MXPA06009198A - Therapeutic amide derivatives - Google Patents

Abstract

The present invention relates to compounds of the formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein:A and B independently represent CH2 or O, with the proviso that A and B are not simultaneously O;Cy represents one of the following Formula (II) optionally substituted by one to three groups selected from hydroxy, halogen, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl, C1-6alkylamino and amino;R1 and R2 are independently selected from hydroxy, halogen, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl and C3-8 cycloalkyl;n represents an integer from 0-4;X is hydrogen, hydroxy, halogen or C1-6alkoxy;Y is oxy, thio, a 1-4 membered alkylene, a 2-4 membered alkylene ether, 2-4 membered alkylene thioether or an oxyethyleneoxy group, optionally substituted by 1 to 4 groups independently selected from hydroxy, halogen, C1-6alkyl, C1-6alkoxyand C1-6 haloalkyl;Z is CH or N;and p represents an integer from 0-5 when Z is CH or 0-4 when Z is N;when p represents 2 or more, two of R2s may be taken together with the carbon atoms to which they are attached to form a 5-8 membered cycloalkyl ring to processes for the preparation of, intermediates used in the preparation of, compositions containing such compounds and the uses of such compounds as antagonists of the NMDA NR2B receptor.

Description

AMIDA THERAPEUTIC DERIVATIVES FIELD OF THE TECHNIQUE This invention relates to amide derivatives and processes for their preparation, to intermediates used in their preparation, to compositions containing them and to the uses of such derivatives.

BACKGROUND OF THE INVENTION The amide derivatives of the present invention are antagonists of the NMDA NR2B receptor (N-metii-D-aspartate), and have various therapeutic applications, particularly in the treatment of pain, stroke, traumatic brain injury, Parkinson's disease, Alzheimer's, depression, anxiety, migraine or similar. Glutamate has a double role in the central nervous system (CNS) as an essential amino acid and as a principal excitatory neutrotransmitter. There are two main classes of receptors, ionotropic and metabotropic. The ionotropic receptors are classified into three main subclasses, N-methyl-aspartate (NMDA), 2-amino-3- (methyl-3-hydroxyisoxazol-4-yl) propionic acid (AMPA) and kainate. There is considerable preclinical evidence that hyperalgesia and allodynia subsequent to lesions in peripheral tissues or nerves are not only due to an increased sensitivity of the primary afferent nociceptors at the site of injury, but also depend on mid-central changes by the NMDA receptor in synaptic excitability. In humans, it has also been discovered that NMDA receptor antagonists reduce color perception and sensitization. In addition, overactivation of the NMDA receptor is a key event to induce the death of neuronal cells under pathological conditions of acute and chronic forms of neurodegeneration. However, although inhibition of the NMDA receptor has therapeutic utility in the treatment of pain and neurodegenerative diseases, there are significant susceptibilities to many available NMDA receptor antagonists that can produce potentially serious minority effects. The NMDA subunits are distributed differentially in the CNS. Especially, it is believed that NR2B is restricted to the forebrain and laminae I and II of the dorsal horn. The more discrete distribution of the NR2B subunit in the CNS may sustain a profile of fewer minority effects of agents that act selectively at this site. For example, selective NMDA NR2B antagonists may have clinical utility for the treatment of neuropathic pain and other pain states in humans with a reduced side-effect profile compared to existing NMDA antagonists (S. Boyce, et al., Neuropharmacology, 38, p.611-623 (1999)).

International Patent Application No. (WO) 0208928 describes a variety of benzamide compounds, which are NMDA NR2B antagonists, for example, the compound (i) shown below: Compound (i) shows an IC50 of < 3 mM in the HERG potassium channel. W09967203 discloses cyclohexyl derivatives which, as claimed, are useful in the treatment of pain. There is a need to provide novel NMDA NR2B antagonists that are good drug candidates. In particular, the preferred compounds must be potently linked to the NR2B receptor and show functional activity as antagonists while showing little affinity for other receptors. They must be well absorbed from the gastrointestinal tract, must be metabolically stable and must possess favorable pharmacokinetic properties. They must be non-toxic and show few side effects. In addition, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated. In particular, it would be desirable to provide a selective NMDA NR2B antagonist with reduced activity in the potassium channel HERG.

DETAILED DESCRIPTION OF THE INVENTION Therefore, the invention provides a compound of formula (D or a pharmaceutically acceptable salt or solvate thereof, where: A and B independently represent CH2 or O, with the proviso that A and B are not simultaneously O; Cy represents one of the following optionally substituted with one to three groups selected from hydroxy, halogen, C1-6 alkyl, C-? 6 alkoxy, C? -6 haloalkyl, C-i alkylamino. 6 and amino; R1 and R2 are independently selected from hydroxy, halogen, C1-6 alkyl, C-? 6 alkoxy, C1-6 haloalkyl and C3-8 cycloalkyl; n represents a number between 0-4; X is hydrogen, hydroxy, halogen or C1-6 alkoxy; Y is oxy, thio, a 1-4 membered alkylene, a 2-4 membered alkylene ether, 2-4 membered alkylene thioether or an oxyethyleneoxy group, optionally substituted with 1 to 4 groups independently selected from hydroxy, halogen , alkyl of C -? "6, C 1-6 alkoxy and haloalkyl of C -? - 6; Z is CH or N; and p represents a number from 0 to 5 when Z is CH or from 0 to 4 when Z is N, when p represents 2 or more, two of R2 can be taken together with the carbon atoms to which they are attached to form a cycloalkyl ring of 5-8 members. In the above definitions, halo means fluorine, chlorine, bromine or iodine. Alkyl, alkylene and alkoxy groups containing the required number of carbon atoms may be branched or unbranched. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of alkylene include methylene, ethylene, n-propylene, 1-methylethylene, n-butylene, 1-methylpropylene, 2-methylpropylene and 1,1-dimethylethylene. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Haloalkyl defines an alkyl group substituted with one or more halogen groups. Examples of haloalkyl include difluoromethyl, trifluoromethyl and pentafluoroethyl. The 2-4 membered alkylene ether defines a chain of 2 to 4 in which one member is oxygen and at least one of the other members is C-? -C3 alkylene. Examples of 2-4 membered alkylene ether groups include oxymethylene, methyleneoxy, ethyleneoxy, oxyethylene and methyleneoxymethylene. Examples of 2-4 membered alkylene thioether groups include thiomethylene, methylenethio, ethylenethio and thioethylene. Examples of 5-8 membered cylcoalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In a preferred aspect (A), the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Cy is selected from 4-hydroxyphenyl, 1 - / -pyrazol-4-yl, 2- oxo-2,3-dihydro-1,3-benzoxazol-6-yl, 2-hydroxy-4-pyridyl, 5-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-oxoindoline, 3-amino-4-pyrazolyl and 2-hydroxy-5-pyridyl, unsubstituted or substituted by halogen, for example fluorine or C 1-6 alkyl, for example, methyl, more preferably 4-hydroxyphenyl unsubstituted or substituted by fluorine, more preferably substituted by fluorine in ortho position with respect to the phenolic hydroxy group, and A, B, R1, R2, n, p, X, Y and Z are as defined above.

In another preferred aspect (B), the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Cy is as defined above, in its broadest aspect or in a preferred aspect, more preferred or most preferred in (A), n is 0 and A, B, R1, R2, p, X, Y and Z are as defined above. In another preferred aspect (C), the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Cy is as defined above, in its broadest aspect or in a preferred aspect, more preferred or most preferred in (A) or (B), n is as defined above, in its broadest aspect or in a preferred aspect in (B), p is 0-2 and R2 is selected from fluorine, chlorine, d-β alkyl, for example methyl, ethyl, isopropyl or n-propyl, methoxy or trifluoromethyl, more preferably methoxy, chloro, fluoro and methyl, and A, B, R1, X, Y and Z are as defined above. In another preferred aspect (D), the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Cy is as defined above, in its broadest aspect or in a preferred aspect, more preferred or most preferred in (A), (B) or (C), n is as defined above, in its broadest aspect or in a preferred aspect in (B) or (C), and R2 are as have defined above, in its broadest aspect or in a preferred or more preferred aspect in (C), X is hydrogen, fluorine, hydroxy or methoxy, more preferably hydrogen or hydroxy, and A, B, R1, Y and Z are as have been defined previously. In another preferred aspect (E), the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Cy is as defined above, in its broadest aspect or in a preferred aspect, more Preferred or most preferred in (A), (B) or (C) or (D), n is as defined above, in its broadest aspect or in a preferred aspect in (B), (C) or ( D), p and R2 are as defined above, in their broadest aspect or in a preferred or more preferred aspect in (C) or (D), X is as defined above, in its broadest aspect or in a Preferred or most preferred aspect in (D), Y is methylene, oxyethyleneoxy, oxymethylene, methyleneoxy, methyleneoxymethylene, ethyleneoxy, oxyethylene or oxy, most preferably methyleneoxy and A, B, R1, and Z are as defined above. In another preferred aspect (F), the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Cy is as defined above, in its broadest aspect or in a preferred aspect, more Preferred or most preferred in (A), (B), (C), (D) or (E), n is as defined above, in its broadest aspect or in a preferred aspect in (B), ( C), (D) or (E), p and R2 are as defined above, in their broadest aspect or in a preferred or more preferred aspect in (C), (D) or (E), X is as defined above, in its broadest aspect or in a preferred aspect or in a more preferred aspect in (D) or (E), Y is as defined above, in its broadest aspect or in a preferred or more preferred aspect in (E), Z TS C and A, B and R1 are as defined above. In another preferred aspect (G), the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Cy is as defined above, in its broadest aspect or in a preferred aspect, more Preferred or most preferred in (A), (B), (C), (D), (E) or (F), n is as defined above, in its broadest aspect or in a preferred aspect in ( B), (C), (D), (E) or (F), p and R2 are as defined above, in their broadest aspect or in a preferred or more preferred aspect in (C), (D), (E) or (F), X is as defined above, in its broadest aspect or in a preferred aspect or in a more preferred aspect in (D), (E) or (F), and is as it has been defined above, in its broadest aspect or in a preferred aspect or in a more preferred aspect in (E) or (F), Z is as defined above, in its broadest aspect or in a preferred aspect in (F) , group Y is in position for and in conf iguration \ rans with respect to X, and A, B and R1 are as defined above. The preferred individual groups A, B, Cy, R1, R2, n, p, X, Y and Z are those defined by groups A, B, C, R1, R2, n, p, X, Y and Z in the Examples section shown below. Particularly preferred compounds of the invention include those in which each variable in Formula (I) is selected from among the preferred groups for each variable. Even more preferred compounds of the invention include those in which each variable in Formula (I) is selected from the most preferred or most preferred groups of each variable. A specific compound according to the invention is selected from the list consisting of: 4-Hydroxy-N-. { [c / s-4- (phenoxymethyl) cyclohexyl] methyl} benzamide; 4-Hydroxy- / V- ( {sup.c / s-4 - [(4-methoxyphenoxy) methyl] cyclohexyl} methyl) benzamide; / V-. { [c / s-4- (benzyloxy) cyclohexyl] methyl} -4-hydroxybenzamide; ? - ( { c / s-4 - [(4-chlorobenzyl) oxy] cyclohexyl} methyl) -4-hydroxybenzamide; ? / - ( { c / s-4 - [(3-chlorobenzyl) oxy] cyclohexyl} methyl) -4-hydroxybenzamide; 4-H¡drox¡-V-. { [c / s-4- (4-methoxyphenoxy) cyclohexyl] meth} benzamide; ? / -. { [c / s-4- (4-Chlorophenoxy) cyclohexyl] methyl} -4-hydroxybenzamide; 4-Hydroxy -? / -. { [1-hydroxy-4- (phenoxymethyl) cyclohexyl] methyl} benzamide; [- ( { trans-4 - [(4-Fluorophenoxy) methy1] -1-hydroxycyclohexyl] methyl) -4-hydroxy-benzamide; ? / - ( { tra / 7s-4 - [(3-Fluorophenoxy) methyl] -1-hydroxycyclohexyl] methyl) -4-hydroxy-benzamide; ? / - ( { traps-4 - [(2-Fluorophenoxy) methyl] -1-hydroxycyclohexyl} methyl) -4-hydroxy-benzamide; ? / - ( { tra / 7s-4 - [(2,6-Dfluorophenoxy) methyl] -1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide; ? - ( { trans-4 - [(3,5-Difluorophenoxy) methyl] -1-hydroxycyclohexyl} .methyl) -4- hydroxybenzamide; [- ( { trans-4 - [(3-Chlorophenoxy) methyl] -1-hydroxy-cyclohexyl} methyl) -4-h idroxy benzamida; A / - ( { Trar / s-4 - [(4-Chlorophenoxy) methyl] -1-hydroxycyclohexyl] methyl) -4-hydroxybenzamide; 4-Hydroxy -? / - ( { Trar) s-1-hydroxy-4 - [(2-methylphenoxy) methyl] cyclohexyl} methyl) benzamide; 4-Hydroxy- / V- ( { Tratra-1-hydroxy-4 - [(3-methylphenoxy) methyl] cyclohexyl} methyl) benzamide; 4-Hydroxy- / V- ( { Traps-1-hydroxy-4 - [(4-methyloxy) methyl] cyclohexyl] methyl) benzamide; / -. { trans -4 - [(Benzyloxy) methyl] -1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide; ? / - [(traps-4. {[[(2-Fluorobenzyl) oxy] methyl} -1-hydroxycyclohexyl) methyl] -4-hydroxybenzamide; ? / - [(trans -4- { [(4-Fluorobenzyl) oxy] methyl} -1-hydroxycyclohexyl) methyl] -4-hydroxybenzamide; 4-Hydroxy- / V-. { [trans-1-hydroxy-4- (2-phenoxyethyl) cyclohexyl] methyl} benzamide; ? / - ( { trans-4- [2- (2-Fluorophenoxy) ethyl] -1-hydroxycyclohexyl] methyl) -4-hydroxybenzamide; ? / - ( { trans-4- [2- (3-Fluorophenoxy) ethyl] -1-hydroxycyclohexyl} .methyl) -4- hydroxybenzamide; ? / - ( { trans-4- [2- (4-Fluorophenoxy) ethyl] -1-hydroxycyclohexyl} .methyl) -4- hydroxybenzamide; / V-. { [trans -4- (Benzyloxy) -1-hydroxycyclohexyl] methyl} -4- hydroxybenzamide; ? / -. { [traps-4- (4-Chlorophenoxy) -1-hydroxycyclohexyl] methyl} -4-hydroxybenzamide; ? / -. { [c / 's-4- (4-Chlorophenoxy) -1-hydroxydichohexyl] methyl} -4-hydroxybenzamide; ? / -. { [trans -4- (4-Chlorophenoxy) -1-hydroxycyclohexyl] methyl} 3-fluoro-4-hydroxybenzamide; ? / -. { [C / S-4- (4-Chlorophenoxy) -1-hydroxycyclohexyl] methyl} 3-fluoro-4-hydroxybenzamide; (+) - 4-hydroxy-V-. { [5S- (phenoxymethyl) tetrahydro-2 / - / - pyrran-2S-yl] methyl} benzamide; (-) - 4-hydroxy- / V-. { [5R- (phenoxymethyl) tetrahydro-2H-pyran-2R-yl] methyl} benzamide; 4-hydroxy- / V-. { [5S- (benzyloxymethyl) tetrahydro-2H-pyrn-2S-yl] methyl} benzamide; 4-hydroxy -? / -. { [5R- (benzyloxymethyl) tetrahydro-2H-pyran-2:? -yl] methyl} benzamide; (-) - 4-Hydroxy-A / -. { [(3R, 6S) -6- (phenoxymethyl) tetrahydro-2H-pyran-3-yl] metll} benzamida; (+) - 4-Hydroxy -? / - [(3S, 6) -6- (phenoxymethyl) tetrahydro-2 / -piran-3-yl] methyl} benzamide; ? - ( { tra / 7s-4 - [(2-Fluorobenzyl) oxy] -1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide; 3-Fluoro-? / - ( { Trans -4- [2- (2-fluorophenoxy) ethyl] -1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide; trans- / V-. { [4- (4-Chlorophenoxy) cyclohexyl] methyl} 3-fluoro-4-hydroxybenzamide; c / s -? -. { [4- (4-Chlorophenoxy) cyclohexyl] methyl} 3-fluoro-4-hydroxybenzamide; / V-. { [c / s-4- (4-Fluorophenoxy) cyclohexyl] methyl} -4-hydroxybenzamide; 3-Fluoro -? / -. { [c / s-4- (4-fluorophenoxy) cyclohexyl] methyl} -4-hydroxybenzamide; ? / - ( { trarjs-4- [2- (2-Fluorophenoxy) ethyl] -1-hydroxycyclohexyl} .methyl) -1yr-pyrazole-4-carboxamide; 4-Hydroxy-A / -. { [c / s-4- (2-phenylethoxy) cyclohexyl] methyl} benzamide; 2-Fluoro-4-hydroxy -? / -. { [tra / 7s-1-hydroxy-4- (phenoxymethyl) cyclohexyl] methyl} benzamide; A / - ( { Traps-4 - [(Benzyloxy) methyl] -1-hydroxycyclohexyl} methyl) -3-fluoro-4-hydroxybenzamide; ? / - ( { c / s-4 - [(Benzyloxy) methyl] cyclohexyl}. methyl) -4-hydroxybenzamide; 3-Fluoro-4-hydroxy-A / -. { [trar / s-1-hydroxy-4- (phenoxymethyl) cyclohexyl] methyl} benzamide; 3-Fluoro-4-hydroxy-A / -. { [tra / 7S-1-hydroxy-4- (2-phenoxyethyl) cyclohexyl] methyl} benzamide; 3-FIuoro- / V - [(tra / 7S-4- { [(4-fluorobenzyl) oxy] methyl.} -1- hydroxycyclohexyl) methyl] -4-hydroxybenzamide; 3-Fluoro- / V- ( { Tra / 7s-4 - [(2-fluorophenoxy) methyl] -1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide; 3-Fluoro-? / - ( { Trar / s-4 - [(4-fIuorophenoxy) methyl] -1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide; 4-Hydroxy-A / - [(tra / 7S-1-hydroxy-4-. {[[(5-methylpyridin-2-yl) oxy] methyl} cyclohexyl) methyl] benzamide; ? / - [(trarís-4-Benzyl-1-hydroxycyclohexyl) methyl] -4-hydroxybenzamide; 3-Fluoro-? / - [(trans-4. {[[(2-fluorobenzyl) oxy] methyl} -1-hydroxycyclohexyl) methyl] -4-hydroxybenzamide; 6-Hydroxy-A / -. { [c / s-4- (2-phenetoxy) cyclohexyl] methyl} nicotinamide; ? / -. { [c / s-4- (2-Phenylethoxy) cyclohexyl] methyl} -1 - / - pyrazole-4-carboxamide; ? / -. { [C / S-4- (Phenoxymethyl) cyclohexyl] meth} -1H-pyrazole-4-carboxamide; ? -. { [c / s-4- (2-Phenoxyethyl) cyclohexyl] methyl-1H-pyrazole-4-carboxamide; ? / - ( { c / '.s-4 - [(3-Fluorophenoxy) methyl] cyclohexyl}. mephyl) -1 / - / - pyrazole-4-carboxamide; / V- ( { C / s-4 - [(4-Fluorophenoxy) methyl] cyclohexyl] methyl) -1H-pyrazole-4-carboxamide; ? / - ( { (2?, 5 / :?) - 5 - [(4-Fluorophenoxy) methyl] tetrahydro-2 / - / - pyran-2-yl.} MetiI) -1 / - pyrazole -4-carboxamide; TO/-. { [c / s-4- (4-Methoxybenzyl) cyclohexyl] methyl} -1 - / - p -razol-4-carboxamide; 3-Amino -? / - [(c / s-4-benzylcyclohexyl) methyl] -1H-pyrazole-4-carboxamide; ? / - ( { (2R, 5R) -5 - [(4-Chlorophenoxy) methyl] tetrahydro-2 H -pyran-2-yl.} Methyl) -1 / - / - pyrazole-4-carboxamide; 3-Amino -? / - ( { (2R, 5 /?) - 5 - [(4-fluorophenoxy) methyl] tetrahydro-2 H -pyran-2-yl.] Methyl) -1 H-pyrazole -4-carboxamide; 3-Amino -? - ( { (2R, 5R) -5 - [(4-chlorophenoxy) methyl] tetrahydro-2H-pyrn-2-yl.} Metl) -1 H -pyrazol-4-carboxamide; and 3-Amino -? / - ( { (2R, 5R) -5 - [(4-ethylphenoxy) methyl] tetrahydro-2H-pyran-2-yl.} methyl) -1H-pyrazole-4-carboxamide; or a pharmaceutically acceptable salt or solvate thereof. A suitable sub-formula of the compounds of formula (I) can be represented by the formula (la) or a pharmaceutically acceptable salt or solvate thereof, wherein: R1A, R2A or R3A are independently selected from hydrogen, halogen, C1-6 alkyl, C-? 6 alkoxy, C-? 6 haloalkyl or C3-cycloalkyl; XA is hydrogen or hydroxy; Y is oxy, an alkylene group of 1 to 4 members, an alkylene ether group of 2 to 4 members or an oxyethyleneoxy group; and ZA is C or N. The pharmaceutically acceptable salts of the compounds of formula (I) include the basic salts thereof. Suitable basic salts are formed from bases that form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. As a reference for suitable salts, see "andbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth, (Wiley-VCH, Weinheim, Germany, 2002) A pharmaceutically acceptable salt of a compound of formula (I) can be prepared easily mixing solutions of the compound of formula (I) and the desired base, as appropriate.The salt can be precipitated in the solution and collected by filtration or recovered by evaporation of the solvent.The degree of ionization can vary from completely ionized or almost non-ionized The compounds of the invention can exist in both unsolvated and solvated forms.The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example The term "hydrate" is used when said solvent is water, and complexes are also within the scope of the invention. or the clathrates, drug-host molecule inclusion complexes where, in contrast to the solvates mentioned above, the drug and the host molecule are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized or non-ionized. For a review of such complexes see J Pharm Sci, 64 (8), 1269-1288 of Haleblian (August 1975). Hereinafter, all references to compounds of formula (I) include reference to salts, solvates and complexes thereof and to solvates and complexes of the salts thereof. The compounds of the present invention include compounds of formula (I) as defined hereinabove, polymorphs, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined hereafter in this document, and compounds of the formula (I) labeled with isotopes.

As indicated, the invention includes all polymorphs of the compounds of formula (I) as defined hereinabove. The so-called "prodrugs" of the compounds of formula (I) are also within the scope of the invention. Thus, certain derivatives of compounds of formula (I) which may have little or no pharmacological activity per se may, when administered in or on the body, give rise to compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and" Bioreversible Carriers in Drug Design, "Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association.) Prodrugs according to the invention can be produced, for example, by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as "pro-residues" as it is described, for example, in "Design of Prodrugs" H Bundgaard (Elsevier, 1985) Some examples of prodrugs according to the invention include: (i) when the compound of formula (I) contains an alcohol functionality (-OH) , an ether thereof, for example, by substitution of hydrogen with (C6) alkanoyloxymethyl; and (ii) when the compound of formula (I) contains a primary or secondary amino functionality (NHR, where R? H), an amide thereof, for example, by substitution of one or both hydrogens with alkanoyl of (CrC 0) ). In the references mentioned above, other examples of substitution groups can be found according to the above examples and examples of other types of prodrugs. The compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. When a compound of formula (I) contains an alkenyl or alkenylene group, geometric isomers cisArans (or Z / E) can be formed and when the compound contains, for example, a keto or oxime group, a tautomeric isomerism ("tautomerism") can occur. ). It should be understood that a single compound can show more than one type of isomerism. All stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I) are included within the scope of the present invention, including compounds that show more than one type of isomerism and mixtures of one or more thereof.

The cis? Trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include the chiral synthesis of an optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, high pressure chiral liquid chromatography.

(HPLC). Alternatively, the racemate (or a racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol or, in the case where the compound of formula (I) contains an acidic moiety, a suitable base. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and convert one or both diastereomers to the corresponding pure enantiomers by means well known to those skilled in the art. The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50% isopropanol, typically 2 to 20% and 0 to 5% of an alkylamine, typically 0.1% diethylamine. The concentration of the eluate produces the enriched mixture.

Stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994). The present invention also includes all pharmaceutically acceptable isotope-labeled compounds of formula (I) in which one or more atoms are replaced by atoms having the same atomic number, but different atomic mass or mass number in comparison with the atomic mass or mass number that is normally found in nature. Examples of suitable isotopes for inclusion in the compounds of the invention include hydrogen asotopes such as 2H and 3H, carbon, such as 11C, 13C and 14C, of chlorine, such as 36CI, of fluorine, such as 18F, of iodine, such as 123l and 125l, of nitrogen, such as 13N and 15N, of oxygen, such as 150, 17O and 18O, of phosphorus, such as 32P, and of sulfur, such as 35S. Certain compounds labeled with sotopes of formula (I), for example, those incorporating a radioactive isotope, are useful in studies of drug distribution and / or tissue substrates. The radioactive isotopes tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and detection means. Substitution with heavier isotopes such as deuterium, ie, 2H, may produce certain therapeutic advantages as a result of increased metabolic stability, for example, a longer half-life in vivo or lower dosing requirements and therefore may be preferred in some circumstances. Substitution with positron emission isotopes, such as 11C, 18F, 15O, and 13N, may be useful in Positron Emission Topography (PET) studies to examine receptor occupancy in the substrate. The isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an isotope-labeled reagent instead of the unlabelled reagent previously employed. . The pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be substituted with isotopes, for example, D2O, d6-acetone and d-DMSO. The compounds of the present invention are antagonists of the NMDA NR2B receptor (N-methyl-D-aspartate) and have several therapeutic applications, particularly in the treatment of pain, stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, depression, anxiety, migraine or the like. The compounds of the present invention are useful for the general treatment of pain, particularly neuropathic pain. Physiological pain is an important protective mechanism designed to warn of the danger of potentially damaging stimuli from the external environment. The system works through a specific set of primary sensory neurons and is activated exclusively by noxious stimuli through peripheral transduction mechanisms (Millan 1999 Prog. Neurobio, 57: 1-164, as a reference). These sensory fibers are known as nociceptors and are characterized by small diameter axons with low conduction velocities. The nociceptors encode the intensity, duration and quality of the noxious stimuli and, thanks to their topographically organized projection to the spinal cord, the location of the stimulus. Nociceptors are found in nociceptive nerve fibers of which there are two main types, A-delta fibers (myelinated) and C fibers (unmyelinated). The activity generated by the entrance of the nociceptor is transferred, after a complex processing in the dorsal horn, directly or through nuclei of retransmission of the cerebral stem, to the ventrobasal thalamus and later to the cortex, where the sensation of pain is generated. In acute severe pain and in chronic pain, the same pathways may be involved that are driven by pathophysiological processes and, as such, may fail to provide a protective mechanism and instead contribute to the debilitating symptoms associated with a wide range of disease states. . Pain is a feature of many injuries and disease states. When a substantial injury occurs in a body tissue, due to disease or trauma, the characteristics of nociceptor activation are altered. Sensitization occurs in the periphery, locally around the lesion and centrally where the nociceptors end. This leads to a hypersensitivity at the site of the injury and in nearby normal tissue. In acute pain, these mechanisms can be useful and allow the healing process to take place and the hypersensitivity returns to normal when the lesion has healed. However, in many chronic pain states, hypersensitivity lasts longer than the healing process, which is usually due to an injury to the nervous system. This injury usually leads to maladaptation of the afferent fibers (Woolf & amp;; Salter 2000 Science 288: 1765-1768). Clinical pain is present when discomfort and abnormal sensitivity are among the patient's symptoms. Patients tend to be quite heterogeneous and may present different symptoms of pain. There are several typical subtypes of pain: 1) spontaneous pain that can be dull, burning or throbbing; 2) painful responses to noxious stimuli are exaggerated (hyperalgesia); 3) the pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Although patients with back pain, arthritis pain, CNS trauma or neuropathic pain may have similar symptoms, the underlying mechanisms are different and, therefore, may require different treatment strategies. Therefore, pain can be divided into several distinct areas by its different pathophysiologies, including nociceptive, inflammatory, neuropathic pain, etc. It should be noted that some types of pain have multiple etiologies and, therefore, can be classified in more than one area, for example, back pain. Cancer pain can have nociceptive and neuropathic components. Nociceptive pain is induced by injury to a tissue or by intense stimuli that have the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors to the site of the lesion and sensitize the spinal cord to the level of its termination. Afterwards, it is retransmitted through the spinal tract to the brain where pain is perceived (Meyer et al., 1994 Textbook of Pain 13-44). The activation of the nociceptors activates two different types of afferent nerve fibers. The myelinated A-delta fibers transmit rapidly and are responsible for the sensations of sharp and throbbing pain, while unmyelinated C fibers transmit at lower velocity and drive the dull pain. Acute moderate to severe nociceptive pain is a prominent feature of sprained / sprained pain, postoperative pain (pain after any type of surgical procedure), post-traumatic pain, burns, myocardial infarction, acute pancreatitis and renal colic, but it is not limited to these pains. In addition, acute pain syndromes related to cancer are usually due to therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormone therapy and radiation therapy. Acute nociceptive pain of moderate to severe is a prominent feature, but without limitation, of cancer pain that may be pain related to tumors (eg, bone pain, headache and faciai, visceral pain) or associated with anti-cancer therapy. cancer (for example, post-chemotherapy syndromes, post-surgical chronic pain syndromes, post-radiation syndromes), back pain that may be due to hernias or ruptured invertebral discs or abnormalities in the lumbar facet joints, sacroiliac joints , paraspinal muscles or the posterior longitudinal ligament. Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (IASP definition). The injury to the nerve can be caused by trauma and disease and, therefore, the term "neuropathic pain" encompasses many disorders with different etiologies. These include, but are not limited to, diabetic neuropathy, post-herpetic neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, Carpus Tunnel Syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia or deficiencies. of vitamins. Neuropathic pain is pathological because it does not have a protective role. It is usually present after the original cause has dissipated, usually lasting for years, and significantly reducing the quality of life of patients (Woolf and Mannion 1999 Lancet 353: 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even among patients with the same disease (Woolf & amp;; Decosterd 1999 Pain Supp. 6: S141-S147; Woolf and Mannion 1999 Lancet 353: 1959-1964). They include spontaneous pain, which may be continuous, or paroxysmal pain and abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally harmless stimulus). The inflammatory process is a complex series of biochemical and cellular events activated in response to tissue injury or the presence of foreign substances, resulting in swelling and pain (Levine and Taiwo 1994: Textbook of Pain 45-56). Arthritic pain constitutes the majority of the population of inflammatory pains. Rheumatoid disease is one of the most common chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact etiology of RA is unknown, but current hypotheses suggest that both genetic factors and microbiological factors may be important (Grennan &Jayson 1994 Textbook of Pain 397-407). It has been estimated that nearly 16 million Americans have symptomatic osteoarthritis (OA) or a degenerative joint disease, most of which are over 60 years old and this number is expected to increase to 40 million as the age of the population increases , making this a public health problem of enormous magnitude (Houge &Mersfelder 2002 Ann Pharmacother, 36: 679-686, McCarthy et al., 1994 Textbook of Pain 387-395). Most patients with OA seek medical attention due to pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in advanced stages of life. Other types of inflammatory pain include, but are not limited to, inflammatory bowel diseases (IBD).

Other types of pain include, but are not limited to: musculoskeletal disorders including, but not limited to, myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, pyomyositis. - Central pain or "thalamic pain", defined as pain caused by injury or dysfunction of the nervous system including, but not limited to, central pain that appears after a stroke, multiple sclerosis, spinal cord injury, Parkinson's disease and epilepsy. - Cardiac and vascular pain including, but not limited to, angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleroderma, skeletal muscle ischemia. - Visceral pain and gastrointestinal disorders. The viscera include the organs of the abdominal cavity. These organs include the sexual organs, spleen and part of the digestive system. The pain associated with the viscera can be divided into visceral digestive pain and non-digestive visceral pain. The gastrointestinal (Gl) disorders usually found include functional bowel disorders (FBD) and inflammatory bowel diseases (IBD). These Gl disorders include a wide range of disease states that are currently only moderately controlled, including - in the case of FBD, gastroesophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome ( FAPS) and - in the case of IBD, Crohn's disease, ileitis and ulcerative colitis, all these conditions regularly producing visceral pain. Other types of visceral pain include pain associated with dysmenorrhea, pelvic pain, cystitis, and pancreatitis. - Headache including, but not limited to, migraine, migraine with aura, migraine without aura, headaches in clusters and tension headache. - Orofacial pain including, but not limited to, dental pain and temporomandibular myofacial pain. Thus, in a further aspect of the present invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of pain, particularly, neuropathic pain. As an alternative aspect, there is provided a method for the treatment of pain, particularly neuropathic pain, which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need of such treatment.

General synthesis All compounds of formula (I) can be prepared by the methods described in the general methods presented below or by the specific methods described in the Examples section and in the Preparations section or by routine modifications thereof. The present invention also includes any one or more of these methods for preparing the compounds of formula (I), in addition to any new intermediates used therein. In the following general methods, Cy, R1, R2, R3, A, B, n, p, X, Y and Z are as previously defined for a compound of formula (I), unless otherwise indicated. The methods exemplify the preparation of compounds of formula (I) wherein Y and X are in the trans configuration. Those skilled in the art will appreciate that compounds with cis configuration can be prepared from the appropriate regiospecific starting materials or by removal of the alternative regioisomer from a mixture of intermediates or cis and trans final compounds. According to process (A), a compound of formula (I), wherein Y is -O- or - (CH2) qO- and q is 1-3, can be prepared by reaction of a compound of formula (a) ) or (llb) with a compound of formula (III) under conventional Mitsunobu conditions, for example diisopropyl azodicarboxylate and Ph3P, in a suitable solvent such as tetrahydrofuran.

According to process (B), a compound of formula (I), wherein Y is - (CH 2) rOCH 2 - yr is 0-2, can be prepared by reaction of a compound of formula (lie), with a compound of formula (IV) (Efc) (IV) where LG is a suitable leaving group, such as bromide, using a suitable base such as sodium hydride, in a suitable solvent such as dimethylformamide. According to process (C), a compound of formula (I), wherein Z is N, Y is - (CH2) rO- and r is 0-3, can be prepared by reaction of a compound of formula (I) ), where r is 0-3, with a compound of formula where LG is a suitable leaving group, for example halogen, under suitable alkylation conditions, for example sodium hydride in a suitable solvent, such as DMF, at a high temperature and in the presence of microwaves. A compound of formula (lla-c) can be prepared by reacting a compound of formula (Va) or (Vb) with a compound of formula (VI) (Va) (Vb) (VI) where q is 1-3, P is a suitable hydroxy protecting group, for example benzyl, under suitable acid / amine coupling conditions, for example using N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide and 1-hydroxybenzotriazole (HOBT), in a suitable solvent such as dimethylformamide, followed by removal of the P group under conventional conditions, for example by hydrogenation. A compound of formula (Va) or (Vb), wherein X is H, can be prepared from a compound of formula (Vlla) or (Vllb) (Vlla) (VH) where P is as defined above and Z'O is a suitable leaving group such as mesylate or tosylate, by treatment with a suitable azide, such as sodium azide, in a suitable solvent such as dimethylformamide, a a high temperature, followed by reduction of the azide to amino under conventional conditions, such as hydrogenation. A compound of formula (Va) or (Vb), wherein A = B = C and X is OH, can be prepared from a compound of formula (Vlll) by treatment with a suitable cyanide, such as trimethylsilyl cyanide, with zinc iodide in toluene at a reduced temperature, followed by reduction of the resulting cyano group with a suitable reducing agent, such as lithium aluminum hydride and separation of the cis isomer or desired trans The compounds of formula (Vlla) and (Vllb) can be prepared from a compound of formula (IXa) or (IXb) (Ka) (IX) where R is a suitable ester group, for example methyl, by reduction with a suitable agent, for example lithium aluminum hydride, followed by activation of the hydroxy group with Z 'under suitable conditions. According to process (D), a compound of formula (I) can be prepared by reaction of a compound of formula (VI), with a compound of formula (X) (X) under suitable acid / amine coupling conditions, such as N-ethyl-NH 3 -d-methylaminopropyl) carbodimide and 1-hydroxybenzotriazole (HOBT) in a suitable solvent, such as dimethylformamide. A compound of formula (X), wherein A = B = C and X is OH, can be prepared from a compound of formula (XI) by reaction with a suitable cyanide compound, such as trimethylsilyl cyanide, with zinc iodide in a suitable solvent, such as toluene, at a reduced temperature, followed by reduction with a suitable reducing agent, such as lithium aluminum hydride, and separation of the desired isomer. A compound of formula (X), wherein X is H, can be prepared from a compound of formula (XII) wherein Z'O is as defined above, by treatment with a suitable azide, such as sodium azide, in a suitable solvent such as dimethylformamide, at an elevated temperature, followed by reduction of the azide to amino under conventional conditions, such as hydrogenation.

A compound of formula (XII) can be prepared from a compound of formula (Xlla) wherein R is a suitable ester group, for example methyl, by reduction with a suitable agent, for example lithium aluminum hydride, followed by activation of the hydroxy group with Z 'under suitable conditions. A compound of formula (X) wherein Y is - (CH2) qO- and q is 1-3, can be prepared by reacting a compound of formula (IV) with a compound of formula (Xllla) or (Xlllb) (Xffla) (XlUb) where P 'is a suitable N-protecting group, such as Boc, under conditions of Mitsunobu type, as described above, followed by deprotection of the P' group under conventional conditions. A compound of formula (X) wherein Y is - (CH2) rOCH2- and r is 0-2 can be prepared by reaction of a compound of formula (IV) with a compound of formula (XI I le) (xme) wherein P 'is as defined above, under conventional nucleophilic displacement conditions, as described above, followed by deprotection of the P1 group under conventional conditions. The compounds of formula (Xllla-c), wherein A = B = C and X is OH, can be prepared from a compound of formula (XIV) wherein q is 0-3, by reaction with a suitable cyanide compound, such as trimethylsilyl cyanide, with zinc iodide in a suitable solvent, such as toluene at a reduced temperature, followed by reduction with a suitable reducing agent, such as lithium aluminum hydride, and separation of the desired cis or trans isomer. A compound of formula (Xllla-c), wherein X is H, can be prepared from a compound of formula (Va) or (Vb) by selective protection of the amino group with a suitable protective group P 'followed by deprotection selective of the protective group P. A compound of formula (X), wherein X is H, can be prepared from a compound of formula (XI) by nitromethylation using nitromethane with a catalytic amount of ethylenediamine at an elevated temperature followed by reduction sequence of the resulting nitro group and the double bond under conventional conditions. A compound of formula (XI), wherein Y is -O- or - (CH2) qO- and q is 1-3, or Y is oxyethyleneoxy, can be prepared by reaction of a compound of formula (III) with a compound of formula (XVa) or (XVb), as appropriate in conditions of Mitsunobu type, as described above, followed by deprotection of the ketone group under conventional conditions. A compound of formula (XI), wherein Y is - (CH2) rOCH2- and r is 0-2 or Y is oxyethyleneoxy, may be prepared by reaction of a compound of formula (XVc) with a compound of formula (IV) or (IVa) ), as appropriate in conventional nucleophilic displacement conditions, as described above. A compound of formula (XI) wherein Y is a 1-4 membered alkylene can be prepared by reaction of a compound of formula (XVd) with a compound of formula (XVe) (XVd) (XVe) where Y 'is a covalent bond or an alkylene of 1-3 alkylene members, under Wittig reaction conditions, followed by hydrogenation of the resulting double bond using a suitable metal catalyst, for example Pd (OH) 2 on carbon in a suitable solvent such as methanol, followed by deprotection of the keto group under suitable conditions. A compound of formula (XI) wherein Y is - (CH2) qOCH2CH2- and q is 0-1, can be prepared by reaction of a compound of formula (XVa), wherein q is 0-1, with a compound of formula (XVI) using a suitable base, such as sodium hydride, in a suitable solvent, such as dimethylformamide, followed by acetylation and subsequent reduction of the OH group under conventional conditions, followed by deprotection of the ketone group. A compound of formula (XII), wherein A = B = C and Y is -0 (CH2) 2- can be prepared by reaction of compound of formula (XVII) with a compound of formula (XVIII) (xvp) (xvm) wherein R is a suitable carboxylic acid ester protecting group, for example methyl, by treatment with p-toluenesulfonic acid in benzene followed by the removal of one of the ether groups using, for example, triethylsilane and trimethylsilyl triflate, followed by reduction of the ester under conventional conditions, for example with lithium aluminum hydride, and after activation of the hydroxy group with 71 under conventional conditions. A compound of formula (XII) wherein A = O and B = C, can be prepared from a compound of formula (XIX) by treatment with a suitable agent, such as p-toluenesulfonic acid, in a suitable solvent such as dichloromethane. A compound of formula (Vlla) in which A = O and B = C, can be prepared from a compound of formula (XX) wherein P is as defined above, by treatment with a suitable agent, such as p-toluenesulfonic acid, in a suitable solvent such as dichloromethane, followed by deprotection of the protecting group. According to a fifth process (E), a compound of formula (I), in which A = B = C and Y represents a 1-4 membered alkylene, can be prepared by reaction of a compound of formula (XXI): (XXI) wherein Y 'represents a covalent bond or a 1-3-membered alkylene, by hydrogenation of the double bond using a suitable metal catalyst, for example Pd (OH) 2 on carbon in a suitable solvent such as methanol. A compound of formula (XXI) can be prepared by reaction of a compound of formula (XXII) with a compound of formula (XVe) as described above (XXII) (XVe) under Wittig reaction conditions. A compound of formula (XXII) can be prepared by reaction of a compound of formula (XXlll) with a compound of formula (VI): under suitable acid / amine coupling conditions as described above, followed by deprotection of the ketone group under suitable conditions. The compounds of formulas (III), (IV), (VI), (VIll), (IX), (Xllc), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) ), (XX) and (XXlll) are known in the art or can be prepared by well-known methods.

The use of protecting groups such as those described above is well known in the art. Suitable protecting groups for use in the processes mentioned above can be found in "Protecting Groups in Organic Synthesis", Greene and Wuts, 3rd Edition, John Wiley and Sons, Inc. The various general methods described above may be useful for the introduction of the desired groups at any stage in the stepwise formation of the required compound and it should be appreciated that these general methods can be combined in different ways in such multi-stage processes. The sequence of the reactions in the multi-stage processes should be chosen in such a way that the reaction conditions used do not affect groups of the molecule that are to be conserved in the final product. The compounds of the invention directed to pharmaceutical use can be administered in the form of crystalline or amorphous products. They can be obtained, for example, as solid beds, powders or films by processes such as precipitation, crystallization, lyophilization, nebulizer drying or evaporative drying. For this purpose, microwave or radiofrequency drying can be used. They can be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or in the form of any combination thereof). Generally, they will be administered in formulation form together with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound (s) of the invention. The choice of excipient will largely depend on factors such as the particular mode of administration, the effect of the excipient on the solubility and stability and on the nature of the dosage form. Pharmaceutical compositions suitable for the administration of compounds of the present invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).

Oral administration The compounds of the invention can be administered orally. Oral administration may involve swallowing the compound, so that it enters the gastrointestinal tract, and / or buccal or sublingual administration may be employed, whereby the compound enters directly into the bloodstream from the mouth. The formulations suitable for oral administration They include solid formulations such as tablets; capsules containing particulates, liquids or powders; pills (including those filled with liquid); chewing gums; gels; multi- and nano-particulates, gels, solid solutions, liposomes, films (including muco-adhesives); ovules nebulizers; and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in hard or soft capsules and typically comprise a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example, in an envelope. The compounds of the invention can also be used in dissolution and rapid disintegration dosage forms such as those described in Expert Opinion in Therapeutic Patents, V \ (6), 981-986 by Liang and Chen (2001). For tablet dosage forms, the drug can be from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form. In addition to the drug, the tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropylcellulose substituted with lower alkyl, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will constitute from 1% by weight to 25% by weight, preferably from 5% by weight to 20% by weight of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelafine, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. The tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80 and glidants such as silicon dioxide and talc. When present, the surfactants may be from 2 wt% to 5 wt% of the tablet and the glidants may be from 0.2 wt% to 1 wt% of the tablet. The tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. The lubricants are generally from 0.25% by weight to 10% by weight, preferably from 0.5% by weight to 3% by weight of the tablet. Other possible ingredients include anti-oxidants, colorants, flavoring agents, preservatives and flavor masking agents.

Exemplary tablets contain up to about 80% drug, from about 10% by weight to about 90% by weight of binder, from about 0% by weight to about 85% by weight of diluent, from about 2% by weight to about 10% by weight. % by weight of disintegrant, and from about 0.25% by weight to about 10% by weight of lubricant. The tablet mixtures can be compressed directly or by a roller to form tablets. The tablet mixtures or mixture portions, as an alternative, can be granulated wet, dry or in the molten state, can be coagulated in the molten state, or can be exempted prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it can even be encapsulated. Tablet formulation is discussed in "Pharmaceutical Dosages Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, New York, 1980. (ISBN 0-8247-6918-X). Solid formulations for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. Modified release formulations suitable for the purposes of the invention are described in U.S. Patent No. 6,106,864. Details of other suitable modified release technologies such as high energy dispersions, osmotic and coated particles can be found in Verna et al., Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). In WO 00/35298 the use of chewing gums is described to achieve a controlled release.

Parenteral Administration The compounds of the invention can also be administered directly to the bloodstream, to the muscle, or to an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration. Suitable devices for parenteral administration include needle injectors (including microneedles), needleless injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9) although, for some applications, they may be formulated more conveniently as a sterile non-aqueous solution or as a dry form to be used together with a suitable vehicle such as sterile pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be easily achieved using conventional pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of formula (I) used in the preparation of parenteral solutions can be increased using appropriate formulation techniques, such as the incorporation of agents that enhance solubility. Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. In this manner, the compounds of the invention can be formulated as a suspension, or as a solid, semi-solid or thixotropic liquid for administration as an implanted reservoir that provides a modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded PGLA microspheres.

TOPICAL ADMINISTRATION The compounds of the invention can also be administered topically to the skin or mucosa, that is, dermally or transdermally.

Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, fine powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulslons. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated - see, for example, J Pharm Sci, 88 (10) 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include administration by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection (e.g., Powderject ™, Bioject ™, etc.). Formulations for topical administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release.

Inhaled / intranasal administration The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (alone or in admixture, eg, in a dry mixture with lactose or in the form of a particle of mixed components). , for example, mixed with phospholipids such as phosphatidylcholine) in a dry powder inhaler or as an aerosol spray with a pressurized container, pump, sprayer, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist) or nebulizer, with or without the use of a suitable propellant such as 1, 1, 1, 2-tetrafluoroethane or 1,1,1,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example chitosan or cyclodextrin. The pressurized container, pump, spray, atomiser or nebuliser contains a solution or suspension of the compounds of the invention comprising, for example, ethanol, aqueous ethanol or extent of release of the active ingredient suitable alternative agent for dispersing, solubilising or , one or more propellants as a solvent and an optional surfactant, such as sorbitan trioleate, oleic acid or an oligolactic acid. Before use in a dry powder or suspension formulation, the product drug is micronized to a size suitable for administration by inhalation (typically less than 5 microns). This can be achieved by any appropriate comminuting method as spiral jet milling, jet milling, fluid bed supercritical fluid processed to form nanoparticles, high pressure homogenisation or spray drying. Capsules (made, for example, from gelatin or HPMC, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier performance as / -leucine, mannitol or magnesium stearate. the lactose may be anhydrous or monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 mg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 .mu.l to 100 .mu.l. a typical formulation may comprising a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.Alternative solvents that can be used in lug of propylene glycol include glycerol and polyethylene glycol. Suitable flavors such as menthol and levomenthol or sweeteners such as saccharin or sodium saccharin can be added to the formulations of the invention intended for inhaled / intranasal administration. Formulations for inhaled / intranasal administration can be formulated to be immediate release and / or modified using, for example, poly (a7-lactide-co-glycolic acid) (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. In the case of inhalers and dry powder aerosols, the dosage unit is determined by means of a valve that delivers a measured quantity. The units according to the invention are typically arranged to administer a metered dose or "pulse" containing the compound of formula (I), which may be administered in a single dose or, more usually, in divided doses throughout the day .

Rectal / Vaginal Administration The compounds of the invention can be administered rectally or vaginally, for example, in the form of suppositories, vaginal suppositories or enemas. Cocoa butter is a traditional suppository base, but other alternatives may be used as appropriate. Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release.

Ocular / aural administration The compounds of the invention can also be administered directly to the eye or ear, typically in the form of drops of a suspension or micronized solution in sterile isotonic saline with adjusted pH. Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable (e.g. sponges with absorbable gel, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and systems of particles or vesicles such as niosomes or liposomes A polymer such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer, for example, gellan gum, together with a preservative such as chloride may be incorporated. of benzalkonium. Such formulations can also be administered by iontophoresis. Formulations for ocular / aural administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release.

Other technologies The compounds of the invention can be combined with soluble macromolecular entities such as cyclodextrin or suitable derivatives thereof or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the modes of administration mentioned above. Drug-cyclodextrin complexes, for example, are generally useful for most dosage forms and routes of administration. Inclusion and non-inclusion complexes can be used. As an alternative to direct complex formation with the drug, the cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in International Patent Applications No. WO 91/11172, WO 94/02518 and WO 98/55148. Thus, as an additional or alternative aspect, the invention provides a pharmaceutical composition which includes a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, together with a suitable excipient. The composition is useful in the treatment of a disease for which an NMDA NR2B receptor antagonist is indicated, particularly pain, stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, depression, anxiety and migraine.

Kit of parts Whenever it is desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the invention that two or more pharmaceutical compositions, at least one of which contains a compound according to the invention, in the form of a kit suitable for the co-administration of the compositions. In this way, the kit of the invention comprises two or more different pharmaceutical compositions, at least one of which contains a compound of formula (I) according to the invention and means for separately maintaining said compositions, such as a container, divided bottle or divided laminate package. An example of such a kit is the known blister-type container used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the different compositions in different dosing intervals, or for evaluating the different compositions from each other. To improve acceptance, the kit typically comprises instructions for administration and can be provided with a reminder.

Dosage For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of 0.1 mg to 1,000 mg, depending, of course, on the mode of administration. The amount of active component in a unit dosage preparation can be varied or adjusted from 0.1 mg to 1 g according to the particular application and potency of the active components. In medical use, the drug can be administered one to three times a day, for example, in the form of capsules of 100 or 300 mg. For therapeutic use, the compounds used in the pharmaceutical method of this invention are administered at the initial dosage of from about 0.01 mg to about 100 mg / kg / day. A daily dosage range of about 0.01 mg to about 100 mg / kg is preferred.

These dosages are based on an average human subject with a weight of approximately 65 to 70 kg. The doctor can easily determine the doses for subjects whose weight is outside this range, such as children and the elderly. For the avoidance of doubt, the references in this document to "treatment" includes references to curative, palliative and prophylactic treatment. The biological activity and safety profile of the compounds of formula (I) can be measured using the assays described below.

NR2B Binding Assay The activity of the cycloalkylene amide compounds of the present invention as NR2B antagonists is determined by their ability to inhibit the binding of the NR2B subunit to its receptor sites using radioactive ligands. The NR2B antagonist activity of the cycloalkylene amide compounds is evaluated using the conventional assay procedure described, for example, in J. Pharmacol., 331, p. 117-126, 1997. This method essentially involves determining the concentration of the individual compound that is required to reduce the amount of radiolabeled NR2B ligands by 50% at their receptor sites, thereby providing the IC50 values characteristic of each compound tested. More specifically, the test is carried out as indicated below. Membranes were prepared by homogenization of forebrain of male CD rats weighing 170-190 g using a glass-Tefion homogenizer in sucrose 0.32 M at 4 ° C. The crude core sediment was removed by centrifugation at 1000xg for 10 minutes and the supernatant was centrifuged at 17,000xg for 25 minutes. The resulting pellet was resuspended in 5 mM Tris acetate pH 7.4 at 4 ° C for 10 minutes to lyse the cell particles and centrifuged again at 17000xg. The resulting pellet (membrane P2) was washed twice in Tris acetate, resuspended to 5.5 mg protein / ml and stored at -20 ° C until use. All manipulations were performed on ice and the stock solution and equipment were kept on ice at all times. For the saturation test, the saturation of the receptor was determined by incubating [3 H] -1 - [(1S *, 2S *) - 2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] -4 phenylpiperidin-4-ol and 50 μg of P2 membrane protein for 60 minutes at room temperature in a final volume of 100 μl of incubation buffer (50 mM Tris HCl, pH 7.4). The total and non-specific binding (in the presence of a 10 μM concentration of 1 - [(1S *, 2S *) - 2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] -4-phenylpiperidin-4 -ol unlabeled) were determined in a concentration range of [3 H] -1 - [(1 S *, 2 S *) - 2-hydroxy-2- (4-hydroxyphenyl) -1-methyl-ethyl] -4-phenylpiperidine- 4-ol (0.625 nM to 60 nM).

For the competition assay, the test compounds were incubated in duplicate with [3H] -1 - [(1 S *, 2S *) - 2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] - 5 nM 4-phenylpiperidin-4-ol and 50 μg of P2 membrane protein for 60 minutes at room temperature in a final volume of 100 μl of 50 mM Tris HCl buffer (pH 7.4). The non-specific binding was determined by a concentration of 10 μM of 1 - [(1S *, 2S *) - 2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] -4-phenylpiperidin-4-ol no marked (25 μl). For all Ki calculations, the KD derived from the saturation obtained in the saturation test was used. All incubations were terminated by rapid vacuum filtration over a Whatman GF / B glass fiber filter paper soaked in polyethyleneimine 0, 2% using a SKATRON cell harvester followed by three washes with ice-cooled filtration buffer (5 mM Tris HCl, pH 7.4). The radioactivity bound to the receptor was quantified by liquid scintillation counting using a Packard LS counter apparatus. The competition trials were carried out counting Wallac filters GF / B in Betaplate scintillation counters (Wallac). The compound prepared in the working example 11 described below was tested with this method and showed a Ki value of 6.2 nM with respect to the binding affinity for the NR2B receptor. In this assay, the compounds of the present invention showed excellent binding activity by the NR2B receptor.

Functional assay of NR2B in human cells HEK293 cells stably expressing the human NR1 b / 2B receptor were used for all functional assays. The cells were cultured in 75-cm2 culture flasks, using Dulbecco's modified Eagle medium (DMEM, high glucose) supplemented with 10% fetal bovine serum, 52 μg / ml Zeocin, 530 μg / ml Geneticin, 100 units / ml penicillin and 100 μg / ml streptomycin. Cells were maintained in a humidified atmosphere with 5% CO2 at 37 ° C and cells with a confluence of 50-60% were collected by 0.05% trypsin containing 0.53 mM EDTA. The day before the experiment, expression of the NR1 b / 2B receptor was induced by 5 μM ponasteron A in DMEM (40 ml) in the presence of 400 μM ketamine to prevent excitotoxicity. The induction was performed for 19-24 hours, using cells with a confluence of 50-60%. The cells were washed with 10 ml of Hepes Krebs-Ringer buffer without Ca2 + (KRH) containing 400 μM ketamine, and fura-2 acetoxymethyl ester was added for 2 hours at room temperature in the presence of 400 μM ketamine in KRH without Ca2 + (10 ml). Subsequently, the cells were collected in 50 ml tubes by means of a pipette and centrifuged at 850 rpm for 2 minutes. The supernatant was removed and the cells were washed with 10 ml of KRH buffer without Ca2 +, followed by another centrifugation. This manipulation was repeated 4 times to remove the ketamine, glutamate and glycine. The cells were re-suspended in KRH buffer without Ca2 + and 50 μl of cell suspension was added to each well of 96-well plates at a density of 100,000 cells / well, followed by the addition of the test compounds dissolved in 50 μl of KRH without Ca2 +. After preincubation for 30 minutes, the agonists (final concentration of 100 μM glutamic acid and 10 μM glycine) dissolved in 25 μL of KRH containing 9 mM Ca2 + (final concentration 1.8 mM) were added. The Fura-2 fluorescence (excitation wavelengths: 340 nm and 380 nm, emission wavelengths 510-520 nm) was monitored with a fluorescence imaging system, FDSS6000. The fluorescence ratio F340 / F380? (ie, the fluorescence ratio immediately after the agonist - the basal fluorescence ratio, calculated as AUC) was used for the evaluation of the effects of the drug on the changes induced by the agonists in the intracellular Ca2 +. The basal fluorescence ratio was determined in the presence of 10 μM MK-801.

Haloperidol-induced catalepsy test in rats Male CD rats were used on an empty stomach (7-8 weeks). Substantial test compound or vehicle was administered subcutaneously and then haloperidol 0.5 mg / kg s.c. Sixty minutes after the injection of haloperidol, the duration of catalepsy was quantified by placing the front legs of the animals on a raised bar and determining the withdrawal latency of the two front legs of the bar. The limit latency was 60 seconds. The experimenter did not know the treatments during the trial.

Dofetilide binding in humans Human HEK293 cells transfected with HERG were prepared and cultured. The collected cells were suspended in 50 mM Tris-HCl (pH 7.4 at 4 ° C) and homogenized using a portable Polytron PT 1200 disruptor at full power for 20 seconds on ice. The homogenates were centrifuged at 48,000 x g at 4 ° C for 20 minutes. Then, the pellets were resuspended, homogenized and centrifuged once more in the same manner. The final pellets were resuspended in an appropriate volume of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl 2 (pH 7.4 at 4 ° C) were homogenized, aliquots were distributed and stored at -80 ° C until use. An aliquot of membrane fractions was used for determination of protein concentration using the BCA protein assay kit (PIERCE) and an ARVOsx plate reader (Wallac). The binding assays were performed in a total volume of 200 μl in 96-well plates. Twenty μl of test compounds were incubated with 20 μl of [3 H] -dofetilide (Amersham, final concentration 0.5 nM) and 160 μl of membrane homogenate (25 μg protein) for 60 minutes at room temperature. The non-specific binding was determined with 10 μM dofetilide at the final concentration. Incubation was stopped by rapid filtration in vacuo on a 0.5% pre-wetted Betaplate GF / B filter using an apparatus to collect Skatron cells with 50 mM Tris-HCl, 10 mM KCl, 10 mM MgCl 2, pH 7.4 at 4 ° C. The filters were dried, placed in sample bags and filled with Betaplate Scint. The radioactivity bound to the filter was quantified by counting in a Wallac Betaplate counter.

Assay HRERG HEK 293 cells stably expressing the potassium HERG channel were used for an electrophysiological study. The methodology for stable transfection of this channel in HEK cells can be found in other references (Z. Zhou et al., 1998, Biophysical journal, 74, pp. 230-241). Before the day of the experiment, the cells were harvested from the culture flasks and cultured on glass coverslips in conventional MEM medium with 10% FCS. The cultured cells were introduced in an incubator at 37 ° C maintained in an atmosphere of 95% O2 / 5% CO2. The cells were studied between 15-28 hours after collection. HERG currents were studied using conventional zone clamping techniques in the whole cell mode. During the experiment, the cells were superfused with an external standard solution of the following composition (mM); NaCl, 130; KCl, 4; CaCl2, 2; MgCl2, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. Whole cell logs were made using a zone clamp amplifier and patch pipettes having a resistance of 1-3 MOhm when filled with the internal standard solution of the following composition (mM); KCl, 130; MgATP, 5; MgCl 2, 1, 0; HEPES, 10; EGTA, 5, pH 7.2 with KOH. Only cells with access resistors below 15 MO and resistance to closure > 1 GO were accepted for further experimentation. The resistance compensation in series was applied up to a maximum of 80%. No escape subtraction was performed. However, the acceptable access resistance depended on the size of the recorded currents and the level of resistance of series resistance that can be used safely. After achieving the entire cell configuration and sufficient for cell dialysis with pipette solution (> 5 min), a conventional voltage protocol was applied to the cell to cause membrane currents. The voltage protocol is as follows. The membrane was depolarized from a holding potential of -80 mV to +20 mV for 1000 ms. This was followed by a voltage drop ramp (speed 0.5 mV msec "1) up to the maintenance potential.The voltage protocol was applied to a cell continuously during the experiment every 4 seconds (0.25 Hz). amplitude of the maximum current induced at approximately -40 mV during the ramp.After the stable evoked current responses in the external solution were obtained, vehicle (0.5% DMSO in standard external solution) was applied for 10-20 minutes by means of a pump Peristaltic Whenever there were minimal changes in the amplitude of the current response evoked in the vehicle control state, the test compound was applied at a concentration of 0.3, 1, 3 or 10 μM for a period of 10 minutes. The 10-minute period included the time during which the supply solution was passing through the tube from the solution tank to the recording chamber by means of the pump. n of cells to the compound solution was more than 5 minutes after the drug concentration in the well of the chamber reached the attempting concentration. There was reversibility. Finally, the cells were exposed to a high dose of dofetilide (5 μM), a specific blocker of IKr, to assess the endogenous insensitive current. All the experiments were carried out at room temperature (23 ± 1 ° C). The evoked membrane currents were recorded in real time in a computer, filtered at 500-1 KHz (Bessel -3dB) and sampled at 1-2 KHz using the zone clamp amplifier and specific software for data analysis. The amplitude of the maximum current, which took place around -40 mV, was measured later in the computer. The arithmetic mean of the ten amplitude values was calculated under control conditions and in the presence of drug. The percentage reduction of IN in each experiment was obtained with the normalized current value using the following formula: IN = (1 - ID / IC) X100, where lD at the mean value of current in the presence of drug e is the value current medium under control conditions. Different experiments were performed for each drug concentration or corresponding time control and the arithmetic mean of each experiment is defined as the result of the study.

Method of PSL in mice A partial ligation surgery of the sciatic nerve (PSL) was performed according to Seltzer et al. (Pain 43, 1990, 205-218). A Von Fray hair test was applied slowly on the surface of the plant of the operated hind paw until the hairs were bent. Each hair was tested ten times in ascending order of strength in different sites of the leg with intervals of one to two seconds between each application. Once the withdrawal response was established, the leg was retested with the same hair. The least amount of force needed to elicit a response was recorded as the threshold for removal of the leg, measured in grams.

In Vitro Micronucleus Assay The in vitro micronucleus assay detects chemically induced micronucleus formation (chromosome disruption and / or loss of the entire chromosome) in vitro, by evaluating treated cultures of Chinese Hamster Ovary cells (CHO-WBL). The growth medium is McCoy's medium 5A supplemented with fetal bovine serum (FBS). The cells are incubated at approximately 37 ° C, with 95% air / 5% CO2 in a humidified chamber. The compound is dissolved in DMSO (dimethyl sulfoxide). The final volume of compound in the medium is 1%. The maximum concentration of compound should be the cytotoxic level or an amount close to this level. With a non-toxic compound, a maximum of 5 mg / ml or the lowest concentration causing precipitation is used. The test conditions include the direct assay and the metabolic activation assay where the compound is tested in the presence of an S9 rat liver fraction induced with Aroclor 1254.

The cultures are started by seeding approximately 1x104 CHO-WBL with exponential growth in McCoy's 5A medium in 8 8-well slide chambers. Twenty-four hours after sowing, the cells are treated with the compounds. In the direct assay, cells are treated with compound and Cytochalasin B for 24 hours. In the metabolic activation assay, the cells are treated with compound in the presence of S9 rat liver fraction for 3 hours, and then the cells are incubated with a new medium including Cytochalasin B for 21 hours. Approximately 24 hours from the start of treatment, the cells are incubated in hypotonic buffer (75 mM KCl) for 5 minutes. After the hypotonic treatment, the cells are fixed in the fixation solution (MeOH: acetic acid = 3: 1 v / v) and fined with acridine orange. One hundred consecutive cells are analyzed by concentration to determine the proportion of these with 1, 2 or > 3 cores per cell and 1000 binucleated cells are analyzed for the presence of micronuclei (at least 500 binucleate cells must be analyzed). A dose-dependent increase two or more times greater than the value of the negative control is considered a positive response.

Serum protein binding Serum protein binding of topical compounds NR2B (1 μM) in humans and ddY mice was measured with an equilibrium dialysis method using a 96-well plate type kit. Soaked Spectra-Por® regenerated cellulose membranes (molecular weight limit 12,000-14,000, 12 mm x 120 mm) were allowed to soak overnight in distilled water, then for 20 minutes in 30% ethanol and finally for 15 minutes in buffer of dialysis (PBS 0.10 M: phosphate buffered saline, pH 7.4). Fresh human and mouse ddY serum (20 ml each) was prepared. Dialysis was prepared with caution of not puncturing or rupturing the membranes and 150 μl of serum was added to one side of each well and 150 μl of dialysis buffer was added to the other side of each well. After 4 hours of incubation at 37 ° C at 60 rpm, the serum and the buffer samples were removed and an aliquot of the collected serum and buffer samples were mixed with the following ratios: 1) 40 μl of serum samples were mixed with 120 μl of buffer 2) 120 μl of buffer samples 40 μl of serum were mixed. Then, the mixed samples were extracted with 600 μl of acetonitrile containing (2R, 3R -2- (d-phenylmethyl) -? / - ( 2-methoxybenzyl) quinuclidin-3-amine at 25 ng / ml (as internal HPLC-MS-MS standard) and was measured with LC / MS / MS analysis Calculations: Unbound substrate fraction, fu = 1 - {([plasma] eq - [buffer] eq) / ([plasma] eq)} where [plasma] eq and [buffer] eq are the substrate concentrations in plasma and buffer, respectively.

Aqueous Solubility The aqueous solubility in media (a) - (c) was determined by method (1) or (2). (1) Vials containing about 1 mg of compound and 1 ml of each medium were stirred for 24 hours at room temperature. The insoluble materials were removed by centrifugation at 10,000 rpm for 10 minutes twice. The supernatants were analyzed by HPLC. (2) Whatman Mini-UniPrep cameras (Clifton, NJ, USA) containing more than 0.5 mg of compound and 0.5 ml of each of the media were shaken overnight (for 8 hours) at room temperature. All samples were filtered through a 0.45 μm PVDF membrane in a Whatman Mini-UniPrep plunger before analysis. The filtrates were analyzed by HPLC. < Means > : (a) Simulated gastric fluid without enzymes (SGN) at pH 1.2: Dissolve 2.0 g of NaCl in 7.0 ml of 10N HCl and enough water to make 1000 ml. (b) Phosphate buffered saline (PBS) at pH 6.5: Dissolve 6.35 g of KH2PO4, 2.84 g of Na2HPO4 and 5.50 g of NaCl in enough water to make up 1000 ml, adjusting the pH of this solution to 6.5. (c) Water for injection (WFI).

Human V1A Binding Assay A paste of CHO cells expressing the human V1a receptor was suspended in a 3-fold volume of wash buffer and cooled with ice (50 mM Tris-HCl, 5 mM MgCl2, protease inhibitors, adjusted pH to 7.4). The cells were homogenized and centrifuged at 25,000 g for 30 minutes at 4 ° C. The pellet was resuspended by homogenization in freezing buffer (50 mM Tris-HCl, 5 mM MgCl 2, 20% glycerol, pH adjusted to 7.4). The membrane homogenate was stored at -80 ° C until use. All handling was done on ice and the mother solution and the equipment were kept on ice at all times. For the saturation assay, receptor saturation was determined by incubating 8-Arg [phenylalanyl-3,4,5-3H] -vasopressin (3H-AVP) and 20 μg of cell membrane protein for 60 minutes at 25 ° C in a final volume of 250 μl of incubation buffer (50 mM Tris-HCl, 25 mM MgCl, 0.05% BSA, pH adjusted to 7.4). The total and non-specific binding (in the presence of a concentration of 1 μM of d (CH2) 5Tyr (Me) AVP [β-mercapto-β, β-cyclopentamethylene-propionyl.O-Me-Tyr ^ Arg ^ -vasopressin (ßMCPVP)) determined in a range of concentrations of 3 H-AVP (from 0.05 nM to 100 nM). For the competition assay, the test compounds were incubated with 0.5 nM 3 H-AVP and 20 μg of cell membrane protein for 60 minutes at 25 ° C in a final volume of 250 μl of incubation buffer (50 mM Tris-HCl , 5 mM MgCl 2, 0.05% BSA, pH adjusted to 7.4).

The non-specific binding was determined with a concentration of 1 μM of ßMCPVP. For all Ki calculations, the KD derived from the saturation obtained in the saturation test was used. All incubations were terminated by filtration through Unifilter Packard GF / C plates pre-soaked with 0.5% polyethylenimine followed by three washes with ice-cooled filtration buffer (50 mM Tris-HCl, 5 mM MgCl2, pH adjusted to 7.4). Then, the plates were again introduced into the incubator at 50 ° C to dry. The bottom of the Unifilter plates were hermetically sealed using Packard plate closures and 50 μl of Microscint 0 was added to each well. The plates were then hermetically sealed with Packard Topseal A and the radioactivity bound to the receptor was determined with a Packard Topcount NXT apparatus. An NMDA NR2B antagonist of the present invention can be usefully combined with another pharmacologically active compound or with two or more other pharmacologically active compounds, particularly for the treatment of pain. For example, an NMDA NR2B antagonist, particularly a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from: (i) opioid analgesics, for example morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorfan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine; (ii) non-steroidal anti-inflammatory drugs (NSAIDs), for example aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, buprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac and their pharmaceutically acceptable salts; (iii) barbiturate sedatives, for example amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, thiopental and their pharmaceutically acceptable salts; (iv) benzodiazepines with sedative action, for example chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and their pharmaceutically acceptable salts, (v) Hi antagonists with sedative action, for example diphenhydramine, pyrilamine, promethazine, chlorpheniramine , chlorocycline and its pharmaceutically acceptable salts; (vi) various sedatives such as glutethimide, meprobamate, metaqualone, dichloralphenazone and their pharmaceutically acceptable salts; (vii) skeletal muscle relaxants, for example baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, orphenadrine and their pharmaceutically acceptable salts, (viii) NMDA receptor antagonists, for example dextromethorphan ((+) - 3-hydroxy-N-methylmorphinan ) and its metabolite dextrorphan((+) - 3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinone and ciS "4- (phosphonomethyl) -2-piperidinecarboxylic acid and their pharmaceutically acceptable salts; (ix) alpha-adrenergic active compounds, for example doxazosin, tamsulosin, clonidine and 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1, 2,3,4-tetrahydro-5-quinol-2-yl) -5- (2-pyridyl) ) quinazoline, (x) tricyclic antidepressants, for example desipramine, imipramine, amitriptyline and nortriptyline, (xi) anticonvulsants, for example carbamazepine and valproate; (xii) tachykinin (NK) antagonists, particularly NK-3, NK- 2 and NK-1, for example, antagonists (aR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8,9, 10,11-tetrahydro-9-methyl-5- (4-methylphenyl) ) -7H- [1, 4] diazocino [2,1-g] [1, 7] naphthyridin-6-13-dione (TAK-637), 5 - [[(2f?, 3S) -2- [(1 R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4-morpholinyl] methyl] -1,2-dlH-dr-3H- 1, 2,4-triazol-3-one (MK-869), lanepitant, dapitant and 3 - [[2-methoxy-5- (trifluo romethoxy) phenyl] methylamino] -2-phenyl-piperidine (2S, 3S) (xiii) muscarinic antagonists, for example oxybutyn, tolterodine, propiverine, tropsium chloride and darifenacin; (xiv) COX-2 inhibitors, for example celecoxib, rofecoxib and valdecoxib; (xv) non-selective COX inhibitors (preferably with Gl protection), for example nitroflurbiprofen (HCT-1026); (xvi) analgesics derived from tar, in particular, paracetamol; (xvii) neuroleptics, such as droperidol; (xvlii) vanilloid receptor agonists, for example, resinferatoxin; (xix) beta-adrenergic compounds such as propranolol; (xx) local anesthetics such as mexiletine; (xxi) corticosteroids, such as dexamethasone; (xxii) serotonin receptor agonists and antagonists; (xxiii) cholinergic (nicotinic) analgesics; (xxiv) various agents such as Tramadol®; (xxv) PDEV inhibitors, such as sildenafil, vardenafil or taladafil; (xxvi) serotonin reuptake inhibitors, for example fluoxetine, paroxetine, citalopram and sertraline; (xxvii) mixed serotonin-noradrenaline reuptake inhibitors, for example milnacipran, venlafaxine and duloxetine; (xxviii) norepinephrine reuptake inhibitors, for example reboxetine; (xxix) atypical anti-psychotics, for example ziprasidone, olanzapine, clozapine, risperidone, sertindole, quetiapine, aripiprazole and amisulpride.

EXAMPLES The following Examples and Preparations illustrate the preparation of compounds of formula (I). The nuclear magnetic resonance (NMR) spectra of 1H were in all cases consistent with the proposed structures. The characteristic chemical shifts (d) are given in parts per million downfield of tetramethylsilane using the conventional abbreviations for the designation of the main peaks: for example s, singlet; d, doublet; t, trlplete; c, quadruplet; m, multiplet; a, wide. Mass spectra (m / z) were recorded using electrospray ionization (ESI) or chemical ionization at atmospheric pressure (APCl). The following abbreviations have been used: CDCI3, deuterochloroform; D6-DMSO, deuterodimethylsulfoxide; CD3OD, deuteromethanol; THF, tetrahydrofuran; MeOH, methanol; EtOH, ethanol; AcOEt, ethyl acetate; DMF, dimethylformamide, EDCI, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide; HOBt, 1-hydroxybenzotriazole; DIAD, diisopropyl azodicarboxylate; TBAF, tetrabutylammonium fluoride; TMSCN, trimethylsilyl cyanide; PPh3, triphenylphosphine; SEMCI, 2- (trimethylsilyl) ethoxymethyl chloride; Pd-C, palladium on carbon; mCPBA, m-chloroperbenzoic acid. "Ammonia" refers to a concentrated solution of ammonia in water with a specific gravity of 0.88. When thin layer chromatography (TLC) is used, it refers to TLC on silica gel using silica gel plates 60 F25, Rf is the distance traveled by a compound divided by the distance traveled by the solvent on a TLC plate.

EXAMPLE 1 4-Hydroxy -? -. { rc s-4- (phenoxymethyl) cyclohex »nmethyl} benzamide DIAD (0.89 mL, 4.5 mmol) was added dropwise to a mixture of 4- (benzyloxy) -? / -. { [c / s-4- (hydroxymethyl) cyclohexyl] methyl} benzamide (1.1 g, 3.0 mmol), phenol (0.42 g, 4.5 mmol) and triphenylphosphine (1.2 g, 4.5 mmol) in THF (10 mL) at 0 ° C. The mixture was stirred at room temperature for 8 hours and quenched with water and 2 N aqueous NaOH. The total mixture was extracted with CH2Cl2. The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 3: 1) to yield 4- (benzyloxy) -? / -. { [c / 's-4- (phenoxymethyl) cyclohexyl] methyl} benzamide. A mixture of 4- (benzyloxy) -N-. { [cis-4- (phenoxymethyl) cyclohexyl] methyl} Benzamide and 10% Pd-C (0.20 g) was hydrogenated at 1 atmosphere for 3 hours. The mixture was filtered through a pad of celite and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 2: 1) to give the title compound (0.68. g). 1 H NMR (CDCl 3) d: 7.66 (d, J = 8.4 Hz, 2 H), 7.31-7.24 (m, 2 H), 6.96-6.84 (m, 5 H), 6.10-6.00 (m, 1 H), 3.86 ( d, J = 6.9 Hz, 2H), 3.42 (t, J = 6.4 Hz, 2H), 2.10-1.40 (m, 10H) ppm. (No OH was observed.) MS (ESI): 340.18 (M + H) +, 338.15 (M-H) ' EXAMPLE 1A Sodium salt of 4-hydroxy- / V-. { Fc / s-4- (phenoxymethyl) cyclohexylmethylbenzamide To a solution of 4-hydroxy- / V-. { [c s-4- (phenoxymethyl) ci-clohexyl] methyl} benzamide (0.68 g, 2.0 mmol) in EtOH (20 ml), 2N aqueous NaOH (0.95 ml) was added and the mixture was concentrated in vacuo. The solid was washed with CH2Cl2 and filtered to give the title compound (0.53 g) as a white solid. 1 H NMR (DMSO-d 6) d: 7.44 (t, J = 5.7 Hz, 1H), 7.37-7.23 (m, 4 H), 6.96-6.88 (m, 3H), 5.97 (d, J = 8.8 Hz, 2H), 3.86 (d, J = 7.0 Hz, 2H), 3.13 (t, J = 6.6 Hz, 2H), 1.96- 1.30 (m, 10H) ppm. MS (ESI): 340.24 (M + H) +, 338.19 (M-H) "IR (KBr) vmax: 3350, 1599, 1547, 1497, 1296, 1246, 1175, 1035 cm EXAMPLE 2 4-Hydroxy- / V- ( { C / s-4-r (4-methoxyphenoxy) methyclocyclohexyl) methyl) benzamide A mixture of 4- (benzyloxy) -? / - ( { C / s-4 - [(4-methoxy-phenoxy) methyl] cyclohexyl} methyl) benzamide (70 mg, 0.15 mmol) and 10% Pd-C (15 mg) in MeOH (10 ml) was hydrogenated at 1 atmosphere for 2 hours. The mixture was filtered through a pad of celite and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (hexane-AcOEt 1: 1) and crystallization from CH2Cl2-hexane to give the title compound (41 mg). 1 H NMR (CDCl 3) d: 7.65 (d, J = 8.6 Hz, 2H), 6.90-6.81 (m, 6H), 6.62 (a, 1 H), 6.13-6.05 (m, 1 H), 3.81 (d, J = 6.8 Hz, 2H), 3.77 (s, 3H), 3.46-3.39 (m, 2H), 2.05-1.40 (m, 10H) ppm. MS (ESI): 370.7 (M + H) +, 367.9 (M-H) "IR (KBr) vmax: 3119, 2926, 1601, 1501, 1450, 1281, 1227, 1177 cm EXAMPLE 3 ? / -. { fc s-4- (Benzyloxy) cyclohexinmethyl} -4-hydroxybenzamide A mixture of 4-hydroxybenzoic acid (0.17 g, 1.2 mmol), [c / s-4- (benzyloxy) cyclohexyl] methylamine (0.25 g, 1.2 mmol) HOBt * H2O (0.21 g, 1.4 mmol) and EDCI (0.27 g) , 1.4 mmol) in DMF (12 ml) was stirred at room temperature for 16 hours. Aqueous 2 N NaOH (10 mL) was added and the mixture was stirred for 1 hour. The mixture was neutralized with 2N aqueous HCl (10 mL) and extracted with AcOEt. The extract was washed with saturated aqueous NaHCO3 and water. The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 1: 1). 1 H NMR (CDCl 3) d: 7.63 (d, J = 8.6 Hz, 2 H), 7.36-7.24 (m, 5 H), 7.09 (s, 1 H), 6.85 (d, J = 8.6 Hz, 2 H), 6.23-6.15 (m, 1H), 4.50 (s, 2H), 3.68-3.62 (m, 1 H), 3.33 (t, J = 6.2 Hz, 2H), 2.00-1.40 (m, 9H) ppm. MS (ESI): 340.21 (M + H) +, 338.18 (M-H) "IR (KBr) vma ?: 3227, 2926, 1612, 1508, 1439, 1277, 1175, 1094, 1045cm "1 EXAMPLE 4 ? / - ( { c / s-4-r (4-Chlorobenzyl) oxpcyclohexyl) methyl) -4-hydroxybenzamide NaH (60%, 9.6 mg, 0.24 mmol) was added to a solution of? - [(c / 's-4-hydroxyclocloxyl) methyl] -4- (methoxymethoxy) benzamide (60 mg, 0.20 mmol) in DMF (1.0 ml) and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 4-chloro-benzyl bromide (49 mg, 0.24 mmol) and the mixture was stirred at room temperature for 2 hours. To the mixture was added 10% HCl-MeOH (2.0 ml) at room temperature and the mixture was stirred at 50 ° C for 30 minutes. The mixture was diluted with AcOEt and washed with saturated aqueous NaHCO3 and water. The organic layer was dried over MgSO4 and evaporated. The residue was purified by prep TLC. (hexane: AcOEt = 1: 2) to give the title compound (2.0 mg). 1 H NMR (CDCl 3) d: 7.65 (d, J = 8.7 Hz, 2 H), 7.32-7.26 (m, 4 H), 6.85 (d, J = 8.6 Hz, 2 H), 6.20-6.10 (m, 1 H), 4.45 (s, 2H), 3.67-3.60 (m, 1 H), 3.37-3.30 (m, 2H), 2.05-1.40 (m, 9H) ppm. (No OH was observed.) MS (ESI): 374.0 (M + H) +, 371.9 (M-H) "EXAMPLE 5 ? / - (c / s-4-f (3-Chlorobenzyl) oxpccyclohexyl} methyl) -4-hydroxybenzamide This compound was prepared with 3-chlorobenzyl bromide by a procedure similar to that of Example 4. 1 H NMR (CDCl 3) d: 7.64 (d, J = 8.6 Hz, 2H), 7.36-7.20 (m, 4H), 6.85 (d , J = 8.7 Hz, 2H), 6.20-6.10 (m, 1 H), 4.46 (s, 2H), 3.67-3.60 (m, 1 H), 3.38-3.30 (m, 2H), 2.05-1.40 (m , 9H) ppm. (Not observed -OH.) MS (ESI): 374.0 (M + H) +, 371.9 (M-H) " EXAMPLE 6 4-Hydroxy- V-. { rc / 's-4- (4-methoxyphenoxy) cyclohexinmet? l} benzamide A mixture of 4- (methoxymethoxy) - / V-. { [c / s-4- (4-methoxyphenoxy) cyclohexyl] methyl} Benzamide (11 mg, 0.027 mmol) and 10% HCl-MeOH (1.0 mL) was stirred at 50 ° C for 30 minutes. The mixture was evaporated. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 1: 2) to give the title compound (10 mg). 1 H NMR (CDCb) d: 7.65 (d, J = 8.6 Hz, 2H), 7.19 (a, 1 H), 6.90-6.79 (m, 6H), 6.28-6.18 (m, 1 H), 4.45-4.38 ( m, 1H), 3.77 (s, 3H), 3.36 (t, J = 6.4 Hz, 2H), 2.10-1.45 (m, 9H) ppm. MS (ESI): 356.24 (M + H) +, 354.21 (M-H) "IR (KBr) vmax: 3327, 2930, 1609, 1506, 1443, 1281, 1229, 1177, 1038 cm" 1 EXAMPLE 7 TO/-. { rcis-4- (4-Chlorophenoxy) cyclohexinmethyl} -4-hydroxybenzamide This compound was prepared with? / -. { [c / 's-4- (4-chlorophenoxy) cyclohexyl] methyl} -4- (methoxymethoxy) benzamide by a procedure similar to that of Example 6. 1 H NMR (CDCl 3) d: 7.69 (s, 1 H), 7.62 (d, J = 8.7 Hz, 2 H), 7.20 (d, J = 8.9 Hz , 2H), 6.90-6.78 (m, 4 H), 6.32-6.22 (m, 1 H), 4.52-4.45 (m, 1H), 3.35 (t, J = 6.3 Hz, 2H), 2.10-1.96 (m , 2H), 1.78-1.40 (m, 7H) ppm. MS (ESI): 360.19 (M + H) +, 358.14 (M-H) "IR (KBr) vmax: 3358, 2928, 1609, 1508, 1489, 1443, 1281, 1242, 1173 cm" 1 EXAMPLE 8 4-Hydroxy- / V-. { ftra / 7S-1-hydroxy-4- (phenoxymethyl) cyclohexinmethyl} benzamide A mixture of 1- (aminomethyl) -4- (phenoxymethyl) cyclohexanol hydrochloride (1.1 g, 4.0 mmol), 4-hydroxybenzoic acid (0.79 g, 4.4 mmol), HOBt «H2O (0.12 g, 0.8 mmol), Et3N ( 1.1 ml, 8.0 mmol), and EDCI (0.92 g, 4.8 mmol) in DMF (40 ml) was stirred at room temperature for 16 hours. Aqueous 2 N NaOH (15 ml) and MeOH (10 ml) were added and the mixture was stirred at room temperature for 4 hours. The mixture was neutralized with 2 N aqueous HCl (15 ml) and extracted with AcOEt.

The extract was washed with saturated aqueous NaHCO3 and water, dried over MgSO 4 and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2: MeOH = 25: 1) to give the title compound (0.43 g). 1 H NMR (DMSO-d 6) d: 7.92 (t, J = 5.5 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.32-7.22 (m, 2H), 6.96-6.76 (m, 5H), 4.73 (a, 1 H), 3.82 (d, J = 6.2 Hz, 2H), 3.40-3.34 (m, 2H), 1.84-1.20 (m, 9H) ppm. (Not observed -OH.) MS (ESI): 356.17 (M + H) +, 354.13 (M-H) "IR (KBr) vmax: 3190, 2931, 2864, 1608, 1541, 1512, 1247, 1174, 1224, 1043 cm "m.p. 189.5 ° C EXAMPLE 9 / V- ( { Trans-4-r (4-Fluorophenoxy) methan-1-hydroxycyclohexyl}. Methyl) -4-hydroxybenzamide A mix of ?/-. { [traps-1-hydroxy-4- (hydroxymethyl) cyclohexyl] methyl} 4- (methoxymethoxy) benzamide (97 mg, 0.30 mmol), 4-fluorophenol (50 mg, 0.45 mmol) and cyanomethylenetributylphosphorane (0.12 g, 0.45 mmol) in toluene (1.5 ml) was stirred at 90 ° C for 1 hour. After cooling to room temperature, the mixture was purified by column chromatography on silica gel (hexane: AcOEt = 2: 1) to give? / - ( { Trans-4 - [(4-fluorophenoxy) methyl] - 1-hydroxycyclohexyl} methyl) -4- (methoxymethoxy) benzamide. The ? - ( { traps-4 - [(4-Fluorophenoxy) methyl] -1-hydroxycyclohexyl}. methyl) -4- (methoxymethoxy) benzamide was dissolved with 10% HCl -MeOH (2.0 ml) and the mixture was stirred at 50 ° C for 30 minutes. After evaporation, the residue was purified by column chromatography on silica gel (CH2Cl2: MeOH = 30: 1) to give the title compound (57 mg) as a white solid. 1 H NMR (DMSO-de) d: 10.00 (a, 1 H), 7.95-7.88 (m, 1 H), 7.73 (d, J = 8.6 Hz, 2H), 7.13-7.05 (m, 2 H), 6.96 -6.90 (m, 2H), 6.79 (d, J = 8.6 Hz, 2H), 4.71 (a, 1 H), 3.80 (d, J = 6.0 Hz, 2H), 3.37 (d, J = 6.0 Hz, 2H ), 1.82-1.60 (m, 5H), 1.35-1.14 (m, 4H) ppm. MS (ESI): 374.21 (M + H) +, 372.13 (M-H) "IR (KBr) vmax: 3379, 2937, 1630, 1611, 1555, 1508, 1248, 1207 cm -1 p.f. 176.4 ° C EXAMPLE 10 ? »* - ( { Tra 7S-4- { (3-Fluorophenoxy) metin-1-hydroxycyclohexyl}. Methyl) -4-hydroxybenzamide This compound was prepared with 3-fluorophenol by a procedure similar to that of Example 9. 1 H NMR (DMSO-d 6) d: 9.97 (a, 1 H), 7.96-7.88 (m, 1 H), 7.73 (d, J = 8.6 Hz, 2H), 7.34-7.24 (m, 1 H), 6.84-6.70 (m, 5H), 4.71 (a, 1 H), 3.84 (d, J = 6.1 Hz, 2H), 3.39-3.34 (m, 2H), 1.84-1.62 (m, 5H), 1.40-1.24 (m, 4H) ppm. MS (ESI): 374.18 (M + H) +, 372.13 (M-H) "IR (KBr) vmax: 3248, 2937, 1630, 1611, 1593, 1508, 1277, 1 36, 1119 cm -1 p.f. 186.0 ° C EXAMPLE 11 ? - ( { trans-4-r (2-Fluorophenoxy) metin-1-hydroxycyclohexyl} .methyl) -4- hydroxybenzamide This compound was prepared with 2-fluorophenol by a procedure similar to that of Example 9. 1 H NMR (DMSO-de) d: 10.00 (a, 1 H), 7.96-7.89 (m, 1 H), 7.73 (d, J = 8.6 Hz, 2H), 7.24-7.07 (m, 3H), 6.96-6.87 (m, 1 H). 6.79 (d, J = 8.6 Hz, 2H), 4.72 (a, 1 H), 3.90 (d, J = 6.4 Hz, 2H), 3.40-3.34 (m, 2H), 1.90-1.62 (m, 5H), 1.40-1.20 (m, 4H) ppm. MS (ESI): 374.22 (M + H) +, 372.16 (M-H) "IR (KBr) vmax: 3252, 2937, 1630, 1611, 1508, 1277, 1256, 1109 cm" 1 p.f.185.0 ° C EXAMPLE 12 / V- ( { Trans-4-r (2,6-Difluorophenoxy) metin-1-hydroxycyclohexyl}. Methyl) -4-hydroxybenzamide This compound was prepared with 2,6-difluorophenol by a procedure similar to that of Example 9. 1 H NMR (DMSO-d 6) d: 10.00 (a, 1 H), 7.97-7.89 (m, 1 H), 7.73 (d, J = 8.8 Hz, 2H), 7.18-7.08 (m, 3H), 6.79 (d, J = 8.6 Hz, 2H), 4.73 (a, 1 H), 3.95 (d, J = 6.0 Hz, 2H), 3.38 -3.34 (m, 2H), 1.82-1.62 (m, 5H), 1.40-1.25 (m, 4H) ppm. MS (ESI): 392.18 (M + H) +, 390.14 (M-H) "IR (KBr) vmax: 3150, 2950, 1638, 1508, 1238 cm" 1 p.f. 153.7 ° C EXAMPLE 13 / V- ( { Tra / 7s-4-f (315-Difluorophenoxy) methyl-1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide This compound was prepared with 3,5-difluorophenol by a procedure similar to that of Example 9. 1 H NMR (DMSO-d 6) d: 10.00 (a, 1 H), 7.95-7.88 (m, 1 H), 7.73 (d, J = 8.6 Hz, 2H), 6.82-6.68 (m, 5H), 4.71 (a, 1 H), 3.86 (d, J = 6.4 Hz, 2H), 3.40-3.34 (m, 2H), 1.85-1.60 ( m, 5H), 1.40-1.20 (m, 4H) ppm. MS (ESI): 392.15 (M + H) +, 390.09 (M-H) "IR (KBr) vmax: 3256, 2941, 1624, 1508, 1466, 1285, 1153, 1115 cm -1 p.f. 102.4 ° C EXAMPLE 14 / V- ( { Trans-4-r2-Chlorophenoxy) methypi-hydroxycyclohexyl > methyl) -4- hydroxybenzamide This compound was prepared with 2-chlorophenol by a procedure similar to that of Example 9. 1 H NMR (DMSO-d 6) d: 9.97 (a, 1 H), 7.96-7.88 (m, 1 H), 7.74 (d, J = 8.6 Hz, 2H), 7.41 (dd, J = 1.7, 8.9 Hz, 1 H), 7.32-7.25 (m, 1H), 7.15 (dd, J = 1.5, 8.2 Hz, 1 H), 6.97-6.90 ( m, 1 H), 6.80 (d, J = 8.6 Hz, 2H), 4.71 (a, 1 H), 3.91 (d, J = 6.4 Hz, 2H), 3.40-3.35 (m, 2H), 1.90-1.60 (m, 5H), 1.40-1.25 (m, 4H) ppm. MS (ESI): 390.17, 392.17 (M + H) +, 388.09, 389.98 (M-H) "IR (KBr) vmax: 3296, 2934, 1634, 1508, 1468, 1281, 1252 cm" 1 p.f. 159.0 ° C EXAMPLE 15 / V- ( { Trans-4-f (3-Chlorophenoxy) methyl-1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide This compound was prepared with 3-chlorophenol by a procedure similar to that of Example 9. 1 H NMR (DMSO-de) d: 10.00 (a, 1 H), 7.96-7.88 (m, 1 H), 7.73 (d, J = 8.8 Hz, 2H), 7.28 (t, J = 8.1 Hz, 1 H), 7.03-6.88 (m, 3H), 6.80 (d, J = 8.6 Hz, 2H), 4.71 (a, 1 H), 3.85 (d, J = 6.1 Hz, 2H), 3.40-3.35 (m, 2H), 1.84-1.60 (m, 5H), 1.40-1.25 (m, 4H) ppm. MS (ESI): 390.15 (M + H) +, 388.06 (M-H) "IR (KBr) vmax: 3179, 2928, 1636, 1593, 1512, 1458, 1286, 1236, 1042 cm -1 p.f. 164.9 ° C EXAMPLE 16 ? - ( { trans-4-1 (4-Chlorophenoxy) methan-1-hydroxycyclohexyl> methyl) -4-hydroxybenzamide This compound was prepared with 4-chlorophenol by a procedure similar to that of Example 9. 1 H NMR (DMSO-d 6) d: 9.99 (a, 1 H), 7.96-7.89 (m, 1 H), 7.73 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 4.72 (a, 1 H) , 3.82 (d, J = QA Hz, 2H), 3.40-3.35 (m, 2H), 1.82-1.60 (m, 5H), 1.40-1.20 (m, 4H) ppm. MS (ESI): 390.13 (M + H) +, 388.08 (M-H) "IR (KBr) vmax: 3198, 2941, 1631, 1508, 1491, 1279, 1244, 1121 cm -1 p.f. 208.2 ° C EXAMPLE 17 4-Hydroxy-W- ( { Trans-7-hydroxy-4-f (2-methylphenoxy) methyl] cyclohexyl} methyl) benzamide This compound was prepared with 2-methylphenol by a procedure similar to that of Example 9. 1H NMR (DMSO-d6) d: 9.99 (a, 1H), 7.96-7.88 (m, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.16-7.09 (m, 2H), 6.92-6.75 (m, 4H), 4.72 (a, 1 H), 3.82 (d, J = 6.0 Hz, 2H), 3.38 (d, J = 5.9 Hz, 2H), 2.16 (s, 3H), 1.86-1.60 (m, 5H), 1.42-1.25 (m, 4H) ppm. MS (ESI): 370.18 (M + H) +, 368.12 (M-H) "IR (KBr) vrnax: 3231, 2936, 1628, 1533, 1497, 1281, 1244, 1121 cm" 1 p.f. 189.1 ° C EXAMPLE 18 4-Hydroxy- / V - ((trans-1-hydroxy-4-r (3-methylphenoxy) methyncyclohexyl) methyl) benzamide This compound was prepared with 3-methylphenol by a procedure similar to that of Example 9. 1 H NMR (DMSO-d 6) d: 9.99 (a, 1 H), 7: 97-7.89 (m, 1 H), 7.73 (d, J = 8.6 Hz, 2H), 7.14 (t, J = 7.9, 1H), 6.82-6.68 (m, 5H), 4.72 (a, 1 H), 3.79 (d, J = 6.0 Hz, 2H), 3.40-3.35 (m, 2H), 2.26 (s, 3H), 1.82-1.62 (m, 5H), 1.40-1.20 (m, 4H) ppm. MS (ESI): 370.21 (M + H) +, 368.13 (M-H) "IR (KBr) vmax; 3227, 2934, 1636, 1611, 1508, 1281, 1157 cm" 1 p.f. 201.40 ° C EXAMPLE 19 4-Hydroxy- / V- ( { Tra / 7S-1-hydroxy-4-F (4-methylphenoxy) methyncyclohexyl} methyl) benzamide This compound was prepared with 4-methylphenol by a procedure similar to that of Example 9. 1 H NMR (DMSO-de) d: 10.00 (a, 1 H), 7.96-7.89 (m, 1 H), 7.73 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.3 Hz, 2H), 6.83-6.76 (m, 4H), 4.72 (a, 1 H), 3.77 (d, J = 6.2 Hz, 2H), 3.40 -3.35 (m, 2H), 2.22 (s, 3H), 1.82-1.60 (m, 5H), 1.40-1.20 (m, 4H) ppm. MS (ESI): 370.21 (M + H) +, 368.16 (M-H) "IR (KBr) vmax: 3246, 2941, 1632, 1508, 1279, 1246, 1119 cm" 1 p.f. 203.1 ° C EXAMPLE 20 4-Hydroxy -? / - ((trans- and -hydroxy-4-r (3-methoxyphenoxy) methyncyclohexyl} .methyl) benzamide Diisopropyl dicarboxylate (0.30 ml, 1.5 mmol) was added dropwise to a mixture of / V-. { [transA-hydroxy-4- (hydroxymethyl) cyclohexyl] methyl} -4- (methoxymethoxy) benzamide (0.32 g, 1.0 mmol), 3-methoxyphenol (0.19 g, 1.5 mmol) and triphenylphosphine (0.39 g, 1.5 mmol) in THF at 0 ° C and the mixture was stirred at room temperature for 2 hours. hours. The mixture was treated with 2N aqueous NaOH and extracted with CH2Cl2. The extract was washed with saturated aqueous NaCl, dried over MgSO and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 1: 1) to give? / - (. {Tratra? S-1-hydroxy-4 - [(3-methoxyphenoxy) methyl] cyclohexyl? l.}. methyl) -4-methoxy-in-methoxy) -benzamide. ? / - ( { Trans-1-hydroxy-4 - [(3-methoxyphenoxy) methyl] cyclohexyl} methyl) -4- (methoxymethoxy) benzamide was dissolved in 10% HCl-MeOH and the The mixture was stirred at 50 ° C for 30 minutes. The mixture was evaporated and the residue was purified by column chromatography on silica gel (CH2Cl2: MeOH = 15: 1), followed by preparative TLC (CH2Cl2: MeOH = 8: 1) to give the title compound (0.21 g) in the form of a white solid. 1 H NMR (DMSO-de) d: 9.96 (a, 1 H), 7.90 (t, J = 5.6, 1 H), 7.73 (d, J = 8.9 Hz, 2H), 7.20-7.11 (m, 1 H) , 6.80 (d, J = 8.6 Hz, 2H), 6.54-6.46 (m, 3H), 4.70 (a, 1 H), 3.80 (d, J = 6.1 Hz, 2H), 3.72 (s, 3H), 3.37 (d, J = 5.8 Hz, 2H), 1.85-1.60 (m, 5H), 1.42-1.20 (m, 4H) ppm. MS (ESI): 386.14 (M + H) +, 384.13 (M-H) 'IR (KBr) vmax: 3229, 2941, 1636, 1587, 1508, 1279, 1155 cm "1 p.f. 190.3 ° C EXAMPLE 21 / V- ( { Traps-4-r (Benzyloxy) metin-1-hydroxycyclohexyl}. Methyl) -4-hydroxybenzamide A mixture of / v- (. {Trart > s-4 - [(benzyloxy) methyl] -1-hydroxycyclohexyl} methyl) -4- (methoxymethoxy) benzamide (0.37 g, 1.0 mmol) and % HCl-MeOH (10 mL) was stirred at 50 ° C for 1 hour. After evaporation, the residue was purified by column chromatography on silica gel (hexane: AcOEt = 2: 3) to give the title compound (0.21 g). 1 H NMR (DMSO-de) d: 9.99 (a, 1 H), 7.91 (t, J = 5.7, 1 H), 7.73 (d, J = 8.6 Hz, 2H), 7.38-7.24 (m, 5H), 6.80 (d, J = 8.6 Hz, 2H), 4.71 (a, 1H), 4.45 (s, 2H), 3.36-3.24 (m, 4H), 1.70-1.54 (m, 5H), 1.36-1.08 (m, 4H) ppm.

MS (ESI): 368.11 (M-H) "IR (KBr) vmax: 3242, 2941, 1609, 1508, 1275, 1115 cm" 1 p.f. 165.7 ° C EXAMPLE 22 / V - [(trans-4- { R (2-Fluorobenzyl) oxymethyl > -1-hydroxycyclohexyl) methyl} -4- hydroxybenzamide NaH (60%, 20 mg, 0.5 mmol) was added to a solution of? / -. { [trans-1-hydroxy-4- (hydroxymethyl) cyclohexyl] methyl} -4- (methoxymethoxy) benzamide (0.16 g, 0.5 mmol) in DMF (2.5 ml) and the mixture was stirred at room temperature for 1 hour. To the mixture was added 2-fluorobenzyl bromide (95 mg, 0.5 mmol) at 0 ° C and the mixture was stirred overnight at room temperature. The mixture was quenched with water and diluted with AcOEt. The organic layer was washed with water and dried over MgSO4. After evaporation, the residue was purified by column chromatography on silica gel (hexane: AcOEt = 2: 1) to yield N - [(trans-4. {[[(2-fluorobenzyl) oxy] methyl.} -1-hydroxycyclohexyl) methyl] -4- (methoxymethoxy) benzamide. The ? - [(trar) s-4-. { [(2-fluorobenzyl) oxy] methyl} -1-hydroxycyclohexyl) methyl] -4- (methoxymethoxy) benzamide was dissolved in 10% HCl-MeOH (2 ml) and the mixture was stirred at 50 ° C for 30 minutes. The mixture was evaporated. After evaporation, the residue was purified by column chromatography on silica gel (hexane: AcOEt = 2: 1) to yield the title compound (32 mg) as a white solid. 1 H NMR (DMSO-d 6) d: 9.95 (a, 1 H), 7.94-7.85 (m, 1 H), 7.73 (d, J = 8.7 Hz, 2H), 7.48-7.12 (m, 4H), 6.80 (d, J = 8.7 Hz, 2H), 4.69 (a, 1 H), 4.50 (s, 2H), 3.36-3.28 (m, 4H) ), 1.70-1.54 (m, 5H), 1.38-1.10 (m, 4H) ppm. MS (ESI): 388.04 (M + H) +, 386.05 (M-H) "IR (KBr) vmax: 3283, 2941, 1634, 1508, 1281, 1223, 1084 cm" 1 p.f. 174.3 ° C EXAMPLE 22-A Sodium salt of / V-r (trans-4- (f (2-Fluorobenzyl) oxpmethyl} -1- hydroxycyclohexyl) methyl-1-4-hydroxybenzamide This compound was prepared with? / - [(trans-4. {[[(2-fluorobenzyl) oxy] methyl] -1-hydroxycyclohexyl) methyl] -4-hydroxybenzamide by a similar procedure to that of Example 1-A. 1 H NMR (DMSO-de) d: 8.17 (a, 1 H), 7.60-7.10 (m, 6H), 6.15 (d, J = 8.4 Hz, 2H), 4.50 (s, 2H), 3.36-3.20 (m , 4H), 1.72-0.98 (m, 9H) ppm.

MS (ESI): 388.05 (ES +), 386.03 (ES-) IR (KBr) vmax: 3288, 2926, 1632, 1456, 1281 cm "1 EXAMPLE 23 TO ? - ((traps-4- { r (3-Fluorobenzyl) oxpmethyl.} -1-hydroxycyclohexyl) methyl-1-4-hydroxybenzamide This compound was prepared with 3-fluorobenzyl bromide by a procedure similar to that of Example 22. 1 H NMR (DMSO-de) d: 9.95 (a, 1 H), 7.93-7.85 (m, 1 H), 7.73 (d, J = 8.6 Hz, 2H), 7.45-7.34 (m, 1 H), 7.20-7.04 (m, 3H), 6.80 (d, J. = 8.7 Hz, 2H), 4.69 (a, 1H), 4.47 (s) , 2H), 3.37-3.27 (m, 4H), 1.73-1.55 (m, 5H), 1.38-1.12 (m, 4H) ppm. MS (ESI): 388.04 (M + H) +, 386.05 (M-H) "IR (KBr) vmax: 3240, 2941, 1626, 1508, 1277, 1117 cm" 1 p.f.167.6 ° C EXAMPLE 24 ? -f (trans-4. {f (4-Fluorobenzyl) oxymethyl} -1-hydroxycyclohexyl) metin-4-hydroxybenzamide This compound was prepared with 4-fluorobenzyl bromide by a procedure similar to that of Example 22. 1 H NMR (DMSO-d 6) d: 9.96 (a, 1 H), 7.93-7.85 (m, 1 H), 7.72 (d, J = 8.8 Hz, 2H), 7.39-7.31 (m, 2H), 7.20-7.12 (m, 2H), 6.79 (d, J = 8.8 Hz, 2H), 4.69 (a, 1 H), 4.43 (s, 2H) ), 3.50-3.25 (m, 4H), 1.70-1.52 (m, 5H), 1.35-1.10 (m, 4H) ppm. MS (ESI): 388.14 (M + H) +, 386.12 (M-H) "IR (KBr) vmax: 3281, 2934, 1624, 1508, 1279, 1225, 1101 cm" 1 p.f. 167.6 ° C EXAMPLE 25 V - [(tra / 7S-4- { F (4-Chlorobenzyl) oxy] methyl.} -1-hydroxycyclohexyl) met.p-4-hydroxybenzamide This compound was prepared with 4-chlorobenzyl bromide by a procedure similar to that of Example 22. 1 H NMR (DMSO-de) d: 7.92-7.83 (m, 1 H), 7.72 (d, J = 8.4 Hz, 2H), 7.44-7.30 (m, 4H), 6.78 (d, J = 8.2 Hz, 2H), 4.70 (a, 1 H), 4.44 (s, 2H), 3.40-3.25 (m, 4H), 1.70- 1.50 (m, 5H), 1.38-1.06 (m, 4H) ppm. (Not observed -OH) MS (ESI): 404.13 (M + H) +, 402.04 (M-H) "IR (KBr) vmax: 3221, 2934, 1630, 1508, 1277, 1111 cm" 1 p.f. 164.1 ° C EXAMPLE 26 4-Hydroxy -? / -. { ftrans-1-hydroxy-4- (2-phenoxyethyl) cyclohexyl methyl} benzamide DIAD (0.35 ml, 1.8 mmol) was added to a mixture of? / -. { [tra-ris-1-hydroxy-4- (2-hydroxyethyl) -cyclohexyl] methyl} -4- (methoxymethoxy) benzamide (0.41 g, 1.2 mmol), phenol (0.17 g, 1.8 mmol) and triphenylphosphine (0.47 g, 1.8 mmol) in THF (5.0 ml) at 0 ° C and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with CH2Cl2 and washed with 2 N aqueous NaOH and water. The organic layer was dried over MgSO and evaporated. The residue was purified by column chromatography on silica gel (hexane-AcOEt 5: 2 to 1: 1) to produce N-. { [trans-1-hydroxy-4- (2-phenoxyethyl) cyclohexyl] methyl} -4- (methoxymethoxy) benzamide. The ?/-. { [trarís-1-hydroxy-4- (2-phenoxyethyl) cyclohexyl] mephile} -4- (methoxymethoxy) benzamide was dissolved in 10% HCl-MeOH (12 ml) and the mixture was stirred at 50 ° C for 30 minutes. After evaporation, the residue was purified by column chromatography on silica gel (CH2Cl2: MeOH = 30: 1) to give the title compound (0.25 g). 1 H NMR (DMSO-de) d: 9.97 (a, 1 H), 7.89 (t, J = 5.8 Hz, 1 H), 7.74 (d, J = 8.7 Hz, 2H), 7.32-7.22 (m, 2H), 6.96-6.76 (m, 5H), 4.67 (a, 1 H), 3.98 (t, J = 6.4 Hz, 2H), 3.40 -3.32 (m, 2H), 1.74-1.10 (m, 11 H) ppm. MS (ESI): 370.12 (M + H) +, 368.11 (M-H) "IR (KBr) vmax: 3231, 2928, 1626, 1508, 1283, 1246, 1119 crrf1 p.f. 168.7 ° C EXAMPLE 27 ? / - ( { trans-4-r2- (2-Fluorophenoxy) ethyl-1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide This compound was prepared with 2-fluorophenol by a procedure similar to that of Example 26. 1 H NMR (DMSO-de) d: 9.96 (a, 1 H), 7.89 (t, J = 6.1 Hz, 1 H), 7.74 (d , J = 8.7 Hz, 2H), 7.24-7.16 (m, 3H), 6.96-6.76 (m, 3H), 4.67 (a, 1 H), 4.06 (t, J = 6.6 Hz, 2H), 3.40-3.32 (m, 2H), 1.74-1.10 (m, 11 H) ppm. MS (ESI): 388.13 (M + H) +, 386.12 (M-H) "IR (KBr) vmax: 3233, 2928, 1632, 1508, 1281, 1113 cm .'- 1 p.f. 178.9 ° C EXAMPLE 28 ? / - ((tra / 7s-4-r2- (3-Fluorophenoxy) ethylM-hydroxycyclohexylmethyl) -4-hydroxybenzamide This compound was prepared with 3-fluorophenol by a procedure similar to that of Example 26. 1 H NMR (DMSO-de) d: 9.97 (a, 1 H), 7.89 (t, J = 5.8 Hz, 1 H), 7.74 (d, J = 8.7 Hz, 2H), 7.35-7.23 (m, 1H), 6.85-6.69 (m, 5H), 4.67 (a, 1 H), 4.00 (t, J = 6.6 Hz, 2H), 3.40 -3.32 (m, 2H), 1.74-1.10 (m, 11 H) ppm. MS (ESI): 388.11 (M + H) +, 386.13 (M-H) "IR (KBr) vmax: 3238, 2930, 1624, 1508, 1281, 1134 cm" 1 p.f. 134.5 ° C EXAMPLE 29 / V- ( { Trans-4-r2- (4-Fluorophenoxy) -etin-1-hydroxy-cyclohexyl} -methyl) -4-hydroxybenzamide This compound was prepared with 4-fluorophenol by a procedure similar to that of Example 26. 1 H NMR (DMSO-de) d: 9.96 (a, 1 H), 7.89 (t, J = 5.6 Hz, 1 H), 7.74 (d, J = 8.7 Hz, 2H), 7.14-7.04 (m, 2H), 6.98-6.88 (m, 2H), 6.80 (d, J = 8.7 Hz, 2H), 4.67 (a, 1 H), 3.96 (t, J = 6.4 Hz, 2H), 3.40-3.32 (m, 2H), 1.74-1.10 (m, 1 1 H) ppm. MS (ESI): 388.13 (M + H) +, 386.11 (M-H) "IR (KBr) vmax: 3285, 2937, 1634, 1508, 1209, 1026 cm" 1 p.f. 177.5 ° C EXAMPLE 30 ? - (ftrans-4- (Be? ncyloxy) -1-hydroxycyclohexinmethyl.} - 4-hydroxybenzamide A mixture of A / -. { [4- (benzyloxy) -1-hydroxycyclohexyl] methyl} -4-. { [2- (trimethylsilyl) ethoxy] methoxy} Benzamide (0.49 g, 1.0 mmol) and TBAF (1.0 M in THF, 5.0 mL) was heated at reflux for 16 h. The mixture was diluted with AcOEt and washed with saturated aqueous NH 4 Cl. The organic layer was dried over MgSO and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2: MeOH = 20: 1) and HPLC (DAICEL CHIRALCEL OJ, hexane: EtOH = 7: 3) to give the title compound (80 mg). 1 H NMR (DMSO-d 6) d: 10.01 (a, 1 H), 8.05-7.97 (m, 1 H), 7.73 (d, J = 8.6 Hz, 2H), 7.32-7.20 (m, 5H), 6.79 ( d, J = 8.6 Hz, 2H), 4.51 (a, 1 H), 4.43 (s, 2H), 3.56-3.49 (m, 1 H), 3.26 (d, J = 6.0 Hz, 2H), 1.80-1.55 (m, 6H), 1.35-1.20 (m, 2H) ppm. MS (ESI): 356.18 (M + H) +, 354.17 (M-H) "IR (KBr) vmax: 3134, 2934, 1607, 1558, 1508, 1279, 1065 cm" 1 EXAMPLE 31 HO rVr aa ? / -. { rtraps-4- (4-Chlorophenoxy) -1-hydroxycyclohexyl} methyl } -4-hydroxybenzamide EXAMPLE 32 V-. { rc s-4- (4-Chlorophenoxy) -1-hydroxy-cyclohexyphenyl} -4-hydroxybenzamide A mixture of 4-hydroxybenzoic acid (0.55 g, 4.0 mmol), 1- (aminomethyl) -4- (4-ciofophenoxy) cyclohexanol (1.0 g, 4.0 mmol), EDCI (0.92 mg, 4.8 mmol) and HOBt »H2O ( 0.74 g, 4.8 mmol) in DMF (40 ml) was stirred at room temperature for 16 hours. The mixture was diluted with AcOEt and washed with saturated aqueous NaHCO3 and water. The organic layer was dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 1: 3) to give the mixture of the title compounds (1.1 g). The mixture was separated by HPLC (DAICEL CHIRALPAK AD, hexane: EtOH: Et2NH = 85: 15: 0.1) to give Example 31 (0.32 g) and Example 32 (0.22 g).

Data for Example 31: 1 H NMR (DMSO-de) d: 9.96 (a, 1H), 8.02 (t, J = 5.9 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 4.62-4.46 (m, 2H), 3.30 (d, J = 5.9 Hz, 2H), 1.92-1.30 (m, 8H) ppm. MS (ESI): 375.9 (M + H) +, 373.9 (M-H) "IR (KBr) vmax: 3234, 2949, 1632, 1508, 1491, 1283, 1238 cm'1 p.f.199.0 ° C Data for Example 32: 1 H NMR (DMSO-de) d: 9.96 (a, 1H), 8.03 (t, J = 5.8 Hz, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 4.55 (a, 1H), 4.35-4.20 (m, 1H), 3.26 ( d, J = 6.1 Hz, 2H), 1.88-1.36 (m, 8H) ppm. MS (ESI): 375.9 (M + H) +, 373.9 (M-H) "IR (KBr) vmax: 3240, 2949, 1632, 1508, 1491, 1281, 1240 cm" 1 p.f.196.6 ° C EXAMPLE 33 / V-. { rtrans-4- (4-Chlorophenoxy) -1-hydroxycyclohexypmethyl} -3-fluoro-4- hydroxybenzamide and EXAMPLE 34 ? / -. { fcis-4- (4-Chlorophenoxy) -1-hydroxycyclohexylmethyl > -3-fluoro-4- hydroxybenzamide These compounds were prepared with 3-fluoro-4-hydroxybenzoic acid by a procedure similar to that of Examples 31 and 32. Data for Example 33: 1 H NMR (DMSO-d 6) d: 8.12 (t, J = 5.9 Hz, 1 H), 7.71-7.52 (m, 2H), 7.28 (d, J = 8.9 Hz, 2H), 7.02-6.90 (m, 3H), 4.56-4.42 (m, 2H), 3.40-3.20 (m, 2H) , 1.92-1.50 (m, 6H), 1.43-1.26 (m, 2H) ppm. (Not observed -OH) MS (ESI): 394.05 (M + H) +, 392.04 (M-H) "IR (KBr) vmax: 3350, 1957, 1639, 1512, 1310, 1238 cm" 1 p.f. 168.5 ° C Data for Example 34: 1 H NMR (DMSO-de) d: 8.11 (t, J = 5.9 Hz, 1 H), 7.72-7.54 (m, 2H), 7.28 (d, J = 8.9 Hz, 2H ), 7.01-6.90 (m, 3H), 4.34-4.20 (m, 1 H), 3.26 (d, J = 6.1 Hz, 2H), 1.86-1.36 (m, 8H) ppm. (No OH was observed) MS (ESI): 394.07 (M + H) +, 392.05 (M-H) "IR (KBr) vmax: 3319, 2941, 1618, 1512, 1489, 1300, 1242 cm" 1 p.f. 168.1 ° C EXAMPLES 35-38 (+) - 4-Hydroxy-? F- (r5S- (phenoxymethyl) tetrahydro-2-pyran-2S-] l] methyl > benzamide (-) - 4-Hydroxy-? Mr5ff- (phenoxymethyl) tetrahydro-2-pyran-2R-illmethyl} benzamide (+) - 4-Hydroxy-V-rr5R * - (phenoxymethyl) tetrahydro-2A / -pyran-2S * - 1] methyl]} b? nzam¡da (-) - 4-Hydroxy -? / - (r5S * - (phenoxymethyl) tetrahydro-2-pyran-2? * - il] methyl) benzamide 4- (methoxymethoxy) -? / - was dissolved. { [5-phenoxymethyl] tetrahydro-2 - / - pyran-2-yl} methyl } Benzamide (678 mg, 1.76 mmol) in 10-20% HCl-MeOH (5 mL) and stirred at room temperature for 2 hours. To this mixture was added H2O (50 ml) and AcOEt (50 ml). The aqueous layer was extracted with AcOEt (50 ml) and the combined organic layers were washed with saturated aqueous NaHCO3 (50 ml) and brine (50 ml), dried over Na2SO and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to give the mixture of the title compounds (0.55 g, 92%). 4 stereoisomers were separated with a chiral column (Chiralpak AD-H, 20 mm Dl x 250 mm (No. ADH0CJ-DE003), DAICEL) using n-Hexane: 2-Propanol: Et2NH = 90: 10: 0.1 as eluent (Speed of flow: 10 ml / minute).

Data for Example 35: Sticky colorless solid, 99% ee, cis-isomer, retention time 33 min 1 H NMR (300 MHz, DMSO) d: 8.26-8.22 (m, 1 H), 7.73-7.69 (m, 2H), 7.31-7.25 (m, 2H), 6.97-6.90 (m, 3H), 6.80-6.75 (m, 2H), 4.17-4.11 (m, 1 H), 4.10-3.90 (m, 2H), 3.56 -3.44 (m, 2H), 3.29-3.19 (m, 2H), 1.95 (sa, 1 H), 1.87-1.67 (m, 2H), 1.50-1.30 (m, 2H) ppm. (Not observed -OH) MS (ESI): 342.1 (M + H) +, 340.1 (M-H) "[a] D = + 12.00 (c = 0.10, MeOH, 26 ° C) Data for Example 36: Sticky colorless solid, 99% ee, cis-isomer, retention time 36 minutes 1 H NMR (300 MHz, DMSO) d: 8.25-8.22 (m, 1 H), 7.72-7.69 (m, 2H), 7.31-7.26 (m, 2H), 6.97-6.90 (m, 3H), 6.78-6.76 (m, 2H), 4.16-4.11 (m, 1 H), 4.04-3.90 (m, 2H), 3.55 -3: 47 (m, 2H), 3.27-3.23 (m, 2H), 1.95 (sa, 1H), 1.86-1.69 (m, 2H), 1.49-1.23 (m, 2H) ppm. (No OH) MS (ESI): 342.1 (M + H) +, 340.1 (M-H) "[a] D = -20.00 (c = 0.04, MeOH, 26 ° C) Data for Example 37: Recrystallized in IPA / IPE; solid white, > 99% ee, trans, retention time 47 min 1 H NMR (300 MHz, CDCl 3) d: 7.71-7.61 (m, 2H), 7.31-7.25 (m, 2H), 6.70-6.85 (m, 5H), 6.53 ( sa, 1 H), 6.22 (sa, 111), 4.23-4.18 (m, 1 H), 3.85- 3.69 (m, 3H), 3.52-3.46 (m, 1 H), 3.30-3.21 (m, 2H) , 2.15-2.11 (m, 1 H), 1.98-1.95 (m, 1 H), .78-1.74 (m, 1 H), 1.48-1.36 (m, 2H) ppm. MS (ESI): 342.1 (M + H) +, 340.1 (MH) "[a] D = + 28.9 (c = 0.18, MeOH, 26 ° C) pf = 152.1 ° C IR (KBr) = 3355.9, 2935.5, 1635.5, 1508.2, 1226.6, 1074.3 cm "1 Data for Example 38: Recrystallized in IPA / IPE; white solid; 99% ee, trans, retention time 51 min 1 H NMR (300 MHz, CDCl 3) d: 7.70-7.67 (m, 2H), 7.30-7.27 (m, 2H), 6.97-6.85 (m, 5H), 6.60-6.35 (m, 2H), 4.23-4.19 (m, 1H), 3.85-3.70 (m, 3H), 3.50-3.46 (m, 1H), 3.30- 3.21 (m, 2H), 2.12 (sa, 1H), 1.98-1.95 (m, 1H), 1.77-1.73 (m, 1 H), 1.52-1.36 (m, 2H) ppm.

MS (ESI): 342.1 (M + H) +, 340.1 (MH) "[a] D = -25.3 (c = 0.19, MeOH, 26 ° C) pf = 152.4 ° C IR (KBr) = 3355.9, 2935.5, 1635.5, 1508.2, 1226.6, 1074.3 cm " EXAMPLES 39-42 4-Hydroxy-? Mr5S- (benzHoxymethyl) tetrahydro-2rt-pyran-2S-illmethyl} benzamide 4-Hydroxy -? / -. { r5f? - (benzyloxymethyl) tetrahydro-2f / -pyran-2i-i! 1meti !} benzamide 4-Hydroxy- / V- (r5f? * - (benzyloxymethyl) tetrahydro-2A / -pran-2S * - nmethiDbenzamide 4-Hydroxy -? / - (r5S * - (benzyloxymethyl) tetrahydro-2-pyran-2 /? * - methyl}. Benzamide 4- (benzyloxymethoxy) -? -. { [5-phenoxymethyl] tetrahydro-2H-pyran-2-yl} methyl } benzamide (1.6 g, 4.0 mmol) in 10-20% HCl-MeOH (10 mL) and stirred at room temperature for 2 hours. To the mixture was added H2O (50 ml) and AcOEt (50 ml). The aqueous layer was extracted with AcOEt (50 ml) and the combined organic layers were washed with saturated NaHCO3 (50 ml) and brine (50 ml), dried over Na2SO and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to give the mixture of the title compounds (1.20 g, 83%). 4 stereoisomers were separated with a chiral column (Chiralpak AD-H, 20 mm Dl x 250 mm (No. ADH0CJ-DE003), DAICEL) using n-Hexane / 2-Propanol / Et2NH = 85: 15: 0.1 as eluent (10 ml / minute).

Data for Example 39: Colorless amorphous, > 99% ee, cis isomer, retention time 18 min 1 H NMR (300 MHz, DMSO) d: 8.25-8.21 (m, 1 H), 7.72-7.69 (m, 2H), 7.38-7.25 (m, 5H), 6.80-6.76 (m, 2H), 4.50 (d, J = 12.3 Hz, 1 H), 4.45 (d, J = 12.3 Hz, 1 H), 3.33-3.79 (m, 1H), 3.61-3.56 (m, 1 H), 3.48-3.43 (m, 3H), 3.28- 3.15 (m, 2H), 1.77-1.59 (m , 3H), 1.44-1.41 (m, 1 H), 1.32-1.19 (m, 1 H) ppm.

(No OH) MS (ESI): 356.1 (M-t-H) +, 354.1 (M-H) ".

Data for Example 40: Colorless amorphous; > 99% ee, cis isomer; retention time 21 min 1 H NMR (300 MHz, DMSO) d: 8.25-8.21 (m, 1 H), 7.72-7.69 (m, 2H), 7.38-7.25 (m, 5H), 6.78-6.76 (m, 2H), 4.50 (d, J = 12.0 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H), 3.83-3.79 (m, 1H), 3.61-3.56 (m, 1H), 3.48-3.43 (m, 3H), 3.28- 3.17 (m, 2H), 1.77-1.59 (m, 3H), 1.45-1.41 (m, 1 H), 1.32-1.19 (m, 1 H) ppm. (No OH) MS (ESI): 356.1 (M + H) +, 354.1 (M-H) ".

Data for Example 41: Colorless amorphous, > 99% ee, trans isomer, retention time 34 min 1 H NMR (300 MHz, DMSO) d: 8.26-8.22 (m, 1 H), 7.71 (d, J = 8.4 Hz, 2H), 7.37-7.25 (m, 5H), 6.77 (d, J = 8.4 Hz, 2H), 4.45 (d, J = 12.6 Hz, 1 H), 4. 40 (d, J = 12.6 Hz, 1H), 3.97-3.94 (m, 1 H), 3.27-3.21 (m, 5H), 3.10-3.03 (m, 1 H), 1.79 (sa, 2H), 1.67- 1.63 (m, 1H), 1.18 (br s, 2H) ppm. (No OH was observed) MS (ESI): 356.1 (M + H) +, 354.1 (MH) "Data for Example 42: Colorless amorphous, 98% ee, trans isomer, retention time 38 min 1 H NMR (300 MHz , DMSO) d: 8.32-8.22 (m, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.38-7.24 (m, 5H), 6.77 (d, J = 8.7 Hz, 2H), 4.45 (d , J = 12.9 Hz, 1 H), 4. 41 (d, J = 12.9 Hz, 1 H), 3.97-3.94 (m, 1 H), 3.27-3.17 (m, 5H), 3.10-3.03 (m, 1 H), 1.79 (sa, 2H), 1.67 -1.64 (m, 1 H), 1.18 (s at, 2H) ppm. (Not observed -OH) MS (ESI): 356.1 (M + H) +, 354.1 (M-H) ".

EXAMPLES 43-46 (-) - 4-Hydroxy -? / - (r (3?, 6S) -6- (phenoxymethyl) tetrahydro-2-pyran-3-yl] methyl.} Benzamide (< -) - 4-Hydroxy- V- (r (3S, 6?) - 6- (phenoxymethyl) tetrahydro-2 / -pyran-3-ylmethyl} benzamide (+) - 4-Hydroxy -? / - (r (3 .6 /?) - 6- (phenoxymethyl) tetrahydro-2H pyran-3-Hmethi-benzanriid (-) - 4-Hydroxy-? r (3S, 6S) -6- (phenoxymethyl) tetrahydro-2-tf-pyran-3-illmethylbenzamide A mix of . { [6- (phenoxymethyl) tetrahydro-2H-pyran-3-yl] methyl} amine (0.13 g), 4-hydroxybenzoic acid (83 mg, 0.60 mmol), HOBt »H2O (0.11 g, 0.72 mmol) and EDCI (0.14 g, 0.72 mmol) in DMF (3.0 ml) was stirred at room temperature for 16 hours. The mixture was diluted with AcOEt and washed with saturated aqueous NaHCO3 and water, dried over MgSO and evaporated. The residue was dissolved with MeOH (3 mL) and 2 N aqueous NaOH (3 mL). The mixture was stirred for 2 hours and neutralized with 2N aqueous HCl (3 mL). All was extracted with AcOEt. The extract was washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and evaporated. The residue was purified by preparative TLC (hexane: AcOEt = 1: 2) to give the mixture of the title compounds. 4 stereoisomers were separated by chiral HPLC (DAICEL Chiralpak AD-H, hexane / EtOH / Et2NH = 85/15 / 0.1).

Data for Example 43 Amorphous colorless, > 99% ee, cis isomer, retention time 25 min 1 H NMR (CDCl 3) d: 7.67 (d, J = 8.6 Hz, 2H), 7.31-7.24 (m, 3H), 6.98-6.82 (m, 4H), 6.47 -6.37 (m, 1 H), 5.89 (a, 1 H), 4.05-3.48 (m, 7H), 2.04-1.50 (m, 5H) ppm. MS (ESI): 342.12 (M + H) + IR (KBr) 3250, 2934, 2860, 1607, 1587, 1508, 1454, 1242 cm'1 Isomer 1: [a] D = - 7.2 (c = 0.- 25, MeOH) Data for Example 44 Amorphous colorless, > 99% ee, cis isomer, retention time 27 minutes 1 H NMR (CDCb) d: 7.67 (d, J = 8.6 Hz, 2H), 7.31-7.24 (m, 3H), 6.98-6.82 (m, 4H), 6.47 -6.37 (m, 1 H), 5.73 (a, 1 H), 4.05-3.48 (m, 7H), 2.04- 1.50 (m, 5H) ppm. MS (ESI): 342.13 (M + H) + IR (KBr) 3250, 2934, 2860, 1607, 1587, 1508, 1454, 1242 cm'1 Isomer 2: [a] D = + 8.8 (c = 0.25, MeOH ) Data for colorless amorphous Example 45, > 99% ee, trans isomer, retention time 59 min 1 H NMR (DMSO-de) d: 9.94 (a, 1 H), 8.25-8.15 (m, 1 H), 7.67 (d, J = 8.7 Hz, 2H) , 7.31-7.23 (m, 2H), 6.96-6.88 (m, 3H), 6.78 (d, J = 8.7 Hz, 2H), 3.96-3.86 (m, 3H), 3.65-3.50 (m, 1 H), 3.16-3.00 (m, 3H), 1.93-1.65 (m, 3H), 1.45-1.10 (m, 2H) ppm. MS (ESI): 342.14 (M + H) +, 340.12 (M-H) ". Isomer 3: [a] D = + 2.4 (c = 0.25, MeOH) Data for Example 46 Amorphous colorless, > 99% ee, trans isomer, retention time 71 min 1 H NMR (DMSO-de) d: 9.93 (a, 1 H), 8.25-8.15 (m, 1 H), 7.67 (d, J = 8.7 Hz, 2H) , 7.31-7.23 (m, 2H), 6.96-6.88 (m, 3H), 6.78 (d, J = 8.7 Hz, 2H), 3.96-3.86 (m, 3H), 3.65-3.50 (m, 1 H), 3.16-3.00 (m, 3H), 1.93-1.65 (m, 3H), 1.45-1.10 (m, 2H) ppm. MS (ESI): 342.13 (M + H) +, 340.10 (M-H) '. Isomer 3: [a] D = - 3.4 (c = 0.50, MeOH) EXAMPLE 47 / V- ( { TraMis-4-f (4-Fluorobenzyl) oxyl-1-hydroxycyclohexyl}. Methyl) -4-hydroxybenzamide To a solution of 4- acetate. { [( { 4 - [(4-fluorobenzyl) oxy] -1-hydroxycyclohexyl] methyl) amino] carbonyl} phenyl (4.0 g, 9.6 millimoles) in MeOH (20 ml) and THF (20 ml) was added 2N aqueous NaOH (9.6 ml) at 0 ° C and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was adjusted to pH 4.0 with 2N aqueous HCl. The solvent was removed in vacuo. The residue was extracted with ethyl acetate (50 ml x 3). The combined organic layer was dried over Na2SO and concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane: methanol = 20: 1 as eluent) and HPLC to yield the title compound as a white solid (248 mg, 7%; 1 H NMR (DMSO). d6) d: 9.97 (a, 1 H), 8.02-7.98 (m, 1 H), 7.74-7.71 (m, 2H), 7.35-7.30 (m, 2H), 7.12-7.06 (m, 2H), 6.81 -6.78 (m, 2H), 4.50 (a, 1 H), 4.41 (s, 2H), 3.52 (a, 1 H), 3.26 (d, J = 6.0 Hz, 2H), 1.79-1.58 (m, 6H), 1.32-1.26 (m, 2H) ppm. MS (ESI): 374.12 (M + H) +, 372.12 (M-H) "IR (KBr) vmax: 2932, 1703, 1508, 1227, 1084, 826 cm" 1 Anal. Caled, for C2? H24NO4F: C, 67.54; H, 6.48; N, 3.75.

Found: C, 67.43; H, 6.47; N; 3.70 p.f. 122.1 ° C, 160.9 ° C EXAMPLE 48 ? / - ( { trans-4-f (2-Fluorobenzyl) oxyM-hydroxycyclohexyl}. methyl) -4-hydroxybenzamide This compound was prepared with 4- acetate. { [( { 4 - [(2-fluorobenzyl) oxy] -1-hydroxycyclohexyl] methyl) amino] carbonyl} phenol by a procedure similar to that of Example 47 in the form of a white solid. H NMR (DMSO-de) d: 9.96 (a, 1 H), 8.01-7.97 (m, 1 H), 7.73-7.70 (m, 2H), 7.44-7.29 (m, 2H), 7.18-7.10 (m , 2H), 6.80-6.77 (m, 2H), 4.50-4.48 (m, 3H), 3.55 (a, 1 H), 3.26 (d, J = 5.9 Hz, 2H), 1.80-1.57 (m, 6H) , 1.31-1.27 (m, 2H) ppm. MS (ESI): 374.08 (M + Hf, 372.04 (MH) "IR (KBr) vmax: 3142, 1607, 1234, 1067, 763 cm" 1 Anal.Called, for C2? H24NO4F: C, 67.54; H, 6.48; N, 3.75 Found: C, 67.32; H, 6.58; N; 3.78 pf 162.9 ° C, 179.9 ° C EXAMPLE 49 3-Fluoro-? - ( { Trans-4-f (3-fluorobenzyl) oxy-1-hydroxy-cyclohexinmethyl} -4- hydroxybenzamide This compound was prepared with 4-hydroxy-3-fluorobenzoic acid and 1- (aminomethyl) -4 - [(3-fluorobenzyl) oxy] cyclohexane by a procedure similar to that of Example 8 in the form of a white solid. 1 H NMR (DMSO-de) d: 8.09-8.07 (m, 1 H), 7.69-7.68 (m, 1 H), 7.57-7.54 (m, 1 H), 7.37-7.29 (m, 1 H), 7.15 -7.04 (m, 3H), 7.00-6.93 (m, 1 H), 4.46 (s, 2H), 3.53 (a, 1 H), 3.28-3.26 (m, 2H), 1.81-1.58 (m, 6H) , 1.32-1.27 (m, 2H) ppm. [No protons of PhOH and OH were observed.] MS (ES): 392.05 (M + H) +, 390.03 (M-H) "IR (KBr) vmax: 2934, 1589, 1110, 785 cm" 1 Anal. Caled, for C21H23NO4F2: C, 64.44; H, 5.92; N, 3.58. Found: C, 64.12; H, 5.95; N, 3.61 p.f. 138.2 ° C EXAMPLE 50 3-Fluoro-V - [(tra / 7s-4- { R (3-fluorobenzyl) oxpmethyl} -1-hydroxycyclohexyl) metip-hydroxybenzamide This compound was prepared with 4-hydroxy-3-fluorobenzoic acid and trans- 7- (aminomethyl) -4-. { [(3-fluorobenzyl) oxy] methyl} cyclohexanol by a procedure similar to that of Example 8 in the form of a white solid. 1 H NMR (DMSO-de) d: 10.48 (a, 1 H), 8.04-8.00 (m, 1 H), 7.71- 7.66 (, 1 H), 7.59-7.55 (m, 1H), 7.43-7.35 (m , 1 H), 7.17-7.06 (m, 3H), 7.01-6.96 (m, 1 H), 4.62 (a, 1 H), 4.47 (s, 2H), 3.34 (m, 2H), 3.29 (d, J = 6.0 Hz, 2H), 1.64-1.60 (m, 5H), 1.33-1.16 (m, 4H) ppm. MS (ESI): 406.07 (M + H) +, 404.09 (M-H) 'IR (KBr) vmax: 3179, 1638, 1516, 1298, 1094 cm'1 Anal. Caled, for C22H25NO4F2: C, 65.17; H, 6.22; N, 3.45. Found: C, 65.14; H, 6.24; N; 3.47 p.f. 132.4 ° C EXAMPLE 51 3-Fluoro- / V- ( {trans-4-f2- (2-fluorophenoxy) ethyl] -1-hydroxycyclohexyl > methyl) -4- hydroxybenzamide This compound was prepared with 4-hydroxy-3-fluorobenzoic acid and trans-1- (aminomethyl) -4- [2- (2-fluorophenyl) ethyl] cyclohexanol by a procedure similar to that of Example 8 in the form of a white solid. 1 H NMR (DMSO-de) d: 10.46 (a, 1 H), 8.04-8.02 (m, 1 H), 7.72-7.71 (m, 1 H), 7.67-7.57 (m, 1 H), 7.22-6.90 (m, 5H), 4.59 (a, 1 H), 4.09-4.04 (m, 2H), 3.37 (m, 2H), 1.68-1.16 (m, 11 H) ppm. MS (ESI): 406.05 (M + H) +, 404.02 (M-H) "IR (KBr) vmax: 3217, 2928, 1634, 1508, 1285, 1113 cm" 1 Anal. Caled, for C22H25NO4F2: C, 65.17; H, 6.22; N 3.45. Found: C, 64.98; H, 6.18; N 3.46; p.f. 184.7 ° C EXAMPLES 52 AND 53 Cis- and Trans- / V-ff4- (4-chlorophenoxy) cyclohexinmethyl} -3-fluoro-4- hydroxybenzamide A mixture of 4- (azidomethyl) cyclohexyl 4-chlorophenyl ether (3.0 g, 11 mmol) and 10% Pd / C (0.3 g) in MeOH (50 mL) was stirred under an atmosphere of H2 at room temperature. After 14 hours, the mixture was filtered through a pad of celite and washed with MeOH (50 ml) and concentrated in vacuo. The residue (0.76 g of 2.5 g, -3.4 mmol) was dissolved in DMF (20 ml) and to this was added 3-fluoro-4-hydroxybenzoic acid (0.5 g, 3.2 mmol), WSC (0.73 g, 3.8 millimoles), HOBt (0.58 g, 3.8 mmol) and Et3N (0.90 mL, 6.4 mmol). After 18 hours, the reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (50 ml) and diluted with AcOEt (50 ml). The aqueous layer was extracted with AcOEt (50 ml x 2) and the combined organic layer was washed with H 2 O (50 ml x 2) and brine (50 ml), dried over MgSO, filtered and concentrated. The residue was dissolved in MeOH (15 ml) and 2N NaOH (10 ml) was added to this solution and the mixture was stirred at room temperature. After 2 hours, saturated aqueous NaHCO3 (50 ml) was added thereto and extracted with AcOEt (100 ml). The aqueous layer was extracted with AcOEt (50 ml) and the combined organic layer was washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 2: 1-1.5: 1) and separation by HPLC to give 3-fluoro-4-hydroxy-β - [(4-phenoxycyclohexyl) methyl] benzamide (94.7 mg, 8% in 2 stages) and? / -. { [4- (4- chlorophenoxy) cyclohexyl] methyl} -3-fluoro-4-hydroxybenzamide (80.7 mg, 6% in 2 steps). The cis? Rans separation of / V-. { [4- (4-chlorophenoxy) cyclohexyl] methyl} -3-fluoro-4-hydroxybenzamide was performed with a chiral column (Chiralcel OJ, 20 mm Dl x 250 mm (No. 53-03-20910), DAICEL) using n-hexane: EtOH: Et2NH = 79:21: 0.1 as eluent (Flow rate = 7 ml / minute) at 40 ° C.

EXAMPLE 52 White solid, 99% ed, trans isomer, retention time 24 minutes. 1 H NMR (300 MHz, CDCl 3) d: 7.59 (dd, J = 11.1, 2.1 Hz, 1 H), 7. 46-7.42 (m, 1 H), 7.24-7.18 (m, 2H), 7.04 (t, J = 8.4 Hz, 1 H), 6.84-6.79 (m, 2H), 6.08 (s a, 1 H), 4.11 (tt, J = 10.8, 4.2 Hz, 1 H), 3.34 (t, J = 6.3 Hz, 2H), 2. 19-2.15 (m, 2H), 1.94-1.90 (m, 2H), 1.71-1.59 (m, 1H), 1.50-1.36 (m, 2H), 1.29-1.07 (m, 2H) ppm. (No OH was observed.) MS (ESI): 378.07 (M + H) +, 376.08 (M-H) "EXAMPLE 53 White solid, 98% ed, cis isomer, retention time 28 min. 1 H NMR (300 MHz, CDCl 3) d: 7.57 (dd, J = 11.1, 2.1 Hz, 1 H), 7.44-7.41 (m, 1 H), 7.24-7.19 (m, 2H), 7.02 (t, J = 8.4 Hz, 1 H), 6.85-6.80 (m, 2H), 6.12 (sa, 1 H), 4.49 (sa, 1 H), 3.35 (t, J = 7.5 Hz, 2H), 2.06-2.02 (m, 2H), 1.72-1.28 (m, 7H) ppm. (No OH was observed.) MS (ESI): 378.10 (M + H) +, 376.07 (M-H) " EXAMPLE 54 ? / -. { rc / s-4- (4-Fluorophenoxy) cyclohexylmethyl} ° 4 ° hydroxybenzamide This compound was prepared with? / -. { [c / s-4- (4-fluorophenoxy) cyclohexyl] methyl} -4- (methoxymethoxy) benzamide by a procedure similar to that of Example 6 in the form of a white solid. 1 H NMR (DMSO-de) d: 9.94 (a, 1 H), 8.22-8.18 (m, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.12-7.06 (rn, 2H), 6.98-6.93 (m, 2H), 6.78 (d, J = 8.7 Hz, 2H), 4.49 (m, 1 H), 3.15-3.11 (m, 2H), 1.87-1.84 (m, 2H), 1.65-1.49 (m, 5H), 1.35-1.26 (m, 2H) ppm. MS (ESI): 344.20 (M + H) \ 342.19 (M-H) 'IR (KBr) vmax: 3283, 2934, 632, 1502, 1202 cm'1 Anal. Caled, for C20H22NO3F: C, 69.95; H, 6.46; N, 4.08. Found: C, 70.10; H, 6.46; N; 4.10. p.f. 170.5 ° C EXAMPLE 55 3-Fluoro -? / -. { rc s-4- (4-fluorophenoxy) cyclohexinmethyl} -4-hydroxybenzamide This compound was prepared with 3-fluoro-4-hydroxybenzoic acid and. { [4- (4-fluorophenoxy) cyclohexyl] methyl} amine by a procedure similar to that of Example 8 in the form of a white solid. 1 H NMR (DMSO-de) d: 8.29 (m, 1 H), 7.64-7.52 (m, 2H), 7.12-7.06 (m, 2H), 6.98-6.93 (m, 4H), 4.50 (a, 1 H), 3.16-3.11 (m, 2H), 1.87-1.26 (m, 9H) ppm. MS (ESI): 362.13 (M + H) +, 360.08 (M-H) "IR (KBr) vmax: 1498, 1436, 833, 760 cm" 1. Anal. Caled, for C20H21NO3F2: C, 66.47; H, 5.86; N, 3.88.

Found: C, 66.35; H, 5.83; N; 3.90. p.f. 149.5 ° C EXAMPLE 56 ? - ( { tra / 7s-4-r2- (2-Fluorophenoxy) et.n-1-hydroxycyclohexyl} methyl) -1-pyrazole-4-carboxamide This compound was prepared with 1 / -pyrazole-4-carboxylic acid and trans-1- (aminomethyl) -4- [2- (2-fluorophenyl) ethyl] cyclohexanol by a procedure similar to that of Example 8 in the form of a solid. White. 1 H NMR (DMSO-de) d: 13.11 (a, 1 H), 8.08 (a, 2H), 7.82-7.78 (m, 1 H), 7.23-7.08 (m, 3H), 6.95-6.87 (m, 1 H), 4.59 (a, 1 H), 4.09-4.04 (m, 2H), 3.31 (m, 2H), 1.68-1.16 (m, 11 H) ppm. MS (ESI): 362.18 (M + H) + IR (KBr) vmax: 3173, 2924, 1636, 1508, 1283, 746 cm'1 Anal. Caled, for C19H24N3O3F: C, 63.14; H, 6.69; N, 11.63.

Found: C, 62.99; H, 6.63; N; 11.61 p.f. 175.1 ° C EXAMPLE 57 / V-ITtrans-1-Hydroxy-4- (phenoxymethyl) cyclohexinmethyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-carboxamide This compound was prepared with 2-oxo-2,3-dihydro-1,3-benzoxazole-6-carboxylic acid by a procedure similar to that of Example 8 in the form of a white solid. 1 H NMR (DMSO-de) d: 11.92 (a, 1H), 8.20-8.11 (m, 1H), 7.81 (s, 1H), 7.78-7.70 (m, 1H), 7.30-7.21 (m, 2H), 7.15 (d, J = 8.1 Hz, 1H), 6.96-6.86 (m, 3H), 4.65 (s, 1 H), 3.82 (d, J = 6.1 Hz, 2H), 3.45-3.35 (m, 2H), 1.83-1.60 (m, 5H), 1.40-1.20 (m, 4H) ppm. MS (ESI): 397.22 (M + H) +, 395.21 (M-H) "IR (KBr) vmax: 2934, 1763, 1601, 1495, 1240, 754 cm" 1 EXAMPLE 58 4-Hydroxy- / V-. { fc / s-4- (2-phenylethoxy) cyclohexyl] | methyl} benzamide This compound was prepared with. { [c / 's-4- (2-phenylethoxy) cyclohexyl] methyl} amine by a procedure similar to that of Example 8 in the form of a white solid. 1 H NMR (DMSO-de) d: 9.92 (a, 1 H), 8.20-8.11 (m, 1 H), 7.70 (d, J = 8.7 Hz, 2H), 7.32-7.14 (m, 5H), 6.78 (d, J = 8.7 Hz, 2H), 3.60-3.40 (m, 3H), 3.10-3.00 (m, 2H), 2.85-2.75 ( m, 2H), 1.80-1.10 (m, 9H) ppm. IR (KBr) vmax: 2922, 1541, 1277, 1238, 1175, 754 cm "1EXAMPLE 59 2-Fluoro-4-hydroxy -? / -. { f (tra / 7s-1-hydroxy-4- (phenoxymethyl) cyclohexylmethyl) benzamide This compound was prepared with 2-fluoro-4-hydroxybenzoic acid or a procedure similar to that of Example 8 in the form of a white solid.

H NMR (DMSO-d6) d: 10.47 (a, 1 H), 7.76-7.45 (m, 2H), 7.31- 7.21 (m, 2H), 6.96-6.85 (m, 3H), 6.72-6.55 (m, 2H), 4.68 (s, 1 H), 3.82 (d, J = 6.2 Hz, 2H), 3.45-3.35 (m, 2H), 1.83-1.60 (m, 5H), 1.40-1.20 (m, 4H) ppm . MS (ESI): 374.23 (M + H) +, 372.24 (M-H) 'IR (KBr) vmax: 3200, 2938, 1495, 1227, 847, 768 cm "1 EXAMPLE 60 / V - ((trans-4-r (Benzyloxy) metin-1-hydroxycyclohexyl} methyl) -3-fluoro-4-hydroxybenzamide This compound was prepared with 3-fluoro-4-hydroxybenzoic acid and trans-1- (aminomethyl) -4 - [(benzyloxy) methyl] cyclohexanol hydrochloride by a procedure similar to that of Example 8. 1 H NMR (300 MHz, DMSO) d: 8.01 (m, 1 H), 7.70-7.55 (m, 2H), 7.37-7.24 (m, 5H), 6.98 (t, J = 8.61 Hz, 1 H), 4.44 (s, 2H), 3.29-3.27 (m, 4H), 1.63-1.60 (m, 5H), 1.32-1.15 (m, 4H) ppm. (No OH was observed.) MS (ESI): 386.16 (M-H) "p.f. = 162.5 ° C IR (KBr) vmax: 3355.9, 2945.1, 1635.5, 1517.9, 1299.9, 1093.6 cm" 1.

Anal. Caled for C22H26NO4F: C, 68.20, H, 6.76, N, 3.62, O, 16.52, F, 4.90. Found: C, 68.12, H, 6.93, N, 3.63.

EXAMPLE 61 ? t '- ( { c /' s-4-r (Benzyloxy) methyclohexyl}. methyl) -4-hydroxybenzamide This compound was prepared with ( {c / s-4- [(benzyloxy) methyl] cyclohexyl} methyl) amine by a procedure similar to that of Example 8. 1 H NMR (CDCl 3) d: 7.65 (d, J = 8.7 Hz, 2H), 7.36-7.24 (m, 5H), 6.86 (d, J = 8.7 Hz, 2H), 6.48 (s, 1 H), 6.10-6.00 (m, 1 H), 4.50 (s, 2H) ), 3.44-3.35 (m, 4H), 1.95-1.35 (m, 10H) ppm. MS (ESI): 354.23 (M + H) +, 352.23 (M-H) " EXAMPLE 62 3-Fluoro-4-hydroxy-? -. { rtrans-1-hydroxy-4- (phenoxymethyl) cyclohexyl methyl} benzamide This compound was prepared with 3-fluoro-4-hydroxybenzoic acid by a procedure similar to that of Example 8. 1 H NMR (DMSO-de) d: 10.46 (a, 1 H), 8.04 (t, J = 5.9 Hz, 1 H ), 7. 73-7.55 (m, 2H), 7.30-7.22 (m, 2H), 7.02-6.88 (m, 4H), 4.63 (a, 1 H), 3.82 (d, J = 6.0 Hz, 2H), 3.37 (d , J = 6.0 Hz, 2H), 1.86-1.58 (m, 5H), 1.40-1.20 (m, 4H) ppm. MS (ESI): 374.04 (M + H) +, 372.03 (M-H) "IR (KBr) vmax: 3296, 2934, 1499, 1242 cm" 1 p.f. 183.5 ° C EXAMPLE 63 3-Fluoro-4-hydroxy- / V-. { ftrans - '? - hydroxy-4- (2-phenoxyethyl) cyclohexin methyl} benzamide This compound was prepared with 3-fluoro-4-hydroxybenzoic acid and trans-1- (aminomethyl) -4- (2-phenoxyethyl) cyclohexanol hydrochloride by a procedure similar to that of Example 8. 1 H NMR (DMSO-de) d: 10.45 (a, 1 H), 8.01 (t, J = 5.9 Hz, 1 H), 7.74-7.54 (m, 2H), 7.32-7.22 (m, 2H), 7.03-6.86 (m, 4H), 4.59 (a, 1 H), 3.98 (t, J = 6.4 Hz, 2H), 3.36 (d, J = 6.4 Hz, 2H), 1.74-1.10 (m, 11 H) ppm. MS (ESI): 388.14 (M + H) \ 386.16 (M-H) "IR (KBr) vmax: 3227, 2956, 1520, 1302 cm" 1 p.f. 164.0 ° C EXAMPLE 64 C > H HO 'r1 3-Fluoro- / V-r (trans-4. {R (4-fluorobenzipoxymethyl) -1-hydroxycyclohexyl) methyl T-4-hydroxybenzamide This compound was prepared with 3-fluoro-4-hydroxybenzoic acid and trans-1- (aminomethyl) -4- hydrochloride. { [(4-fluorobenzyl) oxy] methyl} cyclohexanol by a procedure similar to that of Example 8. 1 H NMR (DMSO-de) d: 10.45 (a, 1H), 8.01 (t, J = 5.9 Hz, 1H), 7.74-7.54 (m, 2H), 7.40-7.30 (m, 2H), 7.22-7.11 (m, 2H), 7.03-6.94 (m, 1H), 4.61 (a, 1H), 4.43 (s, 2H), 3.38-3.24 (m, 4H), 1.70-1.50 (m, 5H), 1.38-1.06 (m, 4H) ppm. MS (ESI): 406.12 (M + H) +, 404.13 (M-H) "IR (KBr) vmax: 3288, 2941, 1639, 1508, 1298 cm" 1 p.f.155.9 ° C EXAMPLE 65 3-Fluoro- / V- ( { Tra / 7s-4-f (2-fluorophenoxy) methyl.} -1-hydroxycyclohexyl > methyl) -4- hydroxybenzamide This compound was prepared with 3-fUuoro-4-hydroxybenzoic acid and trans-1- (aminomethyl) -4 - [(2-fluorophenoxy) methyl] cyclohexanol hydrochloride by a procedure similar to that of Example 8. 1 H NMR (DMSO-de) ) d: 10.46 (a, 1 H), 8.03 (t, J = 5.5 Hz, 1 H), 7.74-7.54 (m, 2H), 7.24-6.88 (m, 5H), 4.63 (a, 1 H), 3.90 (d, J = 6.3 Hz, 2H), 3.42-3.32 (m, 2H), 1.95-1.55 (m, 5H), 1.42-1.22 (m, 4H) ppm. MS (ESI): 392.16 (M + H) +, 390.10 (M-H) "IR (KBr) vmax: 2926, 1562, 1508, 1307, 1250 cm" 1 p.f. 194.6 ° C EXAMPLE 66 3-Fluoro-V- ( {traps-4-r (4-fluorophenoxy) methyll-1-hydroxycyclohexyl}. Methyl) -4-hydroxybenzamide This compound was prepared with 3-fluoro-4-hydroxybenzoic acid and trans-1- (aminomethyl) -4 - [(4-fluorophenoxy) methyl] cyclohexanol hydrochloride by a procedure similar to that of Example 8. 1 H NMR (DMSO) -de) d: 10.47 (a, 1 H), 8.15-7.95 (m, 1 H), 7.78-7.53 (m, 2H), 7.20-6.87 (m, 5H), 4.64 (a, 1 H), 3.80 (d, J = 5.9 Hz, 2H), 3.50-3.25 (rn, 2H), 1.89-1.55 (m, 5H), 1.45-1.18 (m, 4H) ppm. MS (ESI): 392.12 (M + H) +, 390.10 (M-H) "IR (KBr) vmax: 3288, 2926, 1628, 1508, 1299 cm" 1 p.f. 181.6 ° C EXAMPLE 67 4-Hydroxy -? / - r (trans-1-hydroxy-4- (f (5-methylpyridin-2-yl) oxyethyl). Cyclohexyl) methynebenzamide This compound was prepared with? - [(trans-1-hydroxy-4. {[[(5-methylpyridin-2-yl) oxy] methyl] cyclohexyl) methyl] -4- (methoxymethoxy) benzamide by a procedure similar to that of Example 6. 1 H NMR (DMSO-de) d: 9.98 (a, 1 H), 8.06-7.85 (m, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.55-7.47 (m, 1 H), 6.80 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 8.4 Hz, 1 H), 4.71 (a, 1 H), 4.08 (d, J = 6.4 Hz, 2H ), 3.45-3.30 (m, 2H), 2.19 (s, 3H), 1.86-1.52 (m, 5H), 1.43-1.13 (m, 4H) ppm. MS (ESI): 371.10 (M + H) +, 369.08 (M-H) "IR (KBr) vmax: 3358, 2934, 1570, 1512, 1277 cm" 1 p.f. 196.2 ° C EXAMPLE 68 / V-r (traAts-4-Benzyl-1-hydroxycyclohexal) metin-4-hydroxybenzamide A mixture of? / - [(4-benzylidene-1-hydroxycyclohexyl) methyl] -4- (benzyloxy) benzamide (42 mg) and 20% Pd (OH) 2 -C (10 mg) in MeOH (5 ml) Hydrogenated at 4 atmospheres for 10 hours. The mixture was filtered through a pad of celite and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 1: 2), followed by HPLC (DAICEL CHIRALCEL OJ-H, hexane: EtOH: Et2NH = 85: 15: 0.1) to give the title compound (29 mg) in the form of a white solid. 1 H NMR (DMSO-de) d: 9.97 (a, 1 H), 7.95-7.85 (m, 1 H), 7.74 (d, J = 8.6 Hz, 2H), 7.34-7.12 (m, 5H), 6.80 ( d, J = 8.6 Hz, 2H), 4.65 (s, 1 H), 3.45-3.30 (m, 2H), 1.77-1.04 (m, 11 H) ppm. MS (ESI): 340.20 (M + H) +, 338.21 (M-H) "IR (KBr) vmax: 3165, 2925, 1541, 1508, 1285 cm" 1 EXAMPLE 69 3-Fluoro -? - [(trans-4. {F (2-fluorobenzyl) oxymethyl) -1- hydroxycyclohexyl) methyn-4-hydroxybenzamide This compound was prepared with 3-fluoro-4-hydroxybenzoic acid and trans-1- (aminomethyl) -4-. { [(2-fluorobenzyl) oxy] methyl} cyclohexanol by a procedure similar to that of Example 8. 1H "NMR (DMSO-de) d: 8.02 (dd, J = 5.9, 5.7 Hz, 1H), 7.69 (dd, J = 12.5, 2 Hz, 1 H), 7.57 (dd, J = 8.4, 1.5 Hz, 1 H), 7.44 (ddd, J = 7.5, 7.5, 1.6 Hz, 1 H), 7.40-7.32 (m, 1 H), 7.23-7.14 (m, 2H), 6.99 (t, J = 8.6 Hz, 1 H), 4.62 (a, 1 H), 4.50 (s, 2H) 3.25-3.45 (m, 4H), 1.66-1.57 (m, 5H), 1.34-1.10 (m, 4H) ppm. (No OH was observed.) EXAMPLE 70 4-Hydroxy- / V-. { ftrans-4- (phenoxymethyl) cyclohexinmethyl} benzamide This compound was prepared with hydrochloride. { [4- (phenoxymethyl) cyclohexyl] methyl} amine by a procedure similar to that of Example 8. 1 H NMR (CDCl 3) d: 7.67 (d, J = 8.6 Hz, 2H), 7.30-7.24 (m, 2H), 6. 96-6.84 (m, 5H), 6.17-6.08 (m, 1 H), 3.76 (d, J = 6.2 Hz, 2H), 3.36-2.98 (m, 2H), 2.03-0.98 (m, 10H) ppm. (No OH was observed.) MS (ESI): 340.17 (ES +), 338.15 (ES-) EXAMPLE 71 6-Hydroxy -? / '-. { fc / s-4- (2-phenetoxy) cyclohexinmethyl} nicotinamide This compound was prepared with 6-hydroxynicotinic acid and. { [cis-4- (2-phenylethoxy) cyclohexyl] methyl} amine by a procedure similar to that of Example 8 in the form of a white solid. 1 H NMR (DMSO-d 6) d: 11.94 (a, 1 H), 8.19-8.15 (m, 1 H), 7.98-7.97 (m, 1 H), 7.87-7.83 (m, 1 H), 7.30-7.18 ( m, 5H), 6.35-6.32 (m, 1 H), 3.54 (t, J = 6.9 Hz, 2H), 3.47 (a, 1 H), 3.05-3.00 (m, 2H), 2.79 (t, J = 6.9 Hz, 2H), 1.70-1.15 (m, 9H) ppm. MS (ESI): 355.19 (M + H) +, 353.21 (M-H) "IR (KBr) vmax: 3314, 3057, 2928, 2864, 1713, 1605, 1553, 1310, 1090 cm" 1 Anal. Caled, for C 21 H 26 N 2 O 3 F: C, 71.16; H, 7.39; N, 7.90. Found: C, 71.15; H, 7.40; N; 7.90 p.f. 181.8 ° C EXAMPLE 72 / V-. { rc / s-4- (2-Phenylethoxy) cyclohexinmethyl > -1tf-pyrazole-4-carboxamideThis compound was prepared with 1 / -pyrazole-4-carboxylic acid and. { [c / s-4- (2-phenylethoxy) cyclohexyl] methyl} amine by a procedure similar to that of Example 8 in the form of a white solid. 1 H NMR (DMSO-de) d: 13.07 (a, 1H), 8.15 (a, 1 H), 8.00-7.87 (m, 2H), 7.30-7.18 (m, 5H), 3.54 (t, J = 6.9 Hz , 2H), 3.47 (a, 1 H), 3.04-3.00 (m, 2H), 2.81-2.76 (m, 2H), 1.75-1.71 (m, 2H), 1.52-1.16 (m, 7H) ppm.

MS (ESI): 328.25 (M + H) +, 326.19 (M-H) "IR (KBr) vmax: 2853, 1248, 1090 cm" 1 Anal. Caled, for C? 9H25N3O2: C, 69.70; H, 7.70; N, 12.83. Found: C, 69.64; H, 7.66; N; 12.67 p.f. 145.0 ° C EXAMPLE 73 ? / -. { rc / s-4- (phenoxymethyl) cyclohexylmethyl} -1 / V-pyrazole-4-carboxamide This compound was prepared with 1 / - / - pyrazole-4-carboxylic acid (50 mg, 0.4 mmol) and ( { [C / 's-4- (phenoxymethyl) cyclohexyl] methyl} amine hydrochloride (171 mg, 0.7 mmol) by a procedure similar to that of Example 8 in the form of a white solid (25 mg, 18%). 1 H NMR (DMSO-d 6) d: 13.08 (sa, 1 H), 8.13-7.90 (m, 3H), 7.30-7.25 (m, 2H), 6.95-6.88 (m, 3H), 3.87 (d, J = 6.8 Hz, 2H), 3.20-3.15 (m, 2H), 1.90-1.41 (m, 10H) ppm. MS (ESI): 314.21 (M + H) +, 312.15 (M-H) 'IR (KBr) vmax: 3317, 2926, 1626, 1570, 1246, 1036 cm'1 Anal. Caled, for C18H23N3O2: C, 68.98; H, 7.40; N, 13.41. Found: C, 68.68; H, 7.40; N; 13.35 p.f .: 150.1 ° C EXAMPLE 74 and V- (f (3f?, 6S) -6-r (4-Fluorophenoxy) methyethrahydro-2H-pyran-3-yl> methyl) -4-hydroxybenzamide It was prepared? / - ( { (3f?, 6S) -6 - [(4-fluorophenoxy) methyl] tetrahydro-2H-pyran-3-yl.} Methyl) -4-hydroxybenzamide with (. { (3, 6S) -6 - [(4-fluorophenoxy) methyl] tetrahydro-2 / - -pyran-3-yl.} Methyl) amine by a procedure similar to that of Example 8. The cis stereoisomer was separated with a Chiral column (Chiralpak AD-H, 20 mm Dl x 250 mm, DAICEL) using n-Hexane / 2: Propanol: Et2NH = 85: 15: 0.1 as eluent (10 ml / minute). Colorless amorphous, > 99% ee, cis isomer, retention time 24 min 1 H NMR (CDCl 3) d: 7.66 (d, J = 8.6 Hz, 2H), 7.01-6.80 (m, 6H), 6.50-6.25 (m, 2H), 4.08 -3.46 (m, 7H), 2.05-1.50 (m, 5H) ppm. MS (ESI): 360.14 (M + H) +, 358.15 (MH) "IR (KBr) vmax: 3350, 2936, 1609, 1508, 1452, 1207 cm'1 [a] D = - 6.5 (c = 0.4, MeOH) EXAMPLES 75 AND 76 It was prepared? / - ( { (2R *, 5R *) - 5 - [(4-fluorophenoxy) methyl] tetrahydro-2H-pyran-2-yl}. Methyl) -4-hydroxybenzamide with ( { (2S *, 5S *) - 5 - [(4-fluorophenoxy) methyl] tetrahydro-2H-pyran-2-yl.] Methyl) amine by a procedure similar to that of Example 8. The enantiomers were separated with a chiral column (Chiralpak OJ-H, 20 mm ID x 250 mm, DAICEL) using n-Hexane: Ethanol: Et2NH = 85: 15: 0.1 as eluent (10 ml / minute).

EXAMPLE 75 ? / - ( { (2f?, 5?) - 5-r (4-fluorophenoxy) methytrahydro-2-pyran-2-yl> methyl) -4-hydroxybenzamide > 99% ee, retention time 25 minutes. 1 H NMR (DMSO) d: 9.96 (br s, 1 H), 8.24 (t, J = 5.5 Hz, 1 H), 7.72 (d, J = 8.7 Hz, 2H), 7.14-7.05 (m 2H), 7.01- 6.90 (m, 2H), 6.78 (d, J = 8.7 Hz, 2H), 4.14-3.75 (m, 3H), 3.53-3.16 (m, 4H), 2.00-1.65 (m, 3H), 1.50-1.30 ( m, 2H) ppm. MS (ESI): 360.14 (M + H) +, 358.15 (MH) "IR (KBr) vmax: 3350, 2936, 1609, 1508, 1452, 1207 cm" 1 [a] D = -10 (0 = 0.4, MeOH) EXAMPLE 76 /V-ffl2S.5S)-5-r(4-fluorofenoxi)metiratrahydro-2fí-piran-2-il > methyl) -4- hydroxybenzamide > 99% ee, retention time 31 minutes. 1 H NMR (DMSO) d: 9.96 (br s, 1 H), 8.24 (t, J = 5.5 Hz, 1 H), 7.72 (d, J = 8.7 Hz, 2H), 7.14-7.05 (m 2H), 7.01- 6.90 (m, 2H), 6.78 (d, J = 8.7 Hz, 2H), 4.14-3.75 (m, 3H), 3.53-3.16 (m, 4H), 2.00-1.65 (m, 3H), 1.50-1.30 ( m, 2H) ppm. MS (ESI) 360.14 (M + H) +, 358.15 (MH) "IR (KBr) vmax: 3350, 2936, 1609, 1508, 1452, 1207 cm" 1 [a] D = +5 (c = 0.4, MeOH ) EXAMPLE 77 / V-. { rc s-4- (2-Phenoxyethyl) cyclohexylmethyl} -1H-pyrazole-4-carboxamide This compound was prepared with 1-pyrazol-4-carboxylic acid (57 mg, 0.5 millimoles) and hydrochloride. { [c / s-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (118 mg, 0.5 mmol) by a procedure similar to that of Example 8 in the form of a white solid (50 mg, 30%). 1 H NMR (DMSO-de) d: 13.08 (sa, 1 H), 8.12-7.91 (m, 3H), 7.30-7.24 (m, 2H), 6.93-6.88 (m, 3H), 4.01-3.96 (m, 2H), 3.19-3.14 (m, 2H), 1.69-1.42 (m, 12H) ppm. MS (ESI): 328.24 (M + H) +, 326.20 (M-H) "IR (KBr) vmax: 2924, 1636, 1246, 756 cm" 1 Anal. Caled, for C19H25N3O: C, 69.70; H, 7.70; N, 12.83. Found: C, 69.34; H, 7.60; N; 12.72 p.f .: 155.7 ° C EXAMPLE 78 4-Hydroxy- / V-. { c / s-4- (2-phenoxyethoxy) cyclohexyl > methyl } benzamide This compound was prepared with 4- (methoxymethoxy) -? / -. { [c / s-4- (2-phenoxyethoxy) cyclohexyl] methyl} benzamide (81 mg, 0.2 mmol) by a procedure similar to that of Example 6 in the form of a colorless amorphous compound (64 mg, 88%). 1 H NMR (DMSO-de) d: 9.94 (br s, 1H), 8.20-8.16 (m, 1 H), 7.71-7.68 (m, 2H), 7.30-7.25 (m, 2H), 6.95-6.90 (m, 3H), 6.79-6.76 (m, 2H), 4.09-4.06 (m, 2H), 3.70-3.67 (m, 2H), 3.57-3.52 (m, 1 H), 3.10-3.06 (m, 2H), 1.75 -1.26 (m, 9H) ppm.

EXAMPLE 79 or < HX V? V 2-Oxo -? / -. { fc / s-4- (2-phenylethoxy) cyclohexinmethyl} -2,3-dihydro-1,3-benzoxazole- 6-carboxamide This compound was prepared with 2-oxo-2,3-dihydro-1,3-benzoxazole-6-carboxylic acid and hydrochloride. { [c / s-4- (2-phenylethoxy) c -clohexyl] methyl} amine by a procedure similar to that of Example 8 in the form of a white solid. 1 H NMR (DMSO) d: 8.40 (t, J = 5.5 Hz, 1 H), 7.82-7.68 (m, 2H), 7. 35-7.10 (m, 6H), 3.54 (t, J = 7.0 Hz, 2H), 3.51-3.43 (m, 1 H), 3.08 (t, J = 6.2 Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H), 1.82-1.11 (m, 9H) ppm. (NH was not observed.) EXAMPLE 80 3-Fluoro -? / -. { rtrans-4- (4-fluorobenzyl) -1-hydroxycyclohexinmethyl} -4- hydroxybenzamide This compound was prepared with 3-fluoro-4-hydroxybenzoic acid and trans-1- (aminomethyl) -4- (4-fluorobenzyl) cyclohexanol hydrochloride by a procedure similar to that of Example 8 in the form of a white solid. 1 H NMR (DMSO-de) d: 10.48 (a, 1 H), 8.02 (t, J = 5.9 Hz, 1 H), 7.75-7.53 (m, 2H), 7.24-6.94 (m, 5H), 4.59 ( a, 1 H), 3.40-3.30 (m, 2H), 2.55-2.45 (m, 2H), 1.70-1.05 (m, 9H) ppm. MS (ESI): 376.17 (M + H) +, 374.22 (M-H) "IR (KBr) vmax: 3422, 2930, 1643, 1508, 1308, 1223 cm, '- 1 EXAMPLE 81 / V-. { rtrans-4- (4-Fluorobenzyl) -1-hydroxycyclohexylmethyl > -4-hydroxybenzamide This compound was prepared with trans-1- (aminomethyl) -4- (4-fluorobenzyl) cyclohexanol hydrochloride by a procedure similar to that of Example 8 as a white solid. 1 H NMR (DMSO-de) d: 9.98 (a, 1 H), 7.90 (t, J = 5.7 Hz, 1 H), 7.73 (d, J = 8.6 Hz, 2H), 7.25-7.02 (m, 4H), 6.80 (d, J = 8.6 Hz, 2H), 4.66 (a, 1 H), 3.40-3.30 (m, 2H), 2.55 -2.45 (m, 2H), 1.70-1.05 (m, 9H) ppm. MS (ESI): 358.18 (M + H) +, 356.21 (M-H) "IR (KBr) vmax: 3319, 2934, 1608, 1508, 1450, 1221 cm" 1 EXAMPLE 82 e-Hydroxy-AZ-d-c / s ^ -ffenoxymethi cyclohexinmethylinicotinarnide This compound was prepared with 6-hydroxynicotinic acid (80 mg, 0.6 mmol) and copper horn. { [c / s-4- (phenoxfmethyl) cyclohexyl] methyl} amine (147 mg, 0.6 millimole) by a procedure similar to that of Example 8 in the form of a white solid (110 mg, 56%). 1 H NMR (DMSO-d 6) d: 11.94 (br s, 1 H), 8.22-8.18 (m, 1 H), 7.99- 7.98 (m, 1 H), 7.89-7.85 (m, 1 H), 7.31-7.26 (m, 2H), 6.95-6.88 (m, 3H), 6.36-6.32 (m, 1 H), 3.87 (d, J = 8.1 Hz, 2H), 3.21-3.16 (m, 2H), 1.90-1.40 ( m, 10H) ppm. MS (ESI): 341.17 (M + H) +, 339.19 (M-H) 'IR (KBr) vmax: 3339, 2926, 1638, 1545, 1246, 1036 cm'1 Anal. Caled, for C20H24N2O3: C, 70.56; H, 7.11; N, 8.23. Found: C, 70.36; H, 7.15; N; 8.31 p.f .: 189.8 ° C EXAMPLE 83 2-Hydroxy- / V-. { [c / s-4- (2-phenoxyethyl) cyclohexypmethyl > isonicotinamide This compound was prepared with 2-hydroxyisonicotinic acid (63 mg, 0.5 mmol) (Tetrahedron Lett, 1988, 29, 4389) and hydrochloride. { [c / s-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (105 mg, 0.5 mmol) by a procedure similar to that of Example 8 in the form of a white solid (30 mg, 19%). 1 H NMR (DMSO-d 6) d: 11.78 (br s, 1 H), 8.58-8.56 (m, 1 H), 7.45- 7.43 (m, 1 H), 7.30-7.25 (m, 2H), 6.94-6.88 ( m, 3H), 6.71-6.70 (m, 1 H), 6.47-6.44 (m, 1H), 4.00-3.96 (m, 2H), 3.20-3.16 (m, 2H), 1.71-1.39 (m, 12H) ppm. MS (ESI): 355.11 (M + H) \ 353.17 (MH) 'IR (KBr) vmax: 2920, 1639, 1244, 756 cm "1 Anal.Called, for C2? H26N2O3O.1 H2O: C, 70.80; H, 7.41; N, 7.86, Found: C, 70.73; H, 7.17; N; 7.78 pf: 199.9 ° C EXAMPLE 84 6-Hydroxy- / V-. { rcis-4- (2-phenoxyethyl) cyclohexylmethyl} nicotinamide This compound was prepared with 6-hydroxynicotinic acid (63 mg, 0.5 millimoles) and hydrochloride of. { [C / S-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (105 mg, 0.5 mmol) by a procedure similar to that of Example 8 in the form of a white solid (77 mg, 48%). 1 H NMR (DMSO-de) d: 11.93 (br s, 1 H), 8.21-8.17 (m, 1 H), 7.98- 7.97 (m, 1 H), 7.88-7.84 (m, 1 H), 7.30-7.25 ( m, 2H), 6.93-6.88 (m, 3H), 6.35-6.32 (m, 1 H), 4.00-3.96 (m, 2H), 3.19-3.15 (m, 2H), 1.69-1.36 (m, 12H) ppm. MS (ES): 355.20 (M + Hf, 353.27 (M-H) "IR (KBr) vmax: 3329, 2920, 1614, 1246 cm" 1 Anal Caled, for C21H26N2O3: C, 71.16.; H, 7.39; N, 7.90. Found: C, 70.80; H, 7.30; N; 7.93 p.f .: 167.6 ° C EXAMPLE 85 yV- c / 's ^^ - Phenoxyethi cyclohexinmethyndiiJ ^ -pyrazole-S-carboxamide This compound was prepared with 1 H-pyrazole-5-carboxylic acid (50 mg, 0.5 mmol) and hydrochloride. { [c / s-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (105 mg, 0.5 mmol) by a procedure similar to that of Example 8 in the form of a white solid (44 mg, 30%). 1 H NMR (DMSO-de) d: 13.19 (sa, 1 H), 817-8.00 (m, 0.5H), 7.86-7.73 (m, 0.5H), 7.30-7.24 (m, 2H), 6.93-6.88 ( m, 3H), 6.70-6.55 (m, 1H), 4.00-3.96 (m, 2H), 3.22-3.17 (m, 2H), 1.70-1.69 (m, 4H), 1.45-1.40 (m, 8H) ppm . (No proton of NH was observed.] MS (ESI): 328.22 (M + H) +, 326.25 (MH) "IR (KBr) vmax: 3144, 2922, 1634, 1556, 1250, 758 cm" 1 Anal. , for C19H25N3O2: C, 69.70, H, 7.70; N, 12.83 Found: C, 69.63; H, 7.50; N; 12.71 pf: 130.5 ° C EXAMPLE 86 TO/-. { [c / 's-4- (2-Phenoxyethyl) cyclohexypmethyl} -1H-imidazole-4-carboxamide This compound was prepared with 1-imidazole-4-carboxylic acid (35 mg, 0.3 mmol) and copper hydrochloride. { [c / s-4- (2-phenoxleythyl) cyclohexyl] methyl} amine (73 mg, 0.3 mmol) by a procedure similar to that of Example 8 in the form of a white solid (50 mg, 48%). 1 H NMR (DMSO-de) d: 12.43 (sa, 1 H), 7.85-7.80 (m, 1 H), 7.772-7.67 (m, 1 H), 7.60-7.55 (m, 1 H), 7.30-7.25 (m, 2H), 6.94-6.88 (m, 3H), 4.00-3.96 (m, 2H), 3.21-3.16 (m, 2H), 1.71-1.69 (m, 4H), 1.49-1.40 (m, 8H) ppm. MS (ESI): 328.25 (M + Hf, 326.29 (MH) "IR (KBr) vmax: 3323, 2922, 1638, 1560, 1248, 754 cm" 1 Anal.Called, for C19H25N3O2: C, 69.70; H, 7.70; N, 12.83 Found: C, 69.57; H, 7.89; N; 12.83 pf: 169.6 ° C EXAMPLE 87 -Chloro-6-hydroxy- V-. { fc / s-4- (2-phenoxyethyl) cyclohexylmethyl} nicotinamide This compound was prepared with 5-chloro-6-hydroxynicotinic acid (69 mg, 0.4 mmol) and hydrochloride. { [c / s-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (93 mg, 0.4 mmol) by a procedure similar to that of Example 8 in the form of a white solid (46 mg, 30%). 1 H NMR (DMSO-d 6) d: 12.52 (br s, 1 H), 8.29-8.25 (m, 1 H), 8.17-8.16 (m, 1 H), 8.01-8.00 (m, 1 H), 7.30-7.24 (m, 2H), 6.94-6.88 (m, 3H), 4.00-3.96 (m, 2H), 3.20-3.15 (m, 2H), 1.78-1.63 (m, 4H), 1.49-1.35 (m, 8H) ppm. MS (ESI): 389.22 (M + Hf, 387.31 (MH) "IR (KBr) vmax: 3325, 2920, 1665, 1533, 1244 cm" 1 Anal.Called, for C21H25N3O3CI: C, 64.86; H, 6.48; N, 7.20, Found: C, 64.63; H, 6.64; N; 7.06 EXAMPLE 88 3-Fluoro-? ^ - [(c / 's-4- { R (5-fluoropyr5din-2-yl) oxymethyl.} Cyclohexyl) metip-4-hydroxybenzamide This compound was prepared with 3-fluoro-4-hydroxybenzoic acid and [(c / s-4. {[[(5-fluoropyridin-2-yl) oxy] methyl] cyclohexyl) methyl] am The procedure is similar to that of Example 8 in the form of a white solid. 1 H NMR (CDCl 3) d: 7.98 (d, J = 3.0 Hz, 1 H), 7.60-7.29 (m, 3 H), 7.02 (t, J = 8.6 Hz, 1 H), 6.70 (dd, J = 3.6, 9.1 Hz, 1 H), 6.36-6.18 (m, 1 H), 4.15 (d, J = 7.1 Hz, 2H), 3.37 (t, J = 6.6 Hz, 2H), 2.10-1.30 (m, 10H) ppm . (No OH was observed.) MS (ESI): 377.17 (M + Hf, 375.26 (M-H) " EXAMPLE 89 3-Fluoro-4-hydroxy- / V - ((c / s-4-r (pyridin-2-loxi) methyncyclohexyl) methyl) benzamida This compound was prepared with 3-fluoro-4-hydroxybenzoic acid and (. {C / s-4 - [(pyridin-2-yloxy) methyl] cyclohexyl} methyl) amine by a similar procedure to that of Example 8 in the form of a white solid. 1 H NMR (CDCl 3) d: 8.19-8.12 (m, 1 H), 7.63-7.40 (m, 3 H), 7.03 (t, J = 8.4 Hz, 1 H), 6.91-6.84 (m, 1 H), 6.74 ( d, J = 8.2 Hz, 1H), 6.36-6.18 (m, 1 H), 4.18 (d, J = 7.3 Hz, 2H), 3.33 (t, J = 6.4 Hz, 2H), 2.12-1.26 (m, 10H) ppm. (No OH was observed.) MS (ESI): 359.17 (M + Hf, 357.23 (M-H) " EXAMPLE 90 ? / - ( { c / 's-4-r2- (4-Fluorophenoxy) ethoxy-1-cyclohexyl} -methyl) -1-t-pyrazole-4-carboxamide This compound was prepared with 1H-pyrazole-4-carboxylic acid and (. {4- [2- (4-fluorophenoxy) ethoxy] cyclohexyl] methyl) amine by a procedure similar to that of Example 8. 1 H NMR (CDCl 3 ) d: 7.94 (s, 2H), 7.77-6.81 (m, 4H), 6.08 (t, J = 5.9 Hz, 2H), 4.12-4.05 (m, 2H), 3.77-3.70 (m, 2H), 3.65 -3.59 (m, 1 H), 3.32-3.24 (m, 2H), 1.98-1.83 (m, 2H), 1.72-1.35 (m, 7H) (m, 8H) ppm. (NH was not observed.) EXAMPLE 91 3,5-Difluoro-4-hydroxy- / V-. { rc / s-4- (2-phenoxyethyl) cyclohexyl] methyl} benzamide This compound was prepared with 3,5-difluoro-4-hydroxybenzoic acid (93 mg, 0.5 mmol) (J. Fluorine, Chem. 2000, 102, 169) and hydrochloride. { [cis-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (125 mg, 0.5 mmol) by a procedure similar to that of Example 8 as a colorless amorphous compound (74 mg, 35%). 1 H NMR (DMSO-d 6) d: 10.84 (br s, 1 H), 8.41-8.36 (m, 1 H), 7.58- 7.51 (m, 2H), 7.30-7.24 (m, 2H), 6.93-6.88 (m , 3H), 4.01-3.96 (m, 2H), 3.23- 3.18 (m, 2H), 1.82-1.63 (m, 4H), 1.53-1.32 (m, 8H) ppm. MS (ESI): 390.20 (M + Hf, 388.24 (MH) Anal Caled, for C22H25NO3F2O.I H2O: C, 67.54, H, 6.49; N, 3.58. Found: C, 67.33; H, 6.57; N; 3.59 EXAMPLE 92 6-Oxo-V- (rc / s-4- (2-phenoxyethyl) cyclohexypmethyl > -1,4,5,6-tetrahydropyridazine-3-carboxamide This compound was prepared with 6-oxo-1, 4,5,6-tetrahydropyridazine-3-carboxylic acid and hydrochloride. { [c / s-4- (2-phenoxyethyl) cyclohexyl] methyl} amine by a procedure similar to that of Example 8 as a colorless amorphous compound. 1 H NMR (DMSO-d 6) d: 11.05 (s, 1 H), 8.12-8.02 (m, 1 H), 7.33- 7.20 (m, 2H), 6.98-6.86 (m, 3H), 4.04-3.93 (m , 2H), 3.12 (d, J = 6.9 Hz, 2H), 2.72 (d, J = 8.4 Hz, 2H), 2.38 (d, J = 8.6 Hz, 2H), 1.80-1.25 (m, 12H) ppm. MS (ESI): 356.33 (M-H) " EXAMPLE 93 6-Oxo -? / -. { rcis-4- (2-phenoxyethyl) cyclohexylmethyl} -1,6-dihydropyridazine-3-carboxamide This compound was prepared with 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (70 mg, 0.5 mmol) (Chem. Pharm, Bull, 1994, 42, 371) and hydrochloride. { [c / s-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (135 mg, 0.5 mmol) by a procedure similar to that of Example 8 in the form of a white solid (108 mg, 61%). 1 H NMR (DMSO-de) d: 13.39 (sa, 1 H), 8.45-8.40 (m, 1 H), 7.82 (d, J = 10.8 Hz, 1 H), 7.30-7.24 (m, 2H), 6.97 -6.88 (m, 4H), 4.00-3.96 (m, 2H), 3.23-3.18 (m, 2H), 1.81-1.63 (m, 4H), 1.49-1.33 (m, 8H) ppm. MS (ESI): 354.34 (M + Hf IR (KBr) vmax: 3379, 2852, 1657, 1533, 1250, 1007 cm "1 Anal.Called, for C20H25N3O3O.ICH2CI2: C, 66.34; H, 6.98; N, 11.55 Found: C, 66.38; H, 7.07; N; 11.25 pf: 177.5 ° C EXAMPLE 94 / V- ( { C s-4-f2- (2-Fluorophenoxy) et.cyclohexyl.} Methyl) -1H-pyrazole-4-carboxamide This compound was prepared with 1 H-pyrazole-4-carboxylic acid and (. {Cc-s-4- [2- (2-fluorophenoxy)) ethyl] cyclohexyl} methyl) amine hydrochloride by a method similar to that of Example 8. 1 H NMR (DMSO-de) d: 13.08 (a, 1 H), 8.29-7.76 (m, 3H), 7.26-6.86 (m, 4H), 4.13-4.02 (m, 2H), 3.23-3.10 (m, 2H), 1.82-1.28 (m, 12H) ppm. MS (ESI) 346.21 (M + Hf, 344.24 (M-H) "IR (KBr) vmax: 3361, 2926, 1630, 1579, 1504, 1259, 1201 cm" 1 EXAMPLE 95 / V- ( { C / 's-4-r2- (4-Fluorophenoxy) ethoxy-1-cyclohexyl > methyl) -6-hydroxynicotinamide This compound was prepared with 6-hydroxynicotinic acid and (. {4- [2- (4-fluorophenoxy) ethoxy] cyclohexyl} methyl) amine by a procedure similar to that of Example 8. 1 H NMR (DMSO) d: 11.94 (sa, 1 H), 8.19 (t, J = 5.8 Hz, 1 H), 7.98 (d, J = 2.6 Hz, 1 H), 7.86 (dd, J = 2.6, 9.6 Hz, 1 H), 7.16-6.92 (m, 4H), 6.34 (d, J = 9.6 Hz, 1 H), 4.09 -4.03 (m, 2H), 3.70-3.63 (m, 2H), 3.58-3.50 (m, 2H), 3.10-3.01 (m, 2H), 1.84-1.70 (m, 2H), 1.63-1.16 (m, 7H) ppm.

EXAMPLE 96 ? t'-. { íc / 's-4- (2-Phenoxyethyl) cyclohexypmethyl-1H-pyrrole-3-carboxamide This compound was prepared with 1 / - / - pyrrole-3-carboxylic acid (44 mg, 0.4 mmol) and hydrochloride. { [c / 's-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (108 mg, 0.4 mmol) by a procedure similar to that of Example 8 in the form of a yellow solid (33 mg, 25%). 1 H NMR (DMSO-de) d: 11.07 (br s, 1 H), 7.69-7.65 (m, 1 H), 7.30- 7.24 (m, 3H), 6.94-6.88 (m, 3H), 6.73-6.71 (m , 1 H), 6.47-6.44 (m, 1 H), 4.01-3.96 (m, 2H), 3.16-3.12 (m, 2H), 1.74-1.64 (m, 4H), 1.49-1.34 (m, 8H) ppm. MS (ESI): 327.26 (M + Hf, 325.28 (MH) "IR (KBr) vmax: 3204, 2924, 1609, 1568, 1246, 754 cm" 1 Anal.Called, for C2oH26N2O2: C, 73.59.H, 8.03; N, 8.58.

Found: C, 73.24; H, 7.93; N; 8.34 p.f .: 121.0 ° C EXAMPLE 97 2-Oxo- V-. { fc / s-4- (2-phenoxyethyl) cyclohexylmethyl} indoline-5-carboxyamide This compound was prepared with 2-oxoindole-5-carboxylic acid and hydrochloride. { [c s-4- (2-phenoxyethyl) cyclohexyl] methyl} amine by a procedure similar to that of Example 8. 1 H NMR (DMSO-d 6) d: 10.60 (a, 1H), 8.32-8.21 (m, 1H), 7.77-7.68 (m, 2H), 7.34-7.22 (m, 2H), 7.00-6.80 (m, 4H), 4.06-3.93 (m, 2H), 3.53 (s, 2H), 3.27-3.16 (m, 2H), 1.85-1.29 (m, 12H) ppm.

MS (ESI): 393.32 (M + Hf, 391.37 (M-H) "IR (KBr) vmax: 3374, 2920, 1686, 1618, 1489, 1292, 1244 cm" 1 EXAMPLE 98 2-Oxo -? / -. { rc / s-4- (2-phenoxyethyl) cyclohexyphenyl} -112,3,4-tetrahydroquinoline-6-carboxamide This compound was prepared with 2-oxo-1, 2,3,4-tetrahydroquinoline-6-carboxylic acid (77 mg, 0.4 mmol) (Chem. Pharm. Bull. 1986, 34, 682) and hydrochloride of. { [c / s-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (108 mg, 0.4 mmol) by a procedure similar to that of Example 8 in the form of a yellow solid (36 mg, 2%). 1 H NMR (DMSO-de) d: 10.28 (br s, 1 H), 8.29-8.24 (m, 1 H), 7.69-7.63 (m, 2H), 7.30-7.24 (m, 2H), 6.94-6.85 (m , 4H), 4.01-3.97 (m, 2H), 3.23-3.18 (m, 2H), 2.94-2.88 (m, 2H), 2.47-2.45 (m, 2H), 1.78-1.66 (m, 4H), 1.52 -1.36 (m, 8H) ppm. MS (ESI): 407.03 (M + Hf, 405.11 (MH) "Anal.Called, for C25H30N2O3O.6H2O: C, 71.95; H, 7.54; N, 6.71. Found: C, 71.84; H, 7.47; N; 6.49 EXAMPLE 99 3-Met.l-2-oxo -? / - fíc / s-4- (2-phenoxyethyl) cyclohexylmethyl > -2.3-dihydro-1H-benzimidazole-5-carboxamide This compound was prepared with 3-methyl-2-oxo-2,3-dihydro-1 - / - benzimidazole-5-carboxylic acid and hydrochloride. { [c / s-4- (2-phenoxyethyl) cyclohexylmethyl} amine by a procedure similar to that of Example 8. 1 H NMR (CDCl 3) d: 9.32 (a, 1 H), 7.58-7.54 (m, 1 H), 7.45-7.39 (m, 1 H), 7.33-7.24 (m , 2H), 7.09 (d, J = 8.2 Hz, 1 H), 6.98-6.86 (m, 3H), 6.18-6.08 (m, 1H), 4.04-3.94 (m, 2H), 3.53-3.40 (m, 5H), 1.94-1.38 (m, 12H) ppm. MS (ESI): 407.99 (M + Hf, 406.07 (M-H) " EXAMPLE 100 ? / - ( { c / 's-4 - ((2-Fluorophenoxy) methyclohexyl} methyl) -1-pyrazol-4-carboxamide This compound was prepared with 1 - / - pyrazole-4-carboxylic acid (56 mg, 0.5 mmol) and ( { C / s-4 - [(2-fluorophenoxy) methyl] cyclohexyl} methyl) amine (137 mg, 0.5 mmol) hydrochloride by a procedure similar to of Example 8 in the form of a white solid (90 mg, 55%). 1 H NMR (DMSO-d 6) d: 13.08 (sa, 1 H), 8.11-7.97 (m, 3H), 7.23-7.09 (m, 3H), 6.95-6.89 (m, 1 H), 3.96 (d, 2H , J = 5.4 Hz), 3.20-3.15 (m, 2H), 1.93-1.48 (m, 10H) ppm. MS (ESI): 332.14 (M + Hf, 330.16 (MH) "Anal.Called, for C18H22N3O2F: C, 65.24; H, 6.69; N, 12.68. Found: C, 65.19; H, 6.54; N; 12.64 pf: 139.8 ° C EXAMPLE 101 -c Ho c o 2-Oxo- / V-. { rc / s-4- (2-phenoxyethyl) cyclohexylmethyl > -2,3-dihydro-1,3-benzothiazole-6-carboxamide This compound was prepared with 2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid (20 mg, 0.1 mmol) (Chem. Pharm. Bull. 1988, 36, 2253) and sodium hydrochloride. . { [c / s-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (30 mg, 0.1 mmol) by a procedure similar to that of Example 8 in the form of a white solid (28 mg, 67%). 1 H NMR (DMSO-de) d: 8.40-8.36 (m, 1 H), 8.05-8.04 (m, 1 H), 7.80-7.76 (m, 1 H), 7.30-7.24 (m, 2H), 7.17- 7.14 (m, 1 H), 6.94-6.88 (m, 3H), 4.01-3.96 (m, 2H), 3.25-3.20 (m, 2H), 1.72-1.37 (m, 12H) ppm. (NH was not observed.] MS (ESI): 411.04 (M + Hf, 409.10 (MH) "Anal.Called, for C23H26N2O3S: C, 67.29; H, 6.38; N, 6.82. Found: C, 67.27; H , 6.42; N; 6.81 pf: 159.9 ° C, 175.7 ° C EXAMPLE 102 3-Amino- / V-. { rcis-4- (2-phenoxyethyl) cyclohexinmethyl} -1f -pyrazole-4-carboxamide This compound was prepared with 3-amino-1 / - / - pyrazole-4-carboxylic acid (64 mg, 0.5 mmol) and hydrochloride. { [c / s-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (135 mg, 0.5 mmol) by a procedure similar to that of Example 8 in the form of a white solid (81 mg, 47%). 1 H NMR (DMSO-de) d: 11.82-11.69 (m, 1 H), 7.96-7.65 (m, 2H), 7.30-7.25 (m, 2H), 6.93-6.88 (m, 3H), 5.92-5.80 ( m, 1 H), 5.34-5.22 (m, 1H), 4.00-3.96 (m, 2H), 3.15-3.10 (m, 2H), 1.75-1.62 (m, 4H), 1.52-1.32 (m, 8H) ppm. MS (ESI): 343.17 (M + Hf, 341.17 (MH) "Anal.Called, for C19H26N4O2O.2H2O: C, 65.95; H, 7.69; N, 16.19. Found: C, 65.87; H, 7.82; N; 16.01 pf: 129.3 ° C EXAMPLE 103 V-. { fc / s-4- (2-Phenoxyethyl) cyclohexinmethyl) -1 - / - indazole-5-carboxamide This compound was prepared with 1 / - -ndazole-5-carboxylic acid (65 mg, 0.4 millimoles) (Helv. Chim. Acta. 1976, 59, 2618) and hydrochloride . { [C / S-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (108 mg, 0.4 mmol) by a procedure similar to that of Example 8 as a white solid (37 mg, %). 1 H NMR (DMSO-de) d: 13.25 (sa, 1 H), 8.46-8.41 (m, 1 H), 8.32 (s, 1 H), 8.20 (s, 1 H), 7.86-7.83 (m, 1 H), 7.58-7.54 (m, 1 H), 7.30-7.25 (m, 2H), 6.94-6.88 (m, 3H), 4.01-3.97 (m, 2H), 3.28-3.23 (m, 2H), 1.84 -1.63 (m, 4H), 1.54-1.35 (m, 8H) ppm. MS (ESI): 378.12 (M + Hf, 376.16 (MH) Anal Caled, for C23H27N3O2: C, 73.18, H, 7.21; N, 11.13, Found: C, 72.80; H, 7.18; N; 11.08. mp: 144.5 ° C EXAMPLE 104 V-. { rc / 's-4- (2-Phenoxyethyl) cyclohexyphenyl} -1H-1,2,3-triazole-4-carboxamide This compound was prepared with 1 / - / - 1, 2,3-triazole-4-carboxylic acid (45 mg, 0.4 mmol) (J. Amer. Chem. Soc. 1954, 76, 4931) and hydrochloride. { [c / 's-4- (2-phenoxyethyl) cyclohexyl] methyl} amine (108 mg, 0.4 mmol) by a procedure similar to that of Example 8 in the form of a white solid (24 mg, 19%). 1 H NMR (DMSO-de) d: 8.45-8.30 (m, 2H), 7.30-7.23 (m, 2H), 6.94-6.88 (m, 3H), 4.01-3.96 (m, 2H), 3.25-3.20 (m , 2H), 1.71-1.42 (m, 12H) ppm. [NH proton not observed] MS (ESI): 329.10 (M + Hf, 327.12 (MH) "Anal Caled, for C18H24N4O2: C, 65.83, H, 7.37; N, 17.06 Found: C, 65.45; H, 7.08; N; 17.10.pf: 141.2 ° C EXAMPLE 105 ? / - ( { c s-4-f (Pyridin-2-yloxy) methylenecyclohexyl} methyl) -1-pyrazol-4-carboxamide This compound was prepared with 1 / - / - pyrazole-4-carboxylic acid and ( { C / s-4 - [(pyridin-2-yloxy) methyl] cyclohexyl] methyl) amine by a method similar to that of Example 8. 1 H NMR (CDCl 3) d: 13.07 (a, 1 H), 8.21-7.84 (m, 4 H), 7.69 (ddd, J = 8.4, 7.0, 2.1 Hz, 1 H), 6.95 (m, 1 H), 6.80 (d, J = 8.2 Hz, 1H), 4.18 (d, J = 7.1 Hz, 2H), 3.17 (m, 2H) , 1.91 (a, 1H), 1.73 (a, 1H), 1.60-1.31 (m, 8H) ppm. MS (ESI): 315.09 (M + Hf, 313.10 (M-H) "IR (KBr) vmax: 3358, 2849, 1631, 1475, 1435, 1246, 1022, 777 cm" 1 EXAMPLE 106 ? f- ( { c / s-4 - [(3-FluorofTnoxy) methyclohexyl} .methyl) -1H-pyrazole-4-carboxamide This compound was prepared with 1 rV-pyrazole-4-carboxylic acid and ( { [C / s-4- (3-fluorophenoxymethyl) cyclohexyl] methyl.} Amine hydrochloride by a procedure similar to that of Example 8. 1H NMR (DMSO-d6) d: 13.08 (sa, 1 H), 8.00-7.97 (m, 3H), 7.33-7.26 (m, 1 H), 6.85-6.71 (m, 3H), 3.90 (d, J = 6.8 Hz, 2H), 3.16 (t, J = 6.6 Hz, 2H), 1.96-1.85 (m, 1 H), 1.79-1.67 (m, 1 H), 1.58-1.32 (m, 8H) ppm MS ( ESI): 332.12 (M + Hf, 338.15 (MH) 'IR (KBr) vmax: 3348, 2920, 1625, 1577, 1490, 1284, 1134, 1041 cm "1 EXAMPLE 107 / V-. { rc / 's-4- (3-Phenoxypropyl) cyclohexylmethyl} -1H-pyrazole-4-carboxamide This compound was prepared with 1 H-pyrazole-4-carboxylic acid and. { [c / s-4- (3-phenoxypropyl) c? clohexyl] methyl} amine by a procedure similar to that of Example 8. 1 H NMR (DMSO-d 6) d: 13.09 (s, 1 H), 8.15-7.90 (m, 3 H), 7.33- 7.22 (m, 2 H), 6.96-6.87 (m , 3H), 3.94 (t, J = 6.4 Hz, 2H), 3.16 (t, J = 6.4 Hz, 2H), 1.80-1.63 (m, 4H), 1.53-1.25 (m, 10H) ppm. MS (ESI): 342.09 (M + Hf, 340.12 (M-H) 'IR (KBr) vmax: 3310, 2924, 1626, 1604, 1566, 1539, 1499, 1246, 752, 691 cm "1 EXAMPLE 108 3,5-Difluoro-4-hydroxy-iV-. { rc / s-4-phenoxymethyl) cyclohexinmethyl benzamide This compound was prepared with 3,5-d-fluoro-4-hydroxybenzoic acid (87 mg, 0.5 mmol) and hydrochloride. { [c / s-4- (phenoxymethyl) cyclohexyl] methyl} amine (128 mg, 0.5 mmol) by a procedure similar to that of Example 8 as a colorless amorphous compound (49 mg, 26%). 1 H NMR (CDCl 3) d: 7.37-7.25 (m, 5H), 6.96-6.88 (m, 3H), 6.00 (sa, 1 H), 3.88-3.85 (m, 2H), 3.44-3.39 (m, 2H) , 2.03-1.47 (m, 10H) ppm. MS (ESI): 376.05 (M + Hf, 374.06 (M-H) 'Anal.Called, for C2? H23NO3F2O.2H2O: C, 66.55; H, 6.22; N, 3. 70. Found: C, 66.34; H, 6.20; N; 3.65 EXAMPLE 109 / V- ( { C / 's-4-r (4-Fluorophenoxy) methyclohexyl}. Methyl) -1tf-pyrazole-4-carboxamide This compound was prepared with 1 H-pyrazole-4-carboxylic acid (22 mg, 0.2 mmol) and ( { C / s-4 - [(4-fluorophenoxy) methy1clohexyl} methyl) amine hydrochloride (55 mg, 0.2 mmol) by a procedure similar to of Example 8 in the form of a white solid (35 mg, 54%). 1 H NMR (DMSO-d 6) d: 13.08 (s at, 1 H), 8.14 (s at, 1 H), 8.00-7.96 (m, 1 H), 7.88 (s at, 1 H), 7.13-7.07 (m, 2H ), 6.98-6.93 (m, 2H), 3.87-3.84 (m, 2H), 3.20-3.15 (m, 2H), 1.88-1.40 (m, 10H) ppm. MS (ESI): 332.10 (M + Hf, 330.10 (MH) "Anal.Called, for C18H22N3O2F: C, 65.24; H, 6.69; N, 12.68. Found: C, 65.05; H, 6.65; N; 12.67 pf: 147.1 ° C EXAMPLE 110 Hfcis-4- (Benzyloxy) ci ohexyl-1-methyl) -1H-pyrazole-4-carboxamide This compound was prepared with 1 / - / - pyrazole-4-carboxylic acid and. { [c / s-4- (benzyloxy) cyclohexyl] methyl} amine by a procedure similar to that of Example 8. 1 H NMR (DMSO-d 6) d: 13.08 (s, 1 H), 8.23-7.80 (m, 3H), 7.40-7.20 (m, 5H), 4.45 (s, 2H ), 3.63-3.53 (m, 1 H), 3.08 (t, J = 6.4 Hz, 2H), 1.90-1.77 (m, 2H), 1.65-1.20 (m, 7H) ppm. MS (ES1): 314.08 (M + Hf, 312.07 (M-H) "IR (KBr) vmax: 3335, 3126, 2928, 1630, 1580, 1537, 1246, 1065, 735, 696 cm" 1 EXAMPLE 111 V- ( { C / s-4-r (3-Methoxyphenoxy) methyclohexyl} methyl) -1-pyrazol-4-carboxamide This compound was prepared with 1 H-pyrazole-4-carboxylic acid and ( { C / s-4 - [(3-methoxy-phenoxy) methyl] cyclohexyl} methyl) amine by a procedure similar to that of Example 8 1 H NMR (DMSO-de) d: 13.07 (br s, 1 H), 8.20-8.10 (m, 1 H), 8.03-7.95 (m, 1 H), 7.92-7.84 (m, 1 H), 7.16 ( m, 1 H), 6.56-6.46 (m, 3H), 3.86 (d, J = 6.8 Hz, 2H), 3.73 (s, 3H), 3.18 (t, J = 6.8 Hz, 2H), 1.97-1.82 ( m, 1H), 1.80-1.65 (m, 1 H), 1.59-1.30 (m, 8H) ppm. MS (ESI): 344.18 (M + Hf, 342.25 (M-H) " EXAMPLE 112 / V- ( { (2?, 5) -5-r (4-Fluorophenoxy) methytetrahydro-2 y-pyran-2-yl methylene-1-pyrazole-4-carboxamide This compound was prepared with 1H-pyrazole-4-carboxylic acid by a procedure similar to that of Example 75. 1 H NMR (DMSO) d: 13.08 (s a, 1 H), 8.24-7.83 (m, 3H), 7.17-6.92 (m, 4H), 4.17-3.87 (m, 3H), 3.58-3.11 (m, 4H), 2.03-1.26 (m, 5H) ppm.

EXAMPLES 113 AND 114 4 stereoisomers were prepared with 1 / - / - pyrazole-4-carboxylic acid and (. {5- [2- (4-fluorophenoxy) ethyl] tetrahydro-2 / - -pyran-2-yl}. methylene) amine by a procedure similar to that of Example 8. The 4 stereoisomers were separated with a chiral column (Chiralpak AD-H, 20 mm D.l. x 250 mm (No. ADH0CJ-DE003), DAICEL) using n-Hexane: 2-Propanol: Et2NH = 85: 15: 0.1 as eluent (10 ml / minute).

EXAMPLE 113 ? / - (((2 /? 5S) -5-r2- (4-Fluorophenoxy) etintetrahydro-2-pyran-2-yl> methyl) -1-pyrazole-4-carboxamide Retention time 29 minutes - 32 minutes 1 H NMR (DMSO-d) d: 13.28 (a, 1 H), 8.15-7.93 (m, 3 H), 7.10 (t, J 8.8 Hz, 2 H), 6.94 (d, J = 9.0, 4.6 Hz, 2H), 3.99 (t, J = 6.3 Hz, 2H), 3.73 (m, H), 3.55-3.10 (m, 4H), 1.96-1.65 (m, 5H), 1.50-1.35 ( m, 2H) ppm. MS (ESI): 348.16 (M + Hf, 346.17 (M-H) " EXAMPLE 114 V - (((2S, 5 /?) - 5-r2- (4-fluorophenoxy) -tetrahydro-2-pyran-2-yl> metin-1H-pyrazole-4-carboxamide Retention time 39 minutes - 43 minutes. 1 H NMR (DMSO-d) d: 13.09 (a, 1 H), 8.18-7.96 (m, 3H), 7.10 (t, J = 8.9 Hz, 2H), 6.94 (dd, J = 9.2, 4.4 Hz, 2H ), 3.99 (t, J = 6.4 Hz, 2H), 3.73 (m, 1 H), 3.54-3.13 (m, 4H), 1.96-1.61 (m, 5H), 1.50-1.35 (m, 2H) ppm. MS (ESI): 348.09 (M + Hf, 346.11 (M-H) " EXAMPLE 115 - (Fc / 's-4- (4-Methoxybenzyl) cyclohexinmethyl.} -1H-pyrazole-4-carboxamide This compound was prepared with 1H-pyrazole-4-carboxylic acid and . { [c / s-4- (4-methoxybenzyl) cyclohexyl] meth} amine by a procedure similar to that of Example 8. 1 H NMR (DMSO) d: 13.07 (sa, 1 H), 8.19-7.83 (m, 3H), 7.07 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 3.71 ( s, 3H), 3.23-3.11 (m, 2H), 2.50-2.43 (m, 2H), 1.78-1.20 (m, 9H) ppm.

EXAMPLES 116 AND 116 (2) S? T I ? T (1R, 3S) -3- (2-Phenylethoxy) cyclohexypemet} -1H-pyrazole-4-carboxamide and JV-. { r (1S, 3?) - 3- (2-Phenylethoxy) cyclohexinmethyl} -1 H-pyrazole-4-carboxamide The ?/-. { [c / s-3- (2-phenylethoxy) cyclohexyl] methyl} -1 / - / - pyrazole-4-carboxamide (0.11 g, 0.34 mmol) was prepared with IH-pyrazole-4-carboxylic acid and. { [(cs-3- (2-phenylethoxy) cyclohexyl) methyl] amine by a procedure similar to that of Example 8, and separated with a chiral column (Chiralcel OJ-H, 20 mm Dl x 250 mm (No. OJH0CJ- DH004), DAICEL) using n-Hexane / EtOH / Et2NH = 93/7 / 0.1 as eluent (Flow rate: 10 ml / minute) to give the title compounds.

EXAMPLE 116 First peak: (32 mg) retention time 39.8 minutes, > 99% us 1 H NMR (DMSO-de) d: 13.08 (s, 1H), 8.15-7.95 (m, 3H), 7.32-7.12 (m, 5H), 3.61 (t, J = 7.1 Hz, 2H), 3.28-2.96 ( m, 3H), 2.76 (t, J = 7.1 Hz, 2H), 2.08-1.90 (m, 2H), 1.78-1.40 (m, 3H), 1.27-0.70 (m, 4H) ppm. MS (ESI): 328.15 (M + Hf, 326.23 (M-H) " EXAMPLE 116 (2) Second peak: (27 mg) retention time 45.3 minutes, > 99% ee The 1 H NMR data was identical to that of Example 116. MS (ESI): 328.15 (M + Hf, 326.23 (M-H) " EXAMPLE 117 3-Amino-V-f (c / 's-4-benzylcyclohexyl) methan-1 / -pyrazol-4-carboxamide This compound was prepared with 3-amino-1 - / - pyrazole-4-carboxylic acid (38 mg, 0.3 mmol) and [(c / s-4-benzylcyclohexyl) methyl] amine (61 mg, 0.3 mmol) by a procedure similar to that of Example 8 in the form of a white solid (8.8 mg, 9%). 1 H NMR (DMSO-de) d: 11.80-11.69 (m, 1 H), 7.93-7.64 (m, 2H), 7.30-7.15 (m, 5H), 5.86-5.27 (m, 2H), 3.16-3.12 ( m, 2H), 2.56-2.53 (m, 2H), 1.67-1.40 (m, 10H) ppm. MS (ESI): 313.23 (M + Hf, 311.13 (M-H) ' EXAMPLE 118 0? H? Ft or ? p (c / s-4-Benzylcyclohexyl) methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxamide This compound was prepared with 2-oxo-1, 2,3,4-tetrahydroquinoline-6-carboxylic acid (57 mg, 0.3 mmol) and [(c / s-4-benzylcidhexyl) methyl] amine (61 mg, 0.3 mmol) ) by a procedure similar to that of Example 8 in the form of a white solid (35 mg, 31%). 1 H NMR (DMSO-de) d: 10.27 (sa, 1H), 8.28-8.23 (m, 1 H), 7.69-7.63 (m, 2H), 7.30-7.15 (m, 5H), 6.88-6.85 (m, 1 H), 3.25-3.20 (m, 2H), 2.94-2.88 (m, 2H), 2.56-2.45 (m, 4H), 1.73-1.29 (m, 10H) ppm. MS (ESI): 377.21 (M + Hf, 375.20 (MH) Anal Caled, for C24H28N2O2O.I H2O: C, 76.20; H, 7.51; N, 7.41 Found: C, 76.11; H, 7.57; N; 7.31 mp 188.5 ° C EXAMPLE 119 V- (2?, 5 /?) - 5-r (3,4-difluorophenoxy) methintetrahydro-2H-pyran-2-yl > methyl) -1-pyrazole-4-carboxamide To a solution of. { [(5S) -5- (Hydroxymethyl) tetrahydro-2 / - -pyran-2-yl] methyl} tere-butyl carbamate (300 mg, 1.22 mmol) and 3,4-difluorophenol (397.7 mg, 3.06 mmol) in THF (4.9 ml) were added PPh3 (737.7 mg, 2.81 mmol) and DIAD (0.56 ml, 2.32 millimoles) at 0 ° C. The mixture was irradiated with microwaves at 180 ° C for 5 minutes. The mixture was then cooled to room temperature and diluted with AcOEt. The organic layer was washed with 2 N aqueous NaOH and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on silica gel (hexane: AcOEt = 50: 1-20: 1) to give (. {(2R, 5R) -5 - [(3,4-difluorophenoxy) methyl) ] tert-butyl tetrahydro-2 / - / - pyran-2-yl.} methyl) carbamate (55.5 mg, 0.155 mmol). This was dissolved in HCl-MeOH (1 ml) and the mixture was stirred at 40 ° C for 2 hours. The mixture was evaporated to give the crude amine. The amine was dissolved in DMF (2 ml) and 1-pyrazole-4-carboxylic acid (17.4 mg, 0.155 mmol), Et3N (0.064 ml, 0.466 mmol), HOBt (28.5 mg, 0.186 mmol) and WSC were added. (35.6 mg, 0.186 mmol) at 0 ° C. The mixture was stirred at room temperature overnight. 2N aqueous NaOH was added to the mixture and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with AcOEt and the organic layer was washed with brine. The organic layer was dried over Na2SO, filtered and evaporated. The crude product was purified by column chromatography on silica gel (CH2Cl2: MeOH = 20: 1) to give the title compound. 1 H NMR (DMSO-d) d: 13.08 (a, 1 H), 8.17-7.92 (m, 3 H), 7.35-7.25 (m, 1 H), 7.13-7.05 (m, 1 H), 6.84-6.75 ( m, 1 H), 4.14 (t, J = 9.1 Hz, 1 H), 4.03-3.87 (m, 2H), 3.58-3.11 (m, 4H), 1.94 (a, 1 H), 1.88-1.64 (m , 2H), 1.53-1.29 (m, 2H) ppm. MS (ESI): 352.20 (M + Hf, 350.15 (M-H) ' EXAMPLE 120 AND EXAMPLE 121 To a suspension of LiAIH4 (119.7 mg, 3.15 mmol) in THF (10 mL) was added the solution of 2- (azidomethyl) -5 - [(4-chlorophenoxy) methyl] tetrahydro-2-pyran (444.3 mg, 1.58 mmol) in THF (6 ml) at 0 ° C. Then, the mixture was stirred at 0 ° C for 1.25 hours. The reaction was quenched with Na2SO4 »10H2O (1.6 g, 4.97 millimoles) and KF (200 mg, 3.44 millimoles). The mixture was stirred at room temperature for 1 hour. The mixture was filtered through a pad of celite and the filtrate was evaporated to give the crude compound. To a solution of the crude compound in DMF (5 ml) was added 1H-pyrazole-4-carboxylic acid (177.1 mg, 1.58 mmol), HOBt (290.4 mg, 1.90 mmol) and WSC (363.5 mg, 1.90 mmol). at 0 ° C. The mixture was stirred at room temperature overnight. To the mixture was added 2N aqueous NaOH and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with AcOEt and the organic layer was washed with brine. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on silica gel (CH2Cl2: MeOH = 20: 1) to give the mixture of 4 stereoisomers. The 4 stereoisomers were separated with a chiral column (Chiralcel OJ-H, 20 mm Dl x 250 mm (No. OJH0CJ-DH004), DAICEL) using n-Hexane: EtOH: Et2NH = 88: 12: 0.1 as eluent (18.9 ml /minute).

EXAMPLE 120 V-ffl2?, 5?) - 5-r (4-Chlorophenoxy) methytrahydro-2-pyran-2-yl > methyl) -1-pyrazole-4-carboxamide Retention time 12 minutes - 20 minutes (13 minutes) 1 H NMR (DMSO-d) d: 13.10 (a, 1 H), 8.23-7.83 (m, 3 H), 7.33 (d, J = 9.0 Hz, 2 H), 6.99 (d, J = 8.8 Hz, 2H), 4.14 (t, J = 9.0 Hz, 1 H), 4.05-3.86 (m, 2H), 3.58-3.12 (m, 4H), 1.95 (a, 1 H), 1.89-1.66 (m, 2H), 1.53-1.20 (m, 2H) ppm. MS (ESI): 350.05 (M + Hf, 348.06 (M-H) " EXAMPLE 121 / V- (2S, 5S) -5-r (4-Chlorophenoxy) methintetrahydro-2 Y-pyran-2-yi > metin-1H-pyrazole-4-carboxamide Retention time 20 minutes - 24 minutes (22 minutes) 1H NMR (DMSO-d) d: 13.09 (a, 1 H), 8.20-7.85 (m, 3H), 7.32-7.28 (m, 2H), 7.04-6.94 (m, 2H), 4.14 (t, J = 8.7 Hz, 1 H), 4.05-3.86 (m, 2H), 3.60-3.10 (m, 4H), 1.95 (a, 1 H), 1.86-1.64 (m , 2H), 1.53-1.20 (m, 2H) ppm. MS (ESI): 350.04 (M + Hf, 348.06 (M-H) " EXAMPLE 122 or cuo / V-f (c / s-4-Benzylcyclohexyl) metin-2-hydroxyquinoline-6-carboxamide This compound was prepared with 2-hydroxyquinoline-6-carboxylic acid (38 mg, 0.2 mmol) and [(c / s-4-benzylcyclohexyl) methyl] amine (53 mg, 0.2 mmol) by a procedure similar to of Example 8 in the form of a white solid (26 mg, 34%). 1 H NMR (DMSO-de) d: 11.93 (br s, 1 H), 8.46-8.42 (m, 1 H), 8.18- 8.17 (m, 1 H), 7.97-7.94 (m, 2H), 7.33-7.25 ( m, 3H), 7.18-7.16 (m, 3H), 6.57-6.53 (m, 1 H), 3.29-3.24 (m, 2H), 2.58-2.55 (m, 2H), 1.83-1.64 (m, 2H) , 1.44-1.30 (m, 8H) ppm. MS (ESI): 375.06 (M + Hf, 373.08 (MH) "Anal.Called, for C 24 H 26 N 2 O 2 O 4 H 2 O: C, 75.52; H, 7.08; N, 7.34. Found: C, 75.18; H, 6.94; N; mp: 236.7 ° C EXAMPLE 123 ? / -. { ((2 5 /?) ° 5-rf4 ° Methylphenoxy) metiptetrahydro-2-pyran-2-yl > methyl) -1-pyrazole-4-carboxamide This compound was prepared with p-cresol by a procedure similar to that of Example 119. The cis and trans isomers were separated with a chiral column (Chiralcel OJ-H, 20 mm Dl x 250 mm (No. OJH0CJ-DH004), DAICEL) using 5 minutes - 7 minutes (5 minutes) 1 H NMR (DMSO-d) d: 13.10 (a, 1 H), 8.21-7.86 (m, 3H), 7.08 (d, J = 8.1 Hz, 2H), 6.84 ( d, J = 8.6 Hz, 2H), 4.10 (t, J = 9.0 Hz, 1 H), 3.99-3.87 (m, 2H), 3.57-3.12 (m, 4H), 2.23 (s, 3H), 1.98- 1.65 (m, 3H), 1.52-1.28 (m, 2H) ppm. MS (ESI): 330.10 (M + Hf, 28.12 (M-H) " EXAMPLE 124 3-Amino-? / - ((f2 5) -5-r (4-fiuorophenoxy) metiptetrahydro-2-pyran-2-yl} methyl) -1A-pyrazole-4-carboxamide The 3-amino- / V- ( { (2f? *, 5R *) - 5 - [(4-fluorophenoxy) methyl] tetrahydro-2H-pyran-2-yl. methyl) -1H-plrazole-4-carboxamide was prepared with 3-amino-1 - / - pyrazole-4-carboxylic acid (127 mg, 1.0 mmol) and (. {(2R *, 5R *) - 5- [(4-fluorophenoxy) methyl] tetrahydro-2 / - / - pyran-2-yl.} Methyl) amine (239 mg, 1.0 mmol) by a procedure similar to that of Example 8, and separated with a chiral column (Chiralpak OJ-H, 20 mm Dl x 250 mm (No. OJH0CJ-DH004), DAICEL) using n-Hexane / Ethanol / Et2NH = 85/15 / 0.1 as eluent (10 ml / min) to yield the title compound (50 mg, 14%). ? NMR (DMSO-de) d: 11.73 (sa, 1 H), 7.83-7.67 (m, 2H), 7.14-7.07 (m, 2H), 6.99-6.94 (m, 2H), 5.85 (sa, 1 H) , 4.15-4.08 (m, 1H), 3.99-3.90 (m, 2H), 3.55-3.50 (m, 1H), 3.47-3.37 (m, 1H), 3.27-3.09 (m, 2H), 1.94-1.72 ( m, 3H), 1.43-1.24 (m, 2H) ppm. (1 H was not observed.) MS (ESI): 349.15 (M + Hf, 347.14 (MH) "Anal.Called, for C17Hz? FN4O3O.2H2O: C, 58.01; H, 6.13; N, 15.92. Found: C 58.03; H, 6.34; N; 15.60 EXAMPLE 125 3-Am? No -? / - f ((2 5R) -5-r (4-chlorophenoxy) methytetrahydro-2-tf-pyran-2-yl.} Methyl) -1A / -pyrazole-4-carboxamide This compound was prepared with 4-chlorophenol and 3-amino-1H-pyrazole-4-carboxylic acid by a procedure similar to that of Example 119. 1 H NMR (DMSO-de) d: 13.70 (s, 1H), 7.82-7.65 ( m, 2H), 7.30 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 4.20-3.85 (m, 3H), 3.60-3.05 (m, 4H), 2.00-1.62 (m, 3H), 1.50-1.05 (m, 2H) ppm. (Not observed -NH2.) MS (EST): 365.07 (M + Hf, 363.09 (M-Hf " EXAMPLE 126 and V- (f (2 5 /?) - 5-r 4-Chlorophenoxy) methytetrahydro-2 H -pyran-2-yl methan-3,5-difluoro-4-hydroxybenzamide This compound was prepared with 4-chlorophenol and 3,5-difluoro-4-hydroxybenzoic acid by a procedure similar to that of Example 119. 1 H NMR (DMSO-de) d: 8.52-8.42 (m, 1 H), 7.63-7.46 (m, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.18-4.07 (m, 1 H), 4.02-3.85 (m, 2H), 3.57-3.20 (m, 4H) , 2.00-1.63 (m, 3H), 1.53-1.15 (m, 2H) ppm. (No -OH was observed.) MS (EST): 412.13 (M + Hf, 410.13 (M-Hf " EXAMPLE 127 and V - (((2 5?) - 5-r (4-Ciorophenoxy) methytetrahydro-2-pyran-2-ylmethyl) -2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxamide This compound was prepared with 4-chlorophenol and 2-oxo-1, 2,3,4-tetrahydroquinoline-6-carboxylic acid by a procedure similar to that of Example 119 in the form of a white solid. 1 H NMR (CDCl 3) d: 8.48 (s, 1 H), 7.64 (s, 1 H), 7.59-7.57 (m, 1 H), 7. 27-7.20 (m, 2H), 6.85-6.79 (m, 3H), 6.55-6.52 (m, 1H), 4.17-4.11 (m, 2H), 3. 99-3.93 (m, 1 H), 3.84-3.76 (m, 1 H), 3.68-3.63 (m, 1 H), 3.61-3.53 (m, 1 H), 3. 27-3.18 (m, 1 H), 3.02-2.96 (m, 2H), 2.69-2.64 (m, 2H), 2.1 -1.76 (m, 3H), 1.64-1.40 (m, 1 H), 1.36-1.22 (m, 1 H) ppm. MS (ESI): 429 (M + Hf EXAMPLE 128 ? / - (ff2 5?) - 5-r (4-Chlorophenoxy) methintetrahydro-2H-pyran-2-yl > methyl) -3-methyl-1-pyrazol-4-carboxamide This compound was prepared with 4-chlorophenol and 1 / - / - 3-methylpyrazole-4-carboxylic acid by a procedure similar to that of Example 119. 1 H NMR (CDCl 3) d: 7.86 (s, 1 H), 7.21 (d, J = 8.8 Hz, 2H), 6.96-6.87 (m, 1 H), 6.83 (d, J = 8.8 Hz, 2H), 4.18-4.10 (m, 2H), 3.97-3.92 (m, 1 H), 3.83 -3.67 (m, 3H), 3.21-3.16 (m, 1 H), 2.50 (s, 3H), 2.13-2.03 (m, 1 H) 1.98-1.76 (m, 2H), 1.62-1.39 (m, 1 H), 1.33-1.22 (m, 1 H) ppm. (1 H was not observed.) MS (ESI): 364 (M + Hf EXAMPLE 129 / V - (((2 /? 5 /?) - 5-rf4-Chloro-3-fluorophenoxy) methintetrahydro-2H-pyran-2-yl) metin-1 Y-pyrazole-4-carboxamide This compound was prepared with 4-chloro-3-fluorophenol and 1H-pyrazole-4-carboxylic acid by a procedure similar to that of Example 119. 1 H NMR (DMSO-de) d: 13.09 (s at, 1 H), 8.12-8.03 (m, 3H), 7.46 (t, J = 8.1 Hz, 1 H), 7.14-7.09 (m, 1 H), 6.88-6.84 (m, 1 H), 4.18 (t, J = 8.1 Hz, 1 H), 4.04-3.98 (m, 1 H ), 3.93-3.89 (m, 1 H), 3.55-3.50 (m, 1 H), 3.47-3.40 (m, 1 H), 3.29-3.13 (m, 2H), 1.96-1.70 (m, 3H), 1.50-1.36 (m, 2H) ppm. MS (ESI): 368.03 (M + Hf, 366.03 (M-H) " EXAMPLE 130 3-Amino- / V- (2 5?) - 5-r (4-ethylphenoxy) methytetrahydro-2H-pyran-2-yl > methyl) - 1 H-pyrazole-4-carboxamide This compound was prepared with 4-ethylphenol and 3-amino-1H-pyrazole-4-carboxylic acid by a procedure similar to that of Example 119. 1 H NMR (CDCl 3) d: 7.55 (s, 1 H), 7.11-7.08 (m , 2H), 6.85-6.81 (m, 2H), 6.81-6.72 (m, 1 H), 5.58-5.31 (m, 2H), 4.17-4.07 (m, 2H), 3.98-3.93 (m, 1 H), 3.72-3.49 (m, 3H), 3.14-3.05 (m, 1 H), 2.57 (d, J = 7.5 Hz, 2H), 2.07-1.79 (m, 3H), 1.62-1.35 (m, 2H), 1.19 (t, J = 7.5 Hz, 3H ) ppm. (No NH was observed.) MS (ESI): 359 (M + Hf EXAMPLE 131 / V - (((2, 5f?) - 5-r (4-Cyclopropylphenoxy) methy-tetrahydro-2-pyran-2-yl> methyl) -1-pi pyrazol-4-carboxamide This compound was prepared with 4-cyclopropylphenol by a procedure similar to that of Example 119 in the form of a colorless oil. 1 H NMR (DMSO-d 6) d: 13.09 (br s, 1 H), 8.10-8.03 (m, 3H), 7.00-6.96 (m, 2H), 6.85-6.81 (m, 2H), 4.12-4.06 (m, 1 H), 3.97-3.89 (m, 2H), 3.55-3.49 (m, 1 H), 3.48-3.40 (m, 1H), 3.28-3.18 (m, 2H), 1.93-1.67 (m, 4H), 1.44-1.34 (m, 2H), 0.90-0.83 (m, 2H), 0.59-0.53 (m, 2H) ppm MS (ESI): 356.14 (M + Hf, 354.16 (MH) "Anal.Called, for C20H25N3O3O. 3H2O: C, 66.57; H, 7.15; N, 11. 65. Found: C, 66.41; H, 7.17; N; 11.49 EXAMPLE 132 3-Amino -? / - (2 5?) - 5-f (4-isopropylphenoxy) methytrahydro-2H-pyran-2-yl} methyl) -1H-pyrazole-4-carboxamide This compound was prepared with 4-isopropylphenol and 3-amino-1 H-pyrazole-4-carboxylic acid by a procedure similar to that of Example 119 in the form of a colorless oil. 1 H NMR (DMSO-de) d: 11, 76 (sa, 1 H), 7.86-7.71 (m, 2H), 7.14 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H ), 4.13-4.07 (m, 1 H), 3.99-3.89 (m, 2H), 3.55-3.50 (m, 2H), 3.30-3.08 (m, 2H), 2.87-2.77 (m, 1 H), 1.93 -1.67 (m, 3H), 1.48-1.36 (m, 2H), 1.18-1.15 (m, 6H) ppm. (NH2 was not observed.) MS (ESI): 373.21 (M + Hf, 371.21 (M-H) " EXAMPLE 133 3-Amino -? / - ffl2, 5R) -5-r (4-methyloxy) methylanthrahydro-2-pyran-2-yl > metin- 1 H-pyrazole-4-carboxamide This compound was prepared with p-cresol and 3-amino-1 - / - pi razo i-4-carboxylic acid by a similar procedure ai of Example 119. 1 H NMR (DMSO-d) d: 11.73 (a, 1 H ), 8.20-7.50 (m, 2H), 7.08 (d, J) = 8.3 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.10-5: 20 (m, 2H), 4.10 (t, J = 8.9 Hz, 1 H), 3.97-3.89 (m, 2H) ), 3.53 (dd, J = 11.5, 2.5 Hz, 1 H), 3.45-3.38 (m, 1 H), 3.28-3.22 (m, 1 H), 3.18-3.12 (m, 1 H), 2.24 (s) , 3H), 1.97-1.91 (m, 1 H), 1.87-1.81 (m, 1 H), 1.77-1.68 (m, 1 H), 1.48-1.43 (m, 1 H), 1.39-1.31 ( m, 1 H) ppm. MS (ESI): 345.23 (M + Hf, 343.22 (M-H) " EXAMPLE 134 3-Amino -? / - ffl2 5 /?) - 5 - ((3-fluoro-4-methylphenoxy) methyl-1-tetrahydro-2-pyran-2-yl.} Methyl) -1A / -pyrazole-4-carboxamide This compound was prepared with 3-fluoro-4-cresol and 3-amino-1H-pyrazole-4-carboxylic acid by a procedure similar to that of Example 119. 1 H NMR (DMSO-de) d: 11.70 (a, 1 H) , 8.10-7.50 (m, 2H), 7.15 (d, J = 8.8 Hz, 1 H), 6.78 (dd, J = 11.9, 2.4 Hz, 1 H), 6.71 (dd, J = 8.4, 2.4 Hz, 1 H), 6.20-5.05 (m, 2H), 4.12 (t, J = 9.1 Hz, 1H), 3.96 (d, J = 9.4, 6.7 Hz, 1H), 3.90 (d, J = 11.6 Hz, 1 H) , 3.51 (dd, J = 11.6, 2.6 Hz, 1 H), 3.44-3.38 (m, 1 H), 3.28-3.20 (m, 1 H), 3.18-3.10 (m, 1 H), 2.14 (s, 3H), 1.97-1.69 (m, 1 H), 1.84-1.77 (m, 1 H), 1.76-1.67 (m, 1 H), 1.48-1.42 (m, 1 H), 1.40-1.30 (m, 1 H) ppm. MS (ESI): 363.18 (M + Hf, 361.13 (M-H) ' EXAMPLE 135 / V- (2R, 5f?) - 5-r (3-Fluoro-4-methylphenoxy) methintetrahydro-2-pyran-2-yi > methyl) - 1H-pyrazole-4-carboxamide This compound was prepared with 3-fluoro-4-cresol by a procedure similar to that of Example 119. 1 H NMR (DMSO-d) d: 13.08 (a, 1 H), 8.20-7.85 (m, 3H), 7.15 (t , J = 8.8 Hz, 1 H), 6:78 (dd, J = 11.9, 2.4 Hz, 1 H), 6.70 (dd, J = 8.4, 2.4 Hz, 1 H), 4.12 (t, J = 9.0 Hz, 1 H), 3.96 (dd, J = 9.4, 6.7 Hz, 1 H), 3.90 (d, J = 11.6 Hz, 1 H), 3.52 (dd, J = 11.6, 2.6 Hz, 1 H), 3.47-3.41 ( m, 1 H), 3.37-3.25 (m, 1 H), 3.22-3.15 (m, 1 H), 2.14 (s, 3 H), 1.96-1.90 (m, 1 H), 1.84-1.78 (m, 1 H), 1.76-1.68 (m, 1 H), 1.48-1.43 (m, 1 H), 1.42-1.33 (m, 1 H) ppm. MS (ESI): 348.21 (M + Hf, 346.15 (M-H) " EXAMPLE 136 3-Amino- / V- ( { (2?, 5?) - 5-r (2,3-dihydro-1-yl-inden-5-yloxy) methintetrahydro-2-pyran-2-yl}. methyl) -1H-pyrazole-4-carboxamide This compound was prepared with indan-5-ol and 3-amino-1H-pyrazole-4-carboxylic acid by a procedure similar to that of Example 119. 1 H NMR (DMSO-d) d: 11.81 (a, 1 H), 8.20 -7.50 (m, 2H), 7.08 (d, J = 8.1 Hz, 1 H), 6.84-6.80 (m, 1 H), 6.69 (dd, J = 8.1, 2.2 Hz, 1 H), 6.20-5.00 (m, 2H), 4.09 (t, J = 8.9 Hz , 1 H), 3.97-3.86 (m, 2H), 3.51 (dd, J = 11.6, 2.6 Hz, 1 H), 3.44-3.37 (m, 1 H), 3.27-3.19 (m, 1 H), 3.18 -3.10 (m, 1 H), 2.81 (t, J = 7.4 Hz, 2H), 2.76 (t, J = 7.3 Hz, 2H), 2.03-1.96 (m, 2H), 1.95-1.89 (m, 1 H) ), 1.85-1.78 (m, 1 H), 1.76-1.64 (m, 1 H), 1.48-1.41 (m, 1 H), 1.39-1.29 (m, 1 H) ppm. MS (ESI): 371.12 (M + Hf, 369.14 (M-H) " EXAMPLE 137 ? / - ( { (2?, 5R) -5-rf2,3-Dihydro-1f-inden-5-yloxy) methytetrahydro-2H-pyran-2-yl} methyl) -1H-pyrazole-4-carboxamide This compound was prepared with ndan-5-ol by a procedure similar to that of Example 119. 1 H NMR (DMSO-d) d: 13.08 (a, 1 H), 8.20-7.85 (m, 3 H), 7.08 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 6.89 (dd, J = 8.2, 2.2 Hz, 1H), 4.09 (t, J = 8.9 Hz, 1 H), 3.97-3.88 (m, 2H), 3.52 (dd, J = 11.6, 2.6 Hz, 1 H), 3.47-3.40 (m, 1 H), 3.38-3.24 (m, 1 H), 3.23-3.14 (m, 1 H), 2.81 (t, J = 7.4 Hz, 2H), 2.76 (t, J = 7.3 Hz, 2H), 2.04-1.90 (m, 3H), 1.85-1.78 (m, 1 H), 1.75-1.65 (m, 1 H), 1.49- 1.42 (m, 1 H), 1.40-1.31 (m, 1 H) ppm. MS (ESI): 356.21 (M + Hf, 354.12 (M-H) " PREPARATION 1 c / s-Methyl-4-r (benzylamino) carbon-cyclohexanecarboxylate A mixture of c / s-4- (methoxycarbonyl) cyclohexanecarboxylic acid (35 g, 0.19 mol) (J. Am. Chem. Soc. 1956, 78, 4000-4002.), Benzylamine (22 g, 0.21 mol), EDCI (40 g, 0.21 mol) and HOBt-H20 (5.7 g, 37 mmol) in DMF (380 ml) was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and diluted with AcOEt. The organic layer was washed with 2N aqueous HCl, saturated aqueous NaHCO3 and water, dried over MgSO and concentrated in vacuo to give the title compound (51 g). 1 H NMR (CDCl 3) d: 7.38-7.22 (m, 5H), 5.78 (a, 1 H), 4.44 (d, J = . 8 Hz, 2H), 3.69 (s, 3H), 2.63-2.54 (m, 1 H), 2.30-2.05 (m, 3H), 1.80-1.50 (m, 6H) ppm.

PREPARATION 2 . { c / 's-4 - [(Benzylamino) metipciclohexil) methanol A solution of c / s-methyl 4 - [(benzylamino) carbonyl] cyclohexanecarboxylate (51 g, 0.19 moles) in THF (200 ml) was added dropwise to a suspension of L-IAH (21 g, 0.56 moles) in THF (1.0 L) at 0 ° C and the mixture was heated to reflux for 16 hours. The reaction mixture was added dropwise to a suspension of Na 2 SO 4"10hl 2 O (excess) in CH 2 Cl 2 at 0 ° C and the mixture was stirred at room temperature for 3 hours. The white suspension was filtered and the filtrate was concentrated in vacuo. The residue was dissolved with CH2Cl2 and filtered through cotton. The filtrate was evaporated to give the title compound (40 g, 0.17 mol). 1 H NMR (CDCl 3) d: 7.35-7.20 (m, 5H), 3:78 (s, 2H), 3.52 (d, J = 6.9 Hz, 2H), 2.55 (d, J = 7.1 Hz, 2H), 1.90 -1.30 (m, 10H) ppm. (OH and NH were not observed.) PREPARATION 3 [c7's-4- (Aminomethyl) cyclohexylmethanol A mix of . { c / s-4 - [(benzylamino) methyl] cyclohexyl} methanol (35 g, 0.15 mol) and 20% Pd (OH) 2 w / w-C (3.0 g) in MeOH (300 ml) was hydrogenated at 4 atmospheres for 10 hours. The mixture was filtered through a pad of celite and the filtrate was evaporated to give the title compound (22 g). 1 H NMR (CDCl 3) d: 3.52 (d, J = 6.9 Hz, 2H), 2.61 (d, J = 6.1 Hz, 2H), 1.80-1.30 (m, 10H) ppm. (OH and NH2 were not observed.) PREPARATION 4 4- (Benzyloxy) -? / - (rc s-4- (hydroxymethyl) cyclohexyl] methyl.} Benzamide To a mixture of [c / s-4- (aminomethyl) cyclohexyl] methanol (2.8 g, 20 mmol), triethylamine (3.3 mL, 24 mmol) and DMAP (0.24 g, 2.0 mmol) in CH2Cl2, was added TBSCI (3.3 g, 22 mmol) at 0 ° C and the mixture was stirred at room temperature for 16 hours. Saturated aqueous NaHCO3 was added to the mixture and all was extracted with CH2Cl2. The extract was dried over gSO and evaporated to produce. { [cs-4- ( { [tert-Butyl (d.methyl) silyl] oxy} methyl) cyclohexyl] methyl} Amy A mix of . { [c / s-4- ( { [tert-butyl (dimethyl) silyl] oxy] methyl) clclohexyl] methyl} amine, 4- (benzyloxy) benzoic acid (4.6 g, 20 mmol), EDCI (4.2 g, 22 mmol) and HOBtH20 (3.4 g, 22 mmol) in DMF (40 mL) was stirred at room temperature for 16 h. The mixture was diluted with AcOEt and washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and evaporated to yield 4- (benzyloxy) -? / -. { [c / s-4- ( { [tert-butyl (dimethyl) silyl] oxy} methyl) cyclohexyl] methyl} benzamide. A mixture of 4- (benzyloxy) - / V-. { [c / -s-4- ( { [tert-butyl (d-methyl) s / 1] xl] methyl] cyclohexyl] methyl} Benzamide and TBAF (1.0 M in THF, 30 ml) was stirred at room temperature for 4 hours. The mixture was diluted with AcOEt and washed with 2N aqueous HCl and water, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel (hexane-AcOEt 1: 3) to give the title compound (1.9 g). 1 H NMR (CDCl 3) d: 7.72 (d, J = 8.9 Hz, 2H), 7.46-7.30 (m, 5H), 7. 00 (d, J = 8.9 Hz, 2H), 6.05-5.95 (m, 1 H), 5.11 (s, 2H), 3.56 (dd, J = 5.6, 6.8 Hz, 2H), 3.40 (dd, J = 5.9 , 7.4 Hz, 2H), 1.90-1.40 (m, 10H) ppm. (No OH was observed.) PREPARATION 5 4- (Benzyloxy) - V - ((c / 's-4-r (4-methoxyphenoxy) methyclohexyl} methyl) benzamide Cyanomethylenetributylphosphorane (80 mg, 0.30 mmol) was added to a mixture of 4- (benzyloxy) -A / -. { [C / S-4- (Hydroxymethyl) cyclohexyl] methyl} benzamide (71 mg, 0.2 mmol) and 4-methoxyphenol (37 mg, 0.30 mmol) in benzene (1.0 ml). The mixture was refluxed for 1 hour and purified by column chromatography on silica gel (hexane-AcOEt 4: 1) to give the title compound (84 mg). 1 H NMR (CDCl 3) d: 7.72 (d, J = 8.8 Hz, 2H), 7.46-7.30 (m, 5H), 7.00 (d, J = 8.8 Hz, 2H), 6.83 (s, 4H), 6.10-6.00 (m, 1 H), 5.11 (s, 2H), 3.82 (d, J = 7.0 Hz, 2H), 3.77 (s, 3H), 3.41 (dd, J = 6.2, 7.1 Hz, 2H), 2.06-1.40 (m, 10H) ppm.

PREPARATION 6 rc / s-4- (Benzyloxy) methyl cyclohexyl-methylbenzenesulfonate Triflic acid (1.3 ml) was added to a mixture of (4-hydroxylcyclohexyl) methyl 4-methylbenzenesulfonate (21 g)., 75 millimoles) (J. Org. Chem. 1970, 35, 2386-2390.) And benzyl 2,2,2-trichloroacetimidate (38 g, 0.15 mol) in CH 2 Cl 2 at 0 ° C and the mixture was stirred at room temperature. environment for 16 hours. Saturated aqueous NaHCO3 was added to the mixture and the mixture was extracted with CH2Cl2. The extract was dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel (hexane-AcOEt 10: 1) to give the title compound (13 g). 1 H NMR (CDCl 3) d: 7.78 (d, J = 8.4 Hz, 2 H), 7.40-7.10 (m, 7 H), 4.46 (s, 2 H), 3.86 (d, J = 6.9 Hz, 2 H), 3.65-3.58 (m, 1 H), 2.45 (s, 3H), 1.98-1.24 (m, 9H) ppm.

PREPARATION 7 «Y ° AD ( { [C, fs-4- (Azidomethyl) cyclohexilloxy > methyl) benzene A mixture of [c / s-4- (benzyloxy) cyclohexyl] methyl 4-methylbenzenesulfonate (14 g, 37 mmol) and sodium azide (12 g, 0.19 mol) in DMF (150 ml) was stirred at 85 ° C for 3 hours. The mixture was diluted with AcOEt and washed with water. The organic layer was dried over MgSO and evaporated. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 20: 1) to give the title compound (6.9 g). 1 H NMR (CDCl 3) d: 7.36-7.22 (m, 5H), 4.50 (s, 2H), 3.68-3.61 (m, 1 H), 3.16 (d, J = 6.6 Hz, 2H), 2.04-1.86 (m, 2H), 1.70-1.36 (m, 7H) ppm.

PREPARATION 8 XX, "O rc s-4- (Benzyloxy) cyclohexyl] methylamine A solution of ( { [C / 's-4- (azidomethyl) cyclohexyl] oxy} methyl) benzene (6.9 g, 28 mmol) in THF (20 ml) was added dropwise to a suspension of LiAIH4 (1.6 g, 42 mmol) in THF (140 ml) at 0 ° C and the mixture was stirred at room temperature for 1 h. hour. The mixture was quenched with Na2SO '10H2O (excess) and the white suspension was filtered. The filtrate was evaporated to give the title compound (5.7 g). 1 H NMR (CDCb) d: 7.40-7.22 (m, 5H), 4.50 (s, 2H), 3.66-3.60 (m, 1 H), 2.58 (d, J = 5.7 Hz, 2H), 2.00-1.30 (m , 9H) ppm. (NH2 was not observed.) PREPARATION 9 and V-. { rc / 's-4- (Benzyloxy) cyclohexylmethyl} -4- (methoxymethoxy) benzamide A mixture of 4- (methoxymethoxy) benzoic acid (2.6 g, 14 mlllmoles), [c / s-4- (benzyloxy) cyclohexyl] methylamine (3.0 g, 14 mmol), EDCI (3.2 g, 17 mmol) and HOBt « H 2 O (0.43 g, 2.8 mmol) in DMF (70 ml) was stirred at room temperature for 16 hours. The mixture was diluted with AcOEt and washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and evaporated. The residue was crystallized from CH2Cl2-diisopropyl ether to give the title compound (4.2 g) as a white solid. 1 H NMR (CDCl 3) d: 7.72 (d, J = 8.8 Hz, 2 H), 7.38-7.23 (m, 5 H), 7.06 (d, J = 8.8 Hz, 2 H), 6.18-6.08 (m, 1 H), 5.21 (s, 2H), 4.50 (s, 2H), 3.68-3.62 (m, 1 H), 3.48 (s, 3H), 3.34 (t, J = 6.4 Hz, 2H), 2.04-1.90 (m, 2H) ), 1.75-1.40 (m, 7H) ppm.

PREPARATION 10 / V-f (c / s-4-Hydroxycyclohexyl) methyl-1-4- (methoxymethoxy) benzamide A mix of ?/-. { [c / s-4- (benzyloxy) cyclohexyl] methyl} -4- (methoxymethoxy) benzamide (4.0 g, 10 mmol) and 20% Pd (OH) 2 -C (0.50 g) in EtOH (200 ml) was hydrogenated under an atmosphere of hydrogen at 4 atmospheres and at room temperature for 8 hours. hours. The mixture was filtered through celite and evaporated. The title compound (2.9 g) was produced by crystallization from CH2Cl2 diisopropyl ether as a white solid. 1 H NMR (CDCl 3) d: 7.73 (d, J = 8.2 Hz, 2 H), 7.06 (d, J = 9.0 Hz, 2 H), 6.20-6.10 (m, 1 H), 5.22 (s, 2 H), 4.05-3.98 (m, 1 H), 3.48 (s, 3H), 3.35 (t, J = 6.6 Hz, 2H), 1.84-1.36 (m, 9H) ppm. (No OH was observed.) PREPARATION 11 Trans-4- ( { F4- (Methoxymethoxy) benzoipamino} methyl) cyclohexyl benzoate A mixture of / V - [(c / s-4-hydroxylcyclohexyl) methyl] -4- (methoxymethoxy) benzamide (0.58 g, 2.0 mmol), benzoic acid (0.37 g, 3.0 mmol) and cyanomethylenetributylphosphorane (0.80 g) g, 3.0 mmol) in benzene (10 ml) was heated to reflux for 4 hours. The residue was purified by column chromatography on silica gel (hexane.AcOEt = 3: 1) to give the title compound (0.28 g). 1 H NMR (CDCl 3) d: 8.06-8.00 (m, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.50-7.40 (m, 3H), 7.07 (d, J = 8.8 Hz, 2H), 6.32 -6.20 (m, 1 H), 5.22 (s, 2H), 5.00-4.87 (m, 1 H), 3.48 (s, 3H), 3.34 (t, J = 6.4 Hz, 2H), 2.20-2.10 (m , 2H), 1.98-1.88 (m, 2H), 1.78-1.42 (m, 3H), 1.30-1.12 (m, 2H) ppm.

PREPARATION 12 / V-f (tra / 7s-4-Hydroxycyclohexyl) methyl} -4- (methoxymethoxy) benzamide A mixture of trans-4- ( { [4- (methoxymethoxy) benzoyl] amino} methyl) cyclohexyl benzoate (0.24 g, 0.61 mmol), 2 N aqueous NaOH (3 mL), MeOH ( 3 ml) and THF (3 ml) was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with CH2Cl2. The extract was dried over MgSO and evaporated to give the title compound (0.17 g). 1 H NMR (CDCl 3) d: 7.72 (d, J = 8.8 Hz, 2 H), 7.07 (d, J = 8.6 Hz, 2 H), 6.15-6.00 (a, 1 H), 5.22 (s, 2 H), 3.65- 3.50 (m, 1 H), 3.48 (s, 3H), 3.31 (t, J = 6.6 Hz, 2H), 2.13-1.95 (m, 2H), 1.91-1.80 (m, 2H), 1.65-1.00 (m , 5H) ppm. (No OH was observed.)PREPARATION 13 4- (Methoxymethoxy) - / V-. { rc / 's-4- (4-methoxyphenoxy) cyclohexyl] methyl > benzamide A mixture of / V - [(trans-4-hydroxycyclohexyl) methyl] -4- (methoxymethoxy) benzamide (30 mg, 0.10 mmol), 4-methoxyphenol (19 mg, 0.15 mmol) and cyanomethylenetributylphosphorane (40 mg, 0.15 millimoles) in benzene (0.5 ml) was heated to reflux for 4 hours. The mixture was purified by column chromatography on silica gel (hexane: AcOEt = 3: 1) to give the title compound (11 mg). H NMR (CDCl 3) d: 7.72 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 6.90-6.80 (m, 4H), 6.20-6.05 (m, 1 H), 5.22 (s, 2H), 4.46-4.38 (m, 1 H), 3.77 (s, 3H), 3.48 (s, 3H), 3.36 (t, J = 6.4 Hz, 2H), 2.15-1.40 (m, 9H) ) ppm.

PREPARATION 14 V-. { Ucis-4- (4-Chlorophenoxy) cyclohexinmethi »-4- (methoxymethoxy) benzamide This compound was prepared with 4-chlorophenol by a procedure similar to that of Preparation 13. 1 H NMR (CDCl 3) d: 7.72 (d, J = 8.8 Hz, 2 H), 7.21 (d, J = 9.2 Hz, 2 H), 7.07 (d, J = 8.8 Hz, 2 H), 6.83 (d, J = 9.0 Hz, 2H), 6.20-6.10 (m, 1 H), 5.22 (s, 2H), 4.53-4.46 (m, 1 H), 3.48 (s, 3H), 3.36 (t, J = 6.4 Hz, 2H) , 2.10-2.00 (m, 2H) 1.80-1.40 (m, 7H) ppm.

PREPARATION 15 1- (Aminomethyl) -4- (phenoxymethyl) cyclohexanol hydrochloride 4- (Phenoxymethyl) cyclohexanone (5.0 g, 24 mmol) (Tetrahedron 1969, 25, 2159-2192.) Was added to a mixture of trimethylsilyl cyanide (3.5 ml, 26 mmol) and zinc iodide (0.38 g, 1.2 mmol). ) in toluene (48 ml) at -78 ° C. The mixture was stirred at 0 ° C for 4 hours. The mixture was added dropwise to a suspension of LiAIH4 (1.8 g) in THF (100 ml) at 0 ° C and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with an excess of Na2SO4 * 10H2O and stirred for 4 hours. After filtration, the filtrate was concentrated to give 1- (aminomethyl) -4- (phenoxymethyl) cyclohexanol. 4N HCl in AcOEt (7 mL) was added to a solution of 1- (aminomethyl) -4- (phenoxymethyl) cyclohexanol in EtOH (30 mL) and the mixture was concentrated. The residue was crystallized from MeOH (15 mL) to give 1- (aminomethyl) -4- (phenoxymethyl) cyclohexanol hydrochloride (4.9 g). 1 H NMR (DMSO-de) d: 7.93 (a, 3 H), 7.32-7.24 (m, 2 H), 6.96-6.88 (m, 3 H), 5.08 (a, 1 H), 3.83 (d, J = 6.1 Hz, 2H), 2.83 (s, 2H), 1.85-1.70 (m, 5H), 1.50-1.12 (m, 4H) ppm.

PREPARATION 16 Trans-1- (aminomethyl) -4-r (benzyloxy) metipcyclohexanol hydrochloride 4 - [(Benzyloxy) methyl] cyclohexanone (7.5 g, 34 mmol) was added (J. Med. Chem. 1993, 36, 654-670) to a mixture of Znl2 (0.54 g, 1.7 mmol) and TMSCN (4.8 mL, 36 mmol) in toluene (34 mL) at -78 ° C and the mixture it was stirred at -78 ° C for 3 hours. The mixture was added dropwise to a suspension of L1AIH4 (2.6 g, 68 mmol) in THF (136 ml) at 0 ° C and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with Na 2 SO 4 »10H 2 O (excess) and stirred for 4 hours. After filtration, the filtrate was evaporated. The residue was dissolved with ethanol and 4N HCl in AcOEt (10 ml) was added at 0 ° C. The solvent was removed in vacuo. The residue was crystallized from ethanol to yield the title compound (6.1 g) as a white solid. 1 H NMR (DMSO-de) d: 7.93 (a, 3H), 7.38-7.24 (m, 5H), 5.07 (a, 1 H), 4.45 (s, 2H), 3.28 (d, J = 6.0 Hz, 2H), 2.79 (s, 2H), 1.75-1.00 (m, 9H) ppm.

PREPARATION 17 ? / - ( { trans-4-r (Benzyloxy) methyn-1-hydroxycyclohexyl > methyl) -4- (methoxymethoxybenzamide A mixture of 4- (methoxymethoxy) benzok acid (4.0 g, 22 mmol), trans-1- (aminomethyl) -4 - [(benzyl) methyl] cyclohexanol hydrochloride (6.1 g, 21 mmol), Et 3 N (5.9 mL, 42 mmol), EDCl (4.8 g, 25 mmol) and HOBt ?20 (0.64 g, 4.2 mmol) in DMF (60 mL) was stirred at room temperature for 16 h. The mixture was diluted with AcOEt and washed with saturated aqueous NaHCO3 and water, dried over MgSO4, and evaporated. The residue was crystallized from CH 2 Cl 2 -hexane to yield the title compound (7.2 g) as a white solid. 1 H NMR (CDCl 3) d: 7.75 (d, J = 8.9 Hz, 2 H), 7.96-7.26 (m, 5 H), 7.07 (d, J = 8.9 Hz, 2 H), 6.56-6.46 (m, 1 H), 5.22 (s, 2H), 4.49 (s, 2H), 3.57 (d, J = 5.9 Hz, 2H), 3.48 (s, 3H), 3.33 (d, J = 6.4 Hz, 2H), 2.41 (s, 1 H), 1.90-1.10 (m, 9H) ppm.

PREPARATION 18 V-. { ftra / 7s-1-Hydroxy-4- (hydroxymethyl) cyclohexylmethi} -4- (methoxymethoxy) benzamide A mixture of α- ( { Trans-4 - [(benzyloxy) methyl] -1-hydroxycyclohexyl} methyl) -4- (methoxymethoxy) benzamide (6.5 g, 16 mmol) and Pd (OH) 2 at 20 % -C (0.5 g) in EtOH (160 ml) was hydrogenated at a pressure of 4 atmospheres at room temperature for 4 hours and at 60 ° C for 4 hours. The mixture was filtered through a pad of celite and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2: MeOH = 12: 1) to give the title compound (4.5 g) as a white solid. 1 H NMR (DMSO-de) d: 8.02 (t, J = 5.9 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 5.25 (s, 2H) ), 4.64 (s, 1 H), 4.40 (t, J = 5.1 Hz, 1 H), 3.39-3.30 (m, 5H), 3.24 (d, J = 5.9 Hz, 2H), 1.68-1.55 (m, 4H), 1.44-1.02 (m, 5H) ppm.

PREPARATION 19 8-r2- (Benzyloxy) et'n-1,4-dioxaespiror4,5] decane To a solution of 2- (1,4-dioxaspiro [4.5] dec-8-yl) ethanol (2.0 g, 11 mmol) (J. Am. Chem. Soc. 1991, 113, 8016-8024.) In DMF (20 ml), NaH (60%, 0.48 g, 12 mmol) was added at 0 ° C and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with water and all was extracted with AcOEt. The organic layer was washed with water, dried over MgSO 4 and evaporated. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 10: 1) to give the title compound (2.2 g). 1 H NMR (CDCl 3) d: 7.40-7.22 (m, 5H), 4.50 (s, 2H), 3.93 (s, 4H), 3. 50 (t, J = 6.4 Hz, 2H), 1.80-1.16 (m, 11 H) ppm.

PREPARATION 20 Xu 4-r2- (Benzyloxy) etcyclohexanone A mixture of 8- [2- (benzyloxy) ethyl] -1,4-dioxaespiro [4,5] decane (2.2 g, 8.0 millimoles) and 2N aqueous HCl (40 mL) in THF was stirred at 50 ° C for 3 hours. The mixture was extracted with AcOEt and the extract was washed with Saturated aqueous NaHCO3 and water, dried over MgSO4 and evaporated to give 4- [2- (benzyloxy) ethyl] cyclohexanone (1.9 g). 1 H NMR (CDCl 3) d: 7.40-7.25 (m, 5 H), 4.52 (s, 2 H), 3.54 (t, J = 6.3 Hz, 2 H), 2.45-1.30 (m, 11 H) ppm.

PREPARATION 21 Trans- 1 - (aminomethyl) -4-f2- (benzyloxy) ethyl 1-cyclohexanol hydrochloride A solution of 4- [2- (benzyloxy) ethyl] cyclohexanone (1.9 g) in toluene (16 ml) was added to a mixture of Znl2 (0.13 g, 0.40 mmol) and TMSCN (1.2 ml, 8.8 mmol) in toluene (10 ml), at -78 ° C and the mixture was stirred at -78 ° C for 2 hours. The mixture was added dropwise to a suspension of LiAIH (0.61 g, 16 mmol) in THF (40 ml) at 0 ° C and stirred at room temperature for 1 hour. The mixture was quenched with Na 2 SO 4"10H 2 O (excess) and KF (excess). After filtration, the filtrate was evaporated. The residue was dissolved with ethanol and 4N HCl in AcOEt (3 mL) was added at 0 ° C. The solvent was removed in vacuo. The residue was crystallized from ethanol to yield the title compound (1.5 g) as a white solid. 1 H NMR (DMSO-de) d: 7.89 (a, 3 H), 7.40-7.24 (m, 5 H), 5.00 (a, 1 H), 4.44 (s, 2 H), 3.44 (t, J = 6.3 Hz, 2 H ), 2.79 (s, 2H), 1.75-1.00 (m, 11 H) ppm.

PREPARATION 22 / V - ((trans-4-f2- (Benzyloxy) TethylM-hydroxycyclohexyl}. Methyl) -4- (methoxymethoxy) benzamide This compound was prepared with trans-1- (aminomethyl) -4- [2- (benzyloxy) ethyl] cyclohexanol hydrochloride by a procedure similar to that of Preparation 17. 1 H NMR (CDCl 3) d: 7.75 (d, J = 8.8 Hz, 2H), 7.38-7.24 (m, 5H), 7. 06 (d, J = 8.8 Hz, 2H), 6.55 (t, J = 5.5 Hz, 1 H), 5.20 (s, 2H), 4.49 (s, 2H), 3.58-3.45 (m, 7H), 2.42 ( a, 1 H), 1.86-1.05 (m, 1 1 H) ppm.

PREPARATION 23 Y-. { [tra /? - 1-Hydroxy-4- (2-hydroxyethyl) cyclohexinmethyl} -4- (methoxymethoxy) benzamide A mixture of? / - ( { Trans-4- [2- (benzyloxy) ethyl] -1-hydroxycyclohexyl}. Methyl) -4- (methoxymethoxy) benzamide (1.4 g, 3.2 mmol) and Pd (OH) 2 to 20% -C (0.50 g) in EtOH (60 ml) was hydrogenated at a pressure of 4 atmospheres for 8 hours. The mixture was filtered through a pad of celite and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (hexane-AcOEt 1: 2 to AcOEt alone) to give the title compound (1.0 g). 1 H NMR (CDCl 3) d: 7.76 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 6.65-6.53 (m, 1 H), 5.21 (s, 2H), 3.73-3.64 (m, 2H), 3.58 (d, J = 5.9 Hz, 2H), 3.48 (s, 3H), 2.43 ( a, 1H), 1.88-1.10 (m, 11H) ppm.

PREPARATION 24 1- (Aminomethyl) -4- (benzyloxy) cyclohexanol hydrochloride 4- (Benzyloxy) cyclohexanone (19 g, 94 mmol) (J. Org. Chem. 1982, 47, 3881-3886.) Was added dropwise to a mixture of Znl 2 (1.5 g, 4.7 mmol) and TMSCN (13 ml, 98 mmol) in toluene (100 ml) at 0 ° C and the mixture was stirred at room temperature for 2 hours. The mixture was added dropwise to a suspension of LiAIH (8.5 g, 98 mmol) in THF (400 ml) at 0 ° C and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with Na 2 SO 4 * 10H 2 O (excess) and stirred for 4 hours. After filtration, the filtrate was evaporated. The residue was dissolved with ethanol and 4N HCl in AcOEt (25 ml) was added at 0 ° C. The solvent was removed in vacuo. The residue was crystallized from ethanol to yield the title compound (6.1 g) as a white solid. 1 H NMR (DMSO-d 6) d: 8.00 (a, 3H), 7.40-7.20 (m, 5H), 4.91 (a, 1 H), 4.82-4.44 (m, 2H), 3.60-3.24 (m, 1 H ), 2.80-2.65 (m, 2H), 1.85-1.20 (m, 8H) ppm.

PREPARATION 25 . { f2- (Trimethylsilyl) ethoxy-1-methoxy} ethyl benzoate To a mixture of ethyl 4-hydroxy-benzoate (4.3 g, 26 mmol) and i-Pr2NEt (5.4 mL, 31 mmol) in CH2Cl2 (52 mL), SEMCI (5.0 mL, 28 mmol) at 0 ° was added. C and the mixture was stirred at room temperature for 72 hours. The mixture was diluted with CH2Cl2. All was washed with saturated aqueous NH4CI, dried over MgSO and evaporated to give 4-. { [2- (trimethylsilyl) ethoxy] methoxy} ethyl benzoate (9.0 g). 1 H NMR (CDCl 3) d: 7.99 (d, J = 9.1 Hz, 2 H), 7.05 (d, J = 8.9 Hz, 2 H), 5.27 (s, 2 H), 4.35 (c, J = 7.3 Hz, 2 H), 3.79-3.71 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 0.99-0.89 (m, 2H), -0.01 (s, 9H) ppm.

PREPARATION 26 Acid 4-f F2- (Trimethylsilyl) ethoxyflutoxy} benzoic A mixture of 4-. { [2- (Tritymethylsilyl) ethoxy] methoxy} ethyl benzoate (9.0 g) and 8 N aqueous KOH in EtOH (50 ml) was stirred at room temperature for 6 hours. The mixture was acidified with HCl at 0 ° C. The precipitate was filtered and washed with water to give the title compound (6.7 g) as a white crystal. 1 H NMR (CDCl 3) d: 8.07 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 5.29 (s, 2H), 3.81-3.72 (m, 2H), 1.00-0.92 (m, 2H), 0.00 (s, 9H) ppm.

PREPARATION 27 ? / -. { f4- (Benzyloxy) -1-hydroxycyclohexypmethyl} -4-. { r2- (Trimethyl-silyl) ethoxy-1-methoxy} benzamide A mixture of 4- acid. { [2- (trimethylsilyl) ethoxy] methoxy} benzoic acid (4.0 g, 15 mmol), 1- (aminomethyl) -4- (benzyloxy) cyclohexanol hydrochloride (4.1 g, 15 mmol), Et3N (4.2 mL, 30 mmol), EDCl (3.5 g, 18 mmol) and HOBt * H2O (0.46 g, 3.0 mmol) in DMF (45 mL) was stirred at room temperature for 16 hours. The mixture was diluted with AcOEt. All was washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and evaporated to give the title compound (7.8 g) as a white solid. 1 H NMR (CDCl 3) d: 7.75 (d, J = 8.6 Hz, 2 H), 7.38-7.22 (m, 5 H), 7.07 (d, J = 8.6 Hz, 2 H), 6.57-6.45 (m, 1 H), 5.26 (s, 2H), 4.58-4.50 (m, 2H), 3.82-3.34 (m, 5H), 2.00-1.30 (m, 8H), 1.00-0.91 (, 2H), 0.00 (s, 9H) ppm.

PREPARATION 28 8- (4-Chlorophenoxy) -1,4-dioxaespiror4,51decano DIAD (12 ml, 60 mmol) was added dropwise to a mixture of 1,4-dioxaespiro [4.5] decan-8-ol (6.3 g, 40 millimoles) (J. Chem. Soc, Perkin Trans. 1 , 2002, 2251-2255.), 4-chlorophenol (7.7 g, 60 mmol) and triphenylphosphine (16 g, 60 mmol) in THF (200 ml) at 0 ° C and the mixture was stirred at room temperature for 16 hours. After evaporation, the residue was treated with 2N aqueous NaOH and all was extracted with CH2Cl2. The extract was dried over MgSO and evaporated. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 20: 1 to 5: 1) to give the title compound (6.8 g).

H NMR (CDCl 3) d: 7.22 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 4.40-4.32 (m, 1 H), 3.98-3.94 (m, 4H), 1.96-1.84 (m, 6H), 1.68-1.55 (m, 2H) ppm.

PREPARATION 29 4- (4-Clo Arophenoxy) cyclohexanone A mixture of 8- (4-chlorophenoxy) -1,4-dioxaespyrro [4,5] decane (6.8 g, 25 mmol) and 2 N aqueous HCl (50 ml) in acetone (80 ml) was heated to reflux during 3 hours. The mixture was diluted with AcOEt. All was washed with saturated aqueous NaCl and saturated aqueous NaHCO3, dried over MgSO and evaporated to give 4- (4-chlorophenoxy) cyclohexanone (5.6 g). 1 H NMR (CDCl 3) d: 7.26 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 4.70-4.62 (m, 1 H), 2.74-2.60 (m, 2H), 2.39-2.00 (m, 6H) ppm.

PREPARATION 30 1- (Aminomethyl) -4- (4-chlorophenoxy) cyclohexanol 4- (4-chlorophenoxy) cyclohexanone (5.6 g) was added to a mixture of Znl2 (80 mg, 0.25 mmol) and TMSCN (2.8 g, 28 mmol) in benzene (10 ml) at 0 ° C and the mixture was stirred at room temperature for 30 minutes. The mixture was added dropwise to a suspension of LiOH (2.3 g, 60 mmol) in ether (80 ml) at 0 ° C and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with Na 2 SO 4 »10H 2 O (excess) and the white suspension was filtered. Then, the filtrate was evaporated to give the title compound (6.8 g) as a cis-trans mixture. 1 H NMR (CDCl 3) d: 7.26-7.18 (m, 2H), 6.87-6.80 (m, 2H), 4.55-4.10 (m, 1 H), 2.66-2.62 (m, 2H), 2.16-1.20 (m, 8H) ppm. (OH and NH2 were not observed) PREPARATION 31 2-r (Yodomethyl) tetrahydro-2 f-pyran-5-ipmetanol To a suspension of 12 (16 g, 63.5 mmol) and NaHCO 3 (5.3 g, 64 mmol) in ether (70 ml) and H 2 O (33 ml) was added a solution of 2- (hydroxymethyl) -5-hexen-1. -ol (5.5 g, 42 mmol) in ether (40 ml) at 0 ° C. The mixture was stirred at room temperature for 8 hours. Then, the reaction is quenched by the addition of saturated aqueous Na 2 S 2 O 3 at 0 ° C. The aqueous layer was extracted with ether (50 ml x 2) and the combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane: AcOEt = 1.2: 1) to give the title compound (8.2 g, 75%) as a yellow oil. 1 H NMR (300 MHz, CDCl 3, cis / trans mixture) d: 4.18-3.15 (m, 7H), 1.92-1.29 (m, 5H) ppm. (No OH was observed.) 13 C NMR (75 MHz, CDCl 3, trans major isomer) d: 76.9, 71.2, 64.5, 38.3, 31.0, 26.2, 9.5 ppm. 13 C NMR (75 MHz, CDCl 3, cis major isomer) d: 76.8, 68.7, 62. 9, 35.5, 27.5, 24.0, 10.0 ppm. MS (ESI): 257.0 (M + Hf PREPARATION 32 ? - (r5- (Hydroxymethyl) tetrahydro-2H-pyran-2-ipmethyl) -phthalimide To a solution of 2 - [(iodomethyl) tetrahydro-5-2 / - -pyran-5-yl] methanol (1.8 g, 6.9 mmol) in DMF (45 mL) was added potassium phthalimide (1.8 g, 9.7 mmol) at room temperature and the mixture was stirred at 90 ° C.

After 5 hours, the mixture was cooled to room temperature and H2O (50 ml) was added to this mixture. All was extracted with AcOEt (100 ml X 2). The organic layers were washed with H2O (50 ml X 2) and brine (50 ml), dried over Na2SO, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane: AcOEt = 1: 1.2) to give the title compound (1.3 g, 68%) as a white solid 13 C NMR (75 MHz, CDCl 3) d: 168.3 (major / minor), 133.9 (principal or minority), 133.8 (principal or minority), 131.9 (principal / minority), 123.2 (principal / minority), 74.9 (principal), 74.6 (minority), 70.9 (main), 67.9 (minority), 64.5 (main), 62.5 (minority), 42.5 (main), 42.1 (minority), 38.3 (main), 35.7 (minority), 28.8 (main), 26.0 (main), 25.2 (minority), 23.6 (minority) ppm. MS (ESI): 276.1 (M + Hf PREPARATION 33 ? / - fr5- (Phenoxymethyl) tetrahydro-2 L / -pyran-2-ylmethyl > -ftalimida A mixture of / V-. { [5- (hydroxylmethyl) tetrahydro-2-pyran-2-yl] methyl} Phthalimide (1.2 g, 4.2 mmol), phenol (0.47 g, 5.0 mmol) and PPh3 in THF (20 mL) were added DEAD (40% in toluene, 2.7 g, 6.3 mmol) at 0 ° C and the mixture stirred at room temperature for 15 hours. After, the reaction mixture was quenched by the addition of H 2 O (50 ml) and diluted with AcOEt (50 ml). The aqueous layer was extracted with AcOEt (50 ml) and the combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane: AcOEt = 8: 1-4: 1) to give the title compound (0.67 g, 45%). 1 H NMR (300 MHz, CDCl 3, cisArans mixture) d: 7.88-7.70 (m, 4H), 7.31-7.23 (m, 2H), 6.96-6.82 (m, 3H), 4.16-3.57 (m, 6H), 3.22 -3.15 (m, 1H), 2.15-1.73 (m, 2H), 1.52-1.26 (m, 3H) ppm.

PREPARATION 34 . { f5- (Phenoxymethyl) tetrahydro-2-pyran-2-ipmethyl} amine To a suspension of? / -. { [5- (phenoxymethyl) tetrahydro-2H-pyran-2-yl] methyl} Phthalimide (0.67 g, 1.90 mmol) in EtOH (10 ml) was added hydrazine hydrate (0.14 g, 2.9 mmol) and the mixture was heated to reflux for 3 hours. After evaporation, 10% aqueous NaOH (50 ml) was added and the mixture was stirred for 30 minutes. Then, the aqueous layer was extracted with CHCl3 (30 ml X 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (0.44 g, crude). 1 H NMR (300 MHz, CDCl 3, cisltrans mixture) d: 7.31-7.24 (m, 2H), 6.96-6.86 (m, 3H), 4.23-3.99 (m, 2H), 3.84-3.63 (m, 2H), 3.31 -3.21 (m, 1 H), 2.74-2.64 (m, 2H), 2.17-1.21 (m, 5H) ppm. (NH2 was not observed.) MS (ESI): 222.1 (M + Hf PREPARATION 35 4- (Methoxymethoxy) -? / -. { [(5-phenoxymethyl) tetrahydro-2-pyran-2-yl] methyl} benzamida This compound was prepared with. { [5- (phenoxymethyl) tetrahydro-2 / - / - pyran-2-yl] methyl} amine by a procedure similar to that of Preparation 9 in the form of a white solid. 1 H NMR (300 MHz, CDCl 3, cis-rans mixture) d: 7.77-7.72 (m, 2H), 7.31-7.25 (m, 2H), 7.08-6.86 (m, 5H), 5.22 (s, 2H), 4.22 -3.98 (m, 3H), 3.85-3.63 (m, 3H), 3.48 (s, 311), 3.43-3.18 (m, 2H), 2.17-1.36 (m, 5H) ppm. MS (ESI): 386.17 (M + Hf PREPARATION 36 ? / -. { f5- (Benzyloxymethyl) tetrahydro-2H-pyran-2-methyl} -ftalimida To a solution of? / -. { [5- (hydroxymethyl) tetrahydro-2 / - -pran-2-yl] methyl} Phthalimide (1.3 g, 4.7 mmol) in CH2Cl2 (20 mL) was added with Ag2O (2.2 g, 9.4 mmol) and BnBr (0.84 mL, 7.1 mmol) at room temperature.

After 50 hours, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane-AcOEt 5: 1) to give the title compound (1.6 g, 92%) as a white solid. 3 C NMR (75 MHz, DMSO) d: 168.4 (major), 168.3 (minority), 138.4 (minority), 138.3 (main), 133.8 (main / minority). 132.0 (principal / minority), 128.3 (principal / minor), 127.5 (minority), 127.4 (principal), 127.3 (principal / minor), 123.2 (principal / minority), 74.9 (principal), 74.5 (minority), 73.1 (principal) minority), 72.8 (main), 71.9 (main), 71.2 (main), 70.2 (minority), 68.3 (minority), 42.6 (main), 42.1 (minority), 36.0 (main), 33.9 (minority), 28.9 ( main), 26.4 (main), 25.2 (minority), 23.7 (minority) ppm ' PREPARATION 37 . { f5- (Benzyloxymethyl) tetrahydro-2-pyran-2-ipmethyl} amine This compound was prepared with? -. { [5- (benzyloxymethyl) tetrahydro-2H-pyrn-2-yl] methyl} -fatimidated by a procedure similar to that of Preparation 34. 1 H NMR (300 MHz, CDCl 3, cis / trans mixture) d: 7.37-7.28 (m, 5H), 4.60-4.43 (m, 2H), 4.14-3.97 (m, 1 H), 3.74-3.50 (m, 1 H), 3.33-3.14 (m, 3H), 2.73-2.66 (m, 2H), 1.99-1.17 (m, 5H) ppm. (NH2 was not observed.) MS (ESI): 236.1 (M + Hf.

PREPARATION 38 M0MXy? T °? or 4- (Benzumoxytoxho-? Hf5-phenoxymethiptetrahydro-2-pyran-2-yl.) Methyl) benzamide This compound was prepared with. { [5- (benzyloxymethyl) tetrahydro-2-pyran-2-yl] methyl} amine by a procedure similar to that of Preparation 9. 1 H NMR (300 MHz, CDCl 3, cis-rans mixture) d: 7.76-7.71 (m, 2H), 7. 28-7.37 (m, 5H), 7.04-7.09 (m, 2H), 4.60-4.43 (m, 2H), 3.83-3.75 (m, 1 H), 3.48 (s, 3H), 3.31-3.14 (m, 3H), 1.97-1.31 (m, 5H) ppm. MS (ESI): 400.2 (M + Hf.

PREPARATION 39 2- (BenzyloxymethiO-hex-5-en-1-ol To a solution of 2- (hydroxymethyl) -hex-5-en-1-ol in CH 2 Cl 2 was added BnBr (3.8 mL, 44 mmol) and Ag 2 O (10 g, 44 mmol) at room temperature for 10 hours. Then, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane-AcOEt 7: 1) to give the title compound (5.0 g, 78%) as a colorless oil. ? NMR (300 MHz, CDCl 3) d: 7.38-8.29 (m, 5H), 5.86-5.71 (m, 1 H), 5.04-4.94-7.24 (m, 2H), 4.55 (d, J = 12.2 Hz, 1 H ), 4.49 (d, J = 12.2 Hz, 1 H), 3.45-3.77 (m, 4H), 2.12-2.07 (m, 2H), 1.93-1.85 (m, 1 H), 1.50-1.32 (m, 2H) ) ppm.

PREPARATION 40 2-Benzyloxymethyl-4-oxiran-2-ylbutan-1-ol To a solution of 2- (benzyloxymethyl) -hex-5-en-1-ol in CH 2 Cl 2 was added NaHCO 3 and meta-chloroperbenzole acid (mCPBA) at 0 ° C. After 7 hours, the reaction is quenched by the addition of saturated aqueous NaHCO3 (50 ml). The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with brine (50 ml), dried over MgSO, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane-AcOEt 3: 1-1: 1) to give the title compound (2.6 g, 60%) as a pale yellow oil. 1 H NMR (300 MHz, CDCl 3) d: 7.28-7.38 (m, 5H), 4.54 (d, J = 12.0 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 3.76-3.46 (m , 4H), 2.92-2.87 (m, 1 H), 2.75 (dt, J = 0.7, 4.9 Hz, 1 H), 2.47 (ddd, J = 0.9, 2.7, 4.9 Hz, 1 H), 1.70-1.94 (m, 1 H), 1.69-1.35 (m, 4H) ppm. MS (BSl): 237.1 (M + Hf.

PREPARATION 41 . { 5 - [(Benzyloxy) methyltetrahydro-2-pyran-2-yl} methanol To a solution of 2-benzyloxymethyl-4-oxirane-2-ylbutan-1-ol in CH 2 Cl 2 was added BF 3 OEt 2 at -78 ° C and the mixture was heated to 0 ° C. After 4 hours, the reaction was quenched by the addition of H2O (50 ml). The aqueous layer was extracted with CH2Cl2 (50 ml) and the combined organic layers were washed with brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane-AcOEt 3: 1) to give the title product (1.5 g including unknown impurities) 1 H NMR (300 MHz, CDCl 3, cisArans mixture) d: 7.37- 7.09 (m, 5H), 4.60-4.42 (m, 4H), 3.89-4.16 (m, 2H), 3.70-3.17 (m, 5H), 2.00-1.18 (m, 5H) ppm. (No OH was observed.) PREPARATION 42 -r (Benzyloxy) methyl] -2- (phenoxymethyl) tetrahydro-2H-pyran A mixture of. { 5 - [(benzyloxy) methyl] tetrahydro-2H-pyran-2-yl} methanol (1.5 g, 6.2 mmol), phenol (0.7 g, 7.4 mmol) and PPh3 (2.0 g, 7.4 millimoles) in THF (25 mL) was added DEAD (diethyl azodicarboxylate) (40%) in toluene, 4.0 g ) at 0 ° C and the mixture was stirred at room temperature for 14 hours. The reaction was then quenched by the addition of H 2 O (50 ml) and extracted with AcOEt (50 ml x 2). The combined organic layers were washed with brine (50 ml), dried over MgSO 4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane: AcOEt = 12: 1) to give the title product (0.30 g, 15%) 1 H NMR (300 MHz, CDCl 3, cisArans mixture) d: 7.37 -7.24 (m, 7H), 6.96-6.90 (m, 3H), 4.63-4.42 (m, 2H), 4.20-3.54 (m, 5H), 3.35-3.22 (m, 2H), 2.02-1.72 (m, 3H), 1.55-1.23 (m, 2H) ppm. MS (BSl): 313.2 (M + Hf.

PREPARATION 43 f6- (Phenoxymethyl) tetrahydro-2-pyran-3-yl methanol To a mixture of 5 - [(benzyloxy) methyl] -2- (phenoxymethyl) tetrahydro-2H-pyran (0.3 g, 0.95 mmol) and Pd (OH) 2 / C (20% by weight on carbon, 0.15 g) in THF (5 mL) was added 10-20% HCl-MeOH (0.5 mL). The mixture was stirred under an atmosphere of H2 (4 atmospheres) at room temperature for 5 hours. Then, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane: AcOEt = 2: 1) to give the title compound (0.16 g, 77%) 1 H NMR (300 MHz, CDCl 3, cis-trans mixture) d : 7.31-7.25 (m, 2H), 6. 97-6.90 (m, 3H), 4.21-3.23 (m, 7H), 1.98-1.27 (m, 5H) ppm. (No OH was observed) MS (ESI): 223.0 (M + Hf.

PREPARATION 44 F6- (phenoxymethyl) t? Trahydro-2f / -pyran-3-methylated methanesulfonate Methanesulfonyl chloride (68 μL, 0.88 mmol) was added to a mixture of [6- (phenoxymethyl) tetrahydro-2-pyran-3-yl] methanol (0.16 g, 0.73 mmol) and triethylamine (0.20 mL, 1.5 mmol). in CH2CI2 at 0 ° C and the mixture was stirred at 0 ° C for 2 hours. The mixture was treated with saturated aqueous NaHCO3 and extracted with CH2Cl2. The extract was dried over MgSO and evaporated to give methanesulfonate of [6- (phenoxymethyl) tetrahydro-2-r-pyran-3-yi-methyl (0.20 g). 1 H NMR (CDCl 3) d: 7.32-7.24 (m, 2H), 7.00-6.88 (m, 3H), 4.50-3.24 (m, 7H), 3.04-3.01 (m, 3H), 2.20-1.30 (m, 5H ) ppm.

PREPARATION 45 - (Azidomethyl) -2- (phenoxymethyl) tetrahydro-2-pyran Methanesulfonate of [6- (phenoxymethyl) tetrahydro-2H-pyran-3-yl] methyI (0.20 g) was dissolved with DMF (3.5 ml). To the solution, NaN3 (0.22 g, 3.4 mmol) was added and the mixture was stirred at 100 ° C for 3 hours. After cooling to room temperature, the mixture was diluted with ether and washed with water. The organic layer was dried over MgSO4 and evaporated to give 5- (azidomethyl) -2- (phenoxymethyl) tetrahydro-2-pyran (0.16 g). 1 H NMR (CDCl 3) d: 7.32-7.24 (m, 2H), 7.00-6.88 (m, 3H), 4.20-3.08 (m, 7H), 2.08-1.20 (m, 5H) ppm.

PREPARATION 46 r6- (Phenoxymethyl) tetrahydro-2 / - / - pyran-3-illmethyl} amine A solution of 5- (azidomethyl) -2- (phenoxymethyl) tetrahydro-2H-pyran (0.16 g) in THF (1.0 ml) was added to a suspension of LIAIH (0.64 millimole) in THF (2.0 ml) at 0 ° C. and the mixture was stirred at room temperature for 30 minutes. The mixture was quenched with Na 2 SO 4 OH 2 O (excess) and KF (excess). After stirring for 4 hours, the suspension was filtered and evaporated to give. { [6- (Phenoxymethyl) tetrahydro-2H-pyran-3-yl] methyl} Amyna (0.13 g). 1 H NMR (CDCl 3) d: 7.32-7.24 (m, 2H), 7.00-6.88 (m, 3H), 4.20-2.53 (m, 7H), 2.08-1.10 (m, 5H) ppm.

PREPARATION 47 8-r (4-Fluorobenzyl) oxy1-1,4-dioxaespirof4,51decano NaH (880 mg, 22 mmol, 60%) was washed with n-hexane (5 ml x 2) and the powder was dried under vacuum. To the flask was added THF (5 ml) and cooled to 0 ° C. A solution of 1,4-dioxaspiro [4.5] decan-8-ol (3.2 g, 20 mmol) in THF (15 ml) was added to the suspension and the reaction mixture was stirred at room temperature for 30 minutes. . To the mixture was added a solution of 1- (bromomethyl) -4-fluorobenzene (4.5 g, 24 mmol) in THF (5 ml) at 0 ° C and stirred at room temperature for 17 hours. NaH (400 mg, 10 mmol, 60%) was added to the reaction mixture and the mixture was heated to reflux for 6 hours. Saturated aqueous NaHCO3 (20 mL) was poured into the reaction mixture and all was extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over Na2SO and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane: ethyl acetate = 10: 1 as eluent) to give the title compound as a yellow oil (5.0 g, 94%). 1 H NMR (CDCl 3) d: 7.33-7.27 (m, 2H), 7.04-6.97 (m, 2H), 4.48 (s, 2H), 3.98-3.89 (m, 4H), 3.54-3.48 (m, 1 H) , 1.89-1.71 (m, 6H), 1.60-1.50 (m, 2H) ppm.

PREPARATION 48 4-f (4-Fluorobenzyl) oxy] cyclohexanone This compound was prepared with 8 - [(4-fluorobenzyl) oxy] -1,4-dioxaespiro [4,5] decane by a procedure similar to that of Preparation 20 in the form of a yellow oil. 1 H NMR (CDCl 3) d: 7.36-7.31 (m, 2H), 7.08-7.02 (m, 2H), 4.56 (s, 2H), 3.83-3.81 (m, 1 H), 2.67-2.56 (m, 2H), 2.33-1.98 (m, 6H) ppm.

PREPARATION 49 1- (Aminomethyl) -4-r (4-fluorobenzyl) oxy] cyclohexanol This compound was prepared with 4 - [(4-fluorobenzyl) oxy] cyclohexanone by a procedure similar to that of Preparation 30 in the form of a brown oil. 1 H NMR (CDCl 3, cisArans mixture) d: 7.34-7.16 (m, 2H), 7.05-6.99 (m, 2H), 4.53 (s, 1.4H), 4.47 (s, 0.6H), 3.63-3.61 (m, 0.3H), 3.38-3.29 (m, 0.7H), 2.64 (s, 0.6H), 2.58 (s, 1.4H), 1.90-1.19 (m, 8H) ppm. (OH and NH2 were not observed.) MS (ESI): 254.10 (M + Hf PREPARATION 50 Acetate of 4-. { [(. {4-R (4-Fluorobenzyl) oxy] -1-hydroxycyclohexyl} methyl) amino] carbonyl} phenyl This compound was prepared with 4-acetoxybenzoic acid and 1- (aminomethyl) -4 - [(4-fluorobenzyl) oxy] cyclohexanol by a procedure similar to that of Preparation 9 as a white solid. 1 H NMR (CDCl 3, cisArans mixture) d: 7.83-7.80 (m, 2H), 7.32-7.29 (m, 2H), 7.18-7.15 (m, 2H), 7.08-6.99 (m, 2H), 6.61 (a, 1 H), 4.51-4.46 (m, 2H), 3.52-3.46 (m, 2H), 3.41-3.39 (m, 1 H), 2.35-2.28 (m, 3H), 1.85-1.68 (m, 6H), 1.49-1.41 (m, 2H) ppm. (No OH was observed.) MS (ES1): 416.03 (M + Hf, 414.03 (M-H) " PREPARATION 51 8-r (2-Fluorobenzyl) oxyl-1,4-dioxaespirof4,5ldecane This compound was prepared with 2-fluorobenzyl bromide by a procedure similar to that of Preparation 47. 1 H NMR (CDCl 3) d: 7.49-7.43 (m, 1 H), 7.30-7.20 (m, 1 H), 7.16-6.97 (m, 2H), 4.59 (s, 2H), 3.97-3.91 (m, 4H), 3.59-3.50 (m, 1 H), 1.94-1.73 (m, 6H), 1.63-1.48 (m, 2H) ppm .

PREPARATION 52 4- (2-Fluorobenzyl) oxpcyclohexanone This compound was prepared with 8 - [(2-fluorobenzyl) oxy] -1,4-dioxaespiro [4,5] decane by a procedure similar to that of Preparation 20 in the form of a colorless oil. 1 H NMR (CDCl 3) d: 7.49-7.43 (m, 1 H), 7.33-7.25 (m, 1 H), 7.18-7.03 (m, 2H), 4.66 (s, 2H), 3.88-3.83 (m, 1 H), 2.68-2.58 (m, 2H), 2.32-1.92 (m, 6H) ppm.

PREPARATION 53 1- (Aminomethyl) -4-f (2-fluorobenzyl) oxpcyclohexanol This compound was prepared with 4 - [(2-fluorobenzyl) oxy] cyclohexanone by a procedure similar to that of Preparation 30 in the form of a yellow oil. 1 H NMR (CDCl 3, cisArans mixture) d: 7.49-7.42 (m, 1 H), 7.28-6.99 (m, 3 H), 4.63 (s, 1.4 H), 4.56 (s, 0.6 H), 3.66-3.65 (m , 0.4H), 3.41-3.32 (m, 0.6H), 2.64-2.63 (m, 0.6H), 2.58-2.57 (m, 1.4H), 1.92-1.20 (m, 8H) ppm. [No protons of OH or NH2 were observed.] MS (ESI): 254.07 (M + Hf PREPARATION 54 NXI F Acetate of 4-. { r ({4-f (2-fluorobenzyl) oxyM-hydroxycyclohexyl > methyl) amino-1-carbonyl} phenyl This compound was prepared with 4-acetoxybenzoic acid and 1- (aminomethyl) -4 - [(2-fluorobenzyl) oxy] cyclohexanol by a procedure similar to that of Preparation 9 as a white solid. 1 H NMR (CDCl 3, cisArans mixture) d: 7.83-7.80 (m, 2H), 7.46-7.41 (m, 1 H), 7.29-6.99 (m, 6H), 6.55 (a, 1 H), 4.62 (s, 1.5H), 4.56 (s, 0.5H), 3.52-3.44 (m, 3H), 2.32 (s, 3H), 1.88-1.66 (m, 6H), 1.51 -1.43 (m, 2H) ppm. MS (ESI): 416.06 (M + Hf PREPARATION 55 8-r (3-Fluorobenzyl) oxy-1,4-dioxaespirof4,51decano This compound was prepared with 3-fluorobenzyl bromide by a procedure similar to that of Preparation 47 in the form of a yellow oil. 1 H NMR (CDCl 3) d: 7.33-7.25 (m, 1 H), 7.11-7.05 (m, 2 H), 6.98- 6.91 (m, 1 H), 4.52 (s, 2 H), 3.99-3.91 (m, 4 H) , 3.55-3.48 (m, 1 H), 1.90-1.75 (m, 6H), 1.64-1.50 (m, 2H) ppm.

PREPARATION 56 ° ?? ? rF 4 - [(3-Fluorobenzyl) oxy-1-cyclohexanone This compound was prepared with 8 - [(3-fluorobenzyl) oxy] -1,4-dioxaespiro [4.5] decane by a procedure similar to that of Preparation 20 in the form of a yellow oil. 1 H NMR (CDCl 3) d: 7.36-7.26 (m, 1 H), 7.14-7.08 (m, 2 H), 7.01- 6.95 (m, 1 H), 4.60 (s, 2 H), 3.83-3.81 (m, 1 H ), 2.69-2.57 (m, 2H), 2.32-2.13 (m, 4H), 2.05-1.98 (m, 2H) ppm.

PREPARATION 57 1- (Aminomethyl) -4-r (3-fluorobenzyl) oxylcyclohexanol This compound was prepared with 4 - [(3-fluorobenzyl) oxy] cyclohexanone by a procedure similar to that of Preparation 30 in the form of a yellow oil. 1 H NMR (CDCl 3, cisArans mixture) d: 7.32-7.24 (m, 1 H), 7.11-7.06 (m, 2H), 6.97-6.92 (m, 1 H), 4.55-4.49 (m, 2H), 3.76- 3.31 (m, 1 H), 2.64-2.56 (m, 2H), 2.02-1.13 (m, 8H) ppm. (OH and NH2 were not observed.) MS (ESI): 254.11 (M + Hf PREPARATION 58 8-fr (3-Fluorobenzyl) oxymethyl > -1,4-dioxaespiror4,51decano This compound was prepared with 3-fluorobenzyl bromide and 1,4-dioxaspiro [4.5] dec-8-ylmethanol by a procedure similar to that of Preparation 47 in the form of a colorless oil. 1 H NMR (CDCl 3) d: 7.33-7.26 (m, 1H), 7.10-6.93 (m, 3H), 4.49 (s, 2H), 3.98-3.90 (m, 4H), 3.31 (d, J = 6.6 Hz, 2H), 1.85-1.50 (m, 7H), 1.35-1.21 (m, 2H) ppm.

PREPARATION 59 I Os? P 4-. { r (3-Fluorobenzyl) oxymethyl) cyclohexanone This compound was prepared with 8-. { [(3-fluorobenzyl) oxy] methyl} -1,4-dioxaespiro [4,5] decane by a procedure similar to that of Preparation 20 in the form of a yellow oil. 1 H NMR (CDCl 3) d: 7.35-7.27 (m, 1H), 7.10-6.95 (m, 3H), 4.52 (s, 2H), 3.40 (d, J = 6.1 Hz, 2H), 2.43-2.28 (m, 4H), 2.17-2.06 (m, 3H), 1.55-1.44 (m, 2) ppm.

PREPARATION 60 trans-1- (AminometiQ-4- { r (3-fluorobenzyl) oxy] methyl.} cSclohexanol This compound was prepared with 4-. { [(3-fluorobenzyl) oxy] methyl} cyclohexanone by a procedure similar to that of Preparation 30 in the form of a yellow oil. 1 H NMR (DMSO-de) d: 7.43-7.40 (m, 1 H), 7.16-7.07 (m, 3 H), 4.46 (s, 2 H), 3.28 (d, J = 5.9 Hz, 2 H), 2.46-2.35 (m, 2H), 1.64-1.61 (m, 4H), 1.27-1.01 (m, 5H) ppm. [No protons of NH2 and OH were observed.] MS (ESI): 268.18 (M + Hf PREPARATION 61 8-r2- (2-Fluorophenoxy) et p-1,4-dioxaespiror4,5ldecane This compound was prepared with 2- (1,4-dioxaspiro [4.5] dec-8- 1) ethanol and 2-fluorophenol by a procedure similar to that of Preparation 42 in the form of a colorless oil. 1 H NMR (CDCl 3) d: 7.10-6.84 (m, 4H), 4.09-4.05 (m, 2H), 3.94 (s, 4H), 1.82-1.74 (m, 6H), 1.68-1.51 (m, 3H), 1.38-1.24 (m, 2H) ppm.

PREPARATION 62 4-f2- (2-Fluorophenoxy) ethyl 1-cyclohexanone This compound was prepared with 8- [2- (2-fluorophenoxy) ethyl] 1,4-dioxaespiro [4,5] decane by a procedure similar to that of Preparation 20 as a white solid. 1 H NMR (CDCl 3) d: 7.12-6.91 (m, 4H), 4.16-4.05 (m, 2H), 2.41- 2.36 (m, 4H), 2.18-2.05 (m, 3H), 1.88-1.76 (m, 2H ), 1.56-1.42 (m, 2H) ppm.

PREPARATION 63 trans- • - (Aminomethyl) -4-f2- (2-fluorophenyl) ethynyclohexanol This compound was prepared with 4- [2- (2-fluorophenyl) ethyl] cyclohexanone by a procedure similar to that of Preparation 30 as a white solid. 1 H NMR (DMSO-de) d: 7.28-6.86 (m, 4H), 4.15-3.97 (m, 2H), 2. 48-2.37 (m, 2H), 1.81-0.94 (m, 11 H) ppm. [No protons of NH2 and OH were observed.] MS (ESI): 268.11 (M + Hf PREPARATION 64 4-Hydroxycyclohexanecarboxylate ethyl To a solution of ethyl 4-oxocyclohexanecarboxylate (13.5 g, 79 mmol) in MeOH (150 ml) at 0 ° C was added NaBH 4 (5.3 g, 140 mmol) and the mixture was stirred at room temperature for 3 hours. Then, the reaction was quenched by the addition of H2O (50 mL) and extracted with AcOEt (150 mL x 1.50 mL x 2). The combined organic layer was washed with H2O (50 ml), dried over Na2SO, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane-AcOEt 1.5: 1-1: 1) to give the title compound (12 g, 88%, cisArans = 3: 7) as a clear oil. 1 H NMR (300MHz, CDCl 3, cisArans mixture) 6: 4.17-4.08 (m, 2H), 3.90 (sa, 0.3H), 3.68-3.57 (m, 0.7H), 2.42-1.28 (m, 9H), 1.27- 1.22 (m, 3H) ppm. (No OH was observed.) PREPARATION 65 4- (4-Chlorophenoxy) ethyl cyclohexanecarboxylate To a solution of ethyl 4-hydroxycyclohexanecarboxylate (3.1 g, 18 mmol) in toluene (50 ml) was added PPh3 (5.2 g, 20 mmol) and p-chlorophenol (2.6 g, 20 mmol). To the mixture was added DEAD (40% in toluene, 9.4 g, 21 mmol) at 0 ° C and the mixture was stirred at room temperature for 7 hours. The reaction was quenched by the addition of H 2 O (100 mL) and diluted with AcOEt (100 mL). The aqueous layer was extracted with AcOEt (50 ml) and the combined organic layer was washed with brine (50 ml), dried over MgSO, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 12: 1) to give the title compound (3.5 g, 68%). 1 H NMR (300 MHz, CDC! 3, cisArans mixture) d: 7.24-7.19 (m, 2H), 6.86-6.79 (m, 2H), 4.47-4.40 (m, 1 H), 4.18-4.09 (m, 2H) , 2.44-1.41 (m, 9H), 1 .28-1.24 (m, 3H) ppm.

PREPARATION 66 f4- (4-Chlorophenoxy) cyclohexylmethanol To a suspension of lithium aluminum hydride (1.4 g, 37 mmol) in Et2O (30 mL) was added a solution of ethyl 4- (4-chlorophenoxy) cyclohexanecarboxylate (3.5 g, 12 mmol) in Et 2 O (30 mL) at 0 ° C and the mixture was stirred at room temperature. After 2 hours, the reaction was quenched by the addition of H2O (1.4 ml), 15% NaOH (1.4 ml) and H2O (4.2 ml). The mixture was diluted with AcOEt (50 ml) and stirred for 1 hour. Then, the mixture was filtered and concentrated in vacuo to give the title compound (2.9 g). 1 H NMR (300MHz, CDCl 3, cisArans mixture) d: 7.24-7.19 (, 2H), 6.90-6.79 (m, 2H), 4.49-4.05 (m, 1 H), 3.53-3.47 (m, 2H), 2.20- 1.02 (m, 9H) ppm. (Do not obsess / or OH.) PREPARATION 67 Na x k? Cl 4- (Azidomethyl) cyclohexyl 4-chlorophenyl ether To a solution of [4- (4-chlorophenoxy) cyclohexyl] methanol (2.9 g, crude from the previous procedure) and Et3N (3.5 mL, 25 mmol) in CH2Cl2 (100 mL) was added MsCl (1.2 mL, 15 mL). millimoles) at 0 ° C. After 1.5 hours, the reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (50 ml). The aqueous layer was extracted with CH2Cl2 (30 ml x 2) and the combined organic layer was washed with brine (30 ml), dried over Na2SO, filtered and concentrated in vacuo. The residue was dissolved in DMF (60 ml) and to this solution was added NaN3 (1.6 g, 25 mmol) and stirred at 80 ° C for 3 hours. Then, the reaction was quenched by the addition of saturated aqueous NaHCO3 (30 ml) and extracted with AcOEt (100 ml). The aqueous layer was extracted with AcOEt (50 ml x 2) and the combined organic layer was extracted with H 2 O (50 ml x 2) and brine (50 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane.'AcOEt = 1:15) to give the title compound (3.0 g, 91% in 3 steps). 1 H NMR (300MHz, CDCI 3l cisArans mixture) d: 7.29-7.18 (m, 2H), 6.86-6.79 (m, 2H), 4.50-4.04 (m, 1 H), 3.19 (d, J = 6.42 Hz, 2H) , 2.18-1.10 (m, 9H).

PREPARATION 68 XXJJ 4- (4-Fluorophenoxy) ethyl cyclohexanecarboxylate This compound was prepared with 4-fluorophenol by a procedure similar to that of Preparation 65 in the form of a colorless oil. 1 H NMR (CDCl 3, cisArans mixture) d: 6.98-6.92 (m, 2H), 6.87-6.83 (m, 2H), 4.38-4.11 (m, 3H), 2.42-2.28 (m, 1H), 2.18-1.90 ( m, 4H), 1.76-1.39 (m, 4H), 1.29-1.23 (m, 3H) ppm. PREPARATION 69 x sF f4- (4-Fluorophenoxy) cyclohexyl] methanol This compound was prepared with ethyl 4- (4-fluorophenoxy) cyclohexanecarboxylate by a procedure similar to that of Preparation 66. 1 H NMR (CDCl 3, cisArans mixture) d: 6.99-6.81 (m, 4H), 4.45-3.70 (m, 1 H), 3.54-3.48 (m, 2H), 2.19-1.37 (m, 9H) ppm. (No OH was observed.) PREPARATION 70 1-. { F4- (Azidomethyl) cyclohexinoxy > -4-fluorobenzene This compound was prepared with [4- (4- fluorophenoxy) cyclohexyl] methanol by a procedure similar to that of Preparation 67. 1 H NMR (CDCl 3, cisArans mixture) d: 6.99-6.81 (m, 4H), 4.45 (a, 1 H), 3.21-3.18 (m, 2H), 2.19-1.41 (m, 9H) ppm.

PREPARATION 71 . { [4- (4-Fluorophenoxy) cyclohexylmethyl} amine To a solution of 1-. { [4- (azidomethyl) cyclohexyl] oxy} -4-fluorobenzene (5.6 g, 21 mmol) in MeOH (50 mL) was added 10% Pd-C (0.5 mg) and the whole mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to yield the title compound as a colorless oil (4.4 g). 1 H NMR (DMSO-de, mixture cisArans) d: 8.05 (a, 2H), 7.14-7.06 (m, 2H), 6.98-6.93 (m, 2H), 4.52 (a, 0.8H), 4.19 (a, 0.2 H), 2.81 (d, J = 6.6 Hz, 0.4H), 2.69 (d, J = 6.8 Hz, 1.6H), 2.05-1.08 (m, 9H) ppm. MS (ESI): 224.11 (M + Hf PREPARATION 72 ? / -. { fc / 's-4- (4-Fluorophenoxy) cyclohexylmethyl > -4- (methoxymethoxy) benzamide This compound was prepared with. { [4- (4-fluorophenoxy) cyclohexyl] methyl} amine by a procedure similar to that of Preparation 9 in the form of a white solid. 1 H NMR (DMSO-de) d: 8.34 (m, 1 H), 7.83-7.80 (m, 2H), 7.12-7.04 (m, 4H), 6.98-6.93 (m, 2H), 5.24 (s, 2H) , 4.50 (a, 1 H), 3.38 (s, 3H), 3.18-3.13 (m, 2H), 1.88-1.31 (m, 9H) ppm.

PREPARATION 73 c / s-4- (2-Phenylethoxy) ethyl cyclohexanecarboxylate Yodotrimethylsilane (0.36 ml, 2.5 mmol) was added to a mixture of ethyl 4-oxocyclohexanecarboxylate (8.5 g, 50 mmol) and dimethyl (2-phenylethoxy) silane (9.9 g, 55 mmol) (Synfett 2002, 313-315.) in CH2CI2 (50 ml) at 0 ° C and the mixture was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted with AcOEt (200 ml). The extract was washed with saturated aqueous NaHCO3 (50 ml), dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane-AcOEt 15: 1) to give the title compound (2.7 g). 1 H NMR (CDCl 3) d: 7.35-7.15 (m, 5H), 4.13 (c, J = 7.1 Hz, 2H), 3.60 (t, J = 7.3 Hz, 2H), 3.52-3.40 (m, 1H), 2.87 (t, J = 7.3 Hz, 2H), 2.42-2.24 (m, 1 H), 1.97-1.40 (m, 8H), 1.25 (t, J = 7.1 Hz, 3H) ppm.

PREPARATION 74 Fc / s-4- (2-Fe? Rt¡letoxi) cyclohexillmetar? Ol This compound was prepared with ethyl c / s-4- (2-phenylethoxy) cyclohexanecarboxylate by a procedure similar to that of Preparation 66. 1 H NMR (CDCl 3) d: 7.40-7.12 (m, 5H), 3.81-3.39 (m , 5H), 2.87 (t, J = 7.1 Hz, 2H), 1.95-1.15 (m, 9H) ppm. (No OH was observed.) PREPARATION 75 c / s-4- (Azidomethyl) cyclohexyl 2-phenylethyl ether This compound was prepared with [c / s-4- (2-phenylethoxy) cyclohexyl] methanol by a procedure similar to that of Preparation 67. 1 H NMR (CDCl 3) d: 7.37-7.12 (m, 5H), 3.66-3.48 ( m, 3H), 3.00 (d, J = 6.8 Hz, 2H), 2.87 (t, J = 7.1 Hz, 2H), 1.96-1.17 (m, 9H) ppm.

PREPARATION 76 frc / s-4- (2-Phenylethoxy) cyclohexypmethyl) amine This compound was prepared with c / s-4- (azidomethyl) cyclohexyl 2-phenylethyl ether by a procedure similar to that of Preparation 71. 'H NMR (CDCl 3) d: 7.40-7.14 (m, 5H), 3.72-3.46 ( m, 3H), 2.87 (t, J = 7.3 Hz, 2H), 2.53 (d, J = 5.4 Hz, 2H), 2.00-1.15 (m, 9H) ppm. (NH2 was not observed.) PREPARATION 77 . { fc / s-4- (hydroxymethyl) cyclohexylmethyl > benzyl carbamate Benzyl chloroformate (15 ml, 0.11 mole) was added dropwise to a mixture of [c / s-4- (aminomethyl) cyclohexyl] methanol (14 g, 0.10 mole) and d sosopropylethylamine (21 ml, 0.12 mole) in CH 2 Cl 2 (200 ml) at 0 ° C and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with CH2Cl2 (200 mL) and washed with saturated aqueous NH4CI. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane-AcOEt from 1: 1 to 1: 2) to give the title compound (14 g). 1 H NMR (CDCl 3) d: 7.38-7.26 (m, 5H), 5.10 (s, 2H), 4.80-4.70 (m, 1 H), 3.58-3.50 (m, 2H), 3.20-3.10 (m, 2H) , 1.75-1.20 (m, 10H) ppm. (No OH was observed.) PREPARATION 78 ,? benzyl (. {c.sub.-4-f (benzyloxy) methyclohexyl) methyl) carbamate NaH (88 mg, 2.2 mmol) was added to a solution of. { [c / s-4- (hydroxymethyl) cichlohexyl] methyl} Benzyl carbamate (0.55 g, 2.0 mmol) in THF (4.0 ml) at 0 ° C and the mixture was stirred at room temperature for 30 minutes. To the mixture was added benzyl bromide (0.29 ml, 2.4 mmol) at 0 ° C. The mixture was stirred at room temperature for 7 hours. The mixture was quenched with saturated aqueous NH CI and extracted with CH2Cl2. The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane-AcOEt 8: 1) to give the title compound (0.27 g). 1 H NMR (CDCl 3) d: 7.40-7.24 (m, 10H), 5.09 (s, 2H), 4.80-4.65 (m, 1 H), 4.49 (s, 2H), 3.36 (d, J = 7.1 Hz, 2H ), 3.20-3.08 (m, 2H), 1.90-1.22 (m, 10H) ppm.

PREPARATION 79 -X X ( { C s-4-r (Benzyloxy) methylcyclohexyl.) Methyl) amine A mixture of benzyl ( {sup.c / s-4 - [(benzyloxy) methyl] cyclohexyl] methyl] carbamic acid (0.27 g, 0.73 mmol) and KOH (0.21 g, 3.7 mmol) in EtOH (0.40 ml) was heated to reflux for 3 hours. The mixture was acidified with 2N aqueous HCl (20 ml) and the aqueous layer was washed with AcOEt. The aqueous layer was basified with 2N aqueous NaOH (21 ml) and extracted with CH2Cl2. The extract was dried over MgSO4 and concentrated to give the title compound (0.10 g). 1 H NMR (CDCl 3) d: 7.40-7.25 (m, 5H), 4.50 (s, 2H), 3.37 (d, J = 7.1 Hz, 2H), 2.60 (d, J = 6.6 Hz, 2H), 1.94-1.80 (m, 1 H), 1.64-1.22 (m, 9H) ppm. (NH2 was not observed.) PREPARATION 80 8- (2-Phenoxyethyl) -1,4-dioxaespirof4,51decano This compound was prepared with 2- (1,4-dioxaspiro [4.5] dec-8-yl) ethanol by a procedure similar to that of Preparation 42. 1 H NMR (CDCl 3) d: 7.31-7.24 (m, 2H) , 6.96-6.86 (m, 3H), 3.99 (t, J = 6.4 Hz, 2H), 3.95 (s, 4H), 1.84-1.22 (m, 11 H) ppm.

PREPARATION 81 Tu0X) 4- (2-Phenoxyeti-Cyclohexanone This compound was prepared with 8- (2-phenoxyethyl) -1,4-dioxaespiro [4,5] decane by a procedure similar to that of Preparation 20. 1 H NMR (CDCl 3) d: 7.34-7.25 (m, 2H), 7.00-6.88 (m, 3H), 4.05 (t, J = 6.3 Hz, 2H), 2.45-1.40 (m, 11 H) ppm.

PREPARATION 82 Traps-1- (aminomethyl) -4- (2-phenoxyethyl) cyclohexanol hydrochloride This compound was prepared with 4- (2-phenoxyethyl) cyclohexanone by a procedure similar to that of Preparation 16. 1 H NMR (DMSO-de) d: 7.75 (a, 3 H), 7.32-7.23 (m, 2 H), 6.97- 6.88 (m, 3H), 4.99 (a, 1 H), 3.98 (t, J = 6.4 Hz, 2H), 2.82 (s, 2H), 1.78-1.00 (m, 11 H) ppm. PREPARATION 83 8-. { (4-Fluorobenzyl) oxymethyl) -1,4-dioxaespiror4,51decano This compound was prepared with 4-fluorobenzyl bromide and 1,4-dioxaspiro [4.5] dec-8-ylmethanol by a procedure similar to that of Preparation. 1 H NMR (CDCl 3) d: 7.40-7.24 (m, 2H), 7.10-6.98 (m, 2H), 4.45 (s, 2H), 3.94 (s, 4H), 3.30 (d, J = 6.6 Hz, 2H) , 1.86-1.20 (m, 9H) ppm.

PREPARATION 84 4-. { f (4-Fluorobenzyl) oxymethyl > cyclohexanone This compound was prepared with 8-. { [(4-fluorobenzyl) oxy] methyl} -1,4-dioxaespiro [4,5] decane by a procedure similar to that of Preparation 20. 1 H NMR (CDCl 3) d: 7.35-7.25 (m, 2H), 7.10-7.00 (m, 2H), 4.48 (s) , 2H), 3.38 (d, J = 6.1 Hz, 2H), 2.48-2.00 (m, 7H), 1.56-1.36 (m, 2H) ppm.PREPARATION 85 Hydrochloride of tra / 7s-1- (aminomethyl) -4-. { r (4-fluorobenzyl) oxymethyl > cyclohexanol This compound was prepared with 4-. { [(4-fluorobenzyl) oxy] methyl} cyclohexanone by a procedure similar to that of Preparation 16. 1 H NMR (DMSO-de) d: 7.86 (a, 3 H), 7.39-7.31 (m, 2 H), 7.22-7.13 (m, 2H), 5.04 (a, 1 H), 4.42 (s, 2H), 3.28 (d, J = 6.2 Hz, 2H), 2.79 (s, 2H), 1.75-1.00 (m, 9H) ppm.

PREPARATION 86 8-f (2-Fluorophenoxy) m Xetin-1,4-dioxaespirof4,5ldecane This compound was prepared with 2- (1,4-dioxaspiro [4.5] dec-8- 1) methanol and 2-fluorophenol by a procedure similar to that of Preparation 42. 1 H NMR (CDCl 3) d: 7.12-6.80 (m, 4H), 3.96 (s, 4H), 3.86 (d, J = 6.3 Hz, 2H), 2.00-1.28 (m, 9H) ppm.

PREPARATION 87 4-f (2-Fluorophen? Oxy) methyclohexanone This compound was prepared with 8 - [(2-fluorophenoxy) methyl] -1,4-dioxaespiro [4,5] decane by a procedure similar to that of Preparation 20. 1 H NMR (CDCl 3) d: 7.13-6.80 (m, 4H), 3.94 (d, J = 6.2 Hz, 2H), 2.50-2.16 (m, 7H), 1.68-1.50 (m, 2H) ppm.

PREPARATION 88 Hydrochloride of trar) s-1- (aminomethyl) -4-r (2-fluorophenoxy) metipcyclohexanol This compound was prepared with 4 - [(2-fluorophenoxy) methyl] cyclohexanone by a procedure similar to that of Preparation 16. 1 H NMR (DMSO-de) d: 7.87 (a, 3H), 7.24-7.07 (m, 3H) , 6.96-6.88 (m, 1 H), 5.08 (s, 1 H), 3.9.2 (d, J = 6.4 Hz, 2H), 2.83 (s, 2H), 1.90-1.12 (m, 9H) ppm.

PREPARATION 89 8-r (4-Fluorophenoxy) methan-1,4-dioxaespiror4,51decano This compound was prepared with 2- (1,4-dioxaspiro [4.5] dec-8-yl) methanol and 4-fluorophenol by a procedure similar to that of Preparation 42. 1 H NMR (CDCl 3) d: 7.05-6.70 ( m, 4H), 3.96 (s, 4H), 3.75 (d, J = 6.2 Hz, 2H), 1.96-1.20 (m, 9H) ppm.

PREPARATION 90 4-r (4-Fluorophenoxy) metipcyclohexanone This compound was prepared with 8 - [(4-fluorophenoxy) methyl] -1,4-dioxaespiro [4,5] decane by a procedure similar to that of Preparation 20. 1 H NMR (CDCl 3) d: 7.12-6.72 (m, 4H), 3.84 (d, J = 5.9 Hz, 2H), 2.58-2.12 (m, 7H), 1.70-1.48 (m, 2H) ppm.

PREPARATION 91 Trans-1- (aminomethyl) -4-r (4-fluorophenoxymethyl-cyclohexanol) hydrochloride This compound was prepared with 4 - [(4-fluorophenoxy) methyl] cyclohexanone by a procedure similar to that of Preparation 16. 1 H NMR (DMSO-d 6) d: 7.83 (a, 3 H), 7.18-7.05 (m, 2 H) , 7.00-6.88 (m, 2H), 5.07 (s, 1 H), 3.81 (d, J = 6.2 Hz, 2H), 2.83 (s, 2H), 1.87-1.10 (m, 9H) ppm.

PREPARATION 92 / V-r (trans-1-Hydroxy-4-. {R (5-methylpyridin-2-yl) oxylmethyl}. Cyclohexyl) metin-4- (methoxymethoxy) benzamide A mix of ?/-. { [trans-1-hydroxy-4- (hydroxylmethyl) cyclohexyl] methyl} -4- (methoxymethoxy) benzamide (0.16 g, 0.50 mmol) and NaH (60%, 24 mg, 0.60 mmol) was stirred at room temperature for 30 minutes. To the mixture was added 2-fluoro-5-methylpyridine (78 mg, 0.70 mmol). The mixture was stirred at 200 ° C for 10 minutes with microwave irradiation and quenched with NaHCO3. All was extracted with AcOEt. The extract was washed with water, dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 4: 5) to give the title compound (97 mg). 1 H NMR (CDCl 3) d: 7.90-7.80 (m, 1 H), 7.76 (d, J = 8.9 Hz, 2 H), 7.43-7.33 (m, H), 7.07 (d, J = 8.9 Hz, 2 H), 6.64 (d, J = 8.2 Hz, 1 H), 6.58-6.47 (m, 1 H), 5.22 (s, 2H), 4.13 (d, J = 6.3 Hz, 2H), 3.60 (d, J = 5.9 Hz , 2H), 3.48 (s, 3H), 2.57 (a, 1 H), 2.24 (s, 3H), 2.00-1.77 (m, 5H), 1.60-1.21 (m, 4H) ppm.

PREPARATION 93 8- (Aminomethyl) -1,4-dioxaespiror4,51decan-8-ol This compound was prepared with 8-oxo-1,4-dioxaespiro [4.5] decane by a procedure similar to that of Preparation 30. 1 H NMR (CDCl 3) d: 3.98-3.90 (m, 4H), 2.97 (a, 1 H), 2.02-1.45 (m, 8H) ppm. (NH2 was not observed.) PREPARATION 94 4- (Benzyloxy) - / V-r (8-hydroxy-1,4-dioxaespiror4,51dec-8-yl) methybenzamide This compound was prepared with 4-benzyloxybenzoic acid and 8- (aminomethyl) -1,4-dioxaespiro [4,5] decan-8-ol by a procedure similar to that of Preparation 9. 1 H NMR (CDCl 3) d: 7.75 ( d, J = 8.9 Hz, 2H), 7.50-7.30 (m, 5H), 6. 98 (d, J = 8.9 Hz, 2H), 6.63-6.53 (m, 1 H), 5.10 (s, 2H), 3.96-3.92 (m, 4H), 3.49 (d, J = 5.9 Hz, 2H), 2.96 (a, 1 H), 1.96-1.56 (m, 8H) ppm.

PREPARATION 95 4- (Benzyloxy) - - [(1-hydroxy-4-oxocyclohexyl) methybenzamide This compound was prepared with 4- (benzyloxy) - / V - [(8-hydroxy-1, 4- dioxa spiro [4,5] dec -8-yl) methyl] benzamide by a procedure similar to that of Preparation 20. 1 H NMR (CDCl 3) d: 7.76 (d, J = 8.9 Hz, 2H), 7.46-7.30 (m, 5H), 7.02 (d, J = 8.9 Hz, 2H), 6.60-6.50 (m, 1 H), 5.12 (s, 2H), 3.86 (s, 1 H), 3.37 (d, J = 5.9 Hz, 2H), 2.84-2.68 (m , 2H), 2.36-2.24 (m, 2H), 2.14-2.00 (m, 2H), 1.85-1.70 (m, 2H) ppm.

PREPARATION 96 ? H (4-Benzylidene-1-hydroxycyclohexyl) methyl] -4- (benzyloxy) benzamide A mixture of 4- (benzyloxy) - / V - [(1-hydroxy-4-oxocyclohexyl) methyl] benzamide (0.35 g, 1.0 mmol), diethyl benzylphosphonate (0.46 g, 2.0 mmol) and NaH (60%, 0.16 g, 4.0 mmol) in dimethoxyethane (10 ml) was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted with AcOEt. The extract was washed with saturated aqueous NaCl, dried over MgSO and concentrated. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 3: 2) to give the title compound (42 mg). 1 H NMR (CDCl 3) d: 7.87 (d, J = 8.6 Hz, 2 H), 7.50-7.13 (m, 10 H), 7.01 (d, J = 8.6 Hz, 2 H), 6.54-6.51 (m, 1 H), 6.31 (s, 1 H), 5.12 (s, 2H), 3.57-3.50 (m, 2H), 2.71 -2.23 (m, 5H), 1.90-1.45 (m, 3H) ppm. (No OH was observed.) PREPARATION 97 8-. { r (2-Fluorobenzyl) oxymethyl} -1,4-dioxaespiror4,5Tdecane This compound was prepared with 2-fluorobenzyl bromide and 1,4-dioxaespiro [4,5] dec-8-methanol by a procedure similar to that of Preparation 47. 1 H NMR (CDCl 3) d: 7.46-6.98 (m, 4H ), 4.56 (s, 2H), 3.94 (s, 4H), 3.34 (d, J = 6.6 Hz, 2H), 1.90-1.20 (m, 9H) ppm.

PREPARATION 98 4-. { f (2-Fluorobenzyl) oxy] methyl > cyclohexanone This compound was prepared with 8-. { [(2-fluorobenzyl) oxy] methyl} -1,4- dioxaespiro [4,5] decane by a procedure similar to that of Preparation 20. 1 H NMR (CDCl 3) d: 7.45-7.37 (m, 1 H), 7.34-7.23 (m, 1 H), 7.17 - 7.02 (m, 2H), 4.59 (s, 2H), 3.43 (d, J = 6.0 Hz, 2H), 2.45-2.27 (m, 4H), 2.18- 2.05 (m, 3H), 1.54-1.38 (m , 2H) ppm.

PREPARATION 99 trans-1- (Aminomethyl) -4-. { r (2-fluorobenzyl) oxymethyl} cyclohexanol This compound was prepared with 4-. { [(2-fluorobenzyl) oxy] methyl} cyclohexanone by a procedure similar to that of Preparation 30 in the form of a yellow oil. 1 H NMR (CDCl 3) d: 7.89 (a, 2 H), 7.38 (dd, J = 7.5, 7.3 Hz, 1 H), 7. 27-7.22 (m, 1 H), 7.12 (dd, J = 7.5, 7.3 Hz, 1 H), 7.02 (dd, J = 9, 8.4 Hz, 1 H), 4.53 (s, 2H), 3.31 (s) , 2H), 3.15 (s, 2H), 1.90-1.45 (m, 7H), 1.20-0.98 (m, 2H) ppm. (No OH was observed.) PREPARATION 100 . { r4- (Nitromethyl) c, wiclohex-3-en-1-ynmethoxy} benzene A mixture of 4- (phenoxymethyl) cyclohexanone (3.1 g, 15 mmol) and ethylenediamine (0.10 mL, 1.5 mmol) in nitromethane (60 mL) was heated to reflux for 6 hours. The mixture was concentrated and purified by column chromatography on silica gel (hexane: AcOEt = 10: 1) to give the title compound (3.2 g). 1 H NMR (CDCl 3) d: 7.32-7.24 (m, 2 H), 6.98-6.87 (m, 3 H), 6.00-5.93 (m, 1 H), 4.84 (s, 2 H), 3.86 (d, J = 6.2 Hz , 2H), 2.44-1.94 (m, 6H), 1.58-1.45 (m, 1 H) ppm.

PREPARATION 101 (F4- (Phenoxymethyl) cyclohexylmethyl) amine hydrochloride.

NaBH4 (2.2 g, 59 mmol) was added to a mixture of. { [4- (Nitromethyl) cyclohex-3-en-1-yl] methoxy} Benzene (3.2 g, 13 mmol) and NiCI2 «6H2O in MeOH (130 ml) and THF (65 ml) at 0 ° C and the mixture was stirred for 2 hours. The mixture was absorbed in amine gel (10 g) and evaporated.

The residue was eluted with CH2Cl2-MeOH (10: 1). After evaporation, a mixture of the residue and 10% Pd-C (1.0 g) in EtOH (100 ml) was hydrogenated at 1 atmosphere for 3 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated. To a solution of the residue in AcOEt (20 ml), 4N HCl in AcOEt (3 ml) was added and collected by filtration to give the title compound (1.9 g). 1 H NMR (DMSO-de) d: 8.03 (a, 3H), 7.32-7.24 (m, 2H), 6.96-6.88 (m, 3H), 3.90-3.75 (m, 2H), 2.80-2.60 (m, 2H ), 1.97-0.90 (m, 10H) ppm.

PREPARATION 102 c / s-4-f (D? 'benzylamino) carbonyl] cyclohexanecarboxylate methyl This compound was prepared with dibenzylamine by a procedure similar to that of Preparation 1 in the form of a yellow oil. 1 H NMR (CDCl 3) d: 7.40-7.23 (m, 6H), 7.18-7.13 (m, 4H), 4.57 (s, 2H), 4.47 (s, 2H), 3.72 (s, 3H), 2.63-2.54 ( m, 2H), 2.30-2.23 (m, 2H), 1.92-1.78 (m, 2H), 1.71-1.64 (m, 2H), 1.57-1.44 (m, 2H) ppm.

PREPARATION 103 . { c / s-4-f (Dibenzylamino) metipciclohexyl} methanol To a suspension of LiAIH4 (2.1 g, 55 mmol) in THF (100 ml) was added a solution of methyl c / s-4- [(dibenzylamino) carbonyl] cyclohexanecarboxylate (8.0 g, 22 mmol) in THF (100 g). ml) at 0 ° C, and the mixture was heated to reflux for 3 hours. The mixture was stirred at 70 ° C for 16 hours. To the reaction mixture was added Na2SO '1OH2O (20 g) and KF (2.0 g) and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through a pad of celite and the filtrate was evaporated in vacuo to yield the title compound as a colorless oil (8.4 g). 1 H NMR (CDCl 3) d: 7.37-7.21 (m, 10 H), 3.77-3.66 (m, 1 H), 3.50 (s, 4H), 3.34 (d, J = 6.8 Hz, 2H), 2.27 (d, J = 7.5 Hz, 2H), 1.95-1.31 (m, 8H), 1.06-0.94 (m, 2H) ppm.

PREPARATION 104 Dibencíl. { Ic / s-4- (phenoxymethyl) cyclohexyl] methyl} amine To a solution of. { c / s-4 - [(dibenzylamino) methyl] cyclohexyl} methanol (3.0 g, 9.3 mmol) in toluene (30 ml) was added triphenylphosphine (2.7 g, 10 mmol) and phenol (1.0 g, 10 mmol). After cooling to 0 ° C, DIAD (2.0 ml, 10.2 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3.5 hours. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 10: 1 as eluent) to give the title compound as a white solid (3.5 g, 94%). 1 H NMR (CDCl 3) d: 7.38-7.19 (m, 12H), 6.94-6.83 (m, 3H), 3.67 (d, J = 6.8 Hz, 2H), 3.52 (s, 4H), 2.30 (d, J = 7.6 Hz, 2H), 1.87-1.18 (m, 10H) ppm.

PREPARATION 105 Hydrochloride. { fc / s-4- (phenoxymethyl) cyclohexylmethyl} amine To a solution of dibenzyl. { [c / s-4- (phenoxymethyl) cyclohexyl] meth} amine (3.5 g, 8.8 mmol) in MeOH (150 ml) was added 20% Pd (OH) 2 -C (1.8 g) and the mixture was hydrogenated at a pressure of 4 atmospheres at 50 ° C for 13 minutes. hours. To the reaction mixture was added 10% HCl-MeOH (10 ml) and the mixture was hydrogenated at a pressure of 4 atmospheres at 55 ° C for 10 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. To a solution of the residue in MeOH (60 ml) was added 10% HCl-MeOH (10 ml) and 10% Pd-C (0.9 g). The mixture was hydrogenated at a pressure of 4 atmospheres at 55 ° C for 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. To a mixture of the crude material in AcOEt (15 ml) was added 4N-AcOEt HCl (2.2 ml) and the mixture was stirred at room temperature for 4 hours. The precipitate was filtered, washed with AcOEt and dried under vacuum to yield the title compound as a white solid (820 mg, 37%). 1 H NMR (DMSO-de) d: 7.95-7.84 (m, 3H), 7.31-7.25 (m, 2H), 6.94-6.89 (m, 3H), 3.88 (d, J = 7.0 Hz, 2H), 2.76 ( d, J = 7.1 Hz, 2H), 1.92-1.80 (m, 2H), 1.52-1.47 (m, 8H) ppm.

PREPARATION 106 Acetate of (2S) -2- ( { [(4-methylphenyl) sulfonilloxy.] Methyl) hex-5-en-1-yl To a mixture of (2 /?) -2- (hydroxymethyl) hex-5-en-1-yl acetate (7.9 g, 46 mmol) (Tetrahedron Asymmery 1999, 10, 4057-4064) and triethylamine (19 ml. 0.14 moles) in CH2Cl2 (90 ml), p-TsCl (13 g, 49 mmol) was added at 0 ° C and the mixture was stirred at room temperature for 7 hours. The mixture was washed with saturated aqueous NaCl, dried over MgSO and evaporated. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 8: 1 to 6: 1) to give the title compound (13 g). 1 H NMR (CDCl 3) d: 7.79 (d, J = 8.3 Hz, 2 H), 7.36 (d, J = 8.3 Hz, 2 H), 5.79-5.62 (m, 1 H), 5.03-4.92 (m, 2 H), 4.08-3.89 (m, 4H), 2.46 (s, 3H), 2.09-1.92 (m, 6H), 1.51-1.35 (m, 2H) ppm.

PREPARATION 107 (2S) -2- ( { F (4-Methylphenyl) sulfonilloxy} methyl) -4-oxiran-2-ylbutyl acetate This compound was prepared with (2S) -2- (. {[[(4-methylphenyl) sulfonyl] oxy] -methyl) hex-5-en-1-yl by a procedure similar to that of Preparation 40. 1 H NMR (CDCl 3) d: 7.80 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 4.20-3.87 (m, 4H), 2.91-2.39 (m, 6H), 2.18-1.32 (m, 8H) ppm.

PREPARATION 108 4-Methylbenzenesulfonate of (2S) -2- (hydroxymethyl) -4-oxiran-2-ylbutyl To a solution of (2S) -2- ( { [(4-methylphenyl) sulfonyl] oxy} methyl) -4-oxiran-2-ylbutyl acetate (14 g, 0.37 mmol) in MeOH (200 ml), K2CO3 (10 g, 74 mmol) was added and stirred at 0 ° C for 30 minutes. The mixture was filtered and the filtrate was diluted with AcOEt. It was washed with water, dried over MgSO and evaporated to give the title compound (12 9). 1 H NMR (CDCb) d: 7.80 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 4.19-3.99 (m, 2H), 3.71-3.53 (m, 2H), 2.91 -2.82 (m, 1 H), 2.78-2.71 (m, 1 H), 2.54-2.42 (m, 4H), 2.13-1.12 (m, 5H) ppm. (No OH was observed).

PREPARATION 109 TsC ^ 'X? k? OH 4-Methylbenzenesulfonate of f (3S) -6- (hydroxymethyl) tetrahydro-2-pyran-3-methylmethyl To a solution of (2S) -2- (hydroxymethyl) -4-oxiran-2-ylbutyl 4-methylbenzenesulfonate (10 g, 31 mmol) in CH2Cl2 (100 mL) was added p-TsOH "H2O ( 0.29 g, 1.5 mmol) at 0 ° C and the mixture was stirred at 0 ° C for 1 hour and at room temperature for 30 minutes. The mixture was washed with saturated aqueous NaHCO3, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 3: 2 to 2: 3) to give the title compound (6.1 g). 1 H NMR (CDCl 3) d: 7.87-7.72 (m, 2H), 7.44-7.31 (m, 2H), 4.24-3.05 (m, 7H), 2.46 (s, 3H), 2.10-1.13 (m, 5H) ppm . (No OH was observed).

PREPARATION 110 TsO < '">' Ox. 4-Methylbenzenesulfonate of. { (3S) -6-r (4-fluorophenoxy) methyltetrahydro-2H-pyran-3-yl} methyl This compound was prepared with [(3S) -6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl] methyl 4-methylbenzenesulfonate by a procedure similar to that of Preparation 106. 1 H NMR (CDCl 3) d: 7.85-7.75 (m, 2H), 7.41-7.32 (m, 2H), 7.04-6.72 (m, 4H), 4.30-3.10 (m, 7H), Z55-2.40 (m, 3H), 2.16-1.18 (m, 5H) ppm.

PREPARATION 111 (5 /?) - 5- (Azidomethyl) -2-r (4-fluorophenoxy) metiptetrahydro-2H-pyran This compound was prepared with 4-methylbenzenesulfonate of. { (35) -6 - [(4-Fluorophenoxy) methyl] tetrahydro-2 / V-pyran-3-yl} methyl by a procedure similar to that of Preparation 7. 1 H NMR (CDCl 3) d: 7.05-6.75 (m, 4H), 4.18-3.05 (m, 7H), 2.11-1.17 (m, 5H) ppm.

PREPARATION 112 H2N - "'.. Cx X ( { (3 /?) - 6-f (4-Fluorophenoxy) methytrahydro-2-pyran-3-yl.} Methyl) amine This compound was prepared with (5ft) -5- (azidomethyl) -2 - [(4-fluorophenoxy) methyl] tetrahydro-2-pyran by a procedure similar to that of Preparation 8. 1 H NMR (CDCl 3) d: 7.03- 6.81 (m, 4H), 4.18-2.50 (m, 7H), 2.15-1.11 (m, 5H) ppm. (NH2 was not observed).

PREPARATION 113 2-r (4-Fluorophenoxy) metiphex-5-en-1-ol This compound was prepared with 2-but-3-en-1-ylpropane-1,3-diol by a procedure similar to that of Preparation 104. 1 H NMR (CDCl 3) d: 7.05-6.85 (m, 4H), 5.90- 5.73 (m, 1 H), 5.10-4.95 (m, 2H), 4.05-3.90 (m, 2H), 3.83-3.68 (m, 2H), 2.25-1.98 (m, 3H), 1.93-1.78 (m, 1 H), 1.67-1.48 (m, 2H). (No OH was observed).

PREPARATION 114 2, -r (4-Fluorophenoxy) methan-4-oxiran-2-ylbutan-1-ol This compound was prepared with 2 - [(4-fluorophenoxy) methyl] hex-5-en-1-ol by a procedure similar to that of Preparation 40. 1 H NMR (CDCl 3) d: 7.04-6.74 (m, 4H), 4.05-3.90 (m, 2H), 3.85-3.69 (m, 2H), 30.1-2.90 (m, 1 H), 2.81-2.73 (m, 1H), 2.55-2.47 (m, 1 H), 2.11- 1.48 (m, 5H) ppm. (No OH was observed).

PREPARATION 115 ((2S *, 5S *) - 5-r (4-Fluorophenoxy) methy-tetrahydro-2-pyran-2-yl> methanol This compound was prepared with 2 - [(4-fluorophenoxy) methyl] -4-oxiran-2-ylbutan-1-ol by a procedure similar to that of Preparation 109. 1 H NMR (CDCl 3) d: 7.03-6.75 (m, 4H), 4.15-4.05 (m, 2H), 4.00-3.91 (m, 1 H), 3.70-3.45 (m, 4H), 2.05-1.75 (m, 3H), 1.55-1.34 (m, 2H) ppm. (No OH was observed).

PREPARATION 116 (2S *, 5S *) - 2- (Azidomethyl) -5-r (4-fluorophenoxy) methytetrahydro-2 / y-pyran This compound was prepared with. { (2S *, 5S *) - 5 - [(4-fluorophenoxy) methyl] tetrahydro-2H-pyran-2-yl} methanol by a procedure similar to that of Preparation 67. 1 H NMR (CDCl 3) d: 7.05-6.75 (m, 4H), 4.18-3.95 (m, 3H), 3.70- 3.46 (m, 2H), 3.34-3.15 (m , 2H), 2.05-1.75 (m, 3H), 1.55-1.40 (m, 2H) ppm.

PREPARATION 117 HN XX (((2S *, 5S *) - 5-r (4-Fluorophenoxy) methytetrahydro-2 ^ / - pyran-2-yl> methyl) amine This compound was prepared with (2S *, 5S *) - 2 - (azidomethyl) -5 - [(4-fluorophenoxy) methyl] tetrahydro-2H-pyran by a procedure similar to that of Preparation 8. 1 H NMR (CDCl 3) d: 7.03-6.81 (m, 4H), 4.20-3.95 ( m, 2H), 3.70- 3.60 (m, 1 H), 3.42-3.20 (m, 2H), 2.73-2.64 (m, 2H), 2.15-1.70 (m, 3H), 1.56-1.25 (m, 2H) ppm. (NH2 was not observed).

PREPARATION 118 Methanesulfonate of. { c s-4-F (dibenzylamino) methylcyclohexyl} methyl To a solution of. { c / s-4 - [(dibenzylamino) methyl] cyclohexyl} methanol (35 g, 108 mmol) in dichloromethane (200 ml) was added triethylamine (30 ml, 216 mmol). To the mixture was added methanesulfonyl chloride (10 ml, 130 mmol) at 0 ° C, and the mixture was stirred at 0 ° C for 1 hour. Saturated aqueous NaHCO3 (250 mL) was added to the mixture and the whole mixture was extracted with dichloromethane (100 mL X 3). The combined organic layer was washed with brine (300 ml), dried over Na2SO4 and concentrated in vacuo to yield the title compound as a yellow oil (46 g). 1 H NMR (CDCl 3) d: 7.37-7.19 (m, 10 H), 3.91 (d, J = 7.1 Hz, 2 H), 3.50 (s, 4 H), 2.93 (s, 3 H), 2.28 (d, J = 7.6 Hz , 2H), 1.91-0.98 (m, 10H) ppm.

PREPARATION 119 . { c / S "4-r (Dibenzylamino) methyclohexyl} acetonitrile To a methanesulfonate solution of. { c / s-4 - [(dibenzylamino) methyl] cyclohexyl} methyl (46 g, 108 mmol) in DMSO (200 mL) was added sodium cyanide (8.0 g, 162 mmol) and 15-crown-5 ether (11 mL, 54 mmol) and the reaction mixture was stirred at 60 ° C. C for 19 hours. To the mixture was added H2O (500 mL), and the whole mixture was extracted with AcOEt (200 mL X 3). The combined organic layer was washed with H2O (500 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 10: 1 as eluent) to give the title compound as a white solid (25 g, 68%). 1 H NMR (CDCl 3) d: 7.37-7.20 (m, 10 H), 3.50 (s, 4 H), 2.28 (d, J = 8.1 Hz, 2 H), 2.10 (d, J = 8.1 Hz, 2 H), 1.81-1.78 (m, 2H), 1.58-1.36 (m, 6H), 1.08-1.00 (m, 2H) ppm.

PREPARATION 120 (c s-4-r (Benzylamino) ethyl methoxycyclohexyl acetate To cold EtOH (125 mL) concentrated H2SO4 (63 mL) was added at 0 ° C, and the mixture was stirred at 0 ° C for 10 minutes. To the mixture of. { c / s-4- [(dibenzylamino) methyl] cyclohexyl} acetonitrile (25 g, 74 mmol) in EtOH (40 ml) was added the mixture of H2SO in EtOH solution at 0 ° C. The reaction mixture was heated to reflux for 4.5 hours. After evaporation, the residue was cooled to 0 ° C and H 2 O (100 ml) was added. The mixture was basified with NaOH to pH 8. The whole mixture was extracted with AcOEt (100 ml X 3). The combined organic layer was washed with H2O (200 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 40: 1 as eluent) to give the title compound as a colorless oil (16 g, 61%). 1 H NMR (CDCl 3) d: 7.37-7.19 (m, 10H), 4.16-4.05 (m, 2H), 3.50 (s, 4H), 2.28-2.26 (m, 2H), 2.16-2.07 (m, 2H), 2.00-1.86 (m, 1H), 1.83-1.70 (m, 1 H), 1.58-1.49 (m, 2H), 1.43-1.28 (m, 4H), 1.23 (t, J = 8.1 Hz, 3H), 1.09 -0.99 (m, 2H) ppm. MS (ESI): 380.26 (M + Hf PREPARATION 121 2-. { c s-4-r (Dibenzylamino) metipciclohexyl} ethanol To a suspension of LÍAIH4 (2.4 g, 63 mmol) in THF (150 ml) was added a solution of. { c / s-4 - [(benzylamino) methyl] cyclohexyl} Ethyl acetate (15.8 g, 42 mmol) in THF (200 ml) at 0 ° C and the reaction mixture was stirred at 0 ° C for 1 hour. To the reaction mixture was added Na2SO4'10H2O (24 g) and KF (2.4 g) and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through a pad of celite and the filtrate was evaporated in vacuo to yield the title compound as a yellow oil (15.9 g). 1 H NMR (CDCl 3) d: 7.38-7.19 (m, 10H), 3.61-3.56 (m, 2H), 3.50 (s, 4H), 2.27 (d, J = 7.3 Hz, 2H), 1.85-1.71 (m, 1 H), 1.56-1.34 (m, 9H) , 1.05-0.96 (m, 2H) ppm. [No OH was observed].

PREPARATION 122 Dibenzyl { rc / 's-4- (2-phenoxyethyl) cyclohexyphenyl} amine To a solution of 2-. { c / s-4 - [(dibenzylamino) methyl] cyclohexyl} Ethanol (3.5 g, 10 mmol) in toluene (33 ml) was added with triphenylphosphine (3.0 g, 11 mmol) and phenol (1.1 g, 11 mmol). To the mixture was added diisopropyl azodicarboxylate (2.2 ml, 11 mmol) at 0 ° C and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 40: 1 as eluent) to give the title compound as a colorless oil (4.0 g, 92%). 1 H NMR (CDCl 3) d: 7.34-7.19 (m, 12H), 6.95-6.84 (m, 3H), 3.91-3.86 (m, 2H), 3.50 (s, 4H), 2.28 (d, J = 8.1 Hz, 2H), 1.86-1.73 (m, 1H), 1.62-1.37 (m, 9H), 1.11-1.02 (m, 2H) ppm.

PREPARATION 123 Hydrochloride. { rc / s-4- (2-phenoxyethyl) cyclohexylmethyl} amine To a solution of dibenyl. { [c / 's-4- (2-phenoxyethyl) cyclohexyl] methyl} Amine (8.4 g, 23 mmol) in MeOH (80 mL) was added THF (10 mL). To the mixture was added 10% Pd-C (0.8 g) and ammonium formate (3.3 g, 52 mmol), and the reaction mixture was stirred at 62 ° C for 1 hour. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. To the residue was added H2O (50 ml) and brine (50 ml). The mixture was extracted with CH2Cl2 (50 mL x 3), dried over Na2SO and concentrated in vacuo. To this residue was added AcOEt (30 ml) and the mixture was cooled to 0 ° C. To the mixture was added 4 N-AcOEt HCl (5.5 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, filtered and washed with AcOEt. The solid was recrystallized from 'PrOH (60 ml) to give the title compound as a white solid (3.3 g, 52%). 1 H NMR (DMSO-de) d: 8.06-7.78 (m, 3H), 7.31-7.25 (m, 2H), 6.94-6.89 (m, 3H), 4.00-3.96 (m, 2H), 2.75 (d, J = 5.4 Hz, 2H), 1.82-1.65 (m, 4H), 1.55-1.31 (m, 8H) ppm.

PREPARATION 124 Ethyl 4- (2-hydroxyethoxy) cyclohexanecarboxylate To a solution of 1,4-dioxaespiro [4,5] decane-8-carboxylic acid ethyl ester (5.0 g, 23 mmol) in dichloromethane (80 ml) was added triethylsilane (4.1 ml, 26 mmol) and tert-trifluoromethanesulfonate. butyldimethylsilyl (0.5 ml, 2.3 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 19 hours. To the mixture was added water (100 ml), the whole mixture was extracted with dichloromethane (50 ml x 3) and the combined organic layer was dried over Na2SO and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 2: 1 ~ 1: 1 as eluent) to give the title compound as a yellow oil (1.0 g, 20%). ? NMR (CDCl 3, cisArans mixture) d: 4.21-4.08 (m, 2H), 3.72-3.50 (m, 4.5H), 3.32-3.22 (m, 0.5H), 2.40-1.22 (m, 13H) ppm.

PREPARATION 125 Ethyl 4- (2-phenoxyethoxy) cyclohexanecarboxylate To a solution of ethyl 4- (2-hydroxyethoxy) cyclohexanecarboxylate (1.0 g, 4.7 mmol) in toluene (15 ml) were added triphenylphosphine (1.3 g, 5.1 mmol), phenol (484 mg, 5.1 mmol) and azodicarboxylate. diisopropyl (1.0 ml, 5.1 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and then warmed to room temperature for 2 hours. The reaction mixture was evaporated and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate 8: 1 as eluent) to yield the title compound as a yellow oil (761 mg, 56%) . 1 H NMR (CDCl 3, cisArans mixture) d: 7.30-7.21 (m, 2H), 6.97-6.82 (m, 3H), 4.16-4.09 (m, 4H), 3.86-3.76 (m, 2H), 3.57 (m, 0.25H), 3.40-3.30 (m, 0.75H), 2.36-1.23 (m, 12H) ppm.

PREPARATION 126 rc / s-4- (2-phenoxyethoxy) cyclohexpimethanol To a suspension of LiAIH4 (148 mg, 3.9 mmol) in THF (4 mL) was added a solution of ethyl 4- (2-phenoxyethoxy) cyclohexanecarboxylate (761 mg, 2.6 mmol) in THF (6 mL) at 0 °. C, and the mixture was stirred for 30 minutes. To the reaction mixture was added Na2SO "10H2O (1.4 g) and KF (0.2 g) and the whole mixture was stirred at room temperature for 0.5 hour. The mixture was filtered through a pad of celite and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 3: 1 as eluent) to give the title compound as a colorless oil (111 mg, 17%). 1 H NMR (CDCl 3) d: 7.31-7.23 (m, 2H), 6.97-6.91 (m, 3H), 4.14-4.09 (m, 2H), 3.78-3.74 (m, 2H), 3.64-3.62 (m, 1 H), 3.47 (d, J = 6.1 Hz, 2H), 1.96-1.88 (m, 2H), 1.59-1.38 (m, 7H) ppm. (No OH was observed).

PREPARATION 127 Fc / s-4- (2-phenoxyethoxy) cyclohexyphemethyl methanesulfonate To a solution of [c / s-4- (2-phenoxyethoxy) cyclohexyl] methanol in dichloromethane (1.5 ml) was added triethylamine (0.1 ml, 0.9 mmol). To the mixture cooled to 0 ° C was added a solution of methanesulfonyl chloride (60 mg, 0.5 mmol) in dichloromethane (1.5 ml) and the mixture was stirred at 0 ° C for 0.5 hours. Saturated aqueous NaHCO3 (10 mL) was added to the reaction mixture and the mixture was extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with brine (20 ml x 1), dried over Na 2 SO 4 and concentrated in vacuo to yield the title compound as a yellow oil (126 mg). 1 H NMR (CDCl 3) d: 7.32-7.25 (m, 2H), 6.97-6.91 (m, 3H), 4.14-4.09 (m, 2H), 4.03 (d, J = 7.0 Hz, 2H), 3.77-3.74 ( m, 2H), 3.66-3.64 (m, 1 H), 2.98 (s, 3H), 1.96-1.35 (m, 9H) ppm.

PREPARATION 128 (2- { [C s-4- (Azidomethyl) cyclohexyl] oxy} ethoxy) benzene To a solution of [c / s-4- (2-phenoxyethoxy) cyclohexyl] methyl methanesulfonate (126 mg, 0.4 mmol) in DMF (3 mL) was added sodium azide (50 mg, 0.8 mmol). The reaction mixture was stirred at 90 ° C for 3 hours. Water (20 ml) was added to the mixture and the mixture was extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (30 ml), dried over Na2SO and concentrated in vacuo to yield the title compound as a yellow oil (93 mg). 1 H NMR (CDCl 3) d: 7.31-7.25 (m, 2H), 6.97-6.91 (m, 3H), 4.14-4.10 (, 2H), 3.78-3.74 (m, 2H), 3.64 (m, 1H), 3.13 (d, J = 6.6 Hz, 2H), 1.94-1.89 (m, 2H), 1.52-1.35 (m, 7H) ppm.

PREPARATION 129 . { rc / s-4- (2-Phenoxyethoxy) cyclohexyphenyl} amine To a solution of (2- {[c / s-4- (azidomethyl) cyclohexyl] oxy} ethoxy) benzene (93 mg, 0.3 millimole) in methanol (3 ml) was added 10% Pd. C (9 mg) and stirred at room temperature for 1 hour in an atmosphere of H2 (1 atmosphere). The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to yield the title compound as a yellow oil (78 mg). 1 H NMR (CDCl 3) d: 7.31-7.25 (m, 2H), 6.97-6.91 (m, 3H), 4.14-4.10 (m, 2H), 3.78-3.74 (m, 2H), 3.63-3.62 (m, 1 H), 2.56-2.54 (m, 2H), 1.93-1.87 (m, 2H), 1.50-1.25 (m, 7H) ppm. [No proton of NH2 was observed].

PREPARATION 130 4- (Methoxymethoxy) -? c s-4- (2-phenoxyethoxy) cyclohexylmethyl} benzamide This compound was prepared with. { [c / s-4- (2-phenoxyethoxy) cyclohexyl] methyl} amine (78 mg, 0.3 mmol) by a procedure similar to that of Preparation 17 in the form of a colorless oil (86 mg, 66%) 1 H NMR (CDCl 3) d: 7.73-7.70 (m, 2 H), 7.30-7.26 ( m, 2H), 7.06-7.03 (m, 2H), 6.96-6.91 (m, 3H), 6.16-6.06 (m, 1 H), 5.21 (s, 2H), 4.13-4.10 (m, 2H), 3.78 -3.74 (m, 2H), 3.66-3.61 (m, 1 H), 3.48 (s, 3H), 3.33-3.29 (m, 2H), 1.95-1.93 (m, 2H), 1.67-1.43 (m, 7H) ) ppm. MS (ESI): 414.24 (M + Hf PREPARATION 131 Trans-1- (aminomethyl) -4- (4-fluorobenzyl) cyclohexanol hydrochloride This compound was prepared with 4-fluorobenzylcyclohexanone (WO 2001028987) by a procedure similar to that of Preparation 16. 1H NMR (DMSO-d6) d: 7.80 (a, 3H), 7.27-7.01 (m, 4H), 5.00 ( to, 1 H), 2.89 (s, 2H), 2.59-2.42 (m, 2H), 1.78-0.94 (m, 9H) ppm.

PREPARATION 132 / V, / V-Dibenzyl-1- (c / s-4- { R (5-nitropyridin-2-yl) oxymethyl.} Cyclohexyl) methanamine To a solution of. { c / s-4 - [(dibenzylamino) methyl] cyclohexyl} methanol (0.64 g, 2.0 mmol) in DMF, NaH (60%, 0.18 g, 4.4 mmol) was added at 0 ° C and the mixture was stirred at room temperature for 1 hour. 2-Chloro-5-nitropyridine (0.96 g, 6.0 mmol) was added at 0 ° C and the mixture was stirred at room temperature overnight. The mixture was quenched with water and diluted with AcOEt. The organic layer was washed with water, dried over MgSO 4 and evaporated. The residue was purified by column chromatography on silica gel (hexane-AcOEt 40: 1) to give the title compound (0.51 g). 1 H NMR (CDCl 3) d: 9.04 (d, J = 2.8 Hz, 1 H), 8.33 (dd, J = 2.8, 9.1 Hz, 1 H), 7.47-7.15 (m, 10H), 6.75 (d, J = 9.2 Hz, 1 H), 4.16 (d, J = 6.9 Hz, 2H), 3.52 (s, 4H), 2.30 (d, J = 7.4 Hz, 2H), 2.02-1.09 (m, 10H) ppm.

PREPARATION 133 6- ( { C / 's-4-r (Dibenzylamino) methyncyclohexyl}. Methoxy) pyridin-3-amine A mixture of A /,? / - dibenzyl-1- (c / s-4. {[[(5-nitropyridin-2-yl) oxy] methyl.}. Cyclohexyl) methanamine (0.51 g, 1.1 mmol), Fe (0.31 g, 5.5 mmol), NH 4 Cl (29 mg, 0.55 mmol) in EtOH (10 mL) and water (2 mL) was heated to reflux for 6 hours. To the mixture was added water (20 ml) and extracted with CH2Cl2. The extract was washed with water, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel (hexane-AcOEt 7: 3) to give the title compound (0.44 g).

? NMR (CDCl 3) d: 7.62 (d, J = 3.0 Hz, 1 H), 7.43-7.16 (m, 10H), 7.01 (dd, J = 3.0, 8.7 Hz, 1 H), 6.54 (d, J = 8.7 Hz, 1H), 3.93 (d, J = 7.1 Hz, 2H), 3.51 (s, 4H), 2.29 (d, J = 7.4 Hz, 2H), 2.00-1.15 (m, 10H) ppm. (NH2 was not observed).

PREPARATION 134 ? /.? / - Dibenzyl-1- (cs-4- (r (5-fluoropyridin-2-yl) oxy] methyl &cyclohexyl) methanamine and / V-benzyl-1-phenyl-β / - ( { c / 's-4-f (pyridin-2-ylox?) methyncyclohexyl.) methyl) methanamine To a solution of 6- (. {C / 's-4 - [(dibenzylamino) methyl] cyclohexyl}. Methoxy) pyridin-3-amine (0.22 g, 0.55 mmol) in EtOH was added slowly ethyl nitrite (15% in EtOH, 0.31 ml) at 0 ° C. To the mixture was slowly added HBF4 (42% in water, 0.23 ml) at 0 ° C and the mixture was stirred at 0 ° C for 1 hour. Cold ether was added to the mixture and the insoluble purple oil was washed with cold ether. A mixture of the oil and heptane (0.6 ml) was heated at 100 ° C for 1 hour. Water was added to the mixture and extracted with CH2Cl2. The extract was dried over MgSO4 and evaporated. The residue was purified by preparative TLC (hexane-AcOEt 10: 1) to give the title compounds (61 mg and 23 mg).

N, N-Dibenzyl-1- (cis-4-. {[[(5-fluoropyridin-2-yl) oxy] methyl.} Cyclohexyl) methanamine (61 mg) 1 H NMR (CDCl 3) d: 7.95 (d, J = 2.8 Hz, 1 H), 7.43-7.16 (m, 11 H), 6.64 (dd, J = 3.6, 9.1 Hz, 1 H), 3.98 (d, J = 7.1 Hz, 2H ), 3.51 (s, 4H), 2.29 (d, J = 7.6 Hz, 2H), 2.00-1.13 (m, 10H) ppm. MS (ESI): 419.25 (M + Hf A / -Benzyl-1-phenyl-? / - ( { C / s-4-f (pyridin-2-yloxy) methyl] cyclohexyl) methyl) metanamine (31 mq) 1 H NMR ( CDCI3) d: 8.16-8.09 (m, 1 H), 7.60-7.50 (m, 1 H), 7.43- 7.15 (m, 10H), 6.87-6.65 (m, 2H), 4.02 (d, J = 6.9 Hz , 2H), 3.51 (s, 4H), 1.92 (d, J = 7.4 Hz, 2H), 2.02-1.16 (m, 10H) ppm.

PREPARATION 135 f (c / 's-4- { r (5-Fluoropyridin-2-yl) oxymethyl.} cyclohexyl) methynamine This compound was prepared with? /,? / - dibenzyl-1- (c / s-4. {[[(5-fluoropyridin-2-yl) oxy] methyl.} Cyclohexyl) methanamine by a similar procedure to that of Preparation 123. 1 H NMR (CDCU) d: 8.02-7.94 (m, 1 H), 7.40-7.26 (m, 1 H), 6.75-6.65 (m, 1 H), 4.16 (d, J = 7.3 Hz, 2 H), 2.63 ( d, J = 6.1 Hz, 2H), 2.12-1.20 (m, 10H) ppm. (NH2 was not observed).

PREPARATION 136 (fc / s-4-r (Pyridin-2-yloxy) methylcyclohexyl) methyl) amine This compound was prepared with β-benzyl-1-phenyl-β / - (. {Cc / s-4- [(pyridin-2-yloxy) methyl] cyclohexyl} methyl) methanamine by a procedure similar to that of Preparation 123. 1 H NMR (CDCl 3) d: 8.20-8.11 (m, 1 H), 7.62-7.51 (m, 1 H), 6.91-6.70 (m, 2H), 4.20 (d, J = 7.3 Hz, 2H) , 2.62 (d, J = 6.1 Hz, 2H), 2.12-1.20 (m, 10H) ppm. (NH2 was not observed).

PREPARATION 137 / V, V-Dibenzyl-114-dioxa Aespiror4,5 decane-8-carboxamide This compound was prepared with 1,4-dioxaespiro [4,5] decane-8-carboxylic acid and dibenzylamine by a procedure similar to that of Preparation 1. 1 H NMR (CDCl 3) d: 7.40-7.23 (m, 10H), 4.59 (s, 2H), 4.46 (s, 2H), 3. 95-3.93 (m, 4H), 2.61-2.51 (m, 1 H), 2.10-1.95 (m, 2H), 1.85-1.77 (m, 4H), 1.53-1.42 (m, 2H) ppm.

PREPARATION 138 / V,? / - Dibenzyl-1- (1,4-dioxaespiror4,5] dec-8-yl) methanamine This compound was prepared with? /,? / - dibenzyl-1,4-dioxaespiro [4,5] decane-8-carboxamide by a procedure similar to that of Preparation 2. 1 H NMR (CDCU) d: 7.39-7.18 (m, 10H), 3.96-3.86 (m, 4H), 3.79-3.71 (m, 1 H), 3.51 (s, 4H), 2.24 (d, J = 7.2 Hz , 2H), 1.92-1.80 (m, 3H), 1.75-1.40 (m, 4H), 1.14-0.98 (m, 2H) ppm.

PREPARATION 139 2- ( { 4-r (D¡benzylamino) met¡nc¡clohex¡l) oxy) ethanol To a solution of? , A-dibenzyl-1- (1,4-dioxaspiro [4.5] dec-8-yl) methanamine (2.8 g, 7.9 mmol) in dichloromethane (70 ml) was added diisobutylaluminum hydride (0.93 M in hexane, 15 ml, 16 mmol) at 0 ° C under a nitrogen atmosphere and the mixture was stirred for 3 hours. To the mixture was added Na2SO4-10H2O (12 g) and KF (2 g) and the resulting mixture was stirred for 2 hours at room temperature. After filtration, the filtrate was evaporated to yield the title compound. (2.6 g) H NMR (CDCl 3) d: 7.42-7.16 (m, 10H), 3.75-3.50 (m, 2H), 3.59-3.06 (m, 7H), 2.35-2.10 (m, 2H), 2.11-0.63 (m, 9H) ppm. (No OH was observed).

PREPARATION 140 / V-Dibencil-1-. { 4-r2- (4-fluorophenoxy) ethoxy] cyclohexyl > methanamine This compound was prepared with 2- (. {4- [(dibenzylamino) methyl] cyclohexyl] oxy] ethanol by a procedure similar to that of Preparation 33. 1 H NMR (CDCl 3) d: 7.39-7.17 (m, 10H ), 7.02-6.77 (m, 4H), 4.17- 4.00 (m, 2H), 3.85-3.60 (m, 2H), 3.58-3.49 (m, 5H), 2.26-2.16 (m, 2H), 1.81- 1.11 (m, 9H) ppm.

PREPARATION 141 ( {4-r2- (4-Fluorophenoxy) -ethoxy-cyclohexyl} -methyl) -amine This compound was prepared with? /,? / - dibenzyl-1-. { 4- [2- (4-fluorophenoxy) ethoxy] cyclohexyl} methanamine by a procedure similar to that of Preparation 123. 1 H NMR (CDCl 3) d: 7.03-6.82 (m, 4H), 4.12-4.02 (m, 2H), 3.84-3.70 (m, 2H), 3.66-3.21 (m, 1H), 2.62-2.51 (m, 2H ), 2.17-0.84 (m, 9H) ppm. (NH2 was not observed).

PREPARATION 142 ? /,? / - Dibenzyl-1-. { c / s-4-f2- (2-fluorophenoxy) et.p.cyclohexyl} methanamine This compound was prepared with 2-. { c / s-4- [(d-benzylamino) methyl] cyclohexyl} ethanol and 2-fluorophenol by a procedure similar to that of Preparation 33. 1 H NMR (CDCl 3) d: 7.45-6.81 (m, 14 H), 4.00-3.91 (m, 2 H), 3.51 (s, 4 H), 2.28 (d , J = 7.6 Hz, 2H), 1.93-0.94 (m, 12H) ppm.

PREPARATION 143 Hydrochloride ((c / 's-4-r2- (2-fluorophenoxy) ethycyclohexyl} methyl) amine This compound was prepared with? /, / V-dibenzyl-1-. { c / s-4- [2- (2-fluorophenoxy) etl] cyclohexyl} methanamine by a procedure similar to that of Preparation 123. 1 H NMR (DMSO-de) d: 8.04 (a, 3 H), 7.26-7.06 (m, 3 H), 7.00-6.87 (m, 1 H), 6.06 (t, J = 6.1 Hz, 2H), 2.74 (d, J = 7.3 Hz, 2H), 1.88-1.29 (m, 12H) ppm. PREPARATION 144 Benzyl (benzyl) benzyl (benzyl) benzyl (benzyl) carbamic acid This compound was prepared with. { [cis-4- (hydroxymethyl) cyclohexyl] methyl} Benzyl carbamate and 2-fluorophenol by a procedure similar to that of Preparation 33. 1 H NMR (CDCl 3) d: 7.44-7.22 (m, 5H), 7.14-6.81 (m, 4H), 5.10 (s, 2H), 4.85-4.68 (m, 1 H), 3.96-3.82 (m, 2H), 3.24-3.11 (m, 2H), 2.14-1.19 (m, 10H) ppm.

PREPARATION 145 H2N! YU ( { c / s-4-r (2-Fluorophenoxy) metipciclohexyl.) methyl) amine This compound was prepared with benzyl ( { Cis-4 - [(2-fluorophenoxy) methyl] cyclohexyl) methyl) carbamate by a procedure similar to that of Preparation 79. MS (ESI): 237.10 (M + Hf PREPARATION 146 Carbamate of benzyl ((c / 's-4-f (-fluorophenoxy)) methyclocyclohexyl} methyl) carbamate This compound was prepared with. { [cis-4- (hydroxymethyl) cyclohexyl] methyl} Benzyl carbamate and 3-fluorophenol by a procedure similar to that of Preparation 33. 1 H NMR (CDCl 3) d: 7.37-7.30 (m, 5H), 7.26-7.19 (m, 1 H), 6.68-6.58 (m, 3H ), 5.10 (s, 2H), 4.80-4.72 (m, 1 H), 3.84-3.81 (m, 2H), 3.20-3.15 (m, 2H), 2.13-1.85 (m, 1 H), 1.84-1.30 (m, 9H) ppm. MS (ESI): 372.01 (M + Hf PREPARATION 147 ( { c / s-4-f (3-Fluorophenoxy) methyclohexyl} methyl) amine This compound was prepared with benzyl (. {Cc / s-4 - [(3-fluorophenoxy) methyl] cyclohexyl] methyl] carbamate by a procedure similar to that of Preparation 79. 1 H NMR (CDCl 3 ) d: 7.25-7.13 (m, 1 H), 6.88-6.41 (m, 3H), 3.85-3.81 (m, 2H), 2.48-2.85 (m, 2H), 2.29-1.87 (m, 1 H), 1.84-1.02 (m, 9H) ppm. (NH2 was not observed). MS (ESI): 238.15 (M + Hf PREPARATION 148 ( { c / s-4-r (Dibenzylamino) methyncyclohexyl> methyl) diethyl malonate To a stirred mixture of diethyl malonate (1.1 g, 7.1 millimoles) in DMF (15 ml) was added sodium hydride (0.28 g, 7.1 mmol) at 0 ° C. After stirring for 15 minutes, methane sulfonate was added. { c / 's-4 - [(dibenzylamino) methyl] cyclohexyl} methanol (2.7 g, 6.7 mmol) in DMF (5 ml) and the mixture was heated at 120 ° C for 1 day. The mixture was cooled, quenched with saturated aqueous NaHCO3 and extracted with AcOEt. The organic layer was washed with H2O and brine, dried over MgSO and concentrated. The residue was purified by column chromatography on silica gel (hexane: AcOEt = 7: 1) to give the title compound (0.38 g). 1 H NMR (CDCl 3) d: 7.42-7.17 (m, 10 H), 4.17 (c, J = 7.2 Hz, 4 H) 3.50 (s, 4 H), 3.31 (t, J = 7.7 Hz, 1 H), 2.27 (d , J = 7.5 Hz, 2H), 1.95-1.27 (m, 10H), 1.25 (t, J = 7.2 Hz, 6H), 1.10-0.90 (m, 2H) ppm. MS (ESI): 466.14 (M + Hf PREPARATION 149 Acid 3- (c / s-4-r (dibenzylamino) metipciclohexil) propanóico A mixture of diethyl (. {C.sub./ s-4- [(dibenzylamino) methyl] cyclohexyl.) Methyl) malonate (0.38 g, 0.82 mmol) and 2 N aqueous HCl (4 ml) in acetic acid (4 ml. ) was stirred at 120 ° C for 3 days. The mixture was concentrated and dried in vacuo to give the title compound (0.38 g). MS (ESI): 366.14 (M + Hf, 364.15 (M-H) "PREPARATION 150 3-. { c / s-4-f (Dibenzylamino) methyncyclohexyl} propan-1-ol This compound was prepared with 3- acid. { c / s-4- [(dibenzylamino) methyl] cyclohexyl} propanic by a procedure similar to that of Preparation 103. 1 H NMR (CDCl 3) d: 7.43-7.17 (m, 10 H), 3.67-3.50 (m, 2 H), 3.50 (s, 4H), 2.27 (d, J = 7.5 Hz, 2H), 1.95-0.70 (m, 14H) ppm. (No OH was observed). MS (ESI): 352.14 (M + Hf PREPARATION 151 / V, / V-Dibertil-1-fc / 's-4- (3-phenoxypropyl) cyclohexylmethanamine This compound was prepared with 3-. { c / s-4- [(dibenzylammon) methyl] cyclohexyl} propan-1-ol by a procedure similar to that of Preparation 33.

H NMR (CDCb) d: 7.43-7.16 (m, 12H), 6.97-6.80 (m, 3H), 3.88 (t, J = 6.8 Hz, 2H), 3.51 (s, 4H), 2.34-2.25 (m, 2H), 1.96-0.70 (m, 14H) ppm. MS (ESI): 428.19 (M + Hf PREPARATION 152 . { [c / s-4- (3-Phenoxypropyl) cyclohexylmethyl} amine This compound was prepared with? , / V-dibenzy-1- [c / s-4- (3-phenoxypropyl) cyclohexyl] methanamine by a procedure similar to that of Preparation 103. MS (ESI): 248.17 (M + Hf PREPARATION 153 Dibenzyl (c / s-4-F (4-fluorophenoxy) methylcyclohexyl) methyl) amine This compound was prepared with. { c / s-4- [(dibenzylamino) methyl] cyclohexyl} methanol (1.5 g, 4.6 millimoles) and 4-fluorophenol (570 mg, 5.1 millimoles) by a procedure similar to that of Preparation 104 as a white solid (1.9 g, quantified). 1 H NMR (CDCU) 6: 7.38-7.21 (m, 10H), 6.97-6.91 (m, 2H), 6.79-6.74 (m, 2H), 3.62 (d, J = 6.8 Hz, 2H), 3.51 (s, 4H), 2.30 (d, J = 7.3 Hz, 2H), 1.85-1.23 (m, 10H) ppm.

PREPARATION 154 ( { C / s-4-R (4-fluorophenoxy) methyl] cyclohexyl} methyl) amine hydrochloride This compound was prepared with dibenzyl ( {c / s-4 - [(4-fluorophenoxy) methyl] cyclohexyl} methyl) amine (1.9 g, 4.7 mmol) by a procedure similar to that of Preparation 105 in the form of a white solid (543 mg, 43%). 1 H NMR (DMSO-de) d: 7.96-7.79 (m, 2H), 7.14-7.08 (m, 2H), 6.97-6.92 (m, 2H), 3.86 (d, J = 5.4 Hz, 2H), 2.76 ( d, J = 5.4 Hz, 2H), 1.91-1.79 (m, 2H), 1.51-1.46 (m, 8H) ppm.

PREPARATION 155 Carbamate of benzyl (fc s-4-r (3-methoxyphenoxymethylcyclohexyl) methyl) carbamate This compound was prepared with. { [cis-4- (hydroxymethyl) cyclohexyl] methyl} Benzyl carbamate and 3-methoxyphenol by a procedure similar to that of Preparation 33. 1 H NMR (CDCl 3) d: 7.41-7.29 (m, 5H), 7.17 (t, J = 8.1 Hz, 1H), 6. 53-6.43 (m, 3H), 5.16 (s, 2H), 4.80-4.67 (1H, m), 3.81 (d, J = 6.9 Hz, 2H), 3.79 (s, 3H), 3.17 (d, J = 6.6 Hz, 2H), 2.21-1.90 (m, 1H), 1.78-1.30 (m, 9H) ppm. MS (ESI): 384.17 (M + Hf PREPARATION 156 ( { c / s-4-f (3-Methoxyphenoxy) met.p.-cyclohexyl} methyl) amine This compound was prepared with benzyl ( { Cis-4 - [(3-methoxyphenoxy) methyl] cyclohexyl) methyl) carbamate by a procedure similar to that of Preparation 79. 1 H NMR (DMSO-de) d: 7.16 (t, J = 8.3 Hz, 1 H), 6.56-6.42 (m, 3 H), 3.84 (d, J = 6.9 Hz, 2 H), 3.72 (s, 3 H), 2.47-2.45 (m, 2H), 1.97-1.82 (m, 1 H), 1.61-1.27 (m, 9H) ppm. No NH2 was observed. MS (ESI): 250.13 (M + Hf PREPARATION 157 Diethyl But-3-en-1-yir2- (4-fluorophenoxy) ethyl malonate To a solution of diethyl but-3-en-1-ylmalonate (2.00 g, 9.3 mmol) in DMF was added NaH (448.0 mg, 11.2 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes. Then 1- (2-bromoethoxy) -4-fluorobenzene was added and the mixture was stirred at room temperature for 10.5 hours. The reaction mixture was quenched with water and the mixture was extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on silica gel (hexane: AcOEt = 200: 1 to 20: 1) to give the title compound (2.2 g). 1 H NMR (CDCl 3) d: 7.00-6.90 (m, 2H), 6.80-6.76 (m, 2H), 5.85-5.67 (m, 1 H), 5.07-4.96 (m, 2H), 4.30-4.20 (m, 4H), 4.05-3.95 (m, 2H), 2.45-2.40 (m, 2H), 2.15-1.92 (m, 4H), 1.29-1.15 (m, 6H) PREPARATION 158 2-F2- (4-fluorophenoxy)? Tinhex-5-enoate ethyl To a solution of diethyl but-3-en-1-yl [2- (4-fluorophenoxy) ethyl] malonate (2.21 g, 6.27 mmol) in DMSO (20 mL) and H2O (0.11 mL), LiCl was added. (798 mg, 18.8 mmol) and the mixture was stirred at 150 ° C for 2 days. Then, the mixture was cooled to room temperature and poured into AcOEt / H2O. The mixture was extracted twice with AcOEt and the combined organic layers were washed with brine. The organic layer was dried over Na2SO, filtered and evaporated. The crude product was purified by column chromatography on silica gel (hexane: AcOEt = 100: 1-20: 1) to give the title compound (1.24 g, 4.22 mmol) H NMR (CDCl 3) d: 7.00-6.90 (m, 2H), 6.83-6.75 (m, 2H), 5.86- 5.70 (m, 1 H), 5.10-4.95 (m, 2H), 4.20-4.10 (m, 2H), 4.04-3.85 (m, 2H) ), 2.72-2.55 (m, 1 H), 2.20-1: 52 (m, 6H), 1.24 (t, J = 6.8 Hz, 3H) ppm.

PREPARATION 159 2-r2- (4-Fluorophenoxy) ethene-5-en-1-ol To a suspension of LAH (167.7 mg, 4.42 mmol) in THF (30 mL) was added a solution of ethyl 2- [2- (4-fluorophenoxy) ethyl] hex-5-enoate (1.24 g, 4.42 mmol). in THF (15 ml) at 0 ° C. Then, the mixture was stirred at room temperature for 5.5 hours. The reaction was quenched with Na 2 SO 4"10H 2 O (2.0 g, 6.21 mmol) and KF (0.25 g, 43.0 mmol). The mixture was stirred at room temperature overnight. The mixture was filtered through a pad of celite and the filtrate was evaporated to give the title compound (1.03 g). 1 H NMR (CDCl 3) d: 7.00-6.94 (m, 2H), 6.86-6.81 (m, 2H), 5.89- 5.70 (m, 1H), 5.10-4.90 (m, 2H), 4.10-3: 95 (m , 2H), 3.70-3.55 (m, 2H), 2.20-2.05 (m, 2H), 1.90-1.72 (m, 4H), 1.60-1.40 (m, 1 H) ppm. (It was not observed -OH.) PREPARATION 160 4- (4-Fluorophenoxy) -2- (2-oxiran-2-ylethyl) butan-1-ol To a solution of 2- [2- (4-fluorophenoxy) ethyl] hex-5-en-1-ol (1.03 g, 4.32 mmol) in CH2Cl2 (40 mL), NaHCO3 (942.9 mg, 11.2 mmol) was added. and mCPBA (1.40 g, 8.11 mmol) at 0 ° C and the mixture was stirred at 0 ° C for 30 minutes. Then, the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous Na2S2O3 and the mixture was stirred for 1 hour. The mixture was extracted 3 times with CH2CI2 and the combined organic layers were washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound (1.11 g, 43.6 mmol). 1 H NMR (CDCl 3) d: 7.01-6.94 (m, 2H), 6.90-6.80 (m, 2H), 4.15-3.96 (m, 2H), 3.70-3.58 (m, 2H), 2.96-2.90 (m, 1 H), 2.80-2.74 (m, 1 H), 2.53-2.47 (m, 1 H), 1.90-1.78 (m, 4H), 1.70-1.45 (m, 3H) ppm. (No OH was observed.) PREPARATION 161 . { 5-F2- (4-Fluorophenoxy) ethylethetrahydro-2H-pyran-2-ylmethanol To a solution of 4- (4-fluorophenoxy) -2- (2-oxirane-2-ylethyl) butan-1-ol (1.11 g, 4.37 mmol) in CH2Cl2 (130 mL), p-TsOH = H2O (12.4 mg, 0.066 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous NaHC 3 3 and the mixture was extracted with CH 2 Cl 2. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on silica gel (hexane-AcOEt 9: 1-3: 2) to give the title compound (898.6 mg). 1 H NMR (CDCl 3) d: 7.05-6.90 (m, 2H), 6.86-6.77 (m, 2H), 4.10-3.80 (m, 3H), 3.70-3.10 (m, 4H), 2.10-1.70 (m, 3H) ), 1.60-1.20 (m-, 4H) ppm. (It was not observed -OH.) PREPARATION 162 2- (Azidomethyl) -5-f2- (4-fluorophenoxy) etintetrahydro-2-pyran This compound was prepared with benzyl. { 5- [2- (4- fiuorophenoxy) ethyl] tetrahydro-2H-pyran-2-yl} methanol by a procedure similar to that of Preparation 67. 1 H NMR (CDCl 3) d: 7.00-6.93 (m, 2H), 6.85-6.79 (m, 2H), 4.10-3.85 (m, 3H), 3.70-2.89 (m , 4H), 2.10-1.70 (m, 3H), 1.60-1.10 (m, 4H) ppm.

PREPARATION 163 ( {5-r2- (4-Fluorophenoxy) ethyltrahydro-2H-pyran-2-yl> methyl) amine This compound was prepared with 2- (azidomethyl) -5- [2- (4-fluorophenoxy) ethyl] tetrahydro-2-pyran by a procedure similar to that of Preparation 8. 1 H NMR (CDCl 3) d: 7.05- 6.90 (m, 2H), 6.86-6.75 (m, 2H), 4.06- 3.80 (m, 3H), 3.49 (s, 2H), 2.75-2.68 (m, 2H), 2.15-1.10 (m, 7H) ppm . MS (ESI): 254.17 (M + Hf PREPARATION 164 4- (4"Methoxybenzylidene) ethyl cyclohexanecarboxylate A mixture of NaH (60%, 1.0 g, 25 mmol) and DMSO (20 ml) was stirred for 2 hours at 80 ° C under a nitrogen atmosphere. After cooling to room temperature, diethyl 4-methoxybenzyl phosphate (5.2 g, 20 mmol) was added to the mixture. After 1 hour, ethyl 4-oxo-cyclohexanecarboxylate (3.4 g, 20 mmol) was added to the mixture and the reaction mixture was stirred for 3 hours at 60 ° C. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to yield the title compound (0.39 g) 1 H NMR (CDCl 3) d: 7.12 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.22 (s, 1 H), 4.13 (c, J = 7.1 Hz, 2H), 3.81 (s, 3H), 2.90-2.78 (m, 1 H), 2.57 -1.47 (m, 8H), 1.26 (t, J = 7.1 Hz, 3H) ppm.

PREPARATION 165 c / s-4- (4-Methoxy in ethyl cyclohexanecarboxylate A mixture of ethyl 4- (4-methoxybenzylidene) cyclohexanecarboxylate (0.39 g, 1.4 mmol) and 10% Pd on C (40 mg) in methanol (20 ml) was stirred for 4 hours in a hydrogen atmosphere (4 kg. / cm2). After filtration through a celite pad, the filtrate was evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 12: 1) to yield the title compound (0.29 g) 1 H NMR (CDCl 3) d: 7.06 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.15 (c, J = 7.1 Hz, 2H), 3.79 (s, 3H), 2.57-2.43 (m, 3H), 2.10-1.92 (m, 2H), 1.69 -1.17 (m, 10H) ppm.

PREPARATION 166 H0Xx? Xc rc / s-4- (4-methoxybenzyl) cyclohexylmethanol This compound was prepared with ethyl c / s-4- (4-methoxybenzyl) cyclohexanecarboxylate by a procedure similar to that of Preparation 121. 1 H NMR (CDCl 3) d: 7.06 (d, J = 8.7 Hz, 2H), 6.82 ( d, J = 8.7 Hz, 2H), 3.79 (s, 3H), 3.61-3.54 (m, 2H), 2.52 (d, J = 7.6 Hz, 2H), 1.81-1.20 (m, 9H) ppm. (It was not observed -OH.) PREPARATION 167 1-. { fcis-4- (Azidomethyl) cyclohexyl] methyl} -4-methoxybenzene This compound was prepared with [c / s-4- (4-methoxybenzyl) cyclohexyl] methanol by a procedure similar to that of Preparation 67. 1 H NMR (CDCl 3) d: 7.06 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.25 (d, J = 7.3 Hz, 2H), 2.52 (d, J = 7.6 Hz, 2H), 1.83-1.67 (m, 2H) , 1.62-1.22 (m, 7H) ppm.

PREPARATION 168 . { [c / 's-4- (4-Methoxybenzyl) cyclohexylmethyl} amine This compound was prepared with 1-. { [C / S-4- (Azidomethyl) cyclohexyl] methyl} -4-methoxybenzene by a procedure similar to that of Preparation 8. MS (ESI): 234.15 (M + Hf PREPARATION 169 Methyl 3- (2-phenylethoxy) cyclohexanecarboxylate To a stirred mixture of methyl 3-oxocyclohexanecarboxylate (0.52 g, 3.3 mmol) (J. Am. Chem. Soc. 1987, 109, 3493-3494.) And phenethyl alcohol (0.48 ml, 4.0 mmol) in CH 2 Cl 2 (5 ml. ) was added bismuth chloride (1) (0.53 g, 1.7 mmol) and triethylsilane (1.2 ml, 7.3 mmol) at room temperature. After stirring for 1 day at room temperature, the mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (hexane-AcOEt 10: 1) to give the title compound (0.77 g) as a cis-trans mixture (1: 1). 1 H NMR (CDCl 3) d: 7.35-7.15 (m, 5H), 3.77-3.60 (m, 2H), 3.67 (s, 3H), 3.35-3.15 (m, 0.5H), 2.87 (t, J = 7.4 Hz , 2H), 2.73-2.58 (m, 0.5H), 2.37-1.10 (m, 9H) ppm.

PREPARATION 170 r3- (2-Phenylethoxy) cyclohexylmethanol This compound was prepared as a cis-trans (1: 1) mixture with methyl 3- (2-phenylethoxy) cyclohexanecarboxylate by a procedure similar to that of Preparation 121. 1 H NMR (CDCl 3) d: 7.35-7.16 (m, 5H), 3.74-3.17 (m, 5H), 2.87 (t, J = 7.3 Hz, 2H), 2.15-0.80 (m, 9H) ppm. (It was not observed -OH.) PREPARATION 171 c / s-3- (Azidomethyl) cyclohexyl 2-phenylethyl ether This compound was prepared with [3- (2-phenylethoxy) cyclohexyl] methanol by a procedure similar to that of Preparation 67. 1 H NMR (CDCl 3) d: 7.35-7.16 (m, 5H), 3.68 (t, J = 7.3 Hz , 2H), 3.30-3.15 (m, 1H), 3.16 (d, J = 6.6 Hz, 2H), 2.87 (t, J = 7.3 Hz, 2H), 2.13-1.96 (m, 2H), 1.88-1.50 ( m, 3H), 1.33-0.80 (m, 4H) ppm.

PREPARATION 172 (r (c / s-3- (2-Phenylethoxy) cyclohexylmethyl) amine This compound was prepared with c / s-3- (azidomethyl) cyclohexyl 2-phenylethyl ether by a procedure similar to that of Preparation 8. MS (ESI): 234.25 (M + Hf PREPARATION 173 4- (Benzylidene) ethyl cyclohexanecarboxylate This compound was prepared with diethyl 4-methoxybenzylphosphate by a procedure similar to that of Preparation 163. 1 H NMR (CDCl 3) d: 7.37-7.12 (m, 5H), 6.29 (s, 1H) , 4.13 (c, J = 7.1 Hz, 2H), 2.92-2.79 (m, 1H), 2.59-2.36 (m, 2H), 2.32-2.16 (m, 1 H), 2.14- 1.91 (m, 2H), 1.77-1.46 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H) ppm.

PREPARATION 174 c / s-4-benzylcyclohexanecarboxylate ethyl This compound was prepared with ethyl 4- (benzylidene) cyclohexanecarboxylate by a procedure similar to that of Preparation 164. 1 H NMR (CDCl 3) d: 7.34-7.06 (m, 5H), 4.15 (c, J = 7.1 Hz, 2H) , 2.60-2.42 (m, 3H), 2.10-1.88 (m, 2H), 1.75-1.13 (m, 10H) ppm.

PREPARATION 175 (c / s- -Benzycyclohexyl) methanol This compound was prepared with ethyl c-s-4-benzylcyclohexanecarboxylate by a procedure similar to that of Preparation 121. 1 H NMR (CDCl 3) d: 7.36-7.07 (m, 5H), 3.79-3.49 (m, 3H), 2.64 -2.49 (m, 2H), 1.93-1.18 (m, 10H) ppm. (It was not observed -OH.) PREPARATION 176 1-. { rc / s-4- (Azidomethyl) cyclohexypmethyl} benzene This compound was prepared with (c / s-4-benzylcyclohexyl) methanol by a procedure similar to that of Preparation 67. 1 H NMR (CDCl 3) d: 7.35-7.19 (m, 5H), 3.26 (d, J = 7.3 Hz, 2H), 2.58 (d, J = 7.6 Hz, 2H), 1.88-1.69 (m, 2H), 1.63-1.19 (m, 7H) ppm.

PREPARATION 177 . { fc / s-4- (4-Benzyl) cyclohexylmethyl > amine This compound was prepared with 1-. { [C / S-4- (Azidomethyl) c-chlorhexyl] methyl} benzene by a procedure similar to that of Preparation 8. MS (ESI): 244.15 (M + Hf PREPARATION 178 (4R) -3-Hex-5-enoyl-4-isopropyl-1,3-oxazolidin-2-one To a solution of hex-5-enoic acid (11.24 g, 87.0 mmol), (4R) -4-isopropyl-1,3-oxazolidin-2-one (12.91 g, 113.1 mmol) and DMAP (1.06 g, 8.70 mmol) ) in CH2Cl2, DCC (23.33 g, 113.1 mmol) was added at 0 ° C and the mixture was stirred at 0 ° C for 15 minutes. Then, the mixture was stirred at room temperature overnight and filtered through a pad of celite and the filtrate was washed with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on silica gel (hexane-AcOEt 20: 1-10: 1) to give the title compound (16.60 g, 73.7 mmol). 1 H NMR (CDCl 3) d: 5.90-5.70 (m, 1 H), 5.10-4.95 (m, 2 H), 4.50-4.42 (m, 1 H), 4.35-4.15 (m, 2 H), 3.10-2.80 (m , 2H), 2.46-2.30 (m, 1 H), 2.20- 2.08 (m, 2H), 1.90-1.68 (m, 2H), 0.92 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H) ppm PREPARATION 179 (4R) -3-. { (2S) -2-r (Benzyloxy) metinhex-5-enoyl} -4-isopropyl-1,3-oxazolidin-2-one To a solution of (4R) -3-hex-5-enoyl-4-isopropyl-1,3-oxazolidin-2-one (16.60 g, 73.7 mmol) in CH2Cl2, TiCl4 (8.89 mL, 81.1 mmol) was added. at 0 ° C and the mixture was stirred at 0 ° C for 5 minutes. To the resulting suspension was added dusopropylethylamine (14.1 ml, 81.1 mmol) and the mixture was stirred at 0 ° C for 1 hour. Benzylchloromethyl ether (23.1 ml, 165.8 mmol) was added dropwise and the mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 1.5 hours and quenched by the careful addition of saturated aqueous NH4CI. The mixture was extracted twice with CH2CI2 and the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on silica gel (hexane: AcOEt = 20: 1 to 11: 2) to give the title compound (18.74 g, 54.3 mmol). 1 H NMR (CDCl 3) d: 7.38-7.21 (m, 5H), 5.86-5.68 (m, 1 H), 5.05-4.90 (m, 2H), 4.57-4.40 (m, 3H), 4.35-4.11 (m, 3H), 3.77-3.60 (m, 2H), 2.42-2.25 (m, 1 H), 2.15-2.00 (m, 2H), 1.94-1.78 (m, 1 H), 1.65-1.50 (m, 1 H) , 0.88 (d, J = 7.1 Hz, 3H), 0.78 (d, J = 6.9 Hz, 3H) ppm.

PREPARATION 180 (2?) - 2-r (Benzyloxy) metillhex-5-en-1-ol To a suspension of LAH (6.18 g, 162.9 mmol) in THF (250 mL) was added a solution of (4R) -3-. { (2S) -2 - [(benzyloxy) methyl] hex-5-enoyl} -4-isopropyl-1,3-oxazolidin-2-one (18.74 g, 54.3 mmol) in THF (50 ml) at 0 ° C. Then, the mixture was stirred at 0 ° C for 30 minutes. The reaction was quenched with Na 2 SO 4 0H 2 O (26.24 g, 81.3 mmol) and KF (3.30 g, 56.7 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was filtered through a pad of celite and the filtrate was evaporated to give the crude product. The crude product was then purified by column chromatography on silica gel (hexane: AcOEt = 4: 1) to give the title compound (10.51 g, 47.7 mmol). 1 H NMR (CDCl 3) d: 7.40-7.23 (m, 5H), 5.90-5.68 (m, 1 H), 5.06-4.92 (m, 2H), 4.57-4.48 (m, 2H), 3.81-3.58 (m, 3H), 3.51-3.45 (m, 1 H), 2.59- 2.49 (m, 1 H), 2.13-2.03 (m, 2H), 1.98-1.82 (m, 1 H), 1.50-1.29 (m, 2H) ppm.

PREPARATION 181 . { (5S) -5 - [(Benzyloxy) methyltetrahydro-2H-pyran-2-yl} methanol To a solution of (2R) -2 - [(benzyloxy) methyl] hex-5-en-1-ol (10.51 g, 47.7 mmol) in CH2Cl2 (300 mL) was added NaHCO3 (16.03 g, 190.8 mmol) and mCPBA (23.85 g, 138.2 mmol) at 0 ° C. Then, the mixture was stirred at room temperature for 2 days. The reaction was quenched with saturated aqueous Na 2 S 2 3 3 at 0 ° C and the mixture was stirred at room temperature for 1.5 hours. The mixture was separated and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO and filtered. To the obtained solution was added p-TsOH (907.3 mg, 4.77 mmol). The mixture was stirred at 55 ° C for 1.75 hours. The mixture was cooled to room temperature. The reaction mixture was quenched with saturated aqueous NaHCO 3 and the mixture was extracted with CH 2 Cl 2. The combined organic layers were dried over Na2SO4, and the crude product was purified by column chromatography on silica gel (hexane: AcOEt 3: 1 to 3: 2) to give the title compound (5.61 g, 23.7 mmol). 1 H NMR (CDCl 3) d: 7.45-7.15 (m, 5H), 4.60-4.42 (m, 2H), 4.20-3.97 (m, 1 H), 3.73-3.10 (m, 6H), 2.10-1.20 (m, 5H) ppm. (No OH was observed.) PREPARATION 182 (5S) -2- (Azidomethyl) -5-r (benzyloxy) methyl] tetrahydro-2H-pyran This compound was prepared with. { (5S) -5- [(benzyloxy) methyl] tetrahydro-2H-pyran-2-yl} methanol by a procedure similar to that of Preparation 67. 1 H NMR (CDCl 3) d: 7.40-7.20 (m, 5H), 4.62-4.42 (m, 2H), 4.18-3.97 (m, 1 H), 3.73-3.10 ( m, 6H), 2.00-1.82 (m, 2H), 1.75-1.20 (m, 3H) ppm.

PREPARATION 183 (f (5S) -5-r (Benzyl-1-methyl-1-tetrahydro-2H-pyran-2-yl.) methylamino This compound was prepared with (5S) -2- (azidomethyl) -5 - [(benzyloxy) methyl] tetrahydro-2H-pyran by a procedure similar to that of Preparation 8. 1 H NMR (CDCl 3) d: 7.36-7.26 (m, 5H), 4.60-4.47 (m, 2H), 4.18-3.97 (m, 1 H), 3.30-3.48 (m, 2H), 3.30-3.14 (m, 2H), 2.71-2.66 (m, 3H) ), 2.00-1.22 (m, 5H) ppm.

PREPARATION 184 (((5S) -5-r (benzyloxy) methyl-tert-butyl-2-methyl-2-yl) methyl) tertiary-hydrocarbamate The reaction mixture of (. {(5S) -5 - [(benzyloxy) methyl] tetrahydro-2H-pyran-2-yl.} Methyl) amine (5.51g, 21.1 mmol), Boc2O (5.06 g, 23.2 millimoles) and Et 3 N (8.82 mL, 63.3 mmol) in CH 2 Cl 2 was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO, filtered and evaporated. The crude product was purified by column chromatography on silica gel (hexane-AcOEt 9: 1-17: 3) to give the title compound (7.58 g, 22.6 mmol). 1 H NMR (CDCl 3) d: 7.39-7.24 (m, 5H), 4.98-4.86 (m, 1 H), 4.60-4.40 (m, 2H), 4.12-3.92 (m, 1H), 3.70-3.08 (m, 5H) 3.06-2.86 (m, 1 H), 2.00-1.18 (m, 14H) ppm.

PREPARATION 185 . { r (5S) -5- (hydroxymethyl) tetrahydro-2H-pyran-2-ylmethyl} tert-butyl carbamate This compound was prepared with tert-butyl (3. (5S) -5- [(benzyloxy) methyl] tetrahydro-2H-pyran-2-yl.] methyl) carbamate by a procedure similar to of Preparation 3. 1 H NMR (CDCl 3) d: 4.95 (a, 1 H), 4.12-4.00 (m, 111), 3.90-3.65 (m, 1 H), 3.60-3.10 (m, 4 H), 3.08-2.92 (m, 1 H), 1.93-1.13 (m, 14H) ppm. (No OH was observed.) PREPARATION 186 2 - [(4-Chlorophenoxy) methyphex-5-en-1-ol This compound was prepared with 2-but-3-en-1-ylpropan-1,3-diol and 4-chlorophenol by a procedure similar to that of Preparation 104. 1 H NMR (CDCl 3) d: 7.26-7.17 (m, 2H ), 6.87-6.74 (m, 2H), 5.92-5.72 (m, 1H), 5.09-4.97 (m, 2H), 4.04-3.94 (m, 2H), 3.87-3.65 (m, 2H), 2.20-2.00 (m, 3H), 1.65-1.45 (m, 2H) ppm. (No OH was observed.) PREPARATION 187 2-r (4-Chlorophenoxy) metip-4-oxirane-2-ylbutan-1-ol This compound was prepared with 2 - [(4-chlorophenoxy) methyl] hex-5-en-1-ol by a procedure similar to that of Preparation 40. 1 H NMR (CDCl 3) d: 7.32-7.15 (m, 2H), 6.90-6.72 (m, 2H), 4.06-3.96 (m, 2H), 3.85-3.66 (m, 2H), 3.00-2.90 (m, 1H), 2.78 (t, J = 4.5 Hz, 1 H), 2.13 -1.96 (m, 1H) 1.94-1.50 (m, 5H) ppm. (No OH was observed.) PREPARATION 188 (5-r (4-Chlorophenoxy-2-pyran-2-yl> methanol This compound was prepared with 2 - [(4-chlorophenoxy) methyl] -4-oxiran-2-ylbutan-1-ol by a procedure similar to that of Preparation 109. 1 H NMR (CDCl 3) d: 7.30-7.19 (m, 2H), 6.90-6.76 (m, 2H), 4.25-3.24 (m, 7H), 2.14-1.34 (m, 5H) ppm. (It was not observed -OH.) PREPARATION 189 2- (Azidomethyl) -5-r (4-chlorophenoxy) metyr | tetrahydro-2-pyran This compound was prepared with. { 5 - [(4-chlorophenoxy) methyl] tetrahydro-2H-pyrn-2-yl} methanol by a procedure similar to that of Preparation 67. 1 H NMR (CDCl 3) d: 7.40-7.17 (m, 2H), 6.95-6.72 (m, 2H), 4.23-3.43 (m, 5H), 3.37-3.18 (m , 2H), 2.23-1.92 (m, 2H), 1.90-1.19 (m, 3H) ppm.

EXPERIMENTAL EXAMPLE The NR2B Binding Assay and the Dofetilide Binding Assay in Humans were performed using the method described above. The results of these studies are summarized in Table 1.

TABLE 1 Results of the NR2B Binding Assay and Dofetilide Binding Assay in Humans IC50: the concentration of the individual compound required to reduce the amount of ligand by 50%.

Claims (17)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (I): (D) or a pharmaceutically acceptable salt or solvate thereof, wherein: A and B simultaneously represent CH2 or O, with the proviso that A and B are not simultaneously O; Cy represents one of the following fX H Y Y XY H-l \ -fc? r ^ xx e px XJX JX X JXX optionally substituted with one to three groups selected from hydroxy, halogen, d-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1 alkylamino. 6 and amino; R1 and R2 are independently selected from hydroxy, halogen, C? -6 alkyl, C1-6 alkoxy, C-? 6 haloalkyl and C3-8 cycloalkyl; n represents a number from 0 to 4; X is hydrogen, hydroxy, halogen or C6 alkoxy; Y is oxy, thio, a 1 to 4 membered aiquilene, a 2 to 4 membered alkylene ether, a 2 to 4 membered alkylene thioether or an oxyethyleneoxy group, optionally substituted with 1 to 4 groups independently selected from hydroxy, halogen, C? -6 alkyl, C? -6 alkoxy and haloalkyl of d?; Z is CH or N; and p represents an integer from 0 to 5 when Z is CH or from 0 to 4 when Z is N, when p represents 2 or more, two of R2 can be taken together with the carbon atoms to which they are attached to form a ring cycloalkyl of 5 to 8 members.

2. The compound according to claim 1, further characterized in that A and B represent carbon atoms.

3. The compound according to claim 1, further characterized in that A represents O and B represents C.

4. The compound according to claim 1, further characterized in that A represents C and B represents O. 5.- The compound according to any one of claims 1 to 4, further characterized in that Cy is independently selected from 4-hydroxyphenyl, 1H-pyrazol-4-yl, 2-oxo-2,3-dihydro-1,3-benzoxazole-6 ilo and 2-hydroxy-5-pyridyl optionally further substituted. 6. The compound according to any of claims 1 to 5, further characterized in that Cy represents 4-hydroxyphenyl, optionally further substituted with fluorine or methyl. 7. The compound according to any of claims 1 to 6, further characterized in that n represents O. 8. The compound according to any of claims 1 to 7, further characterized in that R2 represents methoxy, chloro, fluoro or methyl. 9. The compound according to any of claims 1 to 8, further characterized in that p represents 0 to 2. 10. The compound according to any of claims 1 to 9, further characterized in that X is hydrogen or hydroxy. . 11. The compound according to any of claims 1 to 10, further characterized in that Y is selected from methylene, oxyethyleneoxy, oxymethylene, methyleneoxy, methenoxymethylene, ethyleneoxy, oxyethylene and oxy. 12. The compound according to any of claims 1 to 11, further characterized in that Y is in para position and in trans configuration with respect to X. 13. A compound of formula (I) selected from: 4-Hydroxy- ? / -. { [C / S-4- (Phenoxymethyl) cyclohexyl] methyl} benzamide; 4-Hydroxy- / V- ( {sup.c / s-4 - [(4-methoxy-phenoxy) methyl] cyclohexyl} methyl) benzamide; N-. { [cis-4- (benzyloxy) cyclohexyl] methyl} -4-hydroxybenzamide; N- ( { Cis-4 - [(4-chlorobenzyl) oxy] cyclohexyl] methyl) -4-hydroxybenzamide; N- ( { Cis-4 - [(3-chlorobenzyl) oxy] cyclohexyl] methyl) -4-hydroxybenzamide; 4-Hydroxy -? / -. { [c s-4- (4-methoxyphenoxy) cyclohexyl] methyl} benzamida; N-. { [cis-4- (4- Chlorophenoxy) cyclohexyl] methyl} -4-hydroxybenzamide; 4-Hydroxy -? / -. { [1-hydroxy-4- (phenoxymethyl) cyclohexyl] methyl} benzamide; ? / - ( { traps-4 - [(4-Fluorophenoxy) methyl] -1- hydroxycyclohexyl}. methyl) -4-hydroxybenzamide; ? - ( { traps-4 - [(3-Fluorophenoxy) methyl] -1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide; N- ( { Trans-4 - [(2- Fluorophenoxy) methyl] -1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide; A- ( { Trar / s-4- [(2,6-Difluorophenoxy) methyl] -1-hydroxycyclohexyl}. Methyl) -4-hydroxybenzamide; ? / - ( { traps-4 - [(3,5-Difluorophenoxy) methyl] -1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide; ? / - ( { traps-4 - [(3-Chlorophenoxy) mephyl] -1-hydroxy-cyclohexyl} -methyl) -4-hydroxybenzamide; / V- ( { Trarís-4 - [(4-Chlorophenoxy) methyl] -1-hydroxy-cyclohexyl} methyl) -4-hydroxybenzamide; 4-Hydroxy -? - ( { Tratra-1-hydroxy-4 - [(2-methylphenoxy) methyl] cyclohexyl} methyl) benzamide; 4-Hydroxy-A / - ( { Trar / s-1-hydroxy-4 - [(3-methylphenoxy) methyl] cyclohexyl} methyl) benzamide; 4-Hydroxy -? - ( { Tra? S-1-hydroxy-4 - [(4-methylphenoxy) methyl] cyclohexyl} methyl) benzamide; ? / -. { trar / s-4 - [(Bencllox!) metl] -1-hydroxycyclohexyl} methyl) -4-hydroxy-benzamide; ? / - [(tra-4-. {[[(2-Fluorobenzyl) oxy] methyl} -1-hydroxycyclohexyl) methyl] -4-hydroxybenzamide; ? / - [(trarís-4- { [(4-Fluorobenzyl) oxy] methyl.} -1-hydroxycyclohexyl) methyl] -4-hydroxybenzamide; 4-Hydroxy -? -. { [tra-ris-1-hydroxy-4- (2-phenoxyethyl) cyclohexyl] methyl} benzamida; ? / - ( { trans-4- [2- (2-Fluorophenoxy) ethyl] -1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide; N- (trar / s-4- [2- (3-Fluorophenoxy) ethyl] -1-hydroxycyclohexyl] methyl) -4-hydroxybenzamide; / V- ( { Tra / 7s-4- [2- (4-Fluorophenoxy) ethyl] -1-hydroxycyclohexyl}. Methyl) -4-hldroxybenzamide; N-. { [trans -4- (Benzyloxy) -1-hydroxycyclohexyl] methyl} -4- hldroxibenzamide; ? / -. { [trarís-4- (4-Chlorophenoxy) -1-hydroxycyclohexyl] methyl} -4- hydroxybenzamide; ? / -. { [c / s-4- (4-Chlorophenoxy) -1-hydroxylclohexyl] methyl} -4- hydroxybenzamide; ? / -. { [tra / s-4- (4-Chlorophenoxy) -1-hydroxycyclohexyl] methyl} -3- fluoro-4-hydroxybenzamide; ? / - [c / s-4- (4-Chlorophenoxy) -1-hydroxylcyclohexyl] meth} -3- fluoro-4-hydroxybenzamide; (+) - 4-hydroxy -? / -. { [5S- (phenoxymethyl) tetrahydro-2 - / - pyran-2S-yl] methyl} benzamide; (-) - 4-hydroxy -? / -. { [5f? - (phenoxymethyl) tetrahydro-2H-pyran-2 /? - il] methyl} benzamide; 4-hydroxy-A / -. { [5 S - (benzyloxymethyl) tetrahydro-2 - / - pyran-2 S -yl] methyl} benzamida; 4-hydroxy-? - [5f? - (benzyloxymethyl) tetrahydro-2 H -pyran-2-t-yl] methyl} benzamida; (-) - 4-Hydroxy -? / -. { [(3f?, 6S) -6- (phenoxymethyl) tetrahydro-2H-pyrn-3-yl] methyl} benzamide; (+) - 4-Hydroxy- / V - [(3S, 6 /?) - 6- (phenoxymethyl) tetrahydro-2H-pyrn-3-yl] methyl} benzamide; N- ( { Trans-4 - [(2-Fluorobenzyl) oxy] -1-hydroxycyclohexyl} methyl) -4-hydroxylbenzamide; 3-Fluoro-? / - ( { Trans -4- [2- (2-fluorophenoxy) ethyl] -1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide; trarís -? / -. { [4- (4-Chlorophenoxy) cyclohexyl] methyl} -3-fluoro-4-hydroxybenzamide; cis-N-. { [4- (4-Chlorophenoxy) cyclohexyl] methyl} 3-fluoro-4-hydroxybenzamide; N-. { [cis-4- (4-Fluorophenoxy) cyclohexyl] methyl} -4-hydroxybenzamide; 3-Fluoro- / V-. { [c / s-4- (4-fluorophenoxy) cyclohexyl] methyl} -4-Hydroxybenzamide; N- (trans -4- [2- (2-Fluorophenoxy) ethyl] -1-hydroxycyclohexyl] methyl) -1-pyrazol-4-carboxamide; 4- Hydroxy -? / -. { [c / s-4- (2-phenylethoxy) c] cyclohexyl] methyl} benzamida; 2-Fluoro-4-hydroxy -? / -. { [trans-1-hydroxy-4- (phenoxymethyl) cyclohexyl] methyl} benzamide; N- (trans -4- [(Benzyloxy) methyl] -1-hydroxycyclohexyl] methyl) -3-fluoro-4-hydroxybenzamide; N- (cis-4 - [(Benzylloxy) methyl] cyclohexyl] methyl) -4-hydroxybenzamide; 3-Fluoro-4-hydroxy -? / -. { [trar > s-1-hydroxy-4- (phenoxymethyl) cyclohexyl] methyl} benzamlda; 3-Fluoro-4-hydroxy-? / -. { [traA7s-1-hydroxy-4- (2-phenoxyethyl) cyclohexyl] methyl} benzamida; 3-Fluoro -? / - [(trarís-4. {[[(4-fluorobenzyl) oxy] methyl} -1-hydroxycyclocloxyl) methyl] -4-hydroxybenzamide; 3-Fluoro-? - (. {-trans-4 - [(2-fluorophenoxy) -methyl] -1- hydroxycyclohexyl} - methyl) -4-hydroxybenzamide; 3-Fluoro- / V- ( { Trans-4 - [(4-fluorophenoxy) methyl] -1-hydroxycyclohexyl} methyl) -4-hydroxybenzamide; 4-Hydroxy- / V- [(trar? S-1-hydroxy-4. {[[(5-methylpyridin-2-yl) oxy] methyl.}. Cyclohexyl) methyl] benzamide; N- [(tra-ris-4-Benzyl-1-hydroxycyclohexyl) methyl] -4-hydroxybenzamide; 3-Fluoro- / V- [(traps-4. {[[(2-fluorobenzyl) oxy] methyl} -1-hydroxycyclohexyl) methyl] -4-hydroxybenzamide; 6-Hydroxy- / V-. { [c s-4- (2-phenetoxy) cyclohexyl] methyl} nicotinamida; ? / -. { [c / s-4- (2-Phenylethoxy) c -clohexyl] meth} -1 - / - pyrazole-4-carboxamide; N-. { [cis-4- (phenoxymethyl) cyclohexyl] meth} -1H-pyrazole-4-carboxamide; N-. { [cis -4- (2-Phenoxyethyl) cyclohexyl] methyl-1-pyrazol-4-carboxamide; N- ( { Cis-4 - [(3-Fluorophenoxy) methyl] cyclohexyl} methyl) -1H-pyrazole-4-carboxamide; N- ( { Cis-4 - [(4-Fluorophenoxy) methyl] cyclohexyl] methyl) -1 - / - pyrazole-4-carboxamide; ? - ( { (2f?, 5 /?) - 5 - [(4-Fluorophenoxy) methyl] tetrahydro-2-pyran-2-yl.] Methyl) -1H-pyrazole-4-carboxamide; ? r'-. { [c s-4- (4-Methoxybenzyl) cyclohexyl] methyl} -1 / --p -razol-4-carboxamide; 3-Amino -? / - [(c / s-4-benzylcyclohexyl) methyl] -1-pyrazol-4-carboxamide; ? - ( { (2R, 5f?) - 5 - [(4-Chlorophenoxy) methyl] tetrahydro-2 - / - pyran-2-yl.} Methyl) -1H-pyrazole-4-carboxamide; 3-Amino- / V- ( { (2f?, 5í?) - 5 - [(4-fluorophenoxy) methyl] tetrahydro-2H-pyran-2-yl.} Metl) -1 V-pyrazole-4-carboxamide; 3-Amino- / V- ( { (2R, 5ft) -5 - [(4-chlorophenoxy) methyl] tetrahydro-2 H -pyran-2-yl.} Methyl) -1 H -pyrazole-4-carboxamide; and 3-Am \ no-N- ( { (2R, 5R) -5 - [(4-etlphenoxy) methyl] tetrahydro-2 / - / - pyran-2-yl.} methyl) -1 H -pyrazol-4-carboxamide; or a pharmaceutically acceptable salt or solvate thereof. 14. A pharmaceutical composition that includes a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 13, together with a pharmaceutically acceptable excipient. 1

5. The use of a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, according to any of claims 1 to 13 and 14, respectively, for the manufacture of a medicament for the treatment of a mammal, including a human, to treat a disease for which an NMDA NR2B antagonist is indicated. 1

6. The use claimed in claim 15, wherein the disease is selected from pain, stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, depression, anxiety and migraine. 1

7. A combination of a compound of the formula (I), as defined in any one of claims 1 -13, and another pharmacologically active agent. SUMMARY OF THE INVENTION The present invention relates to compounds of the formula (I): ? or a pharmaceutically acceptable salt or solvate thereof, wherein: A and B simultaneously represent CH2 or O, with the proviso that A and B are not simultaneously O; Cy represents one of the following optionally substituted with one to three groups selected from hydroxy, halogen, C? -6 alkyl, C? -6 alkoxy, C -6 haloalkyl, d-alkylamino. 6 and amino; R1 and R2 are independently selected from hydroxy, halogen, C? -6 alkyl, C? -6 alkoxy, C? -6 haloalkyl and C3-8 cycloalkyl; n represents a number from 0 to 4; X is hydrogen, hydroxy, halogen or C1-6 alkoxy; Y is oxy, thio, a 1-4 membered alkylene, a 2- to 4-membered alkylene ether, 2- to 4-membered alkylene thioether or an oxyethyleneoxy group, optionally substituted with 1 to 4 groups independently selected from hydroxy, halogen , C? -6 alkyl, C1-6 alkoxy and C? -6 haloalkyl; Z is CH or N; and p represents a number from 0 to 5 when Z is CH or from 0 to 4 when Z is N; when p represents 2 or more, two R 2 can be taken together with the carbon atoms to which they are attached to form a cycloalkyl ring of 5 to 8 members to processes for the preparation of, to intermediates used in the preparation of, to compositions which they contain such compounds and the uses of such compounds as antagonists of the NMDA NR2B receptor. PFIZER P06 / 1155F