2-(dimethylamino)acetylaminomethyl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0253 trans-(RS)-4-(1H-1,2,3-triazol-1-yl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0254 trans-N-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl-3,5-bis(trifluoromethyl)benzenecarboxamide; 0255 trans-N-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl)-2-(methoxy)benzenemethanamine; 0256 trans-N-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl)-3,5-bis(trifluoromethyl)benzenemethanamine; 0257 cis-N-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl)-3,5-bis(trifluoromethyl)benzenemethanamine; 0258 trans-N-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl)-N-methyl-3,5-bis(trifluoromethyl)benzenemethanamine; 0259 cis- and trans-N-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl)-N-3,5-bis(trifluoromethyl)phenylmethylacetamide; 0260 trans-(RS)-N-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexymethyl)--methyl-3,5-bis(trifluoromethyl)benzenemethanamine; 0261 trans-(RS)--(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexymethylamino)-3,5-bis(trifluoromethyl)benzeneethanol; 0262 trans-(RS)--(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethylamino)-3,5-bis(trifluoromethyl)benzeneethanamine; 0263 cis- and trans-(E)-4-(4-fluorophenyl)-1-(4-phenyl-4-3-3,5-bis(trifluoromethyl)phenylprop-1-enylcyclohexyl)piperidine; 0264 cis- and trans-(E)-4-(4-fluorophenyl)-1-(4-phenyl-4-3-3,5-bis(trifuoromethyl)phenylpropylcyclohexyl)piperidine; 0265 cis- and trans-(RS)-4-(4-fluorophenyl)-1-(4-2-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexyl)piperidine; 0266 cis- and trans-(RS)-4-(4-(4-fluorophenyl)-1-(4-2-oxo-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexyl)piperidine; 0267 1-(1,4-dioxa-8-phenylspiro4.5decan-8-yl)methoxymethyl-3,5-bis(trifluoromethyl)benzene; 0268 1-(4-oxo-1-phenylcyclohexylmethoxymethyl)-3,5-bis(trifluoromethyl)benzene; 0269 cis-1-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene; 0270 trans-1-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene; 0271 (RS)-4-methylene-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide; 0272 cis-(RS)-4-(hydroxymethyl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0273 trans-(RS)-4-(hydroxymethyl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 0274 and pharmaceutically acceptable salts thereof. 0275 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. 0276 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. 0277 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. 0278 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. 0279 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. 0280 The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates. 0281 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. 0282 The preferred compounds of the formula (I) and (Ia) will have the stereochemistry of the 1- and 4-positions as shown in formula (Ib) 22

0283 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). 0284 The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient. 0285 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. 0286 A more detailed description of pharmaceutical compositions that are suitable for the formulation of compounds of the present invention is disclosed in U.S. Pat. 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). 0287 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. 0288 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 U.S. Pat. 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). 0289 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. 0290 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. 0291 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. 0292 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. 0293 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. 0294 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. 0295 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. 0296 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. 0297 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. 0298 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. 0299 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. 0300 According to a general process (A), compounds of formula (I), in which X is C(O)N(R13)CR14R15, may be prepared by the reaction of a compound of formula (II) with a compound of formula (III) 23

0301 in the presence of a base and a coupling reagent. 0302 Suitable bases of use in the reaction include tertiary amines, for example, triethylamine. 0303 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). 0304 The reaction is conveniently effected in a suitable organic solvent such as, for example, dimethylformamide. 0305 According to an alternative general process (B), compounds of formula (I), in which X is C(O)N(R13)CR14R15, may be prepared by the reaction of an amine of formula (III) with an activated carboxylic acid derivative of formula (IV) 24

0306 where L is a leaving group. 0307 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. 0308 A particularly preferred reagent for activating the carboxylic acid group is bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl). 0309 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. 0310 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. 0311 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. 0312 According to another general process (C), compounds of formula (I), in which X is CR14R15N(R13)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 25

0313 using the methods described in processes (A) and (B), above. 0314 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) 26

0315 (wherein R30 is CR14R15NH2 and R31 is CHO, or R30 is CHO and R31 is CR16R17NH2) in the presence of a reducing agent. 0316 Suitable reducing agents for use in this reaction include, for example, sodium cyanoborohydride or sodium triacetoxyborohydride. 0317 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. 0318 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) 27

0319 in the presence of a base. 0320 Suitable bases of use in the reaction include aromatic amines such as pyridine or 4-(dimethylamino)pyridine (DMAP). 0321 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. 0322 According to another general process (F), compounds of formula (I), in which X is CR14R15OC(O), may be prepared by the reaction of a compound of formula (X) with a compound of formula (XI) 28

0323 (provided that R21a is not hydroxy) using a method described in process (E) above. 0324 According to another general process (G), compounds of formula (I), in which X is CR14R15OCR16R17, may be prepared by reacting a compound of formula (X) with a compound of formula (XII) 29

0325 (wherein Hal is a halogen atom such as chlorine, iodine or, preferably, bromine), in the presence of a base such as sodium hydride. 0326 The reaction is conveniently effected in a suitable aprotic solvent such as, for example, dimethylformamide. 0327 According to another general process (H), compounds of formula (I), in which X is CHCHCR18R19, may be prepared by the reaction of a compound of formula (VII) where R30 is CHO with a compound of formula (XIII) 30

0328 in the presence of lithium hexamethyldisilazide. 0329 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. 0330 According to another general process (J), compounds of formula (I), in which X is CR14R15CHCH, may be prepared by the reaction of a compound of formula (VIII) wherein R31 is CHO with a compound of formula (XIV) 31

0331 using the method described in process (H), above. 0332 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. 0333 Thus, according to general process (K.1), compounds of formula (I) in which X is CR14R15N(R13)CR16R17, may be prepared by the interconversion of a compound of formula (I) in which X is either C(O)N(R13)CR14R15 or CR14R15N(R13)C(O), by reaction with a reducing agent. 0334 Suitable reducing agents for use in this reaction include sodium borohydride or borane.tetrahydrofuran complex. 0335 The reaction is conveniently effected in a solvent such as an ether, for example, tetrahydrofuran. 0336 According to another general process (K.2), compounds of formula (I) in which X is CR14R15OCH(CH3) or CH(CH3)OCR14R15, 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, 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. 0337 According to another general process (K.3), compounds of formula (I) in which X is CR14R15OCH(CH2OH) or CH(CH2OH)OCR14R15, 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. 0338 According to another general process (K.4), compounds of formula (I) in which X is CR14R15CR16R17CR18R19, may be prepared by interconversion of a compound of formula (I) in which X is CR14CR16CR18R19 or CR14R15CR16CR18, 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. 0339 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 O, 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. 0340 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). 32

0341 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. 0342 Preferably, where R21a is halogen or hydroxy, or R21a and R21b both represent fluorine or together represent oxo (O), 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. 0343 Further details of suitable procedures for the preparation of compounds of formula (I) will be found in the accompanying Examples. 0344 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: 34

0345 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. 0346 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. 35

0347 Compounds of formula (V) in which R14 and R15 are both hydrogen may be prepared from the corresponding carbonitrile compound of formula (XV) 36

0348 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. 0349 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. 0350 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. 0351 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. 0352 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). 0353 Compounds of formulae (XIII) and (XIV) may be prepared by conventional methods, in particular by the reaction of a compound of formula (XVI) or (XVII), respectively 37

0354 (provided that R21a 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. 0355 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. 0356 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. 0357 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. 0358 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. 0359 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 IC50 at the NK1 receptor of less than 100 nM on said test method. 0360 The following non-limiting Examples serve to illustrate the preparation of compounds of the present invention:

DESCRIPTION 1

Dimethyl 4-Oxo-1-phenyl-1,3-cyclohexanedicarboxylate 0361 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 (2700 mL). The combined organic fractions were washed with water (5500 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/Et2O (80:20) and the residue was triturated with isohexane/Et2O (50:50). The solid was collected and dried in vacuo to give the tide compound as colorless crystals (30 g, 35%). 1H NMR (400 MHz, CDCl1) 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-phenylcyclohexanecarboxylic Acid 0362 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 (5M) 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%). 1H NMR (400 MHz, CDCl3) 7.50-7.29 (5H, 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)-1-3,5-Bis(trifluoromethyl)phenyl-1.2-ethanediol 0363 Osmium tetroxide (2.5 wt % solution in 2-methyl-2-propanol, 1 mL) was added to a mixture of 1-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 (2100 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%). 1H NMR (400 MHz, CDCl3) 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)-1-3,5-Bis(trifluoromethyl)--2-(trimethylsilyl)ethoxymethoxymethylbenzenemethanol 0364 N-Ethyl-N,N-diisopropylamine (465 l, 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)ethyltrimethylsilane (315 l, 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%). 1H NMR (400 MHz, CDCl3) 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)--Methyl-3,5-bis(trifluoromethyl)benzenemethanamine 0365 O-Methylhydroxylamine hydrochloride (19.57 g, 234 mmol) was added to a solution of 1-3,5-bis(trifluoromethyl)phenylethanone (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 (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL), cooled to 020 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)--methyl-3,5-bis(trifluoromethyl)benzenemethanamine hydrochloride as a colorless solid (48.2 g, 100%). 1H NMR (400 MHz, CD3OD) 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 (M1). 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. 1H NMR (400 MHz, CDCl3) 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 Hz). m/z (ES) 258 (M1).

DESCRIPTION 6

(RS)-2-Methoxy--methylbenzenemethanamine Hydrochloride 0366 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 3 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 (MgSO4), 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 (M1-NH3).

DESCRIPTION 7

(RS)--Ethyl-3,5-bis(trifluoromethyl)benzenemethanamine Hydrochloride 0367 Prepared from 1-3,5-bis(trifluoromethyl)phenylpropanone according to the method of Description 6. m/z (ES) 272 (M1), 255 (M1-NH3).

DESCRIPTION 8

Methyl 3,5-Bis(trifluoromethyl)benzeneacetate 0368 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 (2300 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%). 1H NMR (400 MHz, CDCl3) 7.80 (1H, s), 7.75 (2H, s), 3.77 (2H, s), and 3.75 (3H, s).

DESCRIPTION 9

Methyl ,-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetate 0369 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%). 1H NMR (400 MHz, CDCl3) 7.78 (3H, s), 3.69 (3H, s), and 1.65 (6H, s).

DESCRIPTION 10

,-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid 0370 Lithium hydroxide monohydrate (2.13 g, 50.6 mmol) was added to a suspension of methyl ,-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%). 1H NMR (400 MHz, CDCl3) 7.84 (2H, s), 7.80 (1H, s), and 1.68 (6H, s).

DESCRIPTION 11

,-Dimethyl-3,5-bis(trifluoromethyl)benzenemethanamine Hydrochloride 0371 Diphenylphosphoryl azide (0.43 mL, 2 mmol) was added to a solution of ,-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 9020 C. for 18 hours. The mixture was cooled, diluted with ethyl acetate and washed with aqueous sodium carbonate (saturated), dried (MgSO4) 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 (M1), 255 (M1-NH3).

DESCRIPTION 12

(RS)-Methyl -Amino-3,5-bis(trifluoromethyl)benzeneacetate Hydrochloride 0372 Palladium on carbon (5%, 220 mg) was added to a solution of methyl -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 (M1).

DESCRIPTION 13

2-(Cyclopropyloxy)-5-(trifluoromethoxy)phenylmethyl Methanesulfonate 0373 Methanesulfonyl chloride (0.31 mL, 0.46 g, 4.0 mmol) was added dropwise to a stirred, cooled (1020 C.) solution of 2-(cyclopropyloxy)-5-(trifluoromethoxy)benzenemethanol (WO9900368, 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 (250 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 tiHe compound. 1H NMR (400 MHz, CDCl3) 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 0374 A mixture of 4-fluorobenzeneboronic acid (38.7 g, 276 mmol), 4-bromopyridine hydrochloride (48.9 g, 250 mmol), 1,4-butanediylbis(diphenylphosphine-P)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 8020 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. 1H NMR (360 MHz, CDCl3) 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)pyridine 0375 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 020 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 (M1).

DESCRIPTION 16

4-(4-Fluorophenyl)piperidine 0376 Palladium hydroxide on carbon (20%, 5 g) was added to a solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-(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%). 1H NMR (400 MHz, CD3OD) 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 (M1). 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%). 1H NMR (400 MHz, CD3OD) 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 (M1).

DESCRIPTION 17

Benzenebutanal 0377 1,1,1-Tris(acetyloxy)-1,1-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%). 1H NMR (400 MHz, CDCl3) 9.76 (1H, m), 7.31-27 (2H, m), 7.22-7.16 (3H, m), 2.66 (2H, t, J 73 Hz), 2.45 (2H, t, J 7.3 Hz), 1.97 (2H, quin, J 7.3 Hz).

DESCRIPTION 18

Methyl 4-Oxo-1-phenylcyclohexanecarboxylate 0378 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 (250 mL). The combined organic fractions were dried (Na2SO4) 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 4520 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 (250 mL), the combined organic fractions were dried (Na2SO2) and the solvent was evaporated under reduced pressure to give the tide compound (0.98 g, 98%). 1H NMR (250 MHz, CDCl3) 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-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylate, Cis-4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylic Acid and Trans-Methyl 4-4-(4-Fluorophenyl)piperidin-1-y1-1-phenylcyclohexanecaboxylate 0379 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 4oxo-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. 1H NMR (400 MHz, CD3OD) 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 (M1). 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)piperdin-1-yl-1-phenylcyclohexanecarboxylic acid as a colorless solid (1.2 g, 21%). m/z (ES) 382 (M1). 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-yl-1-phenylcyclohexaecarboxylate as a colorless solid, (1.6 g, 27%). 1H NMR (400 MHz, CD3OD) 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 (M1).

DESCRIPTION 20

Trans-4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylic Acid Hydrochloride 0380 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 (E) 382 (M1).

DESCRIPTION 21

Trans-4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexanemethanol 0381 Diisobutylaluminium hydride (1M in hexanes, 1.95 mL, 1.95 mmol) was added slowly to a cooled (7820 C.) solution of trans-methyl 4-4-(4-fluorophenyl)piperidin-1-yl-1-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 (MgSO4) 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 (m1).

DESCRIPTION 22

(RS)--Methyl-8-phenyl-1,4-dioxaspiro4.5decane-8-methanol 0382 A solution of 8-phenyl-1,4-dioxaspiro4.5decane-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 020 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 (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (4.03 g, 96%). 1H NMR (360 MHz, CDCl3) 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), 3.58-3.96 (4H, m), and 7.21-7.38 (5H, m).

DESCRIPTION 23

(RS)--Ethenyl-8-phenyl-1,4-dioxaspiro4.5decane-8-methanol 0383 Prepared from 8-phenyl-1,4-dioxaspiro4.5decane-8-carboxaldehyde (J.Med.Chem. 1975, 18, 593-599) and vinylmagnesium bromide according to the method of Description 22. 1H NMR (400 Mz, CDCl3) 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 (5H, m), 5.09-5.14 (2H, m), 5.55-5.63 (1H, m), and 7.21-7.39 (5H, m).

DESCRIPTION 24

Trans-4-(4-Oxopiperidin-1-yl)-1-phenylcyclohexanecarboxylic Acid Hydrochloride 0384 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-azaspiro4.5decane (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 020 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 (2200 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 (M1).

DESCRIPTION 25

Trans-4-4(Phenylmethyl)piperazin-1-yl-1-phenylcyclohexanecarboxylate Acid Hydrochloride 0385 Prepared from 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 2) and 1-(phenylmethyl) piperazine according to the method of Description 24. m/z (ES) 379 (M1).

DESCRIPTION 26

Cis-(RS)-4-Hydroxy-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide 0386 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-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (Example 18, 1.90 g, 4.1 mmol) in ethanol (60 mL). The mixture was stirred at 020 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 (350 mL). The combined organic fractions were washed with aqueous sodium hydrogen carbonate (saturated, 250 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 4020 C. to give the title compound (1.37 g, 72%). 1H NMR (400 MHz, CD3OD) 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-Methanesulfonyloxy-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0387 Methanesulfonyl chloride (0.9 mL, 11.6 mmol) was added to a stirred, cooled (020 C.) solution of cis-(RS)-4-hydroxy-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (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%). 1H NMR (400 MHz, CDCl3) 7.72 (1H, s), 7.44 (2H, s), 7.42-7.38 (2H, m), 7.35-7.31 (3H, m), 5.41 (1H, d, J 6.9 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-1-3,5-bis(trifluoromethy)phenylethyl-1-phenylcyclohexanecarboxamide 0388 Sodium azide (621 mg, 9.55 mmol) was added to a solution of cis-(RS)-4-methanesulfonyloxy-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide (Description 27, 1.0 g, 1.91 mmol) in dimethylformamide (15 mL) and the mixture was then stirred at 9020 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%). 1H NMR (400 MHz, CDCl3) 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)phenylethyl-1-phenylcyclohexanecarboxamide 0389 Tetrabutylammonium cyanide (153 mg, 0.57 mmol) was dried azeotropically by evaporating toluene under reduced pressure, then a solution of cis-(RS)-4methanesulfonyloxy-N-1-3,5-bis(trifluoromethyl)phenylethyl-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 7020 C. for 24 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (250 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%). 1H NMR (360 MHz, CD3OD) 7.76 (1H, s), 7.66 (2H, s), 7.36-7.22 (5H, m), 5.12 (1H, q, J 7.0 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-phenylcyclohexanecarbonitrile 0390 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 (M1).

DESCRIPTION 31

Trans-4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarbonitrile 0391 Prepared from the mixture of isomers of Description 30 by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (98:2:0.2). m/z (ES) 363 (M1).

DESCRIPTION 32

Trans-4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexanemethanamine 0392 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-yl-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 (M1).

DESCRIPTION 33

2-((2-3,5-Bis(trifluoromethyl)phenylethylthio)benzothiazole 0393 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 (2150 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 (M1).

DESCRIPTION 34

2-((2-3,5-Bis(trifluoromethyl)phenylethylsulfonyl)benzothiazole 0394 Oxone (8.58 g, 14.0 mmol) was added to a mixture of 2-((2-3,5-bis(trifluoromethyl)phenylethylthio)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 (M1).

DESCRIPTION 35

(E)-8-Phenyl-8-3-3,5-bis(trifluoromethyl)phenylprop-1-enyl-1,4-dioxaspiro4.5decane 0395 Lithium hexamethyldisilazide (1M in tetrahydrofuran, 7.0 mL, 7.0 mmol) was added over 10 minutes to a cooled (7820 C.) solution of 8-phenyl-1,4-dioxaspiro4,5decane-8-carboxaldehyde (J.Med.Chem. 1975, 18, 593-599, 1.68 g, 6.8 mmol) and 2-((2-3,5-bis(trifluoromethyl)phenylethylsulfonyl)benzothiazole (Description 34, 2.99 g, 6.8 mmol) in tetrahydrofuran (15 mL) and the mixture was stirred at 7820 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 (330 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 tide compound as a pale yellow oil (2.43 g, 92%). 1H NMR (400 MHz, CDCl3) 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 0396 A slurry of palladium on carbon (10%, 600 mg) in ethanol (10 mnL) 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 Celite 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 (M1).

DESCRIPTION 37

Trans-(RS)-1,1-Dimethylethyl 3-Hydroxy-4-methylpiperidinecarboxylate 0397 Di-tert-butyl dicarbonate (4.32 g, 20 mmol) was added to a solution of trans-(RS)-4methyl-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 L) 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 (MgSO4), 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 (M1).

DESCRIPTION 38

(RS)-1,1-Dimethylethyl 4-Methyl-3-oxopiperidinecarboxylate 0398 1,1,1-Tris(acetyloxy)-1,1-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 (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (1.96 g, 99%). m/z (ES) 157 (M1).

DESCRIPTION 39

(RS)-3,3-Difluoro-4-methylpiperidine Hydrochloride 0399 Diethylaminosulphur trifluoride (1.18 mL, 8.97 mmol) was added to a stirred, cooled (020 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 (250 mL). The combined organic fractions were washed with brine (50 mL), dried (MgSO4) 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 (M1).

DESCRIPTION 40

1-(1,1-Dimethylethyl) 4-Ethyl 4-(2-Propenyl)-1,4-piperidinedicarboxylate 0400 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 (7820 C.) solution of potassium hexamethyldisilazide (29.0 g, 145 mmol) in tetrahydrofuran (150 mL), maintaining the internal temperature below 6520 C. The mixture was stirred at 7820 C. for 30 minutes, then 3-bromopropene (12.6 mL, 145 mmol) was added dropwise over 10 minutes. The mixture was stirred at 7820 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 (3400 mL) and the combined organic fractions were washed with aqueous citric acid (10%, 2250 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%). 1H NMR (400 MHz, CDCl3) 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, J 7 Hz).

DESCRIPTION 41

1,1-Dimethylethyl 1-Oxo-2-oxa-8-azaspiro4.5decane-8-carboxylate 0401 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 7820 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 (2500 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%). 1H NMR (400 MHz, CDCl3) 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 0402 Diisobutylaluminium hydride (1.0M in dichloromethane, 3.60 mL, 3.60 mmol) was added over 10 minutes to a stirred, cooled (7820 C.) solution of 1,1-dimethylethyl 1-oxo-2-oxa-8-azaspiro4.5decane-8-carboxylate (Description 41, 400 mg, 1.57 mmol) in dichloromethane (4 mL) and the mixture stirred at 7820 C. for 3 hours, then at 020 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 (M1).

DESCRIPTION 43

1,1-Dimethylethyl 2-Oxa-8-azaspiro4.5decane-8-carboxylate 0403 Diethyl azodicarboxylate (183 l, 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 020 C. for 90 minutes then at room temperature overnight. The mixture was cooled to 020 C. and further triphenylphosphine (126 mg, 0.48 mmol) and diethyl azodicarboxylate (76 l, 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 (M1-C4H8).

DESCRIPTION 44

2-Oxa-8-azaspiro4.5decane 0404 Methanolic hydrogen chloride (3M, 3 mL) was added to a stirred, cooled (020 C.) solution of 1,1-dimethylethyl 2-oxa-8-azaspiro4.5decane-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 (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (77 mg, 88%). m/z (ES) 142 (M1).

EXAMPLE 1

1-(1,4-Dioxa-8-phenylspiro4.5decan-8-yl)methoxymethyl-2-methoxybenzene 0405 Sodium hydride (60% dispersion in mineral oil, 720 mg, 30.0 mmol) was added to a solution of 8-phenyl-1,4-dioxaspiro4.5decane-8-methanol (J. Org. Chem. 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 (250 mL). The combined organic fractions were washed with water (350 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%). 1H NMR (400 MHz, CDCl3) 7.43-7.40 (2H, m), 7.33-7.29 (2H, m), 7.21-7.13 (3H, m), 6.68 (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-(4-Oxo-1-phenylcyclohexylmethoxymethyl)-2-methoxybenzene 0406 Prepared from 1-(1,4-dioxa-8-phenylspiro4.5decan-8-yl)methoxymethyl-2-methoxybenzene (Example 1) according to the method of Example 10. 1H NMR (400 MHz, CDCl3) 7.50-7.47 (2H, m), 7.41-7.37 (2H, m), 7.30-7.15 (3H, m), 6.89 (1H, td, J 0.7, 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-phenylspiro4.5decan-8-yl)methoxymethyl-2-(cyclopropoxy)-5-(trifluoromethoxy)benzene 0407 Prepared from 8-phenyl-1,4-dioxaspiro4.5decane-8-methanol (J. Org. Chem. 1974, 39, 2311-2313) and 2-(cyclopropyloxy)-5-(trifluoromethoxy)phenylmethyl methanesulfonate (Description 13) according to the method of Example 1. 1H NMR (400 MHz, CDCl3) 7.42 (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

1-(4-Oxo-1-phenylcyclohexylmethoxymethyl)-2-(cyclopropoxy-5-(trifluoromethoxy)benzene 0408 Prepared from 1-(1,4-dioxa-8-phenylspiro4.5decan-8-yl)methoxymethyl-2-(cyclopropoxy)-5-(trifluoromethoxy)benzene (Example 3) according to the method of Example 10. 1H NMR (400 MHz, CDCl3) 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)-1-(-Methyl-8-phenyl-1,4-dioxaspiro4.5decane-8-methoxy)methyl-3,5-bis(trifluoromethyl)benzene 0409 Sodium hydride (60% suspension in mineral oil, 700 mg, 30 mmol) was added in portions to a solution of (RS)--methyl-8-phenyl-1,4-dioxaspiro4.5decane-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 9520 C. for 2.5 hours. The mixture was cooled, poured into water (500 mL) and extracted with diethyl ether (2500 mL). The combined organic fractions were 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 tide compound as a pale oil (4.1 g, 55%). 1H NMR (360 MHz, CDCl3) 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-(-Methyl-4-oxo-1-phenylcyclohexanemethoxy)methyl-3,5-bis(trifluoromethyl)benzene 0410 Prepared from (RS)-1-(-methyl-8-phenyl-1,4-dioxaspiro4.5decane-8-methoxy)methyl-3,5-bis(trifluoromethyl)benzene (Example 5) according to the method of Example 10. 1H NMR (360 MHz, CDCl3) 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

(RS)-1-(-Ethenyl-8-phenyl-1,4-dioxaspiro4.5decane-8-methoxy)methyl-3,5-bis(trifluoromethyl)benzene 0411 Prepared from (RS)--(ethenyl-8-phenyl-1,4-dioxaspiro4.5decane-8-methanol (Description 23) and 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene according to the method of Example 5. 1H NMR (360 MHz, 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)-1-(-Ethenyl-4-oxo-1-phenylcyclohexanemethoxy)methyl-3,5-bis(trifluoromethyl)benzene 0412 Prepared from (RS)-1-(-ethenyl-8-phenyl-1,4-dioxaspiro4.5decane-8-methoxy)methyl-3,5-bis(trifluoromethyl)benzene (Example 7) according to the method of Example 10. 1H NMR (360 MHz, CDCl3) 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-phenylspiro4.5decan-8-yl)methyl 3,5-Bis(trifluoromethyl)benzoate 0413 3,5-Bis(trifluoromethyl)benzoyl chloride (115 l, 0.64 mmol) was added to a solution of 8-phenyl-1,4-dioxaspiro4.5decane-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 l, 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 l, 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 (310 mnL). 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-phenylcyclohexylmethyl 3,5-bis(trifluoromethyl)benzoate. 1H NMR (360 Mz, CDCl3) 1.55-1.73 (5H, 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-1-phenylcyclohexylmethyl 3,5-Bis(trifluoromethyl)benzoate 0414 Hydrochloric acid (2M, 2 mL, 4 mmol) was added to a solution of (1,4-dioxa-8-phenylspiro4.5decan-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 (320 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%). 1H NMR (360 MHz, CDCl3) 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-phenylspiro4.5decan-8-yl)methoxyethenyl-3,5-bis(trifluoromethyl)benzene 0415 A solution of (1,4-dioxa-8-phenylspiro4.5decan-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 Celite and the solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (250 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 CH2Cl2/isohexane (50:50), to give the title compound as a colorless gum (272 mg, 55%). 1H NMR (360 MHz, CDCl3) 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-(1,4-Dioxa-8-phenylspiro4.5decan-8-yl)methoxyethyl-3,5-bis(trifluoromethyl)benzene 0416 Palladium on carbon (5%, 20 mg) was carefully added as an aqueous slurry to a solution of 1-1-(1,4-dioxa-8-phenylspiro4.5decan-8-yl)methoxyethenyl-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%). 1H NMR (360 MHz, CDCl3) 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)-1-1-(4-Oxo-1-phenylcyclohexyl)methoxyethyl-3,5-bis(trifluoromethyl)benzene 0417 Prepared from (RS)-1-1-(1,4-dioxa-8-phenylspiro4.5decan-8-yl)methoxyethyl-3,5-bis(trifluoromethyl)benzene (Example 12) according to the method of Example 10. 1H NMR (360 MHz, CDCl3) 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)--(1,4-Dioxa-8-phenylspiro4.5decan-8-yl)methoxy-3,5-bis(trifluoromethyl) benzeneethanol 0418 Borane tetrahydrofuran complex (1M in THF, 1.2 mL, 1.2 mmol) was added to a cooled (0 C.) solution of 1-1-(1,4-dioxa-8-phenylspiro4.5decan-8-yl)methoxyethenyl-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 (230 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

(RS)--(4-Oxo-1-phenylcyclohexyl)methoxy9 -3,5-bis(trifluoromethyl)benzeneethanol 0419 Prepared from (RS)--(1,4-dioxa-8-phenylspiro4.5decan-8-yl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol (Example 14) according to the method of Example 10. 1H NMR (360 MHz, CDCl3) 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)phenylmethyl4-Oxo-1-phenylcyclohexanecarboxylate 0420 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 isohexane/CH2Cl2 (60:40 increasing to 50:50) to give the title compound (4.5 g, 40%). 1H NMR (360 MHz, CDCl3) 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)phenylmethylcyclohexanecarboxamide 0421 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 (M1).

EXAMPLE 18

(RS)-4-Oxo-1-phenol-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide 0422 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)--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 (350 mL) and the combined organic fractions were washed with hydrochloric acid (2M, 250 mL), aqueous sodium hydrogen carbonate (saturated, 250 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 (M1).

EXAMPLE 19

N-(8-Phenyl-1,4-dioxaspiro4.5decan-8-yl)methyl-3,5-bis(trifluoromethyl) benzenemethanamine 0423 Sodium triacetoxyborohydride (4.77 g, 22.5 mmol) was added to a solution of 8-phenyl-1,4-dioxaspiro4.5decane-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 (250 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 (M1).

EXAMPLE 20

N-(8-Phenyl-1,4-dioxaspiro4.5decan-8-yl)methyl-N-3,5-bis(trifluoromethyl)phenylmethylacetamide 0424 Acetic anhydride (2 mL) was added to a solution of N-(8-phenyl-1,4-dioxaspiro4.5decan-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%, 225 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 (M1).

EXAMPLE 21

N-(4-Oxo-1-phenylcyclohexyl)methyl-N-3,5-bis(trifluoromethyl)phenylmethylacetamide 0425 Prepared from N-(8-phenyl-1,4-dioxaspiro4.5decan-8-yl)methyl-N-3,5-bis(trifluoromethyl)phenylmethylacetamide (Example 20) according to the method of Example 10. 1H NMR (400 MHz, CDCl3) mixture of two rotamers; major rotamer 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 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)phenylprop-1-enylcyclohexanone 0426 Prepared from 8-phenyl-8-3-3,5-bis(trifluoromethyl)phenylprop-1-enyl1,4-dioxaspiro4.5decane (Description 35) according to the method of Example 10. 1H NMR (400 MHz, CDCl3) 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, Jt 15.4, Jd 7.1 Hz), 3.49 (2H, d, J 7.1 Hz), 2.46 (6H, m), and and 2.20 (2H, m).

EXAMPLE 23

(RS)-1-(8-Phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-2-yl Ethanoate and

(RS)-1-(8-Phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3.5-bis(trifluoromethyl)phenylpropan-1-yl Ethanoate 0427 Borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 12 mL, 12 mmol) was added over 10 minutes to a solution of (E)-8-phenyl-8-3-3,5-bis(trifluoromethyl)phenylprop-1-enyl1,4-dioxaspiro4.5decane (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 (2150 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 (2150 mL) and the combined organic fractions were washed with water (2150 mL) and aqueous copper sulfate (5%, 2100 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/EtOAc (99:1 increasing to 95:5), to give: (RS)-1-(8-phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-2-yl ethanoate (803 mg, 38%); 1H NMR (360 MHz, CDCl3) 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-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-1-yl ethanoate (425 mg, 20%); 1H NMR (360 MHz, CDCl3) 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

(RS)-1-(8-Phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-2-ol 0428 Potassium carbonate (2.5 g) was added to a solution of (RS)-1-(8-phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-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 (375 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%). 1H NMR (400 MHz, CDCl3) 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-Hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexanone 0429 Prepared from (RS)-1-(8-phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-2-ol (Example 24) according to the method of Example 10. 1H NMR (400 MHz, 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), and 2.03-1.77 (4H, m).

EXAMPLE 26

Trans-(RS)-1-(4-4-(4-Fluorophenyl)piperidin-1-yl--methyl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene 0430 Prepared from (RS)-1-(-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 (M1).

EXAMPLE 27

Cis-(RS)-1-(-Ethenyl-4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifuoromethyl)benzene and

Trans-(RS)-1-(-Ethenyl-4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene 0431 Prepared from (RS)-1-(-ethenyl-4-oxo-1-phenylcyclohexanemethoxy)methyl-3,5-bis(trifluoromethyl)benzene (Example 8) and 4-(4fluorophenyl)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/NH3(Aq.) (95:5:1): trans-(RS)-1-(4-4-(4-fluorophenyl)piperidin-1-yl--ethenyl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene; 1H NMR (400 MHz, CDCl3) 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 (M1); cis-(RS)-1-(4-4-(4-fluorophenyl)piperidin-1-yl--ethenyl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene; 1H NMR (400 MHz, CDCl3) 1.44-1.68 (10H, 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 (M1).

EXAMPLE 28

Trans-(RS)-4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenyl--3,5-bis(trifluoromethyl) phenylmethoxycyclohexaneethanol 0432 Ozone was bubbled through a stirred, cooled (7820 C.) solution of trans-(RS)-1-(4-4-(4-fluorophenyl)piperidin-1-yl--ethenyl-1-phenylcyclohexanemethoxymethyl)-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 (M1).

EXAMPLE 29

Trans-(RS)-1-(-Ethyl-4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene 0433 A slurry of palladium on carbon (10%, 20 mg) in methanol (10 mL) was added to a solution of trans-(RS)-1-(-ethenyl-4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanemethoxymethyl)-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 Celite and the solvent was evaporated under reduced pressure to give the tide compound as a colorless oil (88 mg, 98%). m/z (ES) 622 (M1).

EXAMPLE 30

Trans-1-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)methyl-2-methoxybenzene 0434 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-phenylcyclohexylmethoxymethyl)-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 mL) and extracted with ethyl acetate (220 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 CH2Cl2/MeOH/NH3(Aq.) (98:2:0.2), to give the title compound. m/z (ES) 488 (M1).

EXAMPLE 31

Trans-1-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)methyl-2-(cyclopropoxy)-5-(trifluoromethoxy)benzene 0435 Prepared from 1-(4-oxo-1-phenylcyclohexylmethoxymethyl)-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 (M1).

EXAMPLE 32

Cis-(RS)-1-1-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)ethyl-3,5-bis(trifluoromethyl)benzene and

Trans-(RS)-1-1-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy) ethyl-3,5-bis(trifluoromethyl)benzene 0436 Prepared from (RS)-1-1-(4-oxo-1-phenylcyclohexyl) methoxyethyl-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-phenylcyclohexylmethoxy)ethyl-3,5-bis(trifluoromethyl)benzene; 1H NMR (400 MHz, 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 (M1); Trans-(RS)-1-1-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)ethyl-3,5-bis(trifluoromethyl)benzene; 1H NMR (360 MHz, CDCl3) 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, J 6.5 Hz), 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 (M1). 0437 The following compounds were prepared as mixtures of cis- and trans-isomers from (RS)-1-1-(4-oxo-1-phenylcyclohexyl)methoxyethyl-3,5-bis(trifluoromethyl)benzene (Example 13) according to the method of Example 55, substituting a suitable amine for piperidine. 1

Cis-(RS)- & Trans-(RS)-m/z (ES)Ex.NRphd 2FormulaM.W.(M 1).33

C28H33F6NO513514 34

C28H33F6NO2529530 35

C31H37F6NO3585586 36

C27H31F6NO2515516 37

C27H31F6NO499500 38

C25H29F6NO473474

0438 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 CH2Cl2/MeOH/Et3N (95:5:1). 2

Trans-(RS)-m/z (ES)Ex.NR2FormulaM.W.(M 1).39

C28H33F6NO513514 40

C28H33F6NO2529530 41

C27H31F6NO499500 42

C25H29F6NO473474

EXAMPLE 43

Cis-(Rs)--(4-Hydroxy-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl) benzeneethanol and

Trans-(RS)--(4-Hydroxy-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl) benzeneethanol 0439 Sodium borohydride (25 mg, 0.65 mmol) was added to a solution of (RS)--(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 (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC column chromatography on silica gel, eluting with CH2Cl2/EtOAc (80:20) to give: trans-(RS)--(4-hydroxy-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl) benzeneethanol (34 mg, 46%); 1H NMR (400 MHz, CD3OD) 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)--(4-hydroxy-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl) benzeneethanol (10 mg, 14%); 1H NMR (400 MHz, CD3OD) 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)--(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)-3,5-bis(trifluoromethyl)benzeneethanol and

Trans-(RS)--(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)-3,5-bis(trifluoromethyl)benzeneethanol 0440 Prepared from (RS)--(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)--(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)-3,5-bis(trifluoromethyl)benzeneethanol; 1H NMR (360 MHz, CDCl3) 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 (M1); Trans-(RS)--(4-4-4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)-3,5-bis(trifluoromethyl)benzeneethanol; 1H NMR (360 MHz, CDCl3) 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 (M1).

EXAMPLE 45

Cis- and Trans-(RS)--1-Phenyl-4-(phenylmethylamino)cyclohexylmethoxy-3,5-bis(trifluoromethyl)benzeneethanol 0441 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 (42 mL), then eluted with methanolic ammonia (2M, 22 mL). The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (151 mg, 83%). 1H NMR and analytical HPLC showed this to be a 1:1 mixture of trans:cis isomers. m/z (ES) 552 (M1). 0442 The following compounds were prepared as mixtures of cis- and trans-isomers from (RS)--(4-oxo-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol (Example 15) according to the method of Example 45, substituting a suitable amine for benzylamine. 3

Cis-(RS)- & Trans-(RS)-m/z (ES)Ex.NR2FormulaM.W.(M 1).46

C27H31F6NO3531532 47

C31H33F6NO2565566 48

C32H35F6NO2579580 49

C27H31F6NO2515516 50

C33H137F6NO2593594 51

C29H30F6N2O2552553 52

C29H30F6N2O2552553 53

C29H30F6N2O2552553 54

C28H29F6NO3541542

EXAMPLE 55

Cis- and Trans-(RS)--(1-Phenyl-4-(piperidin-1-yl)cyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol 0443 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)--(4-oxo-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol (Example 15, 25 mg, 0.05 mmol) and piperidine (16 l, 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 (42 mL), then eluted with methanolic ammonia (2M, 22 mL). The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (20 mg, 70%). 1H NMR and analytical HPLC showed this to be a 1:1 mixture of trans:cis isomers. m/z (ES) 530 (M1). 0444 The following compounds were prepared as mixtures of cis- and trans-isomers from (RS)--(4-oxo-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol (Example 15) according to the method of Example 55, substituting a suitable amine for piperidine. 4

Cis-(RS)- & Trans-(RS)-Ex.NR2FormulaM.W.m/z (ES) (M 1).56

C28H33F6NO3545546 57

C31H37F6NO4601602 58

C28H33F6NO3545546 59

C31H33F6NO2565566 60

C31H34F6N2O2580581 61

C33H35F7N2O2624625 62

C27H31F6NO2515516 63

C24H27F6NO2475476 64

C30H38F6N2O2572573 65

C29H35F6NO2543544 66

C32H33F6NO2577578 67

C29H35F6NO2543544 68

C34H35F6N3O2S663664 69

C29H35F6NO2543544 70

C28H33F6NO2529530 71

C27H31F6NO2S547548 72

C29H35F6NO2543544 73

C29H33F6NO2541542 74

C26H29F6NO4533534 75

C33H42F6N2O2612613 76

C30H37F6NO2557558 77

C29H35F6NO3559560 78

C29H35F6NO3559560 79

C26H29F6NO2501502

0445 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). 5

Ex.NR2StereochemistryFormulaM.W.m/z (ES) (M 1).80

Cis-(RS)-C28H33F6NO2529530 81

Trans-(RS)-C28H33F6NO2529530 82

Cis-(RS)-C28H33F6NO3545546 83

Trans-(RS)-C28H33F6NO3545546 84

Trans-(RS)-C27H31F6NO3531532

EXAMPLE 85

Trans-(RS)--1-Phenyl-4-(phenylmethylamino)cyclohexylmethoxy-3,5-bis(trifluoromethyl)benzeneethanol Hydrochloride and

Cis-(RS)--1-Phenyl-4-(phenylmethylamino)cyclohexylmethoxy-3,5-bis(trifluoromethyl)benzeneethanol Hydrochloride 0446 Benzylamine (1.07 mL, 9.8 mmol) was added to a mixture of (RS)--(4-oxo-1-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 7820 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 CH2Cl2/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)--1-phenyl-4-(phenylmethylamino)cyclohexylmethoxy-3,5-bis(trifluoromethyl)benzeneethanol hydrochloride (1.3 g, 72%). 1H NMR (400 MHz, CD3OD) 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 (M1). 0447 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)--1-phenyl-4-(phenylmethylamino)cyclohexylmethoxy-3,5-bis(trifluoromethyl)benzeneethanol hydrochloride (50 mg, 3%). 1H NMR (400 MHz, CD3OD) 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 (M1).

EXAMPLE 86

Trans-(RS)--1-Phenyl-4-(phenylmethylamino)cyclohexylmethoxy-3,5-bis(trifluoromethyl)benzeneethanol 0448 A sample of trans-(RS)--1-phenyl-4-(phenylmethylamino)cyclohexylmethoxy-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). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound. 1H NMR (400 MHz, CD3OD) 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)--(4-Amino-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl) benzeneethanol 0449 A slurry of palladium on carbon (5%, 20 mg) in methanol (10 mL) was added to a solution of trans-(RS)--1-phenyl-4-(phenylmethylamino)cyclohexylmethoxy-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 Celite, washing with ethanol, and the solvent was evaporated under reduced pressure. The residue was crystallised from Et2O/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 (M1).

EXAMPLE 88

Cis-(RS)--(4-Amino-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol 0450 Prepared from cis-(RS)--1-phenyl-4-(phenylmethylamino)cyclohexylmethoxy-3,5-bis(trifluoromethyl)benzeneethanol hydrochloride (Example 85) according to the method of Example 87. m/z (ES) 462 (M1).

EXAMPLE 89

Trans-(RS)--(4-N-Methyl(phenylmethyl)amino-1-phenylcyclohexylmethoxy)-3,5-bis(trifluoromethyl)benzeneethanol 0451 Prepared from trans-(RS)--1-phenyl-4-(phenylmethylamino)cyclohexylmethoxy-3,5-bis(trifluoromethyl)benzeneethanol (Example 86) according to the method of Example 212. m/z (ES) 566 (M1).

EXAMPLE 90

Trans-(RS)--(4-Methylamino-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl) benzeneethanol 0452 Prepared from trans-(RS)--(4-N-methyl(phenylmethyl)amino-1-phenylcyclohexylmethoxy)-3,5-bis(trifluoromethyl)benzeneethanol (Example 89) according to the method of Example 87. m/z (ES) 476 (M1).

EXAMPLE 91

Trans-(RS)--(4-N-2-(Dimethylamino)acetylamino-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol 0453 Triethylamine (25 L, 0.18 mmol) was added to a mixture of trans-(RS)--(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 (33 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 (42 mL), then eluted with methanolic ammonia (2M, 22 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/Et2N (100:0:1 increasing to 90:10:1), to give the title compound as a colorless solid (12 mg, 36%). m/z (ES) 547 (M1). 0454 The following compounds were prepared from trans-(RS)--(4-amino-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol (Example 87) or trans-(RS)--(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. 6

Trans-(RS)-m/z (ES)Ex.NR2FormulaM.W.(M 1).92

C26H27F6N5O3571572 93

C30H34F6N6O3640641 94

C31H38F6N2O3600601 95

C29H36F6N2O3574575 96

C27H27F6N3O3555556 971

C29H34F6N2O3572573 98

C33H40F6N2O5658659 99

C25H27F6NO3503504 100

100

C27H29F6N5O3585586 101

101

C32H40F6N2O3614615 102

102

C28H29F6N3O3569570 103

103

C30H36F6N2O358658711-Pyrrolidineacetic acid: WO 9519344.

EXAMPLE 104

Trans-(RS,S)-N-(1--Hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohexyl)-2-pyrrolidinecarboxamide 0455 Trifluoroacetic acid (4 drops) was added to a solution of trans-(RS,S)-1,1-dimethylethyl 2-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenyl cyclohexylamino)carbonyl-1-pyrrolidinecarboxylate (Example 98, 5 mg, 8 mol) 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 (33 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 (42 mL), then eluted with methanolic ammonia (2M, 22 mL) and the solvent was evaporated under reduced pressure to give the tide compound as a colorless solid (3 mg, 70%). m/z (ES) 559 (M1).

EXAMPLE 105

Cis- and Trans-(RS)--(1-Phenyl-4-dimethylaminocyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol 0456 A slurry of palladium on carbon (5%, 20 mg) in methanol (10 mL) was added to a solution of (RS)--1-phenyl-4-(phenylmethylamino)cyclohexylmethoxy-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 Celite 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%). 1H NMR and analytical HPLC showed this to be a 1:2 mixture of trans- and cis-isomers. m/z (ES) 490 (M1).

EXAMPLE 106

Trans-(RS)--(4-Cyclopropylmethylamino-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol Hydrochloride 0457 Prepared from trans-(RS)--(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 (M1).

EXAMPLE 107

1,2-Dihydro-5-N-(1--Hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)methylaminomethyl-3H-1,2,4-triazol-3-one 0458 Methyl 2-(2-chloro-1-iminoethyl)hydrazinecarboxylic acid (J. Med. Chem. 1996, 39, 2907-2914; 8 mg, 0.05 mmol) was added to a mixture of trans-(RS)--(4-methylamino-1-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 (220 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 (M1).

EXAMPLE 108

Cis-(RS)-Methyl 1-(1--Hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)piperidine-4-carboxylate and

Trans-(RS)-Methyl 1-(1--Hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)piperidine-4-carboxylate 0459 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)--(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 Elut; 10 mL/500 mg). The cartridge was washed with methanol (42 mL), then eluted with methanolic ammonia (2M, 22 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 (MgSO4) 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: cis-(RS)-methyl 1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenyl cyclohex-4-yl)piperidine-4-carboxylate as a colorless solid (130 mg, 33%); 1H NMR (360 MHz, CD3OD) 1.45-1.94 (10H, 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 (M1); and trans-(RS)-methyl 1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenyl cyclohex-4-yl)piperidine-4-carboxylate as a colorless solid (97 mg, 25%); 1H NMR (360 MHz, CD3OD) 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, J 5.8 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); m/z (ES) 588 (M1).

EXAMPLE 109

Trans-(RS)-1-(1--Hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)piperidine-4-methanol 0460 A solution of diisobutylaluminium hydride (1.0M in toluene, 0.35 mL, 0.35 mmol) was added to a cooled (0 C.) solution of trans-(RS)-methyl 1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-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 tide compound as a colorless solid (40 mg, 84%). m/z (ES) 560 (M1).

EXAMPLE 110

Trans-(RS)-1-(1--Hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)piperidine-4-carboxylic Acid 0461 Potassium hydroxide (38 mg, 0.68 mmol) was added to a solution of trans-(RS)-methyl 1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-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 (25 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 (M1).

EXAMPLE 111

Trans-(RS)-1-(1--Hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)-,-dimethylpiperidine-4-methanol 0462 A solution of trans-(RS)-methyl 1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-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 (M1).

EXAMPLE 112

Trans-(RS)-1-(1--Hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxylmethyl-1-1-phenylcyclohex-4-yl)-N,N-dimethylpiperidine-4-carboxamide 0463 Prepared from trans-(RS)-1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-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 (M1).

EXAMPLE 113

(RS)-Methyl (1-(1--Hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-ylidene)acetate 0464 Methyl (triphenylphosphoranylidene)acetate (261 mg, 0.78 mmol) was added to a solution of (RS)--(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 4020 C. for 16 hours. Additional methyl (triphenylphosphoranylidene) acetate (217 mg, 0.65 mmol) was added and the mixture was stirred at 4020 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%). 1H NMR (360 MHz, CDCl3) 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), 7.48-7.41 (4H, m), 7.53 (2H, s), and 7.77 (1H, s).

EXAMPLE 114

Cis- and Trans-(RS)-Methyl (1-(1--Hydroxymethyl-3,5-bis(trifluoromethyl) phenylmethoxymethyl-1-phenylcyclohex-4-yl)acetate 0465 A slurry of palladium on carbon (5%, 10 mg) in methanol (1 mL) was added to a solution of (RS)-methyl (1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-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 Celite and the solvent was evaporated under reduced pressure to give the title compound as an oil (87 mg, 87%). 1H NMR and analytical HPLC showed this to be a 1:1 mixture of trans- and cis-isomers. 1H NMR (400 MHz, CDCl3) 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-(RS)-1-2-(1-(1--Hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)ethylpyrrolidine and

Trans-(RS)-1-2-(1-(1--Hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenylcyclohex-4-yl)ethylpyrrolidine 0466 A solution of diisobutylaluminium hydride (1.0M in hexane, 0.33 mL, 0.33 mmol) was added dropwise to a cooled (78 C.) solution of (RS)-methyl (1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-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 (42 mL), then eluted with methanolic ammonia (2M, 22 mL). The solvent was evaporated under reduced pressure. The residue was purified by MPLC column chromatography on silica gel, eluting with CH2Cl2/MeOH/Et3N (98:2:0.2) to give: cis-(RS)-1-2-(1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenyl cyclohex-4-yl)ethylpyrrolidine (13 mg, 14%) as a colorless solid; 1H NMR (360 MHz, CD3OD) 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 (M1); and tans-(RS)-1-2-(1-(1--hydroxymethyl-3,5-bis(trifluoromethyl)phenylmethoxymethyl-1-phenyl cyclohex-4-yl)ethylpyrrolidine (10 mg, 11%) as a colorless solid; 1H NMR (360 MHz, CD3OD) 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 (M1).

EXAMPLE 116

Trans-(RS)-Methyl -(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethoxy)-3,5-bis(trifluoromethyl)benzeneacetate 0467 Methyl -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 4020 C. for 1 hour. The mixture was cooled and further methyl -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 4020 C. for 0.5 hour. The mixture was cooled, divided into four portions and poured onto four SCX cartridges (Varian Bond Elut; 10 mL/500 mg). Each cartridge was washed with methanol (41 mL), then eluted with methanolic ammonia (2M, 41 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 (M1).

EXAMPLE 117

Trans-3,5-Bis(trifluoromethyl)phenylmethyl 4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylate 0468 Prepared from 3,5-bis(trifluoromethyl)phenylmethyl 4oxo-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 CH2Cl2/MeOH/Et3N(Aq.) (95:5:1). m/z (ES) 608 (M1).

EXAMPLE 118

Trans-(RS)-1-3,5-Bis(trifluoromethyl)phenylethyl 4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylate 0469 Oxalyl chloride (31 l, 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)--Methyl-3,5-bis(trifluoromethyl)benzenemethanol (93 mg, 0.36 mmol), triethylamine (59 l, 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 (M1).

EXAMPLE 119

Trans-(RS)-2-Hydroxy-2-3,5-bis(trifluoromethyl)phenylethyl 4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylate 0470 Oxalyl chloride (50 l) 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 (1 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 l, 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 (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 90:10:1) to give the title compound. m/z (ES) 638 (M1).

EXAMPLE 120

Trans-(RS)--(2-(Trimethylsilyl)ethoxymethoxymethyl)-3,5-bis(trifluoromethy)phenylmethyl 4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylate 0471 Prepared from trans-4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylic acid hydrochloride (Description 20) and (RS)-1-3,5-bis(trifluoromethyl)--2-(trimethylsilyl)ethoxymethoxymethylbenzenemethanol (Description 4) according to the method of Example 119. m/z (ES) 768 (M1).

EXAMPLE 121

Trans-(RS)--(Hydroxymethyl)-3,5-bis(trifluoromethyl)phenylmethyl 4-4-(4-Fluorophenyl)piperidin-1-yl-1-(phenyl)cyclohexanecarboxylate 0472 Trifluoroacetic acid (0.5 mL) was added to a solution of trans-(RS)--(2-(trimethylsilyl)ethoxymethoxymethyl)-3,5-bis(trifluoromethyl)phenylmethyl 4-4-(4-fluorophenyl)piperidin-1-yl-1-(phenyl)cyclohexanecarboxylate (Example 120, 37 mg, 48 mmol) 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 (M1).

EXAMPLE 122

Trans-(RS)-Methyl -(4-4-(Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylcarbonyloxy)-3,5-bis(trifluoromethyl)benzeneacetate 0473 Methyl -diazo-3,5-bis(trifluoromethyl)benzeneacetate (WO 95/21819, 200 mg, 0.64 mmol) in dichloromethane (2 mL) was added to a mixture of trans-4-4-(4-fluorophenyl)piperidin-1-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 -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 -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 CH2Cl2/MeOH (97.5:2.5) to give the title compound (18 mg, 11%). m/z (ES) 666 (M1).

EXAMPLE 123

Cis-4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl 3,5-Bis(trifluoromethyl)benzoate and

Trans-4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl 3,5-Bis(trifluoromethyl)benzoate 0474 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 l, 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 (320 mL). The combined organic fractions were washed with brine, dried (MgSO4) 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-phenylcyclohexylmethyl 3,5-bis(trifluoromethyl)benzoate (7.8 mg, 3%); 1H NMR (360 MHz, CDCl3) 1.69-1.93 (10H, 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 (M1); and trans-4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl 3,5-bis(trifluoromethyl)benzoate (9 mg, 4%); 1H NMR (360 MHz, CDCl3) 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 (M1).

EXAMPLE 124

Cis-1-Phenyl-4-(4phenylpiperidin-1-yl)-N-3,5-bis(trifluoromethyl)phenylmethylcyclohexanecarboxamide and

Trans-1-Phenyl-4-(4-phenylpiperidin-1-yl)-N-3,5-bis(trifluoromethyl)phenylmethylcyclohexanecarboxamide 0475 Prepared as a mixture of cis- and trans-isomers from 4-oxo-1-phenyl-N-3,5-bis(trifluoromethyl)phenylmethylcyclohexanecarboxamide (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-1-phenyl-4-(4-phenylpiperidin-1-yl)-N-3,5-bis(trifluoromethyl)phenylmethylcyclohexanecarboxamide; 1H NMR (360 MHz, CD3OD) 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 (M1); trans-1-phenyl-4-(4-phenylpiperidin-1-yl)-N-3,5-bis(trifluoromethyl)phenylmethylcyclohexancarboxamide; 1H NMR (360 MHz, CD3OD) 7.74 (1H, s) 7.55 (2H, s), 7.53-7.14 (10H, 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 (M1). 0476 The following compounds were prepared as mixtures of cis- and trans-isomers from (RS)-4-oxo-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (Example 18) according to the method of Example 55, substituting a suitable amine for piperidine. 7

104

Cis-(RS) & Trans-(RS)Ex.NR2FormulaM.W.m/z (ES) (M 1).125

105

C24H26F6N2O472473 126

106

C27H30F6N2O512513 127

107

C28H32F6N2O2542543 128

108

C27H30F6N2O512513 129

109

C31H36F6N2O3598599 130

110

C30H34F6N2O3584585 131

111

C31H33F6N3O577578 132

112

C27H30F6N2O2528529 133

113

C28H32F6N2O526527 134

114

C35H38F6N2O2632633 135

115

C33H41F6N3O609610 136

116

C28H31F6N3O2555556 137

117

C33H34F7N3O621622 138

118

C30H37F6N3O569570 139

119

C29H34F6N2O540541 140

120

C32H32F6N2O574575 141

121

C29H34F6N2O540541 142

122

C34H34F6N4OS660661 143

123

C29H34F6N2O540541 144

124

C28H32F6N2O526527 145

125

C27H30F6N2OS544545 146

126

C29H34F6N2O540541 147

127

C26H28F6N2O3530531 148

128

C33H41F6N3O609610 149

129

C30H36F6N2O554555 150

130

C29H34F6N2O2556557 151

131

C29H34F6N2O2556557 152

132

C26H28F6N2O498499

0477 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)--methyl-3,5-bis(trifluoromethyl)benzenemethanamine hydrochloride. 8

133

Trans-m/z (ES)Ex.RFormulaM.W.(M 1).153

134

C32H37FN2O2500501 1541

135

C33H39FN2O2514515 1552

136

C35H37F7N2O6346351(RS)-2-Methoxy-a-methylbenzenemethanamine Hydrochloride: Description 6. 2(RS)--Ethyl-3,5-bis(trifluoromethyl)benzenemethanamine Hydrochloride: Description 7.

0478 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. 9

137

Trans-m/z (ES)Ex.RFormulaM.W.(M 1).1561

138

C35H37F7N2O634635 1572

139

C35H35F7N2O36646651,-Dimethyl-3,5-bis(trifluoromethyl)benzenemethanamine Hydrochloride: Description 11. 2(RS)-Methyl -Amino-3,5-bis(trifluoromethyl)benzeneacetate Hydrochloride: Description 12.

EXAMPLE 158

Trans-4-4-(4-Fluorophenyl)piperidin-1-yl-N-3-(methoxy)phenylmethyl-1-phenylcyclohexanecarboxamide 0479 Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (40 mg, 0.16 mmol) was added to a solution of trans-4-4-(4fluorophenyl)piperdin-1-yl-1-phenylcyclohexanecarboxylic acid hydrochloride (Description 20, 50 mg, 0.13 mmol) and triethylamine (91 l, 0.65 mmol) in dichloromethane (5 mL) and the mixture was stirred at room temperature for 10 minutes. 3-(Methoxy)benzenemethanamine (18 l, 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 (220 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 (25 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.) (90:4:0.4), to give the title compound (38 mg, 58%). m/z (ES) 501 (M1). 0480 The following compounds were prepared from trans-4-4-(4-flourophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylic acid (Description 20) according to the method of Examples 158, substituting a suitable amine for 3-(methoxy)benzenemethanamine. 10

140

Trans-m/z (ES)Ex.XFormulaM.W.(M 1).1592-ClC31H34ClFN2O5045055065071603-ClC31H34ClFN2O5045055065071612,3-Cl2C31H33Cl2FN2O5385395405415425431622,4-Cl2C31H33Cl2FN2O5385395405415425431633-Cl-4-FC31H33ClF2N2O5225235245251642,4-F2C31H33F3N2O5065071652,6-F2C31H33F3N2O5065071663,5-F2C31H33F3N2O5065071672,3-Me2C33H39FN2O4984991682-CF3C32H34F4N2O5385391693-CF3C32H34F4N2O5385391704-CF3C32H34F4N2O5385391712,4-(OMe)2C33H39FN2O35305311723,5-(OMe)2C33H39FN2O35305311732,4,6-(OMe)3C34H41FN2O45605611742,6-(OMe)2C33H39FN2O35305311753,4-(OMe)2C33H39FN2O35305311762,5-(OMe)2C33H39FN2O3530531

EXAMPLE 177

Trans-(RS)-4-4-(4-Fluorophenyl)piperidin-1-yl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0481 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)--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 CH2Cl2/MeOH/NH3(Aq.) (90:10:1) to give the title compound as a colorless solid (145 mg, 97%). m/z (ES) 621 (M1).

EXAMPLE 178

Trans-(R)-4-4(4-Fluorophenyl)piperidin-1-yl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide and

Trans-(S)-4-4-(4-Fluorophenyl)piperidin-1-yl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0482 The mixture of enantiomers of Example 177 was separated by chiral HPLC (Chirobiotic V; MeOH/Et3N/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)phenylethyl-1-phenylcyclohexanecarboxamide; m/z (ES) 621 (M1); and trans-(S)-4-4-(4-fluorophenyl)piperidin-1-yl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; m/z (ES) 621 (M1).

EXAMPLE 179

Cis-(RS)-4-4-(4-Fluorophenyl)piperidin-1-yl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide Hydrochloride 0483 Prepared from cis-4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexanecarboxylic acid (Description 19) and (RS)--methyl-3,5-bis(trifluoromethyl)benzenemethanamine hydrochloride (Description 5) according to the method of Example 177. m/z (ES) 621 (M1).

EXAMPLE 180

Trans-N-Methyl-1-phenyl-4-(4-phenylpiperidin-1-yl)-N-3,5-bis(trifluoromethyl)phenylmethylcyclohexanecarboxamide 0484 Prepared from 1-phenyl-4-(4-phenylpiperidin-1-yl)-N-3,5-bis(trifluoromethyl)phenylmethylcyclohexanecarboxamide (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 (M1).

EXAMPLE 181

Trans-(RS)-4-4-(4-Fluorophenyl)piperidin-1-yl-N-methyl-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0485 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)phenylethyl-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 l, 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; 25020 mm; 65% MeCN in 0.1% TFA-H2O; 20 mL/min; 210 nm) to give the title compound as a colorless solid, (20 mg, 39%). m/z (ES) 635 (M1).

EXAMPLE 182

Trans-(RS)-4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenyl-N-2-hydroxy-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide 0486 Lithium borohydride (12 mg, 0.55 mmol) was added to a solution of trans-(RS)-methyl -(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylcarbonylamino)-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 (230 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 CH2Cl2/MeOH/NH3(Aq.) (95:5:0.5) to give the title compound (41 mg, 43%). m/z (ES) 637 (M1).

EXAMPLE 183

Trans-(RS)-4-(1,4-Dioxa-8-azaspiro4.5decane-8-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide 0487 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-azaspiro4.5decane (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)--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 CH2Cl2/MeOH/NH3(Aq.) (96:4:0.4) to give the title compound (120 mg, 17%). m/z (ES) 585 (M1).

EXAMPLE 184

Trans-(RS)-4-(4-Oxopiperidin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide 0488 Prepared from trans-4-(4-oxopiperidin-1-yl)-1-phenylcyclohexanecarboxylic acid hydrochloride (Description 24) and (RS)--methyl-3,5-bis(trifluoromethyl) benzenemethanamine hydrochloride (Description 5) according to the method of Example 158. m/z (ES) 541 (M1).

EXAMPLE 185

Trans-(RS)-4-(4-Hydroxypiperidin-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide 0489 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)phenylethylcyclohexanecarboxamide (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 (215 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 (M1).

EXAMPLE 186

Trans-(RS)-4-(But-3-enylamino)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide 0490 (N-Ethylethanaminato)trifluorosulfur (45 l, 59 mg, 0.36 mmol) was added dropwise to a cooled (6020 C.) solution of trans-(RS)-4-(4-hydroxypiperidin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (Example 185, 90 mg, 0.16 mmol) in ethyl acetate (5 mL) and the mixture was stirred at 6020 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 (220 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 (M1).

EXAMPLE 187

Trans-(RS)-4-(4-Hydroxy-4-phenylpiperidin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide 0491 Phenylmagnesium bromide (1M in tetrahydrofuran, 0.3 mL, 0.3 mmol) was added dropwise to a cooled (020 C.) solution of trans-(RS)-4-(4-oxopiperidin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (Example 184, 53 mg, 0.1 mmol) in tetrahydrofuran (2 mL) and the mixture was stirred at 020 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 (210 mL). 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 (41 mL), then eluted with methanolic ammonia (2M, 41 mL). The solvent was evaporated under reduced pressure to give the title compound (45 mg, 75%). m/z (ES) 619 (M1). 0492 The following compounds were prepared from trans-(RS)-4-(4-oxopiperidin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (Example 184) according to the method of Example 187, substituting a suitable Grignard reagent for phenylmagnesium bromide. 11

141

Trans-(RS)m/z (ES)Ex.NR2FormulaM.W.(M 1).188

142

C29H34F6N2O2556557 189

143

C30H32F6N2O2566567 190

144

C35H38F6N2O2632633 191

145

C31H36F6N2O2582583 192

146

C36H36F6N2O2642643

EXAMPLE 193

Trans-(RS)-4-(1,2,3,6-Tetrahydro-4-phenylpyridin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide 0493 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)phenylethylcyclohexanecarboxamide (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 (220 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 (41 mL), then eluted with methanolic ammonia (2M, 41 mL). The solvent was evaporated under reduced pressure to give the title compound (24 mg, 94%). m/z (ES) 601 (M1).

EXAMPLE 194

Trans-(RS)-4-(1,2,3,6-Tetrahydro-4-methylpyridin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide 0494 Prepared from trans-(RS)-4-(4-hydroxy-4-methylpiperidin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (Example 188) according to the method of Example 193. m/z (ES) 539 (M1).

EXAMPLE 195

Trans-(RS)-4-(4-Hydroxy-4-phenylethyl)piperidin-1-yl)-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide 0495 Palladium on carbon (5%, 5 mg) was added to a solution of trans-(RS)-4-(4-hydroxy-4-(phenylethynyl)piperidin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (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 Celite 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 (41 mL), then eluted with methanolic ammonia (2M, 41 mL). The solvent was evaporated under reduced pressure to give the tide compound (20 mg, 86%). m/z (ES) 647 (M1). 0496 The following compounds were prepared from trans-(RS)-4-(4-oxopiperidin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (Example 184) according to the method of Example 55, substituting a suitable amine for piperidine. 12

147

Trans-(RS)m/z (ES)Ex.NR2FormulaM.W.(M 1).196

148

C35H46F6N4O652653 197

149

C34H43F6N3O623624 198

150

C37H41F6N3O657658 199

151

C34H43F6N3O623624 200

152

C39H43F6N5OS743744 201

153

C34H43F6N3O623624 202

154

C33H41F6N3O609610 203

155

C32H39F6N3OS627628 204

156

C34H41F6N3O621622 205

157

C31H37F6N3O3613614 206

158

C38H50F6N4O692693 207

159

C35H45F6N3O637638 208

160

C34H43F6N3O2639640 209

161

C34H43F6N3O2639640 210

162

C31H37F6N3O581582

EXAMPLE 211

Cis-(RS)-4-(Phenylmethyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide and

Trans-(RS)-4-(Phenylmethyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0497 Prepared from (RS)-4-oxo-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (Example 18) and benzylamine according to the method of Example 45: Cis-(RS)-4-(phenylmethyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 1H NMR (400 MHz, CDCl3) 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 (M1); Trans-(RS)-4-(phenylmethyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide; 1H NMR (400 MHz, CDCl3) 7.70 (s, 1H), 7.50-7.42 (6H, m), 7.34-7.21 (6H, m), 5.00 (1H, q, J 7.0 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 (M1).

EXAMPLE 212

Trans-(RS)-4-N-Methyl(phenylmethyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0498 Sodium cyanoborohydride (275 mg, 4.38 mmol) was added to a solution of trans-(RS)-4-(phenylmethyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide (Example 211, 1.2 g, 2.19 mmol) and aqueous formaldehyde (37%, 820 l, 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 (220 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 (M1).

EXAMPLE 213

Trans-(RS)-4-Methylamino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0499 Prepared from trans-(RS)-4-N-methyl(phenylmethyl)amino-N-1-3,5-bis(trifiuoromethyl) phenylethyl-1-phenylcyclohexanecarboxamide (Example 212) according to the method of Example 229. m/z (ES) 473 (M1).

EXAMPLE 214

Trans-(RS)-4-Amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0500 Triphenylphosphine (1.0 g, 3.82 mmol) was added to a solution of trans-(RS)-4-azido-N-1-3,5-bis(trifuoromethyl)phenylethyl-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 (M1), 442 (M1-NH3).

EXAMPLE 215

Trans-(RS)-4-(Dimethylamino)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0501 Palladium hydroxide (50 mg) was added to a solution of trans-(RS)-4-amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-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 (M1).

EXAMPLE 216

Trans-(RS)-4-4-(Phenylbutyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide Hydrochloride 0502 Prepared from trans-(RS)-4-amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide (Example 214) and benzenebutanal (Description 17) according to the method of Example 55. m/z (ES) 591 (M1). 0503 The following compounds were prepared from trans-(RS)-4-amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide (Example 214) according to the method of Example 45, substituting a suitable aldehyde or ketone for benzylamine. 13

163

Trans-(RS)m/z (ES)Ex.NR2FormulaM.W.(M 1).217

164

C26H30F6N2O500501 218

165

C28H32F6N2O526527 219

166

C29H34F6N2O540541 220

167

C31H36F6N2O566567 221

168

C37H48F6N2O650651 222

169

C29H36F6N2O542543 223

170

C30H30F6N2O548549

EXAMPLE 224

Trans-(RS)-4-N-Methyl-4-(phenylbutyl)amino-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0504 Prepared from trans-(RS)-4-4-(phenylbutyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide Hydrochloride (Example 216) according to the method of Example 215. m/z (ES) 605 (M1).

EXAMPLE 225

Trans-(RS)-4-Acetylamino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0505 Acetic anhydride (0.1 mL, 1.1 mmol) was added to a solution of trans-(RS)-4-amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-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 (M1).

EXAMPLE 226

Trans-(RS)-4-(1-Oxo-4-phenylbutyl)amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0506 Prepared from trans-(RS)-4-amino-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide (Example 214) and benzenebutanoic acid (27 mg, 0.16 mmol) according to the method of Example 158. m/z (ES) 605 (M1).

EXAMPLE 227

Cis- and Trans-(RS)-1-Dimethylethyl 4-1-(1-3,5-Bis(trifluoromethyl)phenylethylaminocarbonyl)-1-phenylcyclohexy-4-yl-1-piperazinecarboxylate 0507 Prepared as a mixture of cis- and trans-isomers from (RS)-4-oxo-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (Example 18) and 1,1-dimethylethyl 1-piperazinecarboxylate according to the method of Example 45. m/z (ES) 628 (M1).

EXAMPLE 228

Trans-(RS)-4-4-(Phenylmethyl)piperazin-1-yl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0508 Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.56 g, 6.12 mmol) was added to a mixture of trans-4-4-(phenylmethyl)piperazin-1-yl-1-phenylcyclohexanecarboxylic acid hydrochloride (Description 25, 1.92 g, 5.1 mnol) and triethylamine (3.55 mL, 25.5 mmol) in dichloromethane (200 mL) and the mixture was stirred at room temperature for 15 minutes. (RS)--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 (MgSO4) 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 (M1).

EXAMPLE 229

Trans-(RS)-4-(Piperazin-1-yl)-N-3,5-bis(trifluoromethylphenylethyl-1-phenylcyclohexanecarboxamide 0509 Palladium hydroxide on carbon (20%, 20 mg) was added to a mixture of trans-(RS)-4-4-(phenylmethyl)piperazin-1-yl-N-1-3,5-bis(trifluoromethyl) phenylethyl-1-phenylcyclohexanecarboxamide (Example 228, 700 mg, 1.3 mmol), hydrochloric acid (1M, 2.6 mL) and acetic acid (5 mL) in ethyl acetate (50 mL) and the mixture was shaken under an atmosphere of hydrogen (50 psi) 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/MeOH/NH3(Aq.) (90:10:1), to give the title compound. m/z (ES) 528 (M1). 0510 The following compounds were prepared from trans-(RS)-4-(piperazin-1-yl)-N-1-3,5-bis(trifluoromethyl) phenylethyl-1-phenylcyclohexanecarboxamide (Example 229) according to the method of Example 45, substituting a suitable aldehyde or ketone for (RS)--(4-oxo-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol. 14

171

Trans-(RS)m/z (ES)Ex.RFormulaM.W.(M 1).230

172

C32H35F6N3O2607608 231

173

C31H37F6N3O581582 232

174

C30H37F6N3O569570 233

175

C32H39F6N3O595596 234

176

C36H35F12N3O753754 235

177

C35H39F6N3O2647648 236

178

C34H43F6N3O623624 237

179

C33H43F6N3O611612 238

180

C31H39F6N3O583584 239

181

C32H35F6N3OS623624 240

182

C32H35F6N3OS623624 241

183

C35H39F6N3O631632 242

184

C31H34F6N4OS624625 243

185

C33H36F6N4O618619 244

186

C33H36F6N4O618619 245

187

C33H36F6N4O618619

EXAMPLE 246

Trans-(RS)-4-(4Methylpiperazin-1-yl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0511 Prepared from trans-(RS)-4-(piperazin-1-yl)-N-1-3,5-bis(trifiuoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide (Example 229) according to the method of Example 215. m/z (ES) 542 (M1).

EXAMPLE 247

Trans-(RS)-4-(4-Acetylpiperazin-1-yl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0512 Acetyl chloride (100 l) was added to a solution of trans-(RS)-4-(piperazin-1-yl)-N-1-3,5-bis(trifluoromethyl) phenylethyl-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 (M1). 0513 The following compounds were prepared from trans-(RS)-4-(piperazin-1-yl)-N-1-3,5-bis(trifluoromethyl) phenylethyl-1-phenylcyclohexanecarboxamide (Example 229) according to the method of Example 247, substituting a suitable acid chloride for acetyl chloride. 15

188

Trans-(RS)m/z (ES)Ex.RFormulaM.W.(M 1).248

189

C30H35F6N3O2583584 249

190

C3H37F6N3O2597598 250

191

C34H35F6N3O2631632 251

192

C34H41F6N3O2637638 252

193

C31H35F6N3O2595596 253

194

C35H37F6N3O2645646

0514 The following compounds were prepared from trans-(RS)-4-(piperazin-1-yl)-N-1-3,5-bis(trifluoromethyl) phenylethyl-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. 16

195

Trans-(RS)m/z (ES)Ex.RFormulaM.W.(M 1).254

196

C31H37F6N3O2597598 255

197

C36H45F6N3O2665666 256

198

C35H43F6N3O2651652 257

199

C32H37F6N3O2609610

EXAMPLE 258

Trans-(RS)-4-(Aminomethyl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0515 Raney nickel (10 mg) was added to a solution of trans-(RS)-4-cyano-N-1-3,5-bis(trifluoromethyl) phenylethyl-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/NH3(Aq.) (95:5:0.5), to give the title compound. m/z (ES) 473 (M1).

EXAMPLE 259

Trans-(RS)-4-(N,N-Dimethylaminomethyl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0516 Prepared from trans-(RS)-4-(aminomethyl)-N-1-3,5-bis(trifluoromethyl) phenylethyl-1-phenylcyclohexanecarboxamide (Example 258) according to the method of Example 214. m/z (ES) 501 (M1).

EXAMPLE 260

Trans-(RS)-4-(Piperidin-1-yl)methyl-N-1-3,5-bis(trifluoromethyl)phenylethy-1-phenylcyclohexanecarboxamide 0517 1,5-Dibromopentane (14 l, 0.106 mmol)was added to a mixture of trans-(RS)-4-(aminomethyl)-N-1-3,5-bis(trifluoromethyl) phenylethyl-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 10020 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/MeOH/NH3(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 (25 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 (M1).

EXAMPLE 261

Trans-(RS)-4-(Morpholin-4-yl)methyl-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0518 Prepared from trans-(RS)-4-(aminomethyl)-N-1-3,5-bis(trifluoromethyl) phenylethyl-1-phenylcyclohexanecarboxamide (Example 258) according to the method of Example 260, substituting bis(2-bromoethyl)ether for 1,5-dibromopentane. m/z (ES) 543 (M1).

EXAMPLE 262

Trans-(RS)-4-(N-2-(Dimethylamino)acetylaminomethyl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0519 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 l, 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) phenylethyl-1-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 (225 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 CH2Cl2/MeOH/NH3(Aq.) (95:5:0.5) to give the title compound (50 mg, 85%). m/z (ES) 558 (M1).

EXAMPLE 263

Trans-(RS)-4-(1H-1,2,3-Triazol-1-yl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0520 (Trimethylsilyl)acetylene (0.3 mL, 2.0 mmol) was added to a solution of trans-(RS)-4-azido-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide (Description 28, 50 mg, 0.1 mmol) in toluene and the mixture was stirred at 8020 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 l, 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 (M1), 442 (M1-C2H3N3).

EXAMPLE 264

Trans-N-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexlmethyl)-3,5-bis(trifluoromethyl)benzenecarboxamide 0521 3,5-Bis(trifluoromethyl)benzoyl chloride (54 l, 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 mL/500 mg). The cartridge was washed with methanol (25 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 (M1).

EXAMPLE 265

Trans-N-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl)-2-(methoxy)benzenemethanamine 0522 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 l, 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 (220 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 Elut; 10 mL/500 mg). The cartridge was washed with methanol (25 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 (M1).

EXAMPLE 266

Cis-N-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl)-3,5-bis(trifluoromethyl)benzenemethanamine and

Trans-N-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl)-3,5-bis(trifluoromethyl)benzenemethanamine 0523 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 (MgSO4) 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 (210 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; 25010.0 mm id; 34% MeCN in 0.1% TFA-H2O; 5 ml/min; 210 nm) to give: cis-N-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenyl cyclohexylmethyl)-3,5-bis(trifluoromethyl)benzenemethanamine; 1H NMR (400 MHz, CDCl3) 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 (M1); trans-N-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenyl cyclohexylmethyl)-3,5-bis(trifluoromethyl)benzenemethanamine; 1H NMR (400 MHz, CDCl3) 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 (M1).

EXAMPLE 267

Trans-N-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl)-N-methyl-3,5-bis(trifluoromethyl)benzenemethanamine 0524 Formaldehyde (37% w/v in water, 2 mL), palladium hydroxide on carbon (20%, 10 mg) and acetic acid (24 l, 0.42 mmol) were added to a solution of trans-N-(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl)-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 Elu; 10 ml/500 mg). The cartridge was washed with methanol (25 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 (M1).

EXAMPLE 268

Cis- and Trans-N-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl)-N-3,5-bis(trifluoromethyl)phenylmethylacetamide 0525 Prepared as a mixture of cis- and trans-isomers from N-(4-oxo-1-phenylcyclohexyl)methyl-N-3,5-bis(trifluoromethyl)phenylmethylacetamide (Example 21) and 4-(4-fluorophenyl)piperidine (Description 16) according to the method of Example 55. m/z (ES) 635 (M1).

EXAMPLE 269

Trans-(RS)-N-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethyl)--methyl-3,5-bis(trifluoromethyl)benzenemethanamine 0526 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)phenylethyl-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 (MgSO4), 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). 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 (M1).

EXAMPLE 270

Trans-(RS)--(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethylamino)-3,5-bis(trifluoromethyl)benzeneethanol and

Trans-(RS)--(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethylamino)-3,5-bis(trifluoromethyl)benzeneethanamine 0527 A solution of trans-(RS)-methyl -(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylcarbonylamino)-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 (41 mL), then eluted with methanolic ammonia (2M, 41 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 5020 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 (Na2SO4) 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 6020 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 (Na2SO4) 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 CH2Cl2/MeOH/NH3(Aq.) (95:5:0.5) to give: trans-(RS)--(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethylamino)-3,5-bis(trifluoromethyl)benzeneethanol (25 mg, 16%); 1H NMR (400 MHz, CDCl3) 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 (M1); and trans-(RS)--(4-4-(4-fluorophenyl)piperidin-1-yl-1-phenylcyclohexylmethylamino)-3,5-bis(trifluoromethyl)benzeneethanamine; 1H NMR (360 MHz, CDCl3) 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 (M1).

EXAMPLE 271

Cis- and Trans-(E)-4-(4-Fluorophenyl)-1-(4-phenyl-4-3,5-bis(trifluoromethyl)phenyl-prop-1-enylcyclohexyl)piperidine 0528 Prepared as a mixture of cis- and trans-isomers from (E)-4-phenyl-4-3-3,5-bis(trifluoromethyl)phenylprop-1-enylcyclohexanone Example 22) and 4-(4-fluorophenyl)piperidine (Description 16) according to the method of Example 45. m/z (ES) 590 (M1).

EXAMPLE 272

Cis- and Trans-(E)-4-(4-Fluorophenyl)-1-(4-phenyl-4-3-3,5-bis(trifluoromethyl)phenylpropylcyclohexyl)piperidine 0529 Prepared as a mixture of cis- and trans-isomers from (E)-4-(4-fluorophenyl)-1-(4-phenyl-4-3-3,5-bis(trifluoromethyl)phenylprop-1-enylcyclohexyl) piperidine (mixture of cis- and trans-isomers, Example 271) according to the method of Description 16. m/z (ES) 592 (M1).

EXAMPLE 273

Cis- and Trans-(RS)-4-(4-Fluorophenyl)-1-(4-2-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexyl)piperidine 0530 Prepared as a mixture of cis- and trans-isomers from (RS)-4-2-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexanone (Example 25) and 4-(4-fluorophenyl)piperidine (Description 16) according to the method of Example 45. m/z (ES) 608 (M1).

EXAMPLE 274

Cis- and Trans-(RS)-4-(4-Fluorophenyl)-1-(4-2-oxo-3-3,5-bis(trifluoromethyl)phenylpropylphenylcyclohexyl)piperidine 0531 Prepared as a mixture of cis- and trans-isomers from (RS)-4-(4-fluorophenyl)-1-(4-2-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexyl)piperidine (mixture of cis- and trans-isomers, Example 273) according to the method of Description 17. m/z (ES) 606 (M1).

EXAMPLE 275

1-(1,4-Dioxa-8-phenylspiro4.5decan-8-yl)methoxymethyl-3,5-bis(trifluoromethyl) benzene 0532 Prepared from 8-phenyl-1,4-dioxaspiro4.5decane-8-methanol (J. Org. Chem. 1974, 39, 2311-2313) and 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene according to the method of Example 1. 1H NMR (360 MHz, CDCl3) 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). C24H24F6O3 requires C, 60.76; H, 5.09; found C, 61.15; H, 5.07.

EXAMPLE 276

1-(4-Oxo-1-phenylcyclohexylmethoxymethyl)-3,5-bis(trifluoromethyl)benzene 0533 Pyridinium p-toluenesulfonate (100 mg, 0.4 mmol) was added to a solution of 1-(1,4-dioxa-8-phenylspiro4.5decan-8-yl)methoxymethyl-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%). 1H NMR (360 MHz, CDCl3) 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) C22H20F6O2 requires C, 61.39, H, 4.68; found C, 60.92; H, 4.51.

EXAMPLE 277

Cis-1-(4-4-(4-Fluorophenyl)piperdin-1-yl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene and

Trans-1-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexanemethoxymethyl-3,5-bis(trifluoromethyl)benzene 0534 Prepared from 1-(4-oxo-1-phenylcyclohexylmethoxymethyl)-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-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene; 1H NMR (400 MHz, CDCl3) 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), trans-1-(4-4-(4-Fluorophenyl)piperidin-1-yl-1-phenylcyclohexanemethoxymethyl)-3,5-bis(trifluoromethyl)benzene; 1H NMR (400 MHz, CDCl3) 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 (M1).

EXAMPLE 278

(RS)-4-Methylene-1-phenyl-N-1-35-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide 0535 Methyltriphenylphosphonium bromide (1.71 g, 4.8 mmol) was dried azeotropically by evaporating toluene (320 mL) under reduced pressure, suspended in tetrahydrofan (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-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (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 (350 mL). The combined organic fractions were washed with water (350 mL) and brine (50 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2, to give the title compound as a colorless solid (0.67 g, 73%); 1H NMR (400 MHz, CD3OD) 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-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide and

Trans-(RS)-4-(Hydroxymethyl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide 0536 9-Borabicyclo3.3.1nonane (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)phenylethylcyclohexanecarboxamide (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 5020 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 (320 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-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide (113 mg, 60%), 1H NMR (400 MHz, CD3OD) 7.76 (1H, s), 7.71 (2H, s), 7.31 (2H, d, J 7.5 Hz), 7.25 (2H, t, J 7.5 Hz), 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 (2, m); and trans-(RS)-4-(hydroxymethyl)-N-1-3,5-bis(trifluoromethyl)phenylethyl-1-phenylcyclohexanecarboxamide (34 mg, 18%), 1H NMR (400 MHz, CD3OD) 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, J 7.0 Hz), 3.29 (2H, d, J 6.6 Hz), 2.68 (1H, m), 1.90 (2H, m), (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). 0537 The following compound was prepared from trans-(RS)--(4-methylamino-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol (Example 90) and 1H-imidazole-4-acetic acid according to the method of Example 91. 17

200

m/z (ES)Ex.ABNR2StereochemistryFormulaM.W.(M 1).280CH2OHH

201

Trans-(RS)-C29H31F6N3O3583584

0538 The following compounds were prepared according to the method of Example 45, substituting a suitable ketone for (RS)--(4-oxo-1-phenylcyclohexyl)methoxy-3,5-bis(trifluoromethyl)benzeneethanol, and a suitable amine for benzylamine, followed by separation of diastereoisomers by chromatography on silica gel. 18

202

m/z (ES)Ex.ABNR2StereochemistryFormulaM.W.(M 1).281HH

203

Cis-(RS)-C30H35F6NO2555556 282HH

204

Trans-(RS)-C30H35F6NO2555556 283MeH

205

Trans-(RS)-C29H33F8NO563564 284MeH

206

Cis-(RS)-C31H37F6NO2569570 285MeH

207

Trans-(RS)-C31H37F6NO2569570 286MeH

208

Trans-(RS)-C27H30F6N2O2528529 287MeH

209

Trans-(RS)-C33H34F6N2O2604605 288CH2OHH

210

Cis-(RS)-C31H37F6NO3585586 289CH2OHH

211

Trans-(RS)-C31H37F6NO3585586

0539 The following compounds were prepared from trans-(RS)-4-(4-oxopiperidin-1-yl)-1-phenyl-N-1-3,5-bis(trifluoromethyl)phenylethylcyclohexanecarboxamide (Example 184) according to the method of Example 187, substituting a suitable Grignard reagent for phenylmagnesium bromide. 19

212

m/z (ES)Ex.ABNR2StereochemistryFormulaM.W.(M 1).290MeH

213

Trans-(RS)-C32H40F6N2O2598599 291MeH

214

Trans-(RS)-C31H38F6N2O2584585 292MeH

215

Trans-(RS)-C32H40F6N2O2598599 293MeH

216

Trans-(RS)-C30H36F6N2O2570571

EXAMPLE 294

Cis-(RS)- and Trans-(RS)-1-(4-2-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexyl)piperidine 0540 Prepared as a 1:1 mixture of diastereoisomers from (RS)-4-2-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexanone (Example 25) and piperidine according to the method of Example 45. 1H NMR (400 MHz, CDCl3) 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 (M1).

EXAMPLE 295

(RS)-1-(8-Phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-1-ol 0541 Potassium carbonate (1.75 g, 12.7 mmol) was added to a solution of (RS)-1-(8-phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-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 (250 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (334 mg, 88%). 1H NMR (400 MHz, CDCl3) 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)phenylpropyl-4-phenylcyclohexanone 0542 Prepared from (RS)-1-(8-phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-1-ol (Example 295) according to the method of Example 10. 1H NMR (400 MHz, CDCl3) 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)phenylpropyl-4-phenylcyclohexyl)piperidine 0543 Prepared from (RS)-4-1-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexanone (Example 296) and piperidine according to the method of Example 45, followed by separation of diastereoisomers by chromatography on silica gel. 1H NMR (400 MHz, CDCl3) 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 (M1).

EXAMPLE 298

Cis-(RS)-4-(4-Fluorophenyl)-1-(4-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexyl)piperidine; and

Trans-(RS)-4-(4-Fluorophenyl)-1-(4-1-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexyl)piperidine 0544 Prepared from (RS)-4-1-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-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 CH2Cl2/MeOH/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)phenylpropyl-4-phenylcyclohexyl)piperidine; 1H NMR (400 MHz, CDCl3) 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, J 9 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 (M1); and. trans-(RS)-4-(4-fluorophenyl)-1-(4-1-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexyl)piperidine; 1H NMR (400 MHz, CDCl3) 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 (M1).

EXAMPLE 299

Trans-4-(4-Fluorophenyl)-1-(4-1-oxo-3-3,5-bis(trifluoromethyl)phenylpropyl-4-phenylcyclohexyl)piperidine 0545 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (28 mg, 0.066 mmol) was added to a solution of trans-(RS)-4-(4-fluorophenyl)-1-(4-1-hydroxy-3-3,5-bis(trifluoromethyl)phenylpropyl-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 Elut; 10 mL/500 mg). The cartridge was washed with methanol (42 mL), then eluted with methanolic ammonia (2M, 22 mL). The solvent was evaporated under reduced pressure to give the title compound (13.1 mg, 94%). 1H NMR (400 MHz, CDCl3) 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 (M1).

EXAMPLE 300

(RS)-1-(4-Oxo-1-phenylcyclohexyl)-3-3,5-bis(trifluoromethyl)phenylpropan-2-yl Ethanoate 0546 Prepared from (RS)-1-(8-phenyl-1,4-dioxaspiro4.5decan-8-yl)-3-3,5-bis(trifluoromethyl)phenylpropan-2-yl ethanoate (Example 23) according to the method of Example 10. 1H NMR (400 MHz, CDCl3) 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-phenylcyclohexyl-3-3,5-bis(trifluoromethyl)phenylpropan-2-yl Ethanoate 0547 Prepared from (RS)-1-(4-oxo-1-phenylcyclohexyl)-3-3,5-bis(trifluoromethyl)phenylpropan-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 CH2Cl2/MeOH (95:5). 1H NMR (400 MHz, CDCl3) 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 (M1).