MXPA99000108A - Espiro-piperidine derivatives and their use as therapeutic agents - Google Patents

Abstract

Certain substituted spiro-piperidine derivatives of the structural formula (1): are tachykinin receptor antagonists for use, for example, in the treatment or prevention of pain, inflammation, migraine, emesis and post-herpetic neuralgia

Description

ESPIRO-PIPERIDINE DERIVATIVES AND THEIR USE AS THERAPEUTIC AGENTS This invention relates to a class of azacyclic compounds that are useful as tachykinin antagonists. More particularly, the compounds of the invention are spiro-substituted azacyclic derivatives. The description of the international patent (PCT) no. WO 94/20500 (published September 15, 1994), discloses spiroazacyclic derivatives as substance P antagonists. In particular, WO 94/20500 relates to spirocyclic piperidine derivatives which contain a 1, 8-diazane core. spiro [5.5] undecane. Now another class of non-peptide compounds has been found which are potent antagonists of tachykinins, especially of substance P.

In addition, the compounds of the present invention exhibit a high level of hepatic stability, as measured, for example, by conventional liver microsome analysis. Furthermore, by virtue of its unique cyclopropyl ether radical, a preferred subclass of the compounds of the present invention possesses a high degree of oral bioavailability together with a high affinity for the human NKi receptor. The present invention provides compounds of the formula (I): m wherein: R1 represents hydrogen, hydroxy, Q-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, cycloalkyl-1, C1-6 alkoxy, fluoro-alkoxy Q-6, alkoxy Ci-β-C1 alkyl -4, C 1-4 alkoxy, C 1-4 alkoxy, C 2-7 fluoroalkoxy alkoxy, C 3-7 cycloalkoxy, C 1-4 cycloalkyl, phenoxy, benzyloxy, cyano, halogen, NRaRb, SRa, SOR, S02Ra , OS02Ra, NRaCOR ", CORa, C02Ra or CONRaRb, where each Ra and Rb independently represents hydrogen, C1-4 alkyl or fluoroC1-4alkyl, R2 represents hydrogen, halogen, C1-6alkyl or O-βalkoxy; when R2 is adjacent to R1, they can be linked together in such a way that a 5- or 6- membered, saturated or unsaturated ring is formed, which contains one or two atoms selected from nitrogen, oxygen and sulfur, which ring is optionally substituted by a group selected from C1-4 alkyl, CF3, = 0 or = s; R3 represents hydrogen, halogen, -6-alkyl, fluoro-C1-6alkyl, C6-6alkoxy, fluoro-C1-6alkoxy, C3-7 cycloalkyl, C3-7 cycloalkyl-cyanoalkyl, SRa, SORa, S02Ra, NRaRb , NRaCOR14, COR *, C02Ra, CONRaR or Cu alkyl substituted by cyano, C02Ra or CONRaRb, where Ra and Rb are as previously defined; R4 represents hydrogen, halogen, Ct-6 alkyl, C6-alkoxy, CF3, OCF3, NÜ2, CN, SRa, SOR ", SOzRa, C02Ra, CONRaRb, C2-6 alkenyl, C2-6 alkynyl or alkyl C1-4 substituted by alkoxy .4, where Ra and Rb are as previously defined; R 5 represents hydrogen, halogen, C 1-6 alkyl, CF 3 or O-β alkoxy substituted by C 1-4 alkoxy; Rβ represents hydrogen, CORa, C02Ra, COCONRaRb, COCO2Ra, C1-6alkyl optionally substituted by a group selected from (C02Ra, CONRaRb, hydroxy, CN, CORa, NRaRb, C (NOH) NRaRb, CONHphenyl (alkyl dCOC02Ra, CONHNRaRb, C (S) NRaR, CONRaalkyl C? -6R12, CONRiC2-6, C2-6 CONRiSalquinyl, COCONRaR, CONRaC (NRb) NRaRb, CONRaheteroaryl and phenyl optionally substituted by one, two or three substituents selected from C 1-6 alkyl, alkoxy C1-6, halogen and trifluoromethyl), or R6 represents a group of the formula -CH2C = CCH2NR7R8 where R7 and R8 are as defined above, or R6 represents O-6 alkyl, optionally substituted by oxo, substituted by a heterocyclic ring of 5 members or 6 members containing 1, 2 or 3 nitrogen atoms optionally substituted by = O or = S and optionally substituted by a group of the formula ZNR7R8 wherein: Z is C 1-6 alkylene or C 3-6 cycloalkyl; R7 is hydrogen or C1-4 alkyl, C3-7 cycloalkyl, cycloalkyl C 3-7-Cw alkyl, or C 2-4 alkyl substituted by C 1-4 alkoxy or hydroxyl; R8 is hydrogen or C1-4alkyl, C7 cycloalkyl, C3-7 cycloalkyl --- alkylCu or C2-4alkyl substituted by C1-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring, containing one or two heteroatoms selected from N, O and S; or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 atoms in the ring, optionally substituted by one or two groups selected from hydroxy or C? -4 alkoxy, optionally substituted by an alkoxy group C1-4 or hydroxyl and optionally containing a double bond, ring which may optionally contain an oxygen or sulfur atom in the ring, a group S (O) or S (0): > , or a second nitrogen atom that will be part of a radical NH or NRC, where Rc is C 1-4 alkyl optionally substituted by hydroxy or C 1-4 alkoxy; or R7, R8 and the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R7 and the nitrogen atom to which they are attached, form a heteroaliphatic ring of 4 to 7 ring atoms, which may optionally contain an oxygen atom in the ring; each of R9 and R10 independently represents hydrogen, halogen, G6 alkyl, CH2ORe, oxo, C02Ra or CONRaRb, where Ra and R are as previously defined and Re represents hydrogen, alkyl -6 or phenyl; R12 represents ORa, CONRaRb or heteroaryl; R 13 represents hydrogen or C 1-6 alkyl; R 14 represents C 1-6 alkyl, G-6 alkoxy, fluoro-G-6 alkyl or phenyl; X is an oxygen atom or two hydrogen atoms; and the dashed line represents an optional double bond; and pharmaceutically acceptable salts thereof. A particular subclass of compounds of formula (I) is one in which: R 1 represents G-6 alkoxy, C 1-6 fluoro-alkoxy, C 1-6 alkoxy-C 1-4 alkyl, fluoro-C 1-6 alkoxy-C 1-6 alkyl ? -4, C2-6 alkenyloxy, C3-7 cycloalkoxy, phenoxy, benzyloxy, cyano, halogen or NRaRb, wherein each of Ra and Rb independently represents hydrogen or C1_1alkyl; R 3 represents halogen, C 1-6 alkyl, fluoroalkyl Ci-e, alkoxy G-6, fluoro-C 1-6 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkyl or cyano; R 4 represents hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, CF 3, OCF 3, NO2, CN, SRa, SORa, S02Ra, COzRa, CONRaRb, C2-6 alkenyl, C2-6 alkynyl or alkyl C1-4 substituted by C1-4 alkoxy, wherein each of R and Rb independently represents hydrogen or C1-4 alkyl; X is two hydrogen atoms; and and pharmaceutically acceptable salts thereof. A preferred class of compounds of formula (I) is one in which R1 is hydroxy, C1-6 alkyl, C2-6 alkenyl, alkoxy G.-6, fluoro-alkoxy G-6, alkenyloxy C2-6, cycloalkoxy C3-7, cycloalkyl C3-7 --- ICOXIC1-, cyano, NRaRb , SRa, OS02Ra, or R1 together with the group R2 form a saturated 5-membered ring containing an oxygen atom. A particularly preferred class of compounds of formula (I) is that in which R 1 is a C 1-6 alkoxy, fluoro-C 1-6 alkoxy or C 3-7 cycloalkoxy group, especially methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, cyclopropoxy or cyclobutoxy. More especially, R1 is methoxy or cyclopropoxy. An even more preferred class of compounds of the present invention is one in which R1 is a cyclopropoxy group. Another preferred class of compounds of formula (I) is that in which R 2 is a hydrogen, fluorine or chlorine atom, especially a hydrogen atom.

Another preferred class of compounds of formula (I) is one in which R3 is hydrogen, halogen, fluoro-alkyl -6, fluoro-alkoxy -6, cyano, NR Rb, or NRaCOR14 (where R14 is preferably methyl, methoxy, trifluoromethyl or phenyl). Also preferred is the class of compounds of formula (I) wherein R3 is a halogen atom or a fluoro-C6-alkoxy group, especially fluorine, trifluoromethoxy or 2,2,2-trifluoroethoxy. More especially, R3 is trifluoromethoxy. Another preferred class of compounds of formula (I) is that in which R 4 is a hydrogen atom or a fluorine atom. Another preferred class of compounds of formula (I) is that in which R5 is a hydrogen atom. Another preferred class of compounds of formula (I) is that in which R6 is a hydrogen atom. Also preferred is the class of compounds of formula (I) wherein R6 is an alkyl group -6, in particular, CH2CH (CHs) and CH2CH2 and, especially, CH2, substituted by a 5-membered heterocyclic ring containing 2 or 3 nitrogen atoms, as previously defined. In particular, the 5-membered ring is a heterocyclic ring selected from: Particularly preferred heterocyclic rings are selected from: R8 Another preferred class of compounds of formula (I) is one in which one of R9 and R10 is hydrogen and, especially, one in which both R9 and R10 are hydrogen atoms. Another preferred class of compounds of formula (I) is that in which X represents two hydrogen atoms. Preferably, the double bond represented by the dotted line is absent. A preferred group of compounds of the present invention are those of the formula (la) and the pharmaceutically acceptable salts thereof: (the) wherein R1, R2, R3, R4 and the broken line are as defined in relation to formula (I). With respect to the compounds of the formula (I), Z (when present) can be a linear, branched or cyclic group. Favorably, Z contains from 1 to 4 carbon atoms and, more favorably, 1 or 2 carbon atoms. A particularly favorable Z group is CH2 With respect to the compounds of the formula (I), R7 can conveniently be a C1-4 alkyl group or a C2-4 alkyl group substituted by a hydroxyl group or C1.2 alkoxy, R8 it may conveniently be a C1 alkyl group. or a C2-4 alkyl group substituted by hydroxyl or C1-2 alkoxy group, or R7 and R8 may be attached such that, together with the nitrogen atom to which they are attached, they form tm azetidinyl, pyrrolidinyl, piperidyl, morpholino group, thiomorpholino, piperazino or piperazino substituted on the nitrogen atom with a C 1-4 alkyl group or tm G 2 -4 alkyl group substituted by a hydroxy or C 1-2 alkoxy group. When the group NR7R8 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring contains a double bond, a particularly preferred group is 3-pyrroline. When the group NR7R8 represents a non-aromatic azabicyclic ring system, such a system can contain between 6 and 12 and, preferably, between 7 and 10 atoms in the ring. Suitable rings include 5-azabicyclo [2, 1, l] hexyl, -azabicyclo [2.2, 1] hepty, 6-azabicyclo [3.2, 1] octyl, 2-azabicyclo [2.2.2] octyl, 6-azabicyclo [3,2,2] nonyl, 6-azabicyclo [3.3, l] nonyl, 6-azabicyclo [3,2,2] decyl, 7-azabicyclo [4.3, 1] decyl, 7-azabicyclo [4.4, 1] undecyl and 8-azabicyclo [5.4, 1] dodecyl, especially 5-azabicyclo [2.2, 1] heptyl and -azabicyclo [3.2, 1] octyl. When R8 represents n C2-4 alkyl group substituted by a 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S, suitable rings include pyrrolidino, piperidino, piperazino, morpholino, or thiomorpholino. Particularly preferred are nitrogen-containing heteroaliphatic rings, especially the pyrrolidino and morpholino rings. Particularly suitable ZNR7R8 radicals include those in which Z is CH2 or CH2CH2 and NR7R8 is amino, methylamino, dimethylamino, diethylamino, azetidinyl, pyrrolidino and morpholino. In particular, Z is preferably CH 2 and NR 7 R 8 is preferably dimethylamino, azetidinyl or pyrrolidino, especially dimethylamino.

When any variable appears more than once in the formula (I) or in any substituent, each time it appears, its definition is independent of its definition in all other occasions. As used herein, the term "alkyl" or "alkoxy" as a group or as part of a group means that the group is linear or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. As used herein, the terms "fluoro-C 1-6 alkyl" and "fluoro-C 1-6 alkoxy" mean a C? -6 alkyl or C? -6 alkoxy group in which one or more (in particular, from 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Analogously, the term "fluoro-C 1-4 alkyl" means tm C 1-4 alkyl group in which one or more (in particular, from 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoro-C1-3 alkyl and fluoro-alkoxy G-3 groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3 and, more especially, CF3, OCF3 and OCH2CF3, The cycloalkyl groups mentioned in this document may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable cycloalkylalkyl group can be, for example, cyclopropylmethyl. Analogously, the cycloalkoxy groups mentioned in this document can represent, for example, cyclopropoxy or cyclobutoxy. As used herein, the terms "alkenyl" and "alkynyl", as a group or as part of a group, means that the group is linear or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.

As used herein, the term "heteroaryl", as a group or as part of a group, means a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms selected from N, O, and S. Particular examples of such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl and tetrazolyl. When used herein, the term "halogen" means fluorine, chlorine, bromine and iodine. The most convenient halogens are fluorine and chlorine, of which fluorine is preferred unless otherwise indicated. Specific compounds within the scope of this invention include: (6S, 5R) -3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4,5] dec-3 -one; (6S, 5R, 3S) -3- (2-rnetoxy-5-trifluoromethoxyphenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (+) (6S 5R ^ 3S *) - 3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-azaspir or [4,5] decane; (6S, 5R, 3S) -3- (2-methoxy-5-trifluoromethoxyphex) -6-phenyl-7- (1, 2,4-triazol-3-methylene) -l-oxa-7-aza-spiro [ 4,5] dean; (6S, 5R) -3- (2-isopropoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-ene; Other specific compounds within the scope of this invention include: Other specific compounds within the scope of this invention include: (3-S ', 5i?, 6-S) -3- (2-cyclopropoxy-5- (trifluoromethoxy) feml) -6-phene-1-oxa-7-aza-spiro [4,5] decane; (3i ?, 5R, 6-S) -3- [2-cyclopropoxy-5- (trifluoromethoxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (S-Sdi? / Or - ^ - SP ^ iclopropoxy-S -trifluorornethylJefer-yl-o-phenyl-1-oxa-aza-spiro [4,5] decane, and pharmaceutically acceptable salts thereof. of the present invention, the compounds of formula (I) can be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts and However, other salts may be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable and non-toxic salts Suitable pharmaceutically acceptable salts of the compounds of this invention include the addition salts of acids which, for example, can be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, fumaric acid, p-toluenesulf acid ionic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulfuric acid. The salts of amine groups may also comprise quaternary ammonium salts in which the nitrogen atom of the amino group carries a suitable organic group, such as an alkyl, alkenyl, alkynyl or aralkyl radical. In addition, when the compounds of the invention carry an acid radical, suitable pharmaceutically acceptable salts thereof may include metal salts, such as alkali metal salts, for example, sodium or potassium salts; and alkaline earth metal salts, for example, calcium or magnesium salts. The salts can be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid, in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed under vacuum or by lyophilization, or by exchanging the anions of an existing salt with another anion in an appropriate ion exchange resin. The present invention includes within its scope prodrugs of the compounds of the formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I), which can be easily converted in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985, A prodrug can be a pharmacologically inactive derivative of a biologically active substance (the "parent drug" or the "parent molecule") that requires transformation within the body to release the active drug and has better release properties that the parent drug molecule. The transformation in vivo can be, for example, as a result of some metabolic process, such as the chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulfate ester, or the reduction or oxidation of a susceptible functionality. The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates. The compounds according to the invention have at least three asymmetric centers and, therefore, can exist as enantiomers and diastereoisomers. It should be understood that all such isomers and mixtures thereof are included within the scope of the present invention. Preferred compounds of formula (I) and (la), in which the optional double bond is absent, will have the stereochemistry of positions 3, 5 and 6 which the compound of Example 124 possesses (ie, 3- (5 ), 5- (R) and 6- (S)). So, for example, as shown in the formula (Ib) (Ib) A particularly preferred class of compounds of the formula (I) and (la), in which the optional double bond is absent, is that with the stereochemistry 3- (R), 5- (R), 6- (S) ( for example, the one with the compound of Example 214), that is, as shown in the formula (le) (le) For example, compound 3 (R) of Example 214 is more potent than its epimer 3 (S), Example 124.

It will be appreciated that the preferred definitions of the various substituents mentioned herein may be considered individually or jointly and applied to the generic formula for the compounds of the present invention, as well as to the preferred classes of compounds represented by the formula (la), the formula Ib) and the formula (le). The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) together with a pharmaceutically acceptable carrier or excipient. Preferably, the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or for administration by inhalation or insufflation. To prepare solid compositions, such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, conventional ingredients to form tablets such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, phosphate dicalcium or gums and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention or a pharmaceutically acceptable and non-toxic salt thereof. When said preformulation compositions are said to be homogeneous, it is understood that the active ingredient is dispersed uniformly throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. . This solid preformulation composition is then subdivided into unit dosage forms of the type described above, containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the new composition can be coated or otherwise compounded to provide a dosage form that produces the advantage of prolonged action. For example, the tablet or pill may comprise an internal dosage component and an external dosage component, the latter being in the form of a shell over the first. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allows the internal component to pass intact to the duodenum or delay its release. A variety of materials can be used for such enteric layers or coatings, such materials including various polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate. Liquid forms in which the novel compositions of the present invention may be incorporated for oral or injection administration, include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and emulsions flavored with edible oils such as cottonseed oil, oil of sesame, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include natural and synthetic gums such as tragacanth, gum arabic, alginate, dextran, sodium carboxymethylcellulose, hypromellose, polyvinyl pyrrolidone or gelatin. Preferred compositions for administration by injection, include those comprising a compound of formula (I), as an active ingredient, together with a surfactant (wetting or surfactant) or in the form of an emulsion (such as a water-in-oil emulsion) or oil in water).

Suitable surfactants include, in particular, nonionic agents, such as polyoxyethylene sorbitan (e.g., Tween ™ 20, 40, 60, 80 or 85) and other sorbitans (e.g., Span ™ 20, 40, 60, 80 or 85). ). The compositions with a surfactant will conveniently comprise between 0.05 and 5% surface active agent and, preferably, between 0.1 and 2.5%. It will be appreciated that other ingredients, for example, mannitol or other pharmaceutically acceptable vehicles, may be added, if necessary. Suitable emulsions can be prepared using commercially available fat emulsions, such as Intralipid ™, Liposyn ™, Infonutrol ™, Lipofundin ™ and Lipiphysan ™. The active ingredient can be dissolved in a premixed emulsion composition or, alternatively, it can be dissolved in an oil (for example, soybean oil, safflower oil, cottonseed oil, sesame oil, starch oil or almond oil) and forming an emulsion by mixing with a phospholipid (e.g., egg phospholipids, soy phospholipids or soy lecithin) and water. It will be appreciated that other ingredients, for example, glycerol or glucose, may be added to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5% and 20%. The fat emulsion will preferably contain droplets of fat with dimensions between 0.1 and 1.0 μm, particularly between 0.1 and 0.5 μm, and will have a pH in the range of 5.5 to 8.0. Particularly preferred emulsion compositions are those prepared by mixing tm compound of formula (I) with Intralipid ™ or components thereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation and insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid and solid compositions may contain pharmaceutically acceptable and suitable excipients as indicated above. Preferably, the compositions are administered by the oral or nasal respiratory route to achieve a local or systemic effect. The compositions, preferably in sterile and pharmaceutically acceptable solvents, can be nebulized by the use of inert gases. The nebulized solutions can be breathed directly from the nebulization device or the device M ^ 10 nebulization can be attached to a face mask, tent or a positive pressure intermittent breathing machine. The compositions in solution, suspension or powder can be administered, preferably orally or nasally, from devices that release the formulation in an appropriate manner. The present invention also provides t process for the The preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises associating a compound of formula (I) with • a pharmaceutically acceptable vehicle or excipient. The compounds of formula (I) are valuable in the treatment of a wide variety of clinical conditions that are characterized by the presence of a Excess tachykinin, in particular substance P. Thus, for example, an excess of tachykinin activity, and in particular substance P, is involved in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or, more particularly, depressive disorders, for example, disorders single-episode depressants or recurrent major depression and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders that include post-stress disorder traumatic and acute stress disorder, and generalized anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusory disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with. delusions or hallucinations; delirium, dementia, amnestic disorders and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile dementia, Alzheimer-type dementia, vascular dementia and other dementias, for example, due to HIV disease, to cephalic trauma, disease of Parkinson's disease, Huntington's disease, Pick disease, Creutzfeldt-Jakob disease, or due to multiple etiologies; Parkinson's disease and other extrapyramidal movement disorders, such as medication-induced movement disorders, eg, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, acute neuroleptic-induced akathisia, tardive dyskinesia induced by neuroleptics and postural tremor induced by medication; disorders related to certain substances, produced by the use of alcohol, amphetamines (or substances similar to amphetamines), caffeine, cannabis, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics and anxiolytics , disorders related to substances that include dependencies and abuse, intoxication, withdrawal syndrome, intoxication delirium, withdrawal syndrome delirium, persistent dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders; epilepsy; Down's Syndrome; demyelinating diseases such as MS (Multiple Sclerosis) and ALS (Lateral Sclerosis) Amyotrophic) and other neuropathological disorders such as peripheral neuropathy, for example, diabetic neuropathy and neuropathy induced by chemotherapy, and post-herpetic neuralgia, tiigeminal neuralgia, segmental or intercostal neuralgia and other neuralgia; and vascular brain disorders due to acute or chronic cerebrovascular injuries, such as tm cerebral infarction, subarachnoid hemorrhage or cerebral edema. The activity of tachykinins and, in particular, the activity of substance P, is also involved in nociception and pain. Therefore, the compounds of the present invention will be useful in the prevention or treatment of diseases and conditions in which pain predominates, including soft tissue and peripheral lesions, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculoskeletal pain. , particularly after trauma, spinal pain, myofascial pain syndrome, headaches, episiotomy pain and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, toothache, abdominal pain, gynecological pain, for example, dysmenorrhea, and labor pain; pain associated with nerve root injuries and nerve pain, such as pain associated with peripheral nerve disorders, for example, nerve tightness and brachial plexus avulsions, amputation, peripheral neuropathies, painful tic, atypical facial pain, nerve root pain, and arachnoiditis; pain associated with carcinoma, often called cancerous pain; central nervous system pain, such as pain due to injuries to the spinal cord or brainstem; low back pain, sciatica; ankylosing spondylitis, gout; and pain of scars. Tachykinin antagonists, and in particular substance P, may also be useful in the treatment of respiratory diseases, particularly those associated with excess mucous secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis. , cystic fibrosis and asthma, respiratory distress syndrome in adults and bronchospasm; inflammatory diseases, such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders such as hypersensitivity to poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis and the like; ophthalmic conditions associated with cell proliferation, such as proliferative vireoretinopathy; skin diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis. Tachykinin antagonists, and in particular substance P, may also be useful in the treatment of neoplasms, including breast tumors, neuroganglioblastomas and small cell carcinomas, such as small cell lung cancer. Tachykinin antagonists, and in particular substance P, may also be useful in the treatment of gastrointestinal (Gl) disorders, including inflammatory disorders and Gl tract diseases, such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with neuronal control of viscera, ulcerative colitis, Crohn's disease, irritable bowel syndrome and emesis, including acute, delayed or anticipated emesis, such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, eg, motion sickness, vertigo, fainting and Meniere's disease, surgery, migraine, intercranial pressure variations, gastro-esophageal reflux disease, acid indigestion, excess food or drink, stomach acidity, watery heartburn or regurgitation , pyrosis, for example episodic, nocturnal or food-induced pyrosis as, and dyspepsia. Tachykinin antagonists, and in particular substance P, may also be useful in the treatment of a variety of different conditions including somatic disorders related to stress; sympathetic reflex dystrophy, such as shoulder-hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune augmentation or suppression, such as systemic lupus erythematosus, plasma extravasation resulting from cytokine chemotherapy, disorders of bladder function such as cystitis, hyperkalemia, reflexion of the detrusor of the bladder and incontinence; fibrosing and collagen diseases, such as scleroderma and eosinophil fascioliasis; blood flow disorders caused by vasodilation and vasospastic diseases such as angina, vascular headaches, migraine and Reynaud's disease; and pain or nociception attributable to or related to any of the above conditions, especially the transmission of pain in the migraine. The compounds of formula (I) are also valuable in the treatment of a combination of the above conditions, in particular in the treatment of combined postoperative pain and postoperative nausea and vomiting.

The compounds of formula (I) are particularly useful in the treatment of emesis, including acute, delayed or anticipated emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, movement, surgery, migraine and variations of intercranial pressure. More especially, the compounds of formula (I) are useful in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy, and emesis induced by other pharmacological agents, for example, rolipram. Examples of such chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethylene imine compounds, alkyl sulfonates and other compounds with an alkylating action, such as nitrosoureas, cisplatin and dicarbazine; antimetabolites, for example, folic acid, purine antagonists or pyrimidine, mitotic inhibitors, for example, vinca alkaloids and podophyllotoxin derivatives; and cytotoxic antibiotics. Particular examples of chemotherapeutic agents are described, for example, by D. J. Stewart in Nausea and Vomitingr Recent Research and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Florida, USA (1991) pages 177-203, especially on page 188. Commonly used chemotherapeutic agents include cisplatin, dicarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard) ), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al in Cancer Treatment Reports (1984) 68 (1), 163-172].

The compounds of formula (I) are also useful in the treatment of radiation induced emesis, including radiation therapy such as in the treatment of cancer, or radiation alterations; and in the treatment of postoperative nausea and vomiting. It will be appreciated that the compounds of formula (I) may be presented together with other therapeutic agents as a combined preparation for simultaneous, separate or sequential use for the relief of emesis. Such combined preparations may be, for example, in the form of a double container. Another aspect of the present invention comprises the compounds of formula (I) in combination with a 5-HT3 antagonist, such as ondansetron, granisetron or tropisetron, or with other anti-emetics drugs, for example, a dopamine antagonist, such as metoclopramide or domperidone, or with agonists of the GABAB receptor, such as baclofen. In addition, a compound of formula (I), either alone or in combination with one or more other anti-emetic agents, can be administered in combination with an anti-inflammatory corticosteroid, such as dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, flunisolide, budesonide, or others, such as those described in US Pat. Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712. Dexamethasone (Decadron ™) is particularly preferred. In addition, a compound of formula (I) can be administered in combination with a chemotherapeutic agent, such as an alkylating agent, an antimetabolite, an inhibitor of mitosis or a cytotoxic antibiotic, as described above. In general, currently available dosage forms of the known therapeutic agents will be suitable for use in such combinations.

When tested in the emetis ferret model induced by cisplatin, described by FD Tattersall et al, in Eur. J. Pharmacol., (1993) 250, R5-R6, it was observed that the compounds of the present invention attenuated nausea and vomiting induced by cisplatin. The compounds of formula (I) are also particularly useful in the treatment of pain, nociception and / or inflammation and the disorders associated therewith., such as, for example, neuropathy, such as diabetic neuropathy and that induced by chemotherapy, post-herpetic neuralgia and other neuralgia, asthma, osteoarthritis, rheumatoid arthritis and headaches, including migraine, acute or chronic tension headache, headaches clusters, temporomandibular pain and maxillary sinus pain. The compounds of formula (I) are also particularly useful in the treatment of depression, including depressive disorders, for example, single-episode depressive disorders or recurrent major depression, and dysthymic disorders, depressive neurosis and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and premature awakening, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psycho-motor agitation or irritability, anxiety and phobias; seasonal disorder cash; bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder. The present invention further provides tm compound of formula (I) for use in therapy. According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders related to the excess of tachykinins, especially of the substance P. The present invention it also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, a method comprising administering to a patient in need thereof, a tachykinin reducing amount of a compound of formula ( I) or a composition comprising a compound of formula (I). According to another aspect of the present invention, it may be desirable to treat any of the aforementioned conditions with a combination of a compound according to the present invention and one or more other pharmacologically active agents, suitable for the treatment of the specific condition. The compound of formula (I) and the other pharmacologically active agent (s) can be administered to a patient simultaneously, sequentially or in combination. Thus, for example, for the treatment of respiratory diseases such as asthma, a compound of formula (I) may be used together with a bronchodilator, such as a β2-adrenergic receptor agonist or a tachykinin antagonist acting on the NK-2 receptors. The compound of formula (I) and the bronchodilator can be administered to a patient simultaneously, sequentially or in combination. Analogously, a compound of the present invention with a leukotriene antagonist, such as a leukotriene antagonist, can be employed.

D4, such as a compound selected from those described in the European patent specifications nos. 0480 717 and 0 604 114 and in US Pat. Nos. 4,859,692 and 5,270,324. This combination is particularly useful in the treatment of respiratory diseases such as asthma, chronic bronchitis and cough. Accordingly, the present invention provides a method for the treatment of a respiratory disease, such as asthma, a method comprising administering to a patient in need thereof, an effective amount of a compound of formula (I) and an amount of effective of a bronchodilator. The present invention also provides a composition comprising a compound of formula (I), a bronchodilator and a pharmaceutically acceptable carrier. It will be appreciated that for the treatment or prevention of migraine, a compound of the present invention may be used together with another anti-migraine agent, such as ergotamines or 5-HT ?, agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan. Analogously, for the treatment of a hyperalgesia behavior, a compound of the present invention can be used together with an antagonist of N-methyl D-aspartate (NMDA), such as dizocilpine. For the treatment or prevention of inflammatory conditions in the lower urinary tract, especially cystitis, a compound of the present invention may be used together with an anti-inflammatory agent such as a bradykinin receptor antagonist. The present invention also provides a composition comprising a compound of formula (I), a bronchodilator and a pharmaceutically acceptable vehicle.

It will be appreciated that for the treatment or prevention of pain or nociception, a compound of the present invention may be used together with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) and, in particular, opioid analgesics, especially morphine. Specific anti-inflammatory agents include diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam and sulindac. Opioid analgesics suitable for use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanil, meperidine, methadone, nalbuphine, propoxyphene and pentazocine.; or a pharmaceutically acceptable salt thereof. Preferred salts of these opioid analgesics include morphine sulfate, morphine hydrochloride, morphine tartrate, codeine phosphate, codeine sulfate, dihydrocodeine bitartrate, acetylcholine hydrochloride, hydrocodone bitartrate, hydromorphone hydrochloride, levorphanol tartrate, hydrochloride of oxymorphone, alfentanil hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate, meperidine hydrochloride, methadone hydrochloride, nalbuphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate (2-naphthalenesulfonic acid monohydrate (1: 1) ) and pentazocine hydrochloride. Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient. In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of pain or nociception. It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with an anti-depressant or anti-anxiety agent. Suitable classes of antidepressant agents include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSR1), monoamine oxidase inhibitors (MAOI), reversible monoamine oxidase inhibitors (RIMA), serotonin and norepinephrine reuptake inhibitors (SNRIs), opioid corticotropin release (CRF), α-adrenoreceptor antagonists, and atypical antidepressants. Suitable norepinephrine reuptake inhibitors include tricyclics of tertiary amine and tricyclics of secondary amine. Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine and pharmaceutically acceptable salts thereof. Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof. Suitable selective inhibitors of serotonin reuptake include: fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof. Suitable inhibitors of monoamine oxidase include: isocarboxazide, phenelzine, tianücipromine and selegiline, and pharmaceutically acceptable salts thereof.

Suitable reversible inhibitors of monoamine oxidase include: moclobemide and pharmaceutically acceptable salts thereof. Suitable inhibitors of serotonin and noradrenaline reuptake for use in the present invention include: venlafaxine and pharmaceutically acceptable salts thereof. Suitable CRF antagonists include the compounds described in the Descriptive Memoirs of International Patents Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677. Suitable atypical antidepressants include: bupropion, lithium, nefazodone, trazodone and vuoxazine and pharmaceutically acceptable salts thereof. Suitable classes of anti-anxiety agents include benzodiazepines and 5-HTIA agonists or antagonists, especially partial 5-HTIA agonists and corticotropin releasing factor (CRF) antagonists. Suitable benzodiazepines include: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam and pharmaceutically acceptable salts thereof. Suitable agonists or antagonists of the 5-HTIA receptor include, in particular, the partial agonists of the 5-HTIA receptor buspirone, flesinoxan, gepirone and ipsapirone and pharmaceutically acceptable salts thereof. Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an antidepressant or anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient.

In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an antidepressant or anxiety agent, such as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of depression and / or anxiety It will be appreciated that for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorexic agents. Accordingly, the present invention provides the use of a compound of formula (I) and an anorectic agent for the manufacture of a medicament for the treatment or prevention of eating disorders. The present invention also provides a method for the treatment or prevention of eating disorders, a method comprising administering to a patient in need of such treatment, an amount of a compound of formula (I) and an amount of an anorectic agent. , so that together they provide effective relief. In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) and an anorectic agent, together with at least one pharmaceutically acceptable carrier or excipient. It will be appreciated that the compound of formula (I) and the anorectic agent may be present as a preparation suitable for simultaneous, separate or sequential use for the treatment or prevention of eating disorders. Such combined preparations, for example, can be in the form of a double container.

Therefore, in a further or alternative aspect of the present invention, a product comprising a compound of formula (I) and an anorectic agent is provided as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of disorders. of food. In another embodiment of the present invention, there is provided the use of a compound of formula (I) and an anorectic agent for the manufacture of a medicament for the treatment or prevention of obesity. The present invention also provides a method for the treatment or prevention of obesity, a method comprising administering to a patient in need of such treatment, of an amount of a compound of formula (I) and an amount of an anorectic agent, such that together they provide effective relief. In an alternative embodiment of the present invention, there is provided the use of a compound of formula (I) and an anorectic agent for the manufacture of a medicament for the treatment or prevention of bulimia nervosa. The present invention also provides a method for the treatment or prevention of bulimia nervosa, which method comprises administering to a patient in need of such treatment an amount of tm composed of formula (I) and an amount of an anorectic agent, so that together they provide effective relief. In another embodiment of the present invention, there is provided the use of a compound of formula (I) and an anorectic agent for the manufacture of a medicament for the treatment or prevention of compulsive eating disorders.

The present invention also provides a method for the treatment or prevention of compulsive eating disorders, which method comprises administering to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an anorectic agent , so that together they provide effective relief. In an alternative embodiment of the present invention, there is provided the use of a compound of formula (I) and an anorectic agent for the manufacture of a medicament for reducing total body fat mass in an obese mammal, especially a human being. The present invention also provides a method for reducing total body fat mass in an obese mammal, especially a human being, a method comprising administering to a patient in need of such treatment an amount of a compound of formula (I) and a amount of an anorectic agent, so that together they provide effective relief. Suitable anotonic agents for use in combination with an agent of the present invention include, but are not limited to, aminorex, amphelolamine, amphetamine, benzophetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermin, cyclodextrin, dexfenfluramine, dextroamphetamine, diethylpropion, diffemethoxydine,. -V-etüanfefamina, fenbutiazato, fenfluramina, fenisorex, fenproporex, fludorex, fluminorex, furfuril-metüanfefan-iina, levanfetamina, levofacetoperano, mazindol, mefenorex, methamphepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, fenüopropanolamina, picüorex and sibutramine; and pharmaceutically acceptable salts thereof. Particularly preferred anorectic agents include amphetamine and derivatives thereof, such as amphetamine, benzophetamine, chlorphentermine, clobenzorex, cloforex, clotermin, dexfenfluramine, dextroamphetamine, diethylpropion, iV-ethylamphetamine, fenfluramine, fenproporex, furfuryl-methymphephamine, levamfetamine, mefenorex, mefanfepramone. , mefanfetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, fenüpropanolamine, picüorex and sibutramine; and pharmaceutically acceptable salts thereof. A particularly suitable subclass of anorectic agents are the halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermin, dexfenfluramine, fenflurarnin, picuorex and sibutiamine; and pharmaceutically acceptable salts thereof. Halogenated amphetamine derivatives particularly preferred for use in combination with a compound of the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof. It will be appreciated that for the treatment or prevention of obesity, the compounds of the present invention may also be used in conjunction with a selective inhibitor of serotonin reuptake (SSR1). Accordingly, the present invention provides the use of a compound of formula (I) and an SSRI for the manufacture of a medicament for the treatment or prevention of obesity. The present invention also provides a method for the treatment or prevention of obesity, which method comprises administering to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an SSR1, such so that together they provide effective relief. In another aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of obesity, comprising a compound of the formula (I) and an SSR1, together with at least one pharmaceutically acceptable carrier or excipient. It will be appreciated that the compound of formula (I) and SSR1 may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of obesity. Such combined preparations may be, for example, in the form of a double container. In a further or alternative aspect of the present invention, therefore, there is provided a product comprising a compound of formula (I) and a SSRl as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of obesity. In an alternative embodiment of the present invention, there is provided the use of a compound of formula (I) and an SSR1 for the manufacture of a medicament for reducing total body fat mass in an obese mammal, especially a human being. The present invention also provides a method for reducing total body fat mass in an obese mammal, especially t human, a method comprising administering to the mammal an amount of a compound of formula (I) and an amount of SSR1, such as so that together they provide effective relief. In another aspect of the present invention, there is provided a pharmaceutical composition for reducing total body fat mass in an obese mammal, especially a human being, comprising a compound of formula (I) and an SSR1, together with at least one carrier or pharmaceutically acceptable excipient. Suitable selective inhibitors of serotonin reuptake for use in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine and sertialine and pharmaceutically acceptable salts thereof. As used herein, "obesity" refers to a condition whereby the mammal has a Body Mass Index (BMI), which is calculated as a weight divided by the square of height (kg / m2) of at least 25.9.

Conventionally, people with a normal weight, have a BMI of 19.9 to less than 25.9, Here, obesity can be due to any cause, either genetic or environmental. Examples of disorders that can cause obesity or be the cause of obesity include overeating and bulimia, polycystic ovary disease, craniopharyngioma, Prader-WiHi syndrome, Frohlich syndrome and Type II diabetes, GH-deficient subjects, normal variant of a short stature, Turner syndrome and other pathological conditions that show a lower metabolic activity or a reduction of resting energy expenditure as a percentage of total lean mass, for example, children with acute lymphoblastic leukemia. "Treatment" (of obesity) refers to the reduction of the BMI of the mammal to t value less than about 25.9 and the maintenance of that weight for at least six months. The treatment conveniently produces the reduction of food or calorie intake by the mammal. "Prevention" (of obesity) refers to the prevention of the appearance of obesity if the treatment is administered before the onset of this condition.

Furthermore, if the treatment is started in already obese subjects, it is expected that such a treatment prevents or prevents the progression of the medical consequences of obesity, such as, for example, arteriosclerosis, Type II diabetes, polycystic ovarian disease, diseases cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia and cholelithiasis. Thus, in one aspect, this invention relates to the inhibition and / or complete suppression of lipogenesis in obese mammals, i.e., the excessive accumulation of lipids in fat cells, which is one of the main characteristics of obesity human and animal, as well as a loss of tofal body weight. In another aspect, the invention reduces conditions that are a consequence of the disease, such as the prevention or arrest of the progression of polycystic ovary disease, so that the patient is no longer sterile and increases insulin sensitivity and / or the need to use insulin in a diabetic patient is reduced or eliminated, for example, one with adult onset diabetes or Type II diabetes. Another aspect of the present invention comprises the use of a compound of formula (I) to achieve a chronobiological effect (phase shift of the circadian rhythm) and a relief of circadian rhythm disorders in a mammal. The present invention is further directed to the use of a compound of formula (I) to block the effects of phase shift of light in a mammal. The present invention also relates to the use of a compound of formula (I) to improve or enhance the quality of sleep, in particular, increasing the efficiency of sleep and increasing sleep maintenance, as well as to prevent and treat sleep disorders and sleep disturbances in a mammal. In a preferred embodiment, the present invention provides a method for phase advancement or phase lag in the subject's circadian rhythm, which comprises administering to the subject an appropriate amount of a compound of formula (I) or a pharmaceutically acceptable salt. of the same. The administration to a subject of an appropriate amount of a compound of formula (I) is useful, for example, in the treatment or prevention of the following conditions to achieve chronobiological effects and / or alleviate circadian rhythm phase disorders: sleep-wake program; jet lag; shift work; people who adapt poorly to work and rest programs; resident physicians, nurses, firemen, policemen or people whose duties require alertness or vigilance in the evening or at night, or people deprived of sleep during various periods because of their obligations or responsibilities; workers with animals; infantry or other members of the armed forces whose duties require extreme levels of alertness and vigilance, and persons who may be deprived of sleep in the performance of their duties; that they may be deprived of sleep in the execution of these duties; submariners or people locked up for research, exploration or for industrial purposes, under the sea; miners, cavers, researchers or people locked underground; astronauts in orbit around the Earth, in space missions to the planet or to the planets or outside the solar system, or in training for such missions; blindness or impaired vision or people whose ability to distinguish differences in light and darkness may be permanently or temporarily hindered; psychiatric patients; patients with insomnia; comatose or those who need to remain in a state of unconsciousness for medical, psychiatric or other reasons; residents of North Antarctica or people who live in a climate or climates that have an excess or defect of light or darkness; people suffering from seasonal disorders (SAD), winter depression or other forms of depression; the people with advanced age; patients with Alzheimer's disease or those suffering from other forms of dementia; patients who require medication doses at appropriate times in circadian cycles; patients suffering from the sleep phase delay syndrome, the sleep phase advance syndrome or a sleep phase syndrome that is not 24 hours; and patients suffering from primary or secondary insomnia or insomnia related to the circadian rhythm. The present invention is useful, for example, in the prevention or treatment of conditions associated with the circadian rhythm as well as mental and physical disorders associated with travel through zones with time changes and work shift rotation programs. In a preferred embodiment, the present invention provides a method for the prevention or treatment of a circadian rhythm disorder in a mammal, including the syndrome of time change (jet lag), sleep disorders due to shifts of work, delay syndrome of the sleep phase, sleep phase advancement syndrome and sleep-wake disorder that is not 24 hours, which comprises administering to the mammal an effective amount of a compound of formula (I) or tma pharmaceutically acceptable salt thereof . In another preferred embodiment, the present invention provides a method for shortening the time of restoration of circadian rhythms or in a subject, after a shift of the sleep-wake cycle, which comprises administering to the subject an appropriate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a more preferred embodiment, the present invention provides a method for alleviating the effects of jet lag in a traveler, especially a mammal, which comprises administering to the traveler an amount to increase the vigilance of a compound of formula (I) or a pharmaceutically salt. acceptable of it. The objective of these realizations is to help the body to adjust physiologically to the changes of the sleep and feeding model when crossing several zones with time change. In another more preferred embodiment, the present invention provides a method for restoring the internal circadian clock in a subject, for example, shift workers who change from a daily shift to a night shift or vice versa, which comprises administering to the subject an appropriate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention is further directed to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, to increase or improve the quality of sleep as well as to prevent and treat sleep disturbances and sleep disturbances in a mammal. In particular, the present invention provides a method for improving or increasing the quality of sleep by increasing the efficiency of sleep and increasing sleep maintenance.

In addition, the present invention provides a method for preventing and treating sleep disorders and sleep disturbances in a mammal, comprising the administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention is useful for the treatment of sleep disorders, including Sleep Initiation and Maintenance Disorders (insomnia) ("DIMS") that can occur due to psychophysiological causes, as a consequence of psychiatric disorders (particularly related to anxiety), by the use and abuse of drugs and alcohol (particularly during stages of withdrawal syndrome), DIMS that begins in childhood, nocturnal myoclonus and incessant movement in the legs, and non-specific REM alterations such as those observed in aging. The following results in a subject that are provided by the present invention can be correlated with the improvement of sleep quality: an increase in the value that is calculated from the time a subject sleeps, divided by the time during which the subject is trying to fall asleep; a reduction in sleep latency (the time it takes to fall asleep); a reduction in the number of times you wake up during sleep; a reduction in wakefulness after the onset of sleep; an increase in the total amount of sleep; an increase in the amount and percentage of REM sleep; an increase in the duration and frequency of REM sleep; a reduction of REM sleep fragmentation; an increase in the amount and percentage of slow-wave sleep (ie, phase 3 or 4); an increase in the amount and percentage of phase 2 sleep; a reduction in the number of times the subject wakes up; especially the next morning; an increase in vigilance during the day; and greater maintenance of sleep. Secondary outcomes that can be provided by the present invention include better cognitive function and increased memory retention. In addition, the present invention is useful for the prevention and treatment of sleep disorders and sleep disturbances including sleep problems related to insomnia, hypersomnia, sleep apnea, narcolepsy, nocturnal myoclonus, REM sleep interruptions, jet lag, sleep disorders of shift workers, disomnios, night terror, insomnia related to depression or emotional / mood disorders, dysfunctions associated with sleep (parasomnias), somnambulism and enuresis, and sleep disorders that accompany aging . Sleep disturbances and sleep disturbances are usually characterized by the difficulty of initiating or maintaining sleep or achieving sufficient rest or sleep. In addition, certain drugs can cause sleep reductions REM as a side effect, and the present invention can also be used to correct these types of sleep disorders. The present invention would also be beneficial in the treatment of syndromes, such as fibromyalgia, which are manifested by the inability to restore sleep and muscle pain or apnea during sleep, associated with respiratory disorders during sleep. It will be apparent to one skilled in the art that the present invention is not limited only to sleep disorders and sleep disturbances, but is applicable to a wide variety of conditions that result from a reduction in sleep quality. The compounds of formula (I) can be used alone or in combination with other agents known to be beneficial in altering the circadian rhythm or in improving the efficiency of sleep. For example, the compounds of formula (I) can be administered together with other compounds which, as is known in the art, are useful for suppressing or stimulating the production of melatonin, including melatonergic agents, noradrenergic or serotonergic reuptake blockers, agonists alpha-1-noradrenergics, monoamine oxidase inhibitors, beta-adrenergic blockers and benzodiazepines, such as atenolol; or with other compounds which, as is known in the art, are useful for stimulating the production of melatonin, including tricyclic antidepressants and alpha-2-adrenergic antagonists; or with melatonin precursors such as tryptophan, 5-hydroxytryptophan, serotonin and N-acetylserotonin; as well as melatonin analogs, melatonin agonists and melatonin antagonists. In addition, the compounds of formula (I) can be administered together with other compounds which, as is known in the art, are useful for improving the quality of sleep and preventing and treating sleep disturbances and sleep disturbances, including, for example, sedatives , hypnotics, anxiolytics, antipsychotics, antianxiety agents, mild tranquilizers, melatonin agonists and antagonists, melatonin, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists and simuars, such as: adinazolam, allobarbitel, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctemina, brotizolam, bupropion, busprione, butebarbital, butelbital, capuride, carbochloral, chloral beteine, chloral hydrate, chlordiazepoxide, clomipramine, cloperidone, clorazepate, clorete, clozapine, ciprazepam, desipramine, dexclamol, diazepam, dicloralfenazone, divalproex, dienhydrairin, doxepin, stearlam, etclorvinol, etomidate, fenobam, fltmitiazepam, f lurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbitel, meprobamate, metaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbitai, perlapin, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protipotin, quazepam, reclazepam, roletamide, secobarbital, sertialine, suproclone, temazepam, thioridazine, tracazolate, traclcipromaine, trazodone, triazolam, tiepipam, tricetamide, thiiclofos, trifluoperazine, trimethozin, tii-miprarriin, uldazepam, valproate, venlafaxine, zaleplon, zolazepam, zolpidem, salts, combinations thereof and simuar. The compounds of formula (I) can be administered together with the use of physical procedures such as with light therapy or electrical stimulation. In particular, the compounds of formula (I) can be administered in conjunction with a program of administration of bright light, exposure to light of normal intensity or exposure to dim light or darkness (or even during sleep). In one embodiment of the present invention, the compound of formula (I) is administered by disposing the individual of dark or red glasses at the time of administration to provide additive effects of the treatment plus darkness. In another embodiment of the present invention, the individual wears dark glasses at other times other than the time of administration of the compound of formula (I) to avoid the occurrence of an external phase shift with respect to the resulting phase shift of the compound of formula (I). Accordingly, the present invention further includes within its scope the use of a compound of formula (I), alone or in combination with other agents, to alter the circadian rhythm or for the prevention or treatment of sleep disorders and sleep disturbances. in a mammal. As used herein, the term "mammals" includes animals of economic importance such as bovine, ovine and porcine animals, especially those that produce meat, as well as domestic animals, competition animals, zoo animals and humans, being preferred. these last. It will be appreciated that when any combination described herein is used, both the compound of formula (I) and the other active ingredient (s) will be administered to a patient within a reasonable period of time. . The compounds can be in the same pharmaceutically acceptable carrier and, therefore, can be administered simultaneously. They can be in different pharmaceutical vehicles, as in conventional dosage forms that are taken simultaneously. The term "combination" also refers to the case where the compounds are provided in different dosage forms and are administered sequentially. Thus, by way of example, an active component can be administered as a tablet and then, within a reasonable period of time, the second active component can be administered as an oral dosage form such as a tablet or tma oral dosage form of rapid dissolution. By "rapid dissolution oral formulation" is meant an oral form of administration which, when placed on the tongue of a patient, dissolves in about 10 seconds. A "reasonable period of time" means a period of time that is not more than about 1 hour. That is, for example, if the first active component is provided as a tablet, then the second active component must be administered within a period of one hour, either in the same type of dosage form or in another dosage form that provides the effective release of the medication. The excellent pharmacological profile of the compounds of the present invention offers the opportunity of its use in therapy at low doses, thus reducing the risk of unwanted side effects. In the treatment of conditions associated with an excess of taqttikinins, a suitable dosage level is from about 0.001 to 50 mg / kg per day, in particular, from about 0.01 to about 25 mg / kg, such as about 0. , 05 to approximately 10 mg / kg per day. For example, in the treatment of conditions involving the neurotransmission of pain sensations, an appropriate dosage level is about 0.001 to 25 mg / kg per day, preferably about 0.005 to 10 mg / kg per day and, especially, from about 0.005 to 5 mg / kg per day. The compounds can be administered in a regimen of 1 to 4 times a day, preferably tma or twice a day. In the treatment of emesis using an injectable formulation, a suitable dosage level is from about 0.001 to 10 mg / kg per day, preferably from about 0.005 to 5 mg / kg per day and, especially, from 0.01 to 1 mg / kg per day. The compounds can be administered in a regimen of 1 to 4 times a day, preferably once or twice a day. It will be appreciated that the amount of a compound of formula (I) necessary for use in any treatment will vary not only with the particular compounds or composition selected, but also with the route of administration, the nature of the condition that is going to treat and the patient's age and esteem and, finally, will be at the discretion of the corresponding doctor. According to the general procedure (Al), the compounds of formula (I), in which the double bond represented by the dotted line is absent, can be prepared by the reduction of a corresponding compound of formula (I) in which the line of thiazos represents a double bond, which is referred to hereinafter as a formula (HA) (HA) wherein R1, R2, R3, R4, R5, R6, R9, R10 and X are as defined in relation to formula (I). Suitable conditions for reduction include: catalytic hydrogenation using a metal catalyst, such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as t alcohol, for example, methanol or ethanol, an ester, example, ethyl acetate, or an organic acid, for example acetic acid, or a mixture thereof; or reduction using trifluoroacetic acid or triethylsuan. Analogously, according to the general procedure (A.2), the compounds of formula (I) in which the double bond represented by the broken line is absent and X is two hydrogen atoms, can be prepared by reducing a compound of formula (IIB) (IIB) using the reaction conditions described in the procedure (A.1), above. According to another general procedure (B), the compounds of formtda (I), in which the dashed line represents a double bond, (ie, a compound of formula (IIA), above), can be prepared by the reaction of a compound of formula (III) (III) wherein each R45 is a C1-4 alkyl group, preferably methyl or n-butyl groups, with a compound of formula (IV) (IV) wherein R50 is a leaving group tel as triflate (-OSO2CF3) or tm halogen atom, for example, chlorine, bromine or iodine, especially triflate, bromine or iodine. Conveniently, the reaction is carried out in the presence of üthium chloride and a transition metal catalyst such as triphenphosphine palladium (0). Suitable solvents for the reaction include aromatic hydrocarbons, for example, toluene, polar aprotic solvents, for example, dimethylformamide, or ethers, for example, dioxane, the reaction being carried out at a temperature of about 80 ° C and the reflux temperature of the solvent.

According to another general procedure (C), the compounds of formula (I) can be prepared by the interconversion of tm corresponding compound of formula (I), wherein R6 is H, which is hereinafter referred to as formula (V) by reaction with a compound of formula (VI): wherein R a is a group of the formula R 6, as defined in relation to the formula (I) (other than H) or a precursor thereof and LG is a leaving group such as tm alu group or aru sulphonuoxi (eg example, mesylate or tosyrate) or a halogen atom (eg, bromine, chlorine or iodine); and if R6"is a precursor group, converting it to a R group (process in which any reactive group can be protected and then deprotected if desired.) This reaction can be carried out in a conventional manner, for example in an organic solvent such as ditnetuformamide , in the presence of an acid acceptor such as potassium carbonate.

Alternative methods suitable for the introduction of the R6 group are described, for example, in International Patent Application No. WO 95/18124, According to another general procedure (D), the compounds of formula (I) wherein R1 is C6-C6 alkoxy, C6-6 fluoro-alkoxy, C2-6 alkenoxy, C3-7 cycloalkoxy, C3-7-alkoxyG- or benzoyloxy cycloalkyl, can be prepared by the interconversion of a compound of formula (I) in which R1 is hydroxy, which is referred to hereinafter as formula (VII) (VII) by reaction with a suitable alkyl, fluoroalkyl, alkenyl, cycloalkyl, cycloalkalkyl or aralkyl halide, especially iodide, in the presence of a base. Suitable bases include alkali metal hydrides, such as sodium hydride, in a suitable solvent such as dimethylformamide. The reaction is conveniently carried out at about room temperature. According to another general procedure (E), the compounds of formula (I) can be prepared by the cyclization of a compound of formula (VIII).

(HIV) using suitable dehydrating reagents, for example, methanesulfonyl chloride or benzenesulfonyl chloride in pyridine or thiietuanamine. The reaction is conveniently carried out at a temperature comprised between CPC and 100 ° C, • preferably between room temperature and 80 ° C, using a suitable organic solvent such as dichloromethane, when necessary. The intermediates of formula (VIII) are particularly preferred for controlling the stereochemistry of the 3-position in the compounds of the formula (I). According to another general procedure (F), the compounds of formula (I) in which the broken line represents a double bond (i.e. • compound of formula (HA), above), can be prepared by the dehydration of a compound of formula (IX).

(IX) using an acid such as trifluoroacetic acid. The reaction is conveniently carried out at a temperature between 0 ° C and room temperature, using a suitable solvent such as dichloromethane. According to another general procedure (G), the compounds of Formula (I) in which the double bond represented by the dotted line is absent, can be prepared from a compound of formula (X) (X) and a compound of formula (IV), wherein Hal in the compound of formula (IV) is chlorine, bromine or, preferably, iodine, by a Heck reductive reaction using a palladium catalyst, such as palladium acetate, with, for example, tri-o-toluephosphine, dimethylformamide and tributylamine, or tetiabutylammonium chloride and dimethylformamide and a reducing agent, preferably formic acid or a salt of the Same, such as potassium formate. According to another general procedure (H), the compounds of formula (I) can be prepared from a compound of formula (XX) (XX) by reaction with lithium naphthalenide in tetrahydrofuran. The reaction is preferably carried out at reduced temperature, for example at about -78 ° C. Additional details of the suitable procedures will be found in the appended Examples. The compounds of formula (IIB) can be prepared using the method of the general process (F) described above, with the proviso that X in the compound of formula (IX) is two hydrogen atoms. The intermediates of formula (V) can be prepared in a manner similar to that described in general procedure (B), preferably with an amino protecting group on the piperidine nitrogen present in the compound of formula (III). Suitable amino protecting groups include alkoxycarbonyl groups such as tert-butoxycarbonyl and trichloroethoxycarbonyl, aralkyloxycarbonyl groups such as benzyloxycarbonyl, or aralkyl groups such as benzyl. The removal of the protecting group is carried out by conventional methods, thus, for example, the phorophoxycarbonyl groups can be removed under acidic conditions using, for example, trifluoroacetic acid; the tert-butoxycarbonyl groups, together with the benzyloxycarbonyl and benzyl groups, can also be removed by hydrogenolysis in the presence of a catalyst, for example palladium; and the trichloroethoxycarbonyl groups can be removed with zinc dust. The compounds of formula (III) can be prepared from a compound of formula (XII) (XII) wherein R50 is as previously defined (and is preferably tm thiiflate group or a bromine or iodine atom), by reaction with a compound of the formula (R45) 3Sn-Sn (R45) 3, for example, diamine hexamethyl. The reaction is conveniently carried out in the presence of a base, for example, lithium carbonate and a catalyst such as triphenylphosphine palladium (O). Suitable solvents for the reaction include ethers such as tetrahydrofuran, the reaction being carried out at a temperature between room temperature and 100 ° C, for example, at about 60 ° C. Compounds of formula (XII) wherein X is two hydrogen atoms, can be prepared from a compound of formula (XIII): (XIII) by enolization of the ketone in the presence of a base, for example, sodium hexamethylene diphosphate, followed by the reaction with a reagent capable of introducing a suitable leaving group, for example, wherein R50 is -OSO2CF3, using 2 - [-? -? ^ - bis (thiifluoro-metüsulfonü) ant-no] -5-chloropyridine or triflic anhydride. The reaction is conveniently carried out in a suitable solvent such as ether, for example, tetrahydrofuran, at a reduced temperature, for example, at -80 ° C. The compounds of formula (XIII) can be prepared from a compound of formula (XIV) by the following reaction sequences (Scheme A or Scheme B) or by analogous processes thereto (with the proviso that R9 and R10 are not oxo): SCHEME A SCHEME B (Xm) In a preferred embodiment of the processes mentioned above, R6 is a benzyl group. The reduction reaction described as process (A) above for the preparation of compounds of formula (I), can conveniently replace the benzyl group with a hydrogen atom. From the above discussion, it will be appreciated that the compounds of formula (I) wherein R6 is a hydrogen atom, are particularly preferred precursors for other compounds of formula (I). In an alternative procedure, the compounds of formula (III) wherein X is two hydrogen atoms, can be prepared by the following sequence of reactions (Scheme C) or by analogous processes thereto (with the proviso that R9 and R10 do not be oxo): SCHEME C In another preferred embodiment of the aforementioned processes, R6 is replaced by an amino protecting group, in particular, fer-butoxycarbonyl, which is conveniently removed prior to the reduction of the 7-aza-spiro [4.5] structure. 3-ene (general procedure (A)).

The compounds of formula (VII) can be prepared from the appropriate phenolic precursor (or a protected derivative thereof (eg, benzyloxy)) using the procedures of processes (A), (B) or (C). The compounds of formula (VIII) wherein X is two hydrogen atoms, can be prepared by reduction of a compound of formula (I) wherein X is an oxygen atom, using, for example, a borohydride such as borohydride of lithium or lithium triethylborohydride in tetrahydrofuran, or a hydride such as lithium aluminum hydride or dussobutylaluminum hydride. The compounds of formula (I) wherein X is an oxygen atom, can be prepared by the reduction of a compound of formula (HA) wherein X is an oxygen atom, using, for example, palladium acetate and formate potassium in a suitable solvent, such as dimethylformamide, at elevated temperature, for example at about 80 ° C; or using catalytic hydrogenation with palladium hydroxide or platinum on carbon, preferably in a suitable solvent such as an alcohol, for example methanol, n-ester, for example ethyl acetate, or an organic acid, for example acetic acid, or a mixture thereof; or using sodium borohydride and nickel chloride. In an alternative procedure, the compounds of formula (VIII) can be prepared by the reaction of a compound of formula (XIV) with a Grignard reagent of formula (XV) wherein R60 is a suitable hydroxy protecting group, preferably benzyl and Hal is a halogen atom, preferably chlorine, followed by removal of the R50 protecting group. The use of a chiral intermediate of formula (XV) is particularly suitable for controlling the stereochemistry of the 3-position in the compounds of formula (I). The compounds of formula (XV) can be prepared by conventional procedures well known in the art or based on the procedures described in the Examples herein. In another alternative procedure, the compounds of formula (VIII) can be prepared by the reduction of a compound of formula (XVI) (XVI) using, for example, catalytic hydrogenation in the presence of a metal catalyst such as palladium or platinum, or hydroxides or oxides thereof, preferably in a suitable solvent such as an alcohol, for example, methenol, an ester, eg, acetate of ethyl, or an organic acid, for example acetic acid, or a mixture thereof. The compounds of formula (XVI) can be prepared from a compound of formula (XVII) (XVII) by reaction with a compound of formula (IV), using Heck reducing conditions as described in the general process (G) above. The compounds of formula (XVII) can be prepared from compounds of formula (XIV) and, for example, a Grignard reagent prepared from O-trimethylsilylpropargyl alcohol, using the conventional methodology, followed by removal of the hydroxy protecting group. . According to another method, the compounds of formula (VIII) can be prepared from a compound of formula (XVIII) (XVIII) by reaction with borane in tetrahydrofuran, followed by an oxydative treatment using, for example, hydrogen peroxide and sodium hydroxide. The compounds of formula (XVIII) can be prepared from a compound of formula (XIV) and, for example, a Grignard reagent prepared from 2-aru-3-bromo-propene, using conventional methodology. The compounds of formula (IX) can be prepared by the reaction of a compound of formula (XIII) with a Grignard reagent, prepared from a compound of formula (IV), preferably using magnesium and a bromide of formula (IV) . The coupling reaction is conveniently carried out at reduced temperature, for example, at about 0 ° C, using a suitable solvent tel as an ether, for example, diethyl ether. The compounds of formula (X) can be prepared, for example, by the conversion of a stenan of formula (III) into the corresponding iodide, by treatment with iodine at reduced temperature, for example, at about -78 ° C, in a solvent suitable such as dichloromethane. Then, the iodine can be displaced to give the compound of formula (X) by treatment with, for example, a, a'-azo-isobutyronitrile and thibutibutyl hydride in a suitable solvent, for example, toluene, at an elevated temperature, example, at approximately 100 ° C. Alternatively, the compounds of formula (X) can be prepared by the cyclization of a compound of formula (XIX) (XIX) using the dehydration conditions described above for the general process (E) or using triphenylphosphine and diethylazodicarboxylate in a suitable solvent, such as tetrahydrofuran. The compounds of formula (XIX) can be prepared by partial reduction of an acetylene compound of formula (XVII). The reaction is conveniently carried out by catalytic hydrogenation using a metal catalyst, such as palladium on calcium carbonate, in the presence of a lead poison (for example, the Lindlar catalyst). A person of ordinary skill in the art will quickly be interrupted by other suitable procedures. The compounds of formula (XX) can be prepared from a compound of formula (VII) by reaction with (1-iodo-cycloprop-1-yl) -phenylsulfide. It will be appreciated that the compounds of the formula (I) in which R contains a substituent = O or = S, may exist in tautomeric forms. All such teutomeric forms and mixtures thereof are included in this invention. It is most convenient that the substituent = O or = S in R6 is the substituent = O. When not available in the market, intermediates of formula (IV) above can be prepared, for example, from the corresponding phenol derivative using, for example, the methods described in the appended examples, or by alternative methods that will be readily apparent for a specialist in the art. During any of the above synthetic sequences, sensitive or reactive protecting groups of any of the related molecules may be necessary and / or desirable. This can be achieved by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wüey & Sons, 1991. Protective groups can be eroded at a convenient later stage using procedures known in the art. The compounds exemplified in this invention were tested by the methods indicated on pages 36 to 39 of the International Patent Specification No. WO 93/01165. The compounds were found to be active with an IC 50 at the NKi receptor less than 100 nM in said assay procedure. The 3 (R) epidermal subclass of compounds of the present invention generally had an affinity for the human NK-1 receptor 2 to 5 times higher than that of the corresponding 3 (S) epimers. With the intention of avoiding doubts, the nomenclature used throughout this descriptive memory is based on the following structures: The following non-limiting Examples serve to illustrate the preparation of compounds of the present invention.

DESCRIPTION 1 (2-S l-fere-Butoxycarbonii-2-phenylpiperidin-3-one) Dimethyl sulfoxide (20.80 ml, 22.90 g, 29.3 mmol) in dichloromethene (75 ml) was added dropwise to a cooled solution. (-70 ° C) of oxalic chloride (13.95 ml, 20.30 g, 160 mmol) in dichloromethane (350 ml) The mixture was stirred at -70 ° C for 15 min and then added dropwise to the mixture. gofa (2.S, 3-S) -l-ferc-butoxycarbonii-3-hydroxy-2-phenypiperidine (prepared by the process described in European Patent Specification No. 0 528 495-A; 36.91 g, 133 mmol) in dichloromethane (150 ml) The mixture was stirred at -70 ° C for 20 min and then allowed to warm to -30 ° C. The mixture was cooled to -50 ° C and triethyl amine was slowly added (55 mL). 95 ml, 40.45 g, 400 mmol) The mixture was allowed to warm to 0 ° C and was diluted with ice-cold dichloromethane (250 ml) The mixture was washed with ice-cold aqueous citric acid solution (5 ml). %, 2 x 300 ml) and water (300 ml), dried (MgSO 4) and the solvent was Steam under reduced pressure, giving the title compound as a yellow oil (42.3 g), which was used immediately without further purification.

? NMR (250 MHz, CDCls) d 7.5-7.3 (5H, m), 5.8 (1H, s a), 4.2 (1H, s a), 3.4 (1H, m), 2.6 (2H, m), 2.0 (2H, m) and 1.54 (9H, s).

DESCRIPTION 2 (2-S ', 3i?) - l -' grc-Butoxycarbonii-3-hydroxy-3- (2-rnetalene-3-phenoxypropyl) -2-ferulpiperidine A solution of 3- (chloromagnesium) -2- (phenoxymethyl) ) -l-propene in THF (0.91M, 3 ml) (Louw et al., Tetrahedron, 48, 6087-6104, 1992, prepared from 2.74 mmoles of 3-chloro-2- (phenoxymethyl) - l-propane), was added slowly to a solution of (2-S) -l-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Description 1) in THF (3 ml). The mixture was stirred at room temperature for 1 h, then saturated aqueous ammonium chloride (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried (MgSO) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / EtOAc (100: 0 which was increased to 80:20) to give the title compound. ? NMR (360 MHz, CDCfe) d 7.48 (2H, d, J6.9 Hz), 7.35-7.2 (6H, m), 6.9-6.88 (3H, m), 5, 4 (1H, s), 5.15 (2H, d, J 13.7 Hz), 4.61 (2H, s), 4.11 (2H, m), 3.17 (1H, m), 2 , 66 and 2.59 (2H, AB d, J 14.0 Hz), 1.95 (2H, m), 1.79 (2H, m) and 1.36 (9H, s). m / z (ES +) 424 (M + 1).

DESCRIPTION 3 (5 / ?, 6) -3-Methylene-6-phen-1-oxa-7 - (- 'erc-butoxycarbon) aza-spiro [4,5] decane To a cooled solution (-80 ° C) of ( 2S, 3i?) - l-tórc-butoxicarbonü-3-hydroxy-3- (2-methylene-3-phenoxypro) ü) -2-phenylpiperidine (Description 2, 1.53 g, 3.62 mmol) in THF ( 20 ml) was added n-butyl lithium (2.5M in hexanes, 1.45 ml, 3.62 mmol) followed by a solution of zinc chloride (0.5M in THF, 7.24 ml, 3.62 mmol). ). The solution was allowed to warm to room temperature and tetrakis (thieniphenylphosphine) palladium (0) (0.23 g, 0.2 mmol) was added. The mixture was degassed by bubbling nitrogen and heated to reflux for 16 h. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and 2M NaOH. The organic phase was washed with saturated brine, dried (MgSO 4) and purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% and 5%). Evaporation of the fractions gave (6S, 5R) -3-methylene-6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4.5] decane. ? NMR (360 MHz, CDCls) d 7.58 (2H, d, J 8.4 Hz), 7.32-7.21 (3H, m), 5.23 (1H, s), 5.06 (1H , m), 4.97 (1H, m), 4.39 (2H, AB d, J 13.3 Hz), 3.99 (1H, dd, J 13.3, 4.48 Hz), 2, 83 (1H, ABd, J 15.5 Hz), 2.7 (1H, td J 12.5, 3.93 Hz), 2.5 (1H, ABd, J 15.4 Hz), 2.15 ( 2H, td, J12.4 Hz), 1.69 (2H, m) and 1.46 (9H, s). m / z (ES +) 329 (M + 2H-'BuOCO).

DESCRIPTION 4 (5?, 6-S ^ -3-Keto-6-phenyl-l-oxa-7 - (- 'grc-butoxycarbonu) aza-espiror4,51decano A mixture of ozone and oxygen was bubbled through 45 minutes through of a cooled (-80 ° C) solution of (5i?, 6-S) -3-methylen-6-phene-l-oxa-7 - (- 'e' c-butoxycarbon) aza-spiro [4,5 ] Dean (Description 3; 0.665 g) in CH2Cl2 (5 mL) and methanol (5 mL). After purging the solution with nitrogen, dimethyl sulfide (0.5 ml) was added and subsequently stirred under nitrogen at room temperature for 16 h. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO), evaporated and the residue was purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% and 10%). Evaporation of the fractions gave the title compound. * H NMR (250 MHz, CDCl 3) d 7.58 (2H, d, J6.2 Hz), 7.37-7.26 (3H, m), 5.3 (1H, s), 4.15 and 4.09 (2H, AB d, J 17.4 Hz), 3.97 (1H, m), 2.80 (1H, td, J 12.9, 4.0 Hz), 2.74 and 2.48 (2H, ABd, J 18.1 Hz), 2.29 (2H, m), 1.88-1.63 (2H, m) and 1.44 (9H, s). m / z (ES +) 332 (M + l).

DESCRIPTION 5 (5i?, 6-S ^ -3-Trifluoromethylsulfonuoxy-6-phene-l-oxa-7 - (- 'grc-butoxycarbonu) aza-spiro [4,5] dec-3-ene To a cooled solution (-80 ° C) of 1M sodium hexamethidisidase (0.38 ml, 0.38 mmol) in THF, a solution of (5i?, 6-S) -3-keto-6-phen-1-oxa-7 was added (tert-butoxycarbonu) aza-spiro [4.5] decane (Description 4, 0.105 mg, 0.319 mmol) in THF (3 mL) The solution was stirred for 1 h at -80 ° C and then a solution was added of 2- [N, N-bis (ti-? uoromethylsulfor-u) arnino] -5-chloropyridine (0.163 g, 0.415 mmol) in THF (3 mL) The solution was stirred at -80 ° C for 30 min. and then at room temperature for 30 min before inactivation by the addition of saturated ammonium chloride solution and ethyl acetate.The dried organic phase (MgSO) was purified by chromatography on a column containing silica gel (eluting with hexane which contained increasing proportions of ethyl acetate between 0% and 5%.) Evaporation of the fractions gave the comp Title: H NMR (360 MHz, CDCl 3) d 7.4 (2H, d, J7.3 Hz), 7.3-7.22 (3H, m), 6.01 (1H, t, J2, 13 Hz), 5.13 (1H, s), 4.56 and 4.26 (2H, ABdd, J12.4, 1.97 Hz), 4.10 (1H, dt, J 12.6, 4, 22 Hz), 3.00 (1H, m), 2.28-2.04 (2H, m), 1.88-1.76 (2H, m) and 1.37 (9H, s). m / z (ES +) 464 (M + 1).

DESCRIPTION 6 (5i?, 6-S ^ -3-Trimetüestar ü-6-fenü-l-oxa-7- (ferc-butoxicarbonü) aza-espiror4> 5] dec-3-ene To a degassed solution of (5i? 6-S) -3-thiifluoromethylsulphonoxy-6-phenyl-l-oxa-7- (tert-butoxycarbon) aza-es? Iro [4,5] dec-3-ene (Description 5, 0.482 g, 1.04 mmol ), lithium chloride (0.264 g, 6.25 mmole), lithium carbonate (0.076 g) and hexamethyl diestannane (0.96 g, 2.9 mmole) in THF (10 ml), palladium-thifenuphosphine (0) was added (0.06 g) The solution was degassed and then heated at 60 ° C for 5 h under nitrogen, water (20 ml) and ethyl acetate (20 ml) were added and the dry organic phase was purified by chromatography. in a column containing silica gel (eluting with hexane containing increasing proportions of ethylacetate between 0% and 5%). Evaporation of the fractions gave the title compound as a crystalline solid. 360 MHz, CDC-) d 7.25 (2H, d, J 7.3 Hz), 7.1-7.0 (3H, m), 5.83 (1H, t, J2.5 Hz), 4 78 (1H, s), 4 , 48 and 4.02 (2H, dd, J12.9, 2.3 Hz), 3.96 (1H, dd, J6, 16, 13.4 Hz), 2.95 (1H, td, J 13, 3, 4.5 Hz), 1.84 (1H, m), 1.68 (1H, m), 1.60 (2H, m), 1.19 (9H, s) and 0.0 (6H, s).

DESCRIPTION 7 (-ZS, 3J?) - l - 'Gr.-Butoxycarbonyl-3- (3-hydroxypropyl-l-ü) -2-phenylpiperidin-3-ol O-tr-methylsilyupropargyl alcohol (24.51) was slowly added. ml, 20.47 g, 160 ml) was added to a cooled solution (-10 ° C) of ethylmagnesium bromide (1M in tetrahydrofuran, 160 ml, 160 mmol). The mixture was stirred at 0 ° C for 20 min. and then at room temperature for 2 h. The mixture was cooled to -10 ° C and added dropwise during 30 min. a solution of (2S) -l-phenyl-cethoxycarbonyl-2-phenylpiperidin-3-one (Description 1; 42.3 g) in tetrahydrofuran (200 ml) (internal temperature below -5 ° C). The mixture was stirred at room temperature for 14 h, poured into water (300 ml) and saturated aqueous ammonium chloride (300 ml) and extracted with ethyl acetate (2 x 300 ml). The combined organic fractions were washed with brine (300 ml), dried (MgSO 4) and the solvent was evaporated under red pressure. The residue was dissolved in ethyl acetate (500 ml) and a solution of tetiabutylammonium fluoride (1M in tetrahydrofuran, 160 ml, 160 mmol) was added dropwise. The mixture was stirred at room temperature for 30 min., Water (300 ml) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 300 ml) and the combined organic fractions were washed with water (300 ml) and brine (300 ml), dried (MgSO) and the solvent was evaporated under red pressure to give the crude title compound in the form of an orange oil (45 g). The crude material was purified by flash chromatography on silica gel, eluting with hexane / EtOAc (90:10 increasing to 25:75) to give the title compound as an amber oil (32.2 g). ? NMR (CDCfe) d 7.53-7.55 (2H, m), 7.19-7.35 (3H, m), 5.56 (1H, s), 4.27 (2H, s), 3 , 99-4.03 (1H, m), 3.25 (1H, sa), 2.77-2.81 (1H, m), 2.77 (1H, sa), 2.12-2.20 (1H, m), 1.91-1.99 (2H, m), 1.77-1.83 (1H, m) and 1.39 (9H, s).

DESCRIPTION 8 (5?, 6S) -3-Tributüestannü-6-fenü-l-oxa-7-C-'grc-butoxycarbonii) aza-espiror4,51dec-3-ene It was dissolved (ZS ^ S ^ -l-íe c- crude butoxycarbonyl-S-IS-hydroxypropyl-l-ü) ^ - phenylpiperidin-3-ol (Description 7: 45 g) in toluene (750 ml) and degassed with nitrogen. Tetrakis (triphenylphosphine) palladium (0) (2.30 g, 2.0 mmole) in toluene (600 ml) was added and the mixture was degassed. Tribututan hydride (35.78 ml, 38.71 g, 133 mmol) was added dropwise over 15 minutes with stirring and cooling (internal temperature below 25 ° C). The mixture was stirred at room temperature for 1 h., Then, the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (600 ml) and thifenuphosphine (34.88 g, 133 mmol) was added. A solution of diethyl azodicarboxylate (20.94 ml, 23.16 g, 133 mmol) in tetrahydrofuran (150 ml) was added dropwise with stirring and cooling, and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure, acetonitrile (600 ml) was added and the mixture was extracted with hexane (8 x 150 ml). The hexane fractions were combined and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane / ethyl acetate (100: 0 increasing to 99: 1) to give the title compound as a yellow oil (53.64 g, 67%). % from (2 - ?, 3-S) -l --- grc-butoxycarbonii-3-hydroxy-2-phenylpiperidine). * H NMR (CDCls) d 7.38-7.40 (2H, m), 7.15-7.25 (3H, m), 5.96 (1H, t, J2.3 Hz), 4.93 (1H, s), 4.63 (1H, dd, J2.23, 12.9 Hz), 4.22 (1H, dd, J2.23, 12.9 Hz), 4.09-4.14 ( 1H, m), 3.09-3.17 (1H, m), 1.95-1.99 (1H, m), 1.83-1.86 (1H, m), 1.72-1, 76 (2H, m), 1.40-1.51 (6H, m), 1.38 (9H, s), 1.25-1.32 (6H, m) and 0.86-0.99 ( 15H, m).

DESCRIPTION 9 (2S, 3i?) - Etii 3- (l-tert-Butoxycarbonii-3-hydroxy-2-phenylpiperidin-3-yl) propinoate n-Butyl lithium (2.28 ml, 1.6M solution in hexanes, 3.64 mmol) was added to a cooled solution (-78 ° C) of ethyl propiolate (0.370 ml, 3.64 mmol) in tetrahydrofuran (10 ml). The solution was stirred for 10 min. at -78 ° C after completion of the addition and subsequently (2S) -l - / "grc-butoxycarbonyl-2-phenylpiyridin-3-one (Description 1, 1.0 g, 3.64 mmol) was added. tetrahydrofuran (10 ml), keeping the temperature below -75 ° C. The mixture was stirred for a further 10 min and then warmed to -60 ° C, at which point glacial acetic acid (1 ml) was added. The mixture was warmed to room temperature and poured into saturated aqueous sodium hydrogen carbonate (20 ml) The organic phase was separated and the aqueous phase was extracted with ethyl acetate (20 ml) The combined organic fractions were dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure.The residue was purified by flash column chromatography on silica gel, eluting with hexane / EtOAc (90:10), to give the title compound as a gum (801 mg, 59%). %). W NMR (250 MHz, CDC-b) d 7.50 (2H, m), 7.35 (3H, m), 5.49 (1H, s), 4.25 (2H, q, J7 , 12 Hz), 4.15 (1H, m), 3.02 (1H, m ), 2.23 (2H, m), 2.00 (2H, m), 1.78 (1H, m), 1.37 (9H, s) and 1.29 (3H, t, J7.12 Hz ). m / z (ES +) 374 (M + 1).

DESCRIPTION 10 (S ^^ - S ^ -ferc-Butoxycarboni-o-fenu-S-tributüestannü-l-oxa ^ -za-spiro ^ SIdec-S-en-2-one A mixture of (2S, 3R) -etü 3- (l-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine-3-yl) propinoate (Description 9, 524 mg, 1.4 mmol) and tetraqttis (triphenylphosphine) palladium (0) (50 mg) in toluene (10 ml ) was degassed with nitrogen for 30 min, then tributary tin hydride (0.405 mM, 1.5 mmol) was added dropwise and the resulting mixture was stirred at 23 ° C. for 2 h.The solvent was evaporated under reduced pressure. and the residue was taken up in ethyl acetate (50 ml) The mixture was washed with saturated aqueous sodium hydrogen carbonate (50 ml), dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure.The residue was purified by flash chromatography silica gel to give the title compound as a gum (538 mg, 0.87 mmol, 62%).? NMR (250 MHz, CDCl 3) d 7.63 (1H, s), 7.30 (5H , m), 5.11 (1H, s), 4.17 (1H, m), 3.10 (1H,), 2.19 (1H, m), 1.80 (3 H, m), 1.30-1.50 (12H, m), 1.40 (9H, s), 1.02 (6H, m) and 0.88 (9H, t, J7.22 Hz). m / z (ES +) 619 (M + l) DESCRIPTION 11 2-Bromo ^ r- (trifluoromethoxy) phenol To a cooled solution (0 ° C) of 4-trifluoromethoxyphenol (35.6 g, 0.2 mol) in chloroform (280 ml), a solution of bromine was added dropwise. (32 g, 0.2 mol) in chloroform (50 ml). The solution was stirred at 0 ° C for 1 h. and at room temperature for 2 h. Dichloromethane (200 ml) and water (400 ml) were added and the organic phase was further washed with water (400 ml), with brine (200 ml) and dried (MgSO 4). The solvent was removed and the residue was purified by distillation under reduced pressure to give the title compound. ? NMR (250 MHz, CDCl 3) d 7.38 (1H, d, J 2.1 Hz), 7.13 (1H, dd, J9, 1, 2.1 Hz), 7.03 (1H, d, J9, 1 Hz) and 5.53 (1H, s).

DESCRIPTION 12 2-Bromo-4 - (, trifluoromethoxy) anisole To a solution of 2-bromo-4-thiifluoromethoxyphenol (Description 11, 7.2 g) and potassium carbonate (11.6 g, 0.084 mol) in dimethylformamide (60 ml), added methyl iodide (14.94 ml, 0.24 moles). The solution was stirred for 15 h. at room temperature under nitrogen, after which water (400 ml) and diethyl ether (200 ml) were added and the organic phase was washed with water (4x200 ml), with saturated NaHCO3 (2x200 ml) and with brine (200 ml). ml) and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (0-2%) to give the title compound. ? NMR (250 MHz, CDCl 3) d 7.45 (1H, d, J2.8 Hz), 7.16 (1H, dd, J9.0, 2.8 Hz), 6.88 (1H, d, J9, 0 Hz) and 3.90 (3H, s).

DESCRIPTION 13 2-Bromo-4-thiifluoromethoxy-isopropoxybenzene To a solution of 2-bromo-4-trifluoromethoxyphenol (Description 11: lg, 3.9 mmol) and K2CO3 (l, lg, 7.8 mmol) in dimethylformamide (15 ml), 2-Bromopropane (0.55 mL, 5.9 mmol) was added. The solution was stirred for 14 h. at room temperature under a nitrogen atmosphere. Water (200 ml) and ethyl acetate (3 × 70 ml) were added to the solution and the organic phase was washed with water (100 ml) and with brine (100 ml) and dried (MgSO 4). The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (eluting with 5% ethyl acetate in hexane) to give the title compound. ? NMR (250 MHz, CDCB) d 1.38 (6H, d, J6, l Hz), 4.53 (1H, m), 6.88 (1H, d, J, 9 Hz), 7.12 (1H, dd, J8.8, 2.6 Hz) and 7.43 (1H, d, J 2.8 Hz).

DESCRIPTION 14 2-Bromo-4-thiifluoromethoxy-alyloxybenzene To a solution of 2-bromo-4-thiifluoromethoxyphenol (Description 11; 8 g, 0.03 mol) and K2C? 3 (8.6 g, 0.06 mol) in dimethylformamide (100 ml), water bromide (4 ml, 0.045 mol) was added. The solution was stirred for 4 h. at room temperature under nitrogen, after which water (400 ml) and ethyl acetate (3x100 ml) were added and the organic phase was rinsed with water (200 ml) and saturated brine (200 ml), dried (MgSO4). and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluting with 5% ethyl acetate in hexane) to give the title compound as a yellow oil X H NMR (250 MHz, CDCl 3) d 4.60 (2H, dt) , J 5, 1.6 Hz), 5.33 (1H, dq, J 10.5, 1.4 Hz), 5.48 (1H, dq, J 17.3, 1.6 Hz), 6, 04 (1H, m), 6.86 (1H, d, J9 Hz), 7.13 (1H, dd, J8.4, 2.7 Hz) and 7.45 (1H, d, J2.8 Hz) .

DESCRIPTION 15 2-Bromo-6- (prop-2-enu) -4-trifluoromethoxyphenol 2-Bromo-4-trifluoromethoxy-alyloxybenzene (dec 14; 8.6 g) was heated at 200 ° C for 7 h. and the cooled residue was purified by chromatography on silica gel (eluting with 1% ethyl acetate in hexane) to give 2-bromo-6- (prop-2-enyl) -4-trifluoromethoxyphenol as a yellow oil. * H NMR (250 MHz, CDQb) d 3.43 (2H, d, J6.6 Hz), 5.13 (2H, m), 5.60 (1H, s), 5.98 (1H, m), 6.98 (1H, d, J2 , 4 Hz) and 7.24 (1H, d, 2.4 Hz).

DESCRIPTION 16 2-Bromo-6- (2-hydroxyethyl) -4-thiifluoromethoxyphenol A mixture of ozone was bubbled in oxygen for 4 h. through a cooled solution (-78 ° C) of 2-bromo-6- (prop-2-enü) -4-trifluorornetoxyphenol (Description 15, 5.9 g, 0.02 mole) in dichloromethane (30 ml) and methanol (30 ml). After purging the solution with nitrogen for 1 h., sodium borohydride (0.755 g) was added and then stirred at room temperature for 15 h. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water containing 2 M HCl (20 ml). The organic phase was washed with saturated brine, dried (MgSO 4) and the solvent was evaporated in vacuo. The residue was chromatographed on silica gel (eluting with 20% ethyl acetate in hexane) to give the title compound. JH NMR (250 MHz, CDCl 3) d 2.93 (2H, t, J5.6 Hz), 3.98 (2H, t, J5.4 Hz), 6.96 (1H, d, J2.5 Hz) and 7.3 (lH, d, J2.4 Hz).

DESCRIPTION 17 7-Bro-no-5-trifluoromethoxy-2,3-dihydrobenzofuran To a cooled (0 ° C) solution of triphenylphosphine (6.11 g, 0.0234 mole) in tetrahydrofuran (40 ml), diethylazodicarboxylate (3 ml) was added. , 7 ml, 0.0234 moles). The solution was stirred for 30 min, after which a solution of 2-bromo-6- (2-hydroxyethyl) -4-trifluoromortoxyphenol (Des 16, 5.4 g, 0.018 mol) in tetrahydrofuran was added.

The solution was stirred at room temperature for 15 h. and then the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, the solution was washed with water and saturated brine and dried (MgSO4). After removing the solvent in vacuo, the residue was purified by chromatography on silica gel (eluting with 10% ethyl acetate in hexane) to give the title compound as a pink oil. ? NMR (250 MHz, CDCl 3) d 2.93 (2H, t, J 5.6 Hz), 3.98 (2H, t, J 5.4 Hz), 6.96 (1H, d, J2.5 Hz) and 7.30 (1H, d, J2.4 Hz).

DESCRIPTION 18 l-Benzyloxy-4- (2,2,2-trifluoroethoxy) benzene To the solution of 4-benzyloxyphenol (5 g) and 2,2,2-thiifluoroetura-.-toluenesulfonate (5 g) in dimethylformamide (50 ml), Sodium hydride (dispersion in 60% oil, 2.3 g) was added and the solution was heated at 110 ° C for 16 h. The mixture was cooled, ducted with water and the product extracted into ethyl acetate. The organic phase was washed with water and brine and dried (MgSO). The solvent was removed in vacuo and the residue was chromatographed on silica gel (eluting with 10% diethyl ether / hexane) to give the title compound as a solid, m.p. 72-74 ° C.

DESCRIPTION 19 4- (2,2,2-Trifluoroethoxy) phenol A solution of l-benzyoxy-4- (2,2,2-trifluoroethoxy) benzene (Description 18.5 g) and palladium (10% on carbon; 0.1 g) in methanol (50 ml), was hydrogenated at 50 psi (344.737 kPa) for 12 h. The solution was filtered and the solvent was removed in vacuo to give the title compound as a colorless solid m.p. 60-64 ° C.

DESCRIPTION 20 2-Bromo-4- (2,2,2-thiifluoroethoxy) phenol To a cooled solution (0 ° C) of 4- (2,2,2-trifluoroethoxy) phenol (Description 19) in a mixture of acetic acid and chloroform (20 ml, 1: 1), a solution of bromine (0.83 g) in chloroform (5 ml) was added. The mixture was stirred for 10 min. and it was diluted with chloroform, then washed with water (2x50 ml), dried (MgSQt) and evaporated to give the title compound as an oil. H NMR (250 MHz, CDCfe) d 4.33 (2H, q, J8 Hz), 6.83 (1H, dd, J2.8, 8.8 Hz), 6.97 (1H, d, J8.8 Hz) and 7.10 (lH, d, J2.8 Hz).

DESCRIPTION 21 2-Bromo-4- (2,2,2-thiifluoroethoxy) anisole To a solution of 2-bromo-4- (2,2,2-trifluoroethoxy) phenol (Description 20, 0.6 g) in acetone was added K2CO3 (1 g) and methyl iodide (1 ml). The solution was heated to reflux for 1 h. and then it was vaporized under vacuum. The residue was partitioned between ethyl acetate and water and the organic phase was further washed with water and saturated brine. After drying (MgSO4) the solvent was removed in vacuo to give the title compound as a yellow oil. X H NMR (250 MHz, CDCl 3) d 3.87 (3 H, s), 4.30 (2 H, q, J 8 Hz), 6.82-6.92 (2 H, m) and 7.20 (1 H, d, J 3 Hz).

DESCRIPTION 22 2,5-Bis (2,2,2-thiifluoroethoxy) bromobenzene To a solution of 2-bromo-4- (2,2,2-trifluoroethoxyphenol (Description 20; 0.83 g, 3.06 mmol) and sodium hydride (60% in oil, 0.367 g, 9.18 mmol) in dimethylformamide (10 mL), was added 2,2,2-trifluoroetyl- / -toluenesulfonate (l. , 17g, 4.6-mmol). The mixture was heated at 100 ° C for 10 h, cooled and diluted with ethyl acetate and water. The organic phase was washed with water and saturated brine, dried (MgSO) and evaporated in vacuo. The residue was purified by chromatography on silica gel (eluting with 2% ethyl acetate in hexane) to give the title compound as an oil. ? NMR (250 MHz, CDCl 3) d 4.32 (4H, m), 6.89 (2H, m) and 7.20 (1H, d, J4, 1 Hz) DESCRIPTION 23 2-Bromo-l- (difluoromethoxy) -4- (trifluoromethoxy) benzene To a solution of 2-bromo-4- (trifluoromethoxy) phenol (Description 11; .14 g) in dirnetüform.amide, sodium hydride (0.96 g, 60% in oil) was added slowly. After stirring for 20 min. a slow stream of chlorodifluoromethane was bubbled through the solution for 10 min. The mixture heated to 60 ° C for 2 h., Cooled, diluted with water and the solution extracted with diethyl ether (2x100 ml). the organic phases were combined, washed with water and saturated brine, and dried (MgSO) and evaporated in vacuo. The residue was chromatographed on silica gel (eluting with hexane) to give the title compound as a solid. i H NMR (250 MHz, CDCl 3) d 6.53 (1 H, t, J 7.2 Hz), 7.17-7.29 (2 H, m) and 7.51 (lH, d, J2.5 Hz).

DESCRIPTION 24 2-Bromo-l- (2,2,2-trifluoroethoxy) -4- (trifluoromethoxy) benzene To a solution of 2-bromo-4-trifluoromethoxyphenol (Description 11; 2g) and 2,2,2-trifluoroetü-p- toluene sulfonate in cümetüformamide (30 ml), sodium hydride (2 g, 60% in oil) was added slowly and the mixture was heated at 110 ° C for 12 h. The mixture was cooled, ducted with water (300 ml) and extracted with ethyl acetate (2 x 50 ml). The organic phases were washed with water and saturated brine and dried (MgSO4). The solvent was removed in vacuo and the residue was chromatographed on silica gel (eluting with diethyl ether / hexane (1:10)) to give the title compound as a colorless oil. * H NMR (250 MHz, CDCl 3) d 4.40 (2H, q, J8 Hz), 6.95 (1H, d, J 9 Hz), 7.15-7.20 (1H, m) and 7, 48-7.49 (1H, m).

DESCRIPTION 25 2-Bromo-4-fluoro- (2,2,2-trifluoroethoxy) benzene A th solution of 2-bromo-4-fluorophenol (4 g) and 2,2,2-trifluoroethoxy-β-toluene sulfonate (5 g) in dimethylformamide (40 ml), sodium hydride (1 g, 60% in oil) was slowly added and the mixture was then heated at 110 ° C for 12 h. The solution was cooled, diluted with water (500 ml) and the product extracted into ethyl acetate (2 x 150 ml). The organic phase was washed with saturated NaHCO3 solution, water and saturated brine and dried (MgSO). The solvent was removed in vacuo and the residue was chromatographed on silica gel (eluting with diethyl ether / hexane (1: 5)) to give the title compound as a colorless oil. H NMR (250 MHz, CDCl 3) d 4.36 (2H, q, J8 Hz), 6.91-7.05 (2H, m) and 7.33 (1H, dd, J8, 3 Hz).

DESCRIPTION 26 4- (Methanesulfonyl) phenol Oxone (65.8 g, 0.108 mol) in water (290 i) was added to a cooled solution (ice bath) of 4- (methyl mercapto) phenol (5 g, 36 mmol) in methanol ( 290 ml). The resulting solution was stirred at room temperature for 48 h. and then concentrated to vacuum. The residue was diluted with water (100 ml) and extracted with dichloromethane (10 x 100 ml). The combined organic layers were dried over sodium sulfate and removal of the solvent in vacuo gave the title compound as a tiansparent oil (5.66 g, 92%). ? NMR (250 MHz, CDCl 3) d 7.80-7.75 (2H, d, J 11.7 Hz), 7.28 (1H, sa), 7.01-6.96 (2H, d, Jll, 7 Hz) and 3.08 (3H, s).

DESCRIPTION 27 2-Bromo-4- (methanesulfonyl) phenol A solution of bromine (0.9 ml, 17.45 mmol) in glacial acetic acid (10 ml) was added dropwise to an agitated solution of 4- (methanesulfonyl) phenol ( Description 26; 3 g, 17.45 mmol). The resulting solution was stirred at room temperature for 16 h. Grop to gofa bromine (0.45 ml) in glacial acetic acid (5 ml) was added and the solution was stirred for 2 h. The excess acetic acid and bromine were removed in vacuo and the residue made azeotropic with toluene, to give the desired compound as an off-white solid (3.54g, 81%). ? NMR (250 MHz, CDCls) d 8.06-8.05 (1H, d, J2.3 Hz), 7.73-7.69 (1H, dd, J8.6, 2.3 Hz), 7, 06-7.02 (1H, d, J8.6 Hz) and 3.06 (3H, s).

DESCRIPTION 28 2-Bromo-4- (methanesulfonyl) anisole Potassium carbonate (2.31 g, 16.8 mmol) was added to a solution of 2-bromo-4- (methanesulfonyl) phenol (Description 27, 3.5 g, 14 mmol ) in dirnetilfor-mamida (50 ml). The resulting solution was stirred for 30 min. and methyl iodide (1.04 mL, 16.8 mmol) was added. After stirring for 1 h., The solution was poured into water (200 ml) and extracted with ethyl acetate (2x100 ml). The combined organic extracts were washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave a white solid which was crystallized from diethyl β-ether to give the title compound (2.02 g). * H NMR (250 MHz, CDCl 3) d 8.12-8.11 (1H, d, J2.2 Hz), 7.90-7.86 (1H, dd, J8.7, 2.2 Hz), 7.04-7.00 (1H, d, J8.7 Hz), 3.99 (3H, s) and 3.05 (3H, s).

DESCRIPTION 29 3-Bromo-4- (cyclobutyloxy) thiifluoroanisole 2-bromo-4- (thiifluoromethoxy) phenol (Description 11, 1.5 g, 5.83 mmol) and cyclobutyl bromide (3.0 g, 17.5 mmol) were dissolved. ) in dimethylformamide (10 ml). Potassium carbonate (4.85 g, 35 mmol) was added and the solution was stirred at 50 ° C for 16 h. The solution was allowed to cool to room temperature, poured into a 10% solution of citric acid (50 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave an oil which was chromatographed on silica in 10% ethyl acetate / hexane, to give the title compound as an oil (1.65 g, 91%). ? NMR (250 MHz, CDCl 3) d 7.44-7.42 (1H, m), 7.12-7.07 (1H, m), 6.73-6.70 (1H, d, J9.0 Hz ), 4.71-4.60 (1H, m), 2.52-2.41 (2H, m), 2.30-2.18 (2H, m) and 1.92-1.55 (2H) , m).

DESCRIPTION 30 2- (2-Hydroxyethoxy) -5- (trifluoromethoxy) bromobenzene Prepared from the compound of Description 14 according to the procedure of Description 16. * H NMR (360 MHz, CDCl 3) d 2.20 (1H, t , J 6.3 Hz), 4.0 (2H, q, J5.6 Hz), 4.13 (2H, q, J4.2 Hz), 6.91 (1H, d, J9 Hz), 7, 15 (1H, m) and 7.45 (lH, d, J2.3 Hz).

DESCRIPTION 31 2- (2-Fluoroethoxy) -5- (thiifluoromethoxy) bromobenzene A tma cooled suspension (-78 ° C) of 2- (2-hydroxyethoxy) -5- (trifluoromethoxy) bromobenzene (Description 30, 8.9 g, 30 mmol ) in dichloromethane (80 ml), diethylamine sulfide trifluoride (3.88 ml, 31.5 mmol) was added. The solution was stirred at room temperature for 2 h. and then inactivated by dropwise addition of water (100 ml). The organic layer was separated, washed with brine (100 ml), dried (MgSO 4) and evaporated in vacuo. Purification on silica, eluting with 15% -20% ethyl acetate in hexane, gave the title compound as tm-oil oil (1.9 g, 15%). i H NMR (360 MHz, CDCl 3) d 4.23 (1 H, m), 4.31 (1 H, m), 4.37 (1 H, m), 4.86 (1 H, m), 6.90 (1 H , m), 7.15 (1H, m) and 7.47 (1H, t, J0.7 Hz).

DESCRIPTION 32 2-Bromo-4- (trifluoromethoxy) phenol trifluoromethanesulfonate To a cooled (0 ° C) solution of 2-bromo-4- (trifluoromethoxy) phenol (Description 11, 10 g, 40 mmol) in pyridine (20 ml), add trifluoromethanesulfonic anhydride (7.2 mL, 44 mmol) and the reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated copper (II) sulfate (80 ml) and extracted into ethyl acetate (3 x 60 ml). The organic fractions were washed with water (80 ml) and brine (80 ml), dried (MgSO 4) and evaporated in vacuo. Purification on silica, eluting with hexane, gave the title compound as a clear oil tm (13.1 g, 85%). * H NMR (250 MHz, CDCfe) d 7.28 (1H, m), 7.40 (1H, d, J9, 1 Hz) and 7.58 (1H, d, J2.8 Hz).

DESCRIPTION 33 2- (Eten-1-ü) -5- (trifluoromethoxy) bromobenzene A mixture of 2-bromo-4- (trifluoromethoxy) phenyl trifluoromethanesulfonate (Description 32, 1.8 g, 4.6 mmol), tributyltin (1) , 61 g, 5.1 mmol) and lithium chloride (1.18 g, 27.6 mmol) in A ^ N-dimethylformamide (20 ml), was degassed before the addition of dichloro-bis (thiophenephosphine) palladium ( II). After further degassing, the reaction mixture was heated at 110 ° C for 14 h. The solution was partitioned between water (70 ml) and ethyl acetate (3x50 ml). The combined organic fractions were washed with brine (50 ml), dried (MgSO 4) and evaporated in vacuo. Purification on silica, eluting with hexane, gave the title compound as a clear oil (780 mg, 64%). ? NMR (250 MHz, CDCla) d 5.40 (1H, dd, J 9.1 Hz J 1.8 Hz), 5.70 (1H, dd, J 10.5 Hz, J 0.5 Hz), 7 , 0 (1H, m), 7.16 (1H, m), 7.44 (1H, d, Jl, 4 Hz) and 7.56 (1H, d, J8.7 Hz).

DESCRIPTION 34 2-Benzyloxy-5- (thiifluoromethoxy) bromobenzene 2-Bromo-4- (thiifluoromethoxy) phenol (Description 11.5 g, 20 mmol) was dissolved in iV, iV-dimethylformamide (60 ml), potassium carbonate (5, 4 g, 40 mmol), followed by benzyl bromide (3.5 ml, 30 mmol) and the reaction was stirred at room temperature for 15 h. The reaction was diluted with water (150 ml) and extracted into ethyl acetate (3 x 60 ml). The combined organic fractions were washed with water (100 ml) and brine (100 ml), dried (MgSO) and evaporated in vacuo. Purification on silica, eluting with 2% ethanol acetate and 5% in hexane, gave the title compound as a clear oil (6.7 g, 96%). ? NMR (250 MHz, CDCI-3) d 5.47 (2H, s), 7.23 (1H, d, J9 Hz), 7.43 (1H, dd J8.2, 2.9 Hz) and 7.75 (6H , m).

DESCRIPTION 35 2-Bromo-4- (thiifluoromethy) phenol Prepared from 4- (thiifluoromethyl) phenol according to the procedure of Description 11. * H NMR (250 MHz, CDCl 3) d 7.06 (1H, dd, J8, 5, 0.5 Hz), 7.4 (1H, dd, J 6.5, 2.0 Hz), 7 ^ (1H, d, J 1.7 Hz) and 8.93 (1H, s).

DESCRIPTION 36 l-Benzyloxy-2-bromo-4- (trifluoromethyl) benzene 2-Bromo-4- (trifluoromethyl) phenol (Description 35, 3.85 g) and benzyl bromide (2.36 ml) were dissolved in dimethylformamide and added potassium carbonate (6.8 g). The mixture was stirred at 60 ° C for 3 h. The mixture was diluted with water (200 ml) and extracted with ethyl acetate. The organic fractions were dried (MgSO) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / ethyl acetate (99: 1 increasing to 95: 5) to give the title compound. * H NMR (360 MHz, CDCl 3) d 5.21 (2H, s), 6.98 (1H, d, J8.65 Hz), 7.31-7.51 (6H, m) and 7.82 ( 1H,?, Jl, 7 Hz).

DESCRIPTION 37 (3-S, 5R> 6-S -3- (2-Methoxy-5-thiifluorornetoxüenü) -6-fenü-l-oxa-7 - (- 'grc-butoxycarbonyl) aza-spiro [4,51decan-3 -ol 2-Bromo-4-trifluoromethoxyanisole (Description 12, 417 mg, 1.54 mmol) in portions to magnesium (41 mg, 1.7 mmol) in diethyl ether (1 ml), under a nitrogen atmosphere and the mixture briefly heated to reflux after each addition. After the addition was complete, the mixture was heated to reflux for 30 min, during which time most of the magnesium was dissolved. The solution was cooled to room temperature and was added drop by drop to a cooled (0 ° C) solution of (5i? 6.S) -3-keto-6-phenyl-1-oxa-7- (tert-butoxycarbon). ) aza-spiro [4.5] decane (Description 4, 212 mg, 0.64 mmol) in diethyl ether (10 ml). The mixture was stirred at 0 ° C for 10 min. and at room temperature overnight. Saturated aqueous ammonium chloride (40 ml) was added and the mixture was extracted with ethyl acetate (2 x 40 ml). The combined organic fractions were washed with brine (20 ml), dried (MgSOt) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / hexane (1: 5) to give the title compound as a pale foam (240 mg, 72%). i H NMR (360 MHz, CDCl 3) d 1.47 (9H, s), 1.52-1.71 (3H, m), 2.17-2.22 (1H, m), 2.42 (1H, d, J13.5 Hz), 2.56 (1H, d, J13.5 Hz), 2.77-2.84 (1H, m), 3.89 (3H, s), 3.96-4, 00 (1H, m), 4.20 (1H, d, J 9.5 Hz), 4.29 (1H, d, J 9.5 Hz), 5.78 (1H, s), 6.90 ( 1H, d, J 8.9 Hz), 7.13-7.16 (1H, m), 7.21-7.25 (1H, m), 7.30-7.35 (1H, m) and 7.62 (2H, d, J 7.7 Hz). m / z (ES-) 524 (M + 1).

DESCRIPTION 38 Z- (2S'f3i -) - 3-a-, erc-Butoxycarbonii-3-hydroxy-2-phenylpiperidin-3-y) -2- (2-methoxyphenyl) prop-2-en-l-ol acid was added formic (138 val, 3.77 mmol) to an agitated and degassed solution of (2S, 3?) - l- / grc-butoxycarbonyl-3- (3-hydroxypro-in-1-y) -2-phenylpiperidine- 3-ol (Description 7, 473 mg, 1.43 mmol), palladium (II) acetate (33 mg, 0.14 mmol), tri-o-tolylphosphine (85 mg, 0.28 mmol), tributylamine (1 , 12 ml, 4.87 mmol) and 2-iodoanisole (446 ml, 3.44 mmol) in i, iV-dimethylformamide (3 ml) at room temperature, and the resulting mixture was heated at 70 ° C for 5 h. The mixture was cooled, filtered, diluted with ethyl acetate (50 ml), washed with water (100 ml), hydrochloric acid (2 M, 50 ml) and saturated aqueous sodium chloride (50 ml), dried ( MgSO 4) and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with hexane / ethyl acetate (60:40) to give the title compound as a yellow crystal (220 mg, 35%). ? NMR (360 MHz, CDCls) d 7.41 (2H, d, J7.6 Hz), 7.22-7.34 (4H, m), 7.12 (1H, dd, J l, 7, 7, 4 Hz), 6.94 (1H, t, J7.5 Hz), 6.89 (1H, d, J8.2 Hz), 5.84 (1H, s), 5.00 (1H, s), 4.40 (1H, d, J12.7 Hz), 4.15 (1H, dd, J6.0, 13.1 Hz), 4.05 (1H, d, J12.5 Hz), 3.86 ( 3H, s), 3.44 (1H, dt, J5.6, 12.3 Hz), 2.04-2.18 (1H, m), 1.80-1.96 (3H, m), 1 , 28 (9H, s) and 1.64-1.84 (3H, m). m / z (ES +) 440 (M + l).

DESCRIPTION 39 (-Z> 3 ^, 2'J?) - 3-g - 'grc-Butoxycarbonii-3-hydroxy-2-phenylpiperidine-3-ü) -2 - (' 2-methoxypheni) pro? An- l-ol and (Zy ^ - ^^ '- S ^ -Sd-ferc-butoxycarbonii-S-hydroxy ^ -phenylpiperidin-3-y) -2- (2-methoxypheni) propan-l-ol Palladium hydroxide was added (II) on carbon (20%, 78 mg) to a solution of Z- (2-S ', 3R) -3- (l-' grc-butoxycarbonii-3-hydroxy-2-phenylpiperidine-3-ü) -2- (2-methoxyphenyl) prop-2-en-l-ol (Description 38, 78 mg, 0.18 mmol) and acetic acid (2 ml) in methanol (10 ml) and the mixture was hydrogenated at 50 psi (344,737 kPa) with stirring for 5 h. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (20 ml), washed with saturated sodium carbonate solution (10 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by preparative layer chromatography on silica, eluting with hexane / ethyl acetate (80:20) to give the title compound as a 1: 3 mixture of the 2'R and 2'S epimers (22 mg, 28%). * H NMR (360 MHz, CDGb) d 7.45-7.61 (2H, m, 3R and 3S isomers), 7.16-7.37 (5H, m, 3R and 3S isomers), 6.85- 6.98 (2H, m, 3R and 3S isomers), 5.17 (1H, s, 3R isomer), 5.04 (1H, s, 3S isomer), 3.96-4.04 (1H, m, 3R and 3S isomers), 3.83 (3H, s, 3R isomer), 3.82 (3H, s, 3S isomer), 3.46-3.84 (3H, m, 3R and 3S isomers), 3, 04-3.20 (1H, m, 3R and 3S isomers), 1.64-2.40 (8H, m, 3R and 3S isomers), 1.32 (9H, s, 3S isomer) and 1.27 ( 9H, s, 3R isomer). m / z (ES +) 442 (M + 1).

DESCRIPTION 40 2-Bromo-4-nitrophenol A drop to a drop of bromine (27 ml) was added to a stirred solution of 4-nitrophenol (50 g) in glacial acetic acid (400 ml) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was crystallized from dichloromethane: hexane to give the title compound as a colorless solid (67 g). ? NMR (250 MHz, CDOb) d 8.44 (1H, d, J2.6 Hz), 8.16 (1H, dd, J2.6, 8.9 Hz) and 7.13 (1H, d, J9, 0 Hz).

DESCRIPTION 41 2-Isopropoxy-5-nitrobromobenzene A mixture of 2-bromo-4-nitrophenol (Description 40, 2.5 g), 2-iodopropane (2.2 g) and potassium carbonate (5 g) in acetone (30 ml), it was heated to reflux for 18 h. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane / EtOAc (90:10) to give the title compound (2.8 g, 94%). * H NMR (250 MHz, CDCla) d 8.46 (1H, s), 8.20 (1H, m), 6.93 (1H, m), 4.75 (1H, m) and 1.42 ( 6H, d, J7.5 Hz).

DESCRIPTION 42 2- (Difluoromethoxy) -5-nitiobromobenzene Prepared from the compound of Description 40, according to the procedure of Description 23.? NMR (360 MHz, CDO) d 8.54 (1H, d, J 2.6 Hz), 8.22 (1H, dd, J9.0, 2.6 Hz), 7.38 (1H, d, J9 , 0 Hz) and 6.68 (1H, t, J71.7 Hz).

DESCRIPTION 43 3-Bromo-4-methoxyaniline A mixture of 3-bromo-4-methoxynothiobenzene (15 g, 64.6 mmol) and iron powder (27.3 g, 0.49 mol) in water (100 ml) and acetic acid glacial (25 ml) was heated to reflux for 2 h. The mixture was cooled and filtered through a layer of Hyflo ™, washing with 25% acetic acid / water. The filtrate was extracted with ethyl acetate (2 x 250 ml), the combined organic fractions were dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica, eluting with hexane / EtOAc (60:40) to give the title compound as a brown solid (10.32 g, 79%). m / z (ES +) 202 (M + 1).

DESCRIPTION 44 3-Bromo-4-isopropoxyanuin Prepared from the compound of Description 41 according to the procedure of Description 43. iH NMR (250 MHz, CDCl 3) d 6.91 (1H, d, J2.7 Hz), 6 , 78 (1H, d, J8.6 Hz), 6.57 (1H, dd, J2.9, 8.8 Hz), 4.33 (1H, m) and 1.32 (3H, d, J5, 6 Hz).

DESCRIPTION 45 3-Bromo-4- (difluoromethoxy) aniline Prepared from the compound of Description 42 according to the procedure of Description 43.

DESCRIPTION 46 • 3-Bromo-4- (thiifluoromethoxy) aninine 4-Trifluoromethoxynitrobenzene (4.1 g) was suspended in water (16 ml) and concentrated sulfuric acid (16 ml) and heated to 80 ° C with stirring. It was added by servings for 3 h. potassium bromate (3.7 g) and the mixture was heated at 80 ° C for 2 h. plus. The mixture was cooled to room temperature and poured into ice (100 g). The mixture was extracted with ethyl acetate, the combined organic fractions were dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic acid (2.5 ml) and water (10 ml) and iron powder (2.0 g) was added. The mixture The mixture was refluxed for 2 h, cooled to room temperature and filtered through Celite ™. The filtrate was extracted with ethyl acetate, the organic fractions were dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / EtOAc (3: 1) to give the title compound as a yellow oil.

H NMR (CDCls) d 6.57 (1H, dd), 6.9 (1H, d), 7.06 (1H, dd).

DESCRIPTION 47 N- (3-Bromo-4-methoxyphenyl) trifluoroacetamide Trifluoroacetic anhydride (3.5 ml, 24.7 mmol) was slowly added to an agitated and cooled (0 ° C) solution of 3-bromo-4-methoxyaniline (Description 43). , 5 g, 24.7 mmol) and triethylamine (3.44 mL, 24.7 mmol) in dichloromethene (50 mL). The mixture was stirred at room temperature for 2 h, ducted with dichloromethane (200 ml) and washed with water (2 x 200 ml). The organic layer was dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane / EtOAc (85:15 increasing to 75:25) to give the title compound as a colorless solid (4.4 g, 60%). . iH NMR (250 MHz, CDCk) d 7.79 (1H, d, J2.6 Hz), 7.58 (1H, dd, J2.6, 8.9 Hz), 6.90 (1H, d, J8 , 9 Hz) and 3.90 (3H, s).

DESCRIPTION 48 N- (3-Bromo-4-isopropoxyphenyl) thi-fluoroacetemide Prepared from the compound of Description 44 according to the procedure of Description 43. * H NMR (250 MHz, CDC-b) d 7.79 (1H , sa), 7.76 (1H, d, J2.7 Hz), 7.48 (1H, dd, J8.9, 2.7 Hz), 6.92 (1H, d, J8.9 Hz), 4.55 (1H, sept., J6, l Hz) and 1.38 (6H, d, J6, l Hz).

DESCRIPTION 49 N- [3-Bromo-4- (difluoromethoxy) fenu] trifluoroacetemide Prepared from the compound of Description 45 according to the procedure of Description 43. iH NMR (250 MHz, CDCls) d 8.01 (1H, sa ), 7.94 (1H, d, J2.6 Hz), 7.53 (1H, dd, J8.9, 2.6 Hz), 7.26 (1H, d, J8.9 Hz) and 6, 53 (1H, t, J 73.1 Hz).

DESCRIPTION 50 N-R 3 -Bromo-4- (trifluoromethoxy) phenyl-1-trifluoroacetemide Prepared from the compound of Description 46 according to the procedure of Description 47. * H NMR (360 MHz, CDCl 3) d 8.24 (1H, sa), 7.97 (1H, d, 2.6 Hz), 7.59 (1H, dd, 8.9, 2.6 Hz) and 7.34 (1H, d, J8.9 Hz).

DESCRIPTION 51 N-Metho-3-bromo-4- (thiifluoromethoxy) aninine Sodium hydride (60% dispersion in mineral oil, 870 mg, 21.7 mmol) was added to stirred and cooled solution (0 ° C) of N- [ 3-bromo-4- (faffluoromethoxy) fenu] -trifluoroacetemide (Description 50, 6.3 g, 18.0 mmol) in DMF (50 ml). The mixture was stirred at 0 ° C for 20 min. and methyl iodide (1.35 mL, 21.7 mmol) was added over 5 min. The mixture was stirred at 0 ° C for 45 min. and at room temperature for 4 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic fractions were washed with water (3 x 100 ml) and brine (100 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / CH2Cl2 (3: 1 increasing to 1: 1), to give the title compound as a brown oil (1.20 g, 0.25 g). %). ? NMR (250 MHz, CDC-b) d 7.11 (1H, dq, J 8.9, 1.2 Hz), 6.86 (1H, d, J 2.8 Hz), 6.56 (1H, dd, J 8.9, 2.8 Hz) and 2.83 (3H, s).

DESCRIPTION 52 N- (3-Bromo-4-methoxyuene) -N- (meth) thiifluoroacetemide Sodium hydride (60% dispersion in mineral oil, 0.48 g, 12-mmol) was added to an agitated and cooled solution (0 ° C) ) of N- (3-bromo-4-methoxyphenyl) thiifluoroacetamide (Description 43, 2.98 g, 10 mmol) in dimethylformamide (30 ml). The mixture was stirred at 0 ° C for 30 min. and then methyl iodide (0.75 ml, 1.70 g, 12 mmol) was added. The mixture was stirred at 0 ° C for 30 min. and then at room temperature for 3 h. Water (50 ml) was added and the mixture was extracted with ethyl acetate (3 x 50 ml). The organic fractions were washed with water (4 x 50 ml) and brine (50 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica, eluting with hexane / CH2Cl2 (50:50 increasing to 30:70), to give the title compound as a colorless solid (2.72 g, 87%). iH NMR (250 MHz, CDC-U) d 7.46 (1H, d, J2.4 Hz), 7.18 (1H, dd, J8.7, 2.4 Hz), 6.91 (1H, d , J8.7 Hz), 3.94 (3H, s) and 3.32 (3H, s).

DESCRIPTION 53 N- (3-Bromo-4-isopropoxyl) -N- (meth) thiifluoroacefamide Prepared from the compound of Description 48 according to the procedure of Description 52.? NMR (250 MHz, CDCl 3) d 7.45 (1H, d, J 2.5 Hz), 7.13 (1H, dd, J8.8, 2.5 Hz), 6.90 (1H, d, J8 , 8 Hz), 4.59 (1H, sept., J 6.1 Hz), 3.32 (3H, s) and 1.41 (6H, d, J6, l Hz).

DESCRIPTION 54 N-f3-Bro? No-4- (difluoro-netoxy) phen1-N- (n etui) thiifluoroacetamide Prepared from the compound of Description 49 according to the procedure of Description 52. H NMR (360 MHz, CDCl 3) d 7.56 (1H, d, J2.5 Hz), 7.26 (2H, m), 6.58 (1H, t, J72.6 Hz) and 3.35 (3H, s) .

DESCRIPTION 55 N-r3-Brorno-4- (trifluororoethoxy) phen-1 - N - (- net) trifluoroacetarnide Prepared from the compound of Description 51 according to the procedure of Description 47. H NMR (250 MHz, CDCl 3) d 7 , 59 (1H, d, J 2.3 Hz), 7.39 (1H, da, J9 Hz), 7.27 (1H, da, J9 Hz) and 3.36 (3H, s).

DESCRIPTION 56 2-Methoxy-5- (2,2,2-thiifluoroethylamino) bromobenzene Borane-dimethylsulfide complex (2 M in THF, 6.7 ml, 13.4 mmol) was added to a solution of N- (3-bromobenzene). 4-methoxyphenyl) trifluoroacetamide (Description 52, 2.0 g, 6.7 mmol) in tetrahydrofuran (20 ml) and the mixture was refluxed for 18 h. The mixture was cooled and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (2.1 g). * H NMR (360 MHz, CDCb) d 6.93 (1H, d, J 2.9 Hz), 6.80 (1H, d, J 8.8 Hz), 6.62 (1H, dd, J 8 , 8, 2.9 Hz), 3.82 (3H, s) and 3.71 (3H, m). m / z (ES +) 284, 286 (M + 1).

DESCRIPTION 57 N- (3-Bromo-4-methoxyuene) -N- (2,2,2-trifluoroetu) acetamide Acetic anhydride (1.26 ml, 13.4 mmol) was added to a cooled (0 ° C) solution of 2 ml. -rnetoxy-5- (2,2,2-thiifluoroethylene) brornobenzene (Description 56, 2.1 g) and triethyl amine (1.9 ml, 1.37 g, 13.4 mmol) in dichloromethane, and the mixture was heated refluxed for 18 h. The mixture was cooled and the solvent was evaporated under reduced pressure. 1,2-Dichloroethane (20 ml) was added and the mixture was heated to reflux for 24 h. Additional acetic anhydride (0.6 ml) and triethyl amine (0.95 ml) were added and the mixture was heated to reflux for 24 h, cooled and dichuted with dichloromethane (100 ml). The mixture was ducted with water (3 x 50 ml) and brine (50 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was triturated with ethyl acetate and the solid was collected by vacuum drying to give the title compound as an off-white solid (1.28 g, 59%). NMR (360 MHz, CDCl 3) d 7.44 (1H, d, J 2.5 Hz), 7.17 (1H, dd, J 8.7, 2.5 Hz), 6.93 (1H, d, J 8.7 Hz), 4.29 (2H, q, J8.8 Hz), 3.94 (3H, s) and 1.90 (3H, m). m / z (ES +) 326, 328 (M + 1).

DESCRIPTION 58 2-Ethoxy-5- (trifluoromethoxy) bromobenzene 2-Bromo-4-thiifluoromethoxyphenol (Description 11.1 g) was dissolved in N, N-dimethylformamide (12 ml) and potassium carbonate (1.07 g) was added. Iodoethane (0, 78 ml) and the mixture was stirred at room temperature. Water (150 ml) and ethyl acetate were added and the layers separated. The organic layer was washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with hexane / EtOAc (100: 0 increasing to 95: 5) to give the title compound as a colorless oil (1.02 g). ? NMR (250 MHz, CDCb) d 1.47 (3H, t, J 7.0 Hz), 4.09 (2H, q, J7.0 Hz), 6.85 (1H, d, J9.0 Hz) , 7.11 (1H, m) and 7.43 (1H, m).

DESCRIPTION 59 2-rrifluoromethotthio) bromobenzene A solution of 2-bromothiophenol (2 g) and triethylamine (2.2 ml) in N, N-dimethylformamide was purged with nitrogen for 5 min, metloviologen dichloromethane was added and the mixture was saturated with trifluoromethyl iodide gas. After 40 min., The mixture was poured into ice and extracted with ethyl ether. The organic layer was dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane, to give the title compound as a colorless oil (0.8 g). XH NMR (360 MHz, CDC-b) d 7.30-7.42 (2H, m) and 7.70-7.81 (2H, m). " DESCRIPTION 60 2-Bromo-l- (2,2,2-trifluoroethoxy) -4- (thiifluoromethy) benzene Prepared from the compound of Description 35 according to the procedure of Description 22.? NMR (250 MHz, CDCl 3) d 4.45 (2H, q, J7.9 Hz), 6.97 (1H, d, J8.6 Hz), 7.58 (1H, dd, J10.7, 1, 5 Hz) and 7.85 (1H, d, Jl, 4 Hz).

DESCRIPTION 61 l-Isopropoxy-2-bromo-4- (thiifluoromethyl) benzene Prepared from the compound of Description 35 according to the procedure of Description 41. * H NMR (360 MHz, CDCl 3) d 1.40 (6H, d , J6, l Hz), 4.64 (1H, septete, J 6.1 Hz), 6.94 (1H, d, J 8.8 Hz), 7.49 (1H, dd, J 8.9, 2.1 Hz) and 7.78 (1H, d, J 1.9 Hz).

DESCRIPTION 62 2-Benzyl oxybenzene Benzyl bromide (27.5 ml) was added to a mixture of 2-bromophenol (10 g, 58 mmol) and potassium carbonate (64 g) in DMF (70 ml) and the mixture was stirred at room temperature for 72 h. The mixture was poured into water and extracted with ethyl acetate (2 x). The combined organic fractions were washed with water, dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane / EtOAc (98: 2), to give the title compound (2.9 g). ? NMR (250 MHz, CDCls) d 7.58-7.20 (7H, m), 6.94 (1H, d, J7.9 Hz), 6.84 (1H, t, J7.9 Hz) and 5 , 16 (2H, s).

DESCRIPTION 63 3-Bromo-4-methoxybenzenecarboxamide Oxalyl chloride (1.13 ml, 1.65 g, 13 mmol) was slowly added to a stirred and cooled solution (0 ° C) of 3-bromo-4-methoxybenzoic acid (3 g). , 13 mmol) and DMF (1 drop) in dichloromethane (50 ml) and the mixture was stirred at 0 ° C for 10 min. and then at room temperature for 2 h. Ammonia was bubbled through the mixture for 10 minutes, dichloromethene was added and the mixture was washed with water, dried (MgSQt) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid ( 2.80 g, 86%). ? NMR (250 MHz, DMSO-dβ) d 8.23 (1H, d, J2.2 Hz), 8.08 (1H, sa), 8.03 (1H, dd, J8.6, 2.3 Hz) , 7.47 (1H, sa), 7.30 (1H, d, J8.6 Hz) and 4.03 (3H, s).

DESCRIPTION 64 3-Bromo-4-hydroxybenzoate methylated Sulfuric acid (conc., 10 ml) was added to a solution of 3-bromo-4-hydroxybenzoic acid (10.0 g, 46 min) in methanol (100 ml) and the mixture it was stirred at room temperature for 72 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (250 ml). The mixture was washed with saturated aqueous sodium bicarbonate (2 x 250 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (8.83 g, 83%). . m NMR (250 MHz, CDOb) d 8.19 (1H, d, J 2.0 Hz), 7.92 (1H, dd, J 8.5, 2.0 Hz), 7.05 (1H, d, J8.5 Hz), 5.91 (1H, s) and 3.90 (3H, s).

DESCRIPTION 65 3-Bromo-4- (difluoromethoxy) methyl benzoate Chlorodifluoroacetic acid (1.12 ml, 8.7 mmol) was added to a mixture of methyl 3-bromo-4-hydroxybenzoate (Description 64, 2.0 g , 8.7 mmol) and potassium carbonate (1.2 g, 8.7 mmol) in N, N-dimethylformamide (20 ml) and the mixture was heated at 65 ° C for 16 h. The mixture was cooled, water (100 ml) was added and the mixture was extracted with ethyl acetate (2 x 100 ml). The combined organic fractions were dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / EtOAc (95: 5) to give the title compound as a colorless solid (1.20 g, 49%). iH NMR (250 MHz, CDCls) d 8.31 (1H, d, J 2.0 Hz), 8.22 (1H, dd, J8.5, 2.0 Hz), 7.05 (1H, m) , 6.61 (1H, t, j 73 Hz) and 3.93 (3H, s,).

DESCRIPTION 66 3-Bromo-4- (2,2,2-trifluoroethoxy) methyl benzoate Sodium hydride (60% dispersion in mineral oil, 520 mg, 13.0 mmol) to a stirred and cooled (0 ° C) solution of methyl 3-bromo-4-hydroxybenzoate (Description 64, 3.0 g, 13.0 mmol) in N, N'-dimethylformamide (100 ml. ) and the mixture was stirred at 0 ° C for 15 min. 2,2,2-trifluoroetiuum tosuate (6.61 g, 26.0 mmol) in N, N'-dimethylformamide (50 ml) and the mixture was stirred at 100 ° C dtirant 16 h. The mixture was concentrated under reduced pressure to half its volume and poured into aqueous sodium hydroxide solution (1M, 300 ml). The mixture was extracted with ethyl acetate (2 x 350 ml), the combined organic fractions were dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / EtOAc to give the title compound as a colorless oil (1.37 g, 34%). ? NMR (250 MHz, CDCb) d 8.27 (1H, d, J2, l Hz), 7.99 (1H, dd, J2, l, 8.6 Hz), 6.92 (1H, d, J8.6 Hz), 4.42- 4.52 (2H, quadruplet, J 7.9 Hz) and 3.91 (3H, s).

DESCRIPTION 67 3-Bromo-4- (cyclobutyloxy) methyl benzoate A mixture of methyl 3-bromo-4-hydroxybenzoate (Description 64, 2.3 g, 10 mmol), bromocyclobutane (2.0 g, 15 mmol) and potassium carbonate (2.42 g, 17.5 mmol) in DMF (25 ml) was stirred at room temperature for 3 days and then at 70 ° C for 6 h. The mixture was cooled, ducted with water (150 ml) and extracted with ethyl acetate (4 x 25 ml). The combined organic fractions were washed with aqueous sodium hydroxide (1M, 25 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure to give the title compound as a gum (1.15 g). iH NMR (CDCb) d 1.66-1.77 (1H, m), 1.88-1.93 (1H, m), 2.22-2.31 (2H, m), 2.46-2 , 60 (2H, m), 3.89 (3H, s), 4.75, (1H, pent.p., J7.0 Hz), 6.74 (1H, d, J8.6 Hz), 7 , 91 (1H, dd, J8.6, 2.1 Hz) and 8.23 (1H, d, J2, l Hz).

DESCRIPTION 68 3-Bromo-4- (cyclobutyloxy) benzenecarboxamide Aqueous sodium hydroxide (4 M, 4 ml) was added to a solution of methyl 3-bromo-4- (cyclobutyloxy) benzoate (Description 67, 1.15 g, 4 mmoles) in methanol (15 ml) and the mixture was stirred at room temperature for 20 h. The solvent was evaporated, water (25 ml) was added and the mixture was washed with ethyl acetate (2 x 10 ml). The aqueous layer was acidified with hydrochloric acid (5M) and the resulting suspension was extracted with dichloromethane (2 x 25 ml). The combined organic fractions were dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was suspended in dichloromethane (15 ml) containing DMF (3 drops) and oxalyl chloride (0.44 ml) was added. The mixture was stirred at room temperature for 1.5 h. and then the solvent was evaporated under reduced pressure. The residue was dissolved in THF (5 ml) and added with stirring to concentrated aqueous ammonia (50 ml). The precipitate was collected, washed with water and dried to give the title compound (0.91 g). * H NMR (DMSO-d6) d 1.60-1.88 (2H, m), 2.01-2.12 (2H, m), 2.43-2.51 (1H, m), 3, 34 (3H, s), 4.83 (1H, pent ap, J7, l Hz), 7.00 (1H, d, J8.6 Hz), 7.33 (1H, sa), 7.84 (1H, dd, J8.6, 2.1 Hz), 8.09 (1 H, sa) and 8.10 (1H, d, J2, l Hz).

DESCRIPTION 69 2-Bromo-4- (trifluoromethoxy) benzonitriu A solution of sodium nitrite (2.76 g, 40 mmol) in water (15 ml) was added drop by drop to a suspension of 2-bromo-4- (thiifluoromethoxy) aniline ( 10.2 g, 40 mmol) in a mixture of concentrated hydrochloric acid (20 ml) and water (50 ml) at 0 ° C. The mixture was stirred at 0 ° C for 45 min., Then added dropwise to a mixture of potassium cyanide (11.4 g, 176 mmol) and copper (II) sulfate (6.4 g, 40 mmol). in water (80 ml) at 65 ° C. The mixture was stirred at 65 ° C for 30 min., Cooled to room temperature and filtered through a layer of Hyflo ™, washing with dichloromethane (2 x 200 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (100 ml). The organic fractions were dried and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica, eluting with hexane / EtOAc (75:25), to give the title compound as an oil. * H NMR (360 MHz, CDCls) d 7.12-7.15 (1H, m), 7.56 (1H, s) and 7.72 (1H, d, J8.6 Hz).

DESCRIPTION 70 (2-Bromofenu) methylsulfoxide Oxone (9.7 g) in water (40 ml) was added slowly to a stirred and cooled (0 ° C) solution of 2-bromothioanisole (5 g, 24.6 mmol) and sodium bicarbonate (16 g). g) in acetone (20 ml). The mixture was stirred at room temperature for 16 h. and then water and dichloromethane were added. The layers were separated, the organic phase was dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (80:20 increasing to 40:60) to give the title compound (6.1 g). m / z (ES +) 219 (M + 1).

DESCRIPTION 71 (2-Bromofenü) metulsulphone Oxone ™ (9.7g) in water (40 ml) was added slowly to a stirred and cooled solution (0 ° C) of 2- (bromofenü) methylsulfoxide (Description 70, 24 mmoles) and sodium bicarbonate (16 g) in acetone (20 ml). The mixture was heated at 60 ° C for 2 h. and then water and dichloromethene were added. The layers were separated, the organic phase was dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with hexane / EtOAc (100: 0 increasing to 70:30) to give the title compound (4.1 g) m.p. 106-107 ° C. m / z (ES +) 235.237 (M + 1).

DESCRIPTION 72 (3-S ', 5J?, 6 --- -3- (5-Cyano-2-n? Ethoxyphen) -6-phene-1-oxa-7- (trifluoroacety) aza-spiro4,5Idecano Prepared from Compound of Example 139 according to the procedure of Example 111.? NMR (250 MHz, CDCls) d 1.71-1.81 (3H, m), 2.05-2.28 (3H, m), 2, 05-2.28 (3H, m), 3.24-3.36 (1H, m), 5.55 (1H, s), 6.79-6.83 (1H, d, J12.3 Hz) 7.19-7.32 (4H, m) and 7.42-7.49 (3H, m) m / z (ES-) 445 (M + l).

DESCRIPTION 73 Methyl 3-Bromo-4-hydroxyphenedioate Bromine (16.59 g, 104 mmol) in chloroform (25 ml) was added dropwise to an agitated and cooled mixture (0 ° C) of methyl 4-hydroxyphenetanoate (17, 25 g, 104 mmol) and acetic acid (10 ml) in chloroform (140 ml). The mixture was stirred at 0 ° C for 1 h, ducted with dichloromethene (100 ml), washed with water (2 x 200 ml) and brine (200 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (25.43 g, 100%). * H NMR (360 MHz, CDCl 3) d 7.39 (1H, d, J 2.0 Hz), 7.12 (1H, dd, J 8.3, 2.0 Hz), 6.96 (1H, d, J8.3 Hz), 5.54 (1H, sa), 3.70 (3H, s) and 3.54 (2H, s).

DESCRIPTION 74 Methyl 3-Bromo-4-methoxyphenetanoate Methyl iodide (2.05 ml, 4.68 g, 33 mmol) was added to a mixture of methyl 3-bromo-4-hydroxy-fentanylate (Description 73, 7.35 g, 30 mmol) and potassium carbonate (8.29 g, 60 mmol) in dimethylformamide (30 ml) and the mixture was stirred at room temperature for 16 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic fractions were washed with aqueous sodium hydroxide (1 M, 2 x 100 ml), water (2 x 100 ml) and brine (100 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure to give the Compound of the title as a colorless solid (7.65 g, 100%). ? NMR (360 MHz, CDOb) d 7.47 (1H, d, J2, 1 Hz), 7.18 (1H, dd, J8.4, 2.1 Hz), 6.85 (1H, d, J8, 4 Hz), 3.88 (3H, s), 3.70 (3H, s) and 3.49 (2H, s).

DESCRIPTION 75 (3-S ,, 5R, 6S) -7- (4-Clorobut-2-in-l-ü) -3-r2-isopropoxy-5- (trrfluorometal) phen-1-6-phen-1-oxa-7- aza-espiror4,51decano 1,4-dichlorobutino (0.2 ml) was added to the mixture (3S, 5R, 6S) -3- (2- (2,2,2-trifluoroethoxy) -5-fluorofenu) - 6-Phen-1-oxa-7-aza-spiro [4.5] decane (Example 19, 100 mg) and potassium carbonate (140 mg) in dimethylformamide (1 ml) and the mixture was stirred at room temperature overnight . The mixture was diluted with water (20 ml) and extracted with ether (3 x 5 ml). The combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (95: 5 increasing to 80:20) to give the title compound as a colorless oil (100 mg). m / z (ES +) m / z 506 (M + l).

DESCRIPTION 76 (3-S, .5i?, 6-S) -7- (4-Azidobut-2-in-l-ü) -3-r2-iso? Ropoxy-5- (tirfluorometal) fenül-6-fenü-l -oxa-7-aza-spiror4f51decano Sodium azide (15 mg) was added to a solution of (3S, 5R, 6S) -7- (4-chlorobut-2-yn-l-u) -3- [2-isopro? oxy-5- (trifluoromethyl) phenyl] -6-phe n-l-oxa-7-aza-es? iro [4,5] decane (Description 75, 100 mg) in dimethyl sulfoxide (1 ml). The mixture was stirred at room temperature overnight, ducted with water (20 ml) and extracted with ether (3 x 5 ml). The combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (98 mg). m / z (ES +) m / z 513 (M + l).

DESCRIPTION 77 l-Dimetüammo-4- (trifluoromethoxy) benzene A mixture of l-bromo-4- (trifluoromet? xi) benzene (2.41 g), tris (dimethylamino) borane (1.43 g), sodium t-butoxide (1 , 34 g), tris (dibencideneacetone) dipalladium (18 mg) and o-tolylphosphine (12 mg) in toluene (30 ml) was heated to reflux for 4 h. The mixture was cooled, ducted with water (30 ml) and extracted with ethyl acetate (3 x 10 ml). The combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (99: 1 increasing to 95: 5) to give the title compound as an oil (600 mg). * H NMR (360 MHz, CDCls) d 2.95 (6H, s), 6.66 (2H,?, J 9 Hz) and 7.08 (2H, d, J 8.5 Hz). m / z (ES +) m / z 206 (M + 1).

DESCRIPTION 78 2-Dimetüammo-5- (trifluoromethoxy) bromobenzene. Drip to drop bromine (0.15 ml) was added to a stirred and cooled (0 ° C) mixture of l-dimetüam or-4- (trifluoromethoxy) benzene (Description 77, 600 mg) and sodium carbonate (620 mg) in chloroform (15 ml). The mixture was stirred for 1 h. and it was diluted with water. The organic layer was washed with brine, dried (MgSQt) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (99: 1 increasing to 95: 5), to give the title compound in the form of an oil (300 mg). ? NMR (360 MHz, CDCl.) D 2.79 (6H, s), 7.06 (1H,?, J 9 Hz), 7.14 (1H, dd, J6, 1.5 Hz) and 7.44 (1H, d, J 2.0 Hz). m / z (ES +) m / z 270, 272 (M + l).

DESCRIPTION 79 (2ig.3J?) - l- (Fenumethoxycarbonyl) -2-phenylpiperidin-3-ol (2?, 3?) - 3-hydroxy-2-phenypiperidine dibenzo-buttartrate (prepared by the method of the Descriptive Report of European Patent No. 0528495-A, 35.6 g, 0.1 mol) to a mixture of benzyl chloroformate (21.4 ml, 25.6 g, 0.15 mol), dichloromethane (50 ml) and sodium hydroxide. aqueous (1 M, 500 N). The mixture was stirred vigorously for 1 h. and then more benzyl chloroformate (8.0 mL, 9.56 g, 56 mmol) in dichloromethane (50 mL) was added slowly. The mixture was stirred vigorously overnight, the layers were separated and the aqueous layer was extracted with dichloromethene (100 ml). The combined organic fractions were dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried under vacuum to give the title compound as a colorless solid (29.53 g, 95%). iH NMR (250 MHz, CDCk) d 7.47-7.24 (10H, m), 5.44 (1H, d, J5.7 Hz), 5.14 (1H, d, J 12.4 Hz) ,. 5.07 (1H, d, J12.4 Hz), 4.09 (2H, m), 3.09 (1H, m) and 1.88-1.58 (6H, m).

DESCRIPTION 80 (±) -l- (Phenylmethoxycarbonyl) -2-phenylpiperidin-3-one Dimethyl sulfoxide (9.1 ml, 10.0 g, 128.6 mmol) in dichloromethane (50 ml) was slowly added to a cooled solution (-75 ° C) oxal chloride or (6.9 ml, 10.2 g, 80.4 mmol) in dichloromethane (500 ml). The mixture was stirred at -75 ° C for 15 min. and then (-2 - / ?, 3./) -l- (phenylmethoxycarbonyl) -2- phenylpiperidin-3-ol was added slowly (Description 79, 20.0 g, 64.3 mmol). The mixture was stirred at -75 ° C for 1 h. and then triethylamine (27 ml, 19.5 g, 192.9 mmol) was added. The mixture was stirred at -75 ° C for 1 h. and then at room temperature overnight. The mixture was washed with aqueous citric acid (1M), aqueous sodium hydrogen carbonate, water and brine, dried (MgSO) and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (19.56). g, 98%). * H NMR (250 MHz, CDCk) d 7.39-7.20 (10H, m), 5.74 (1H, sa), 5.17 (2H, sa), 4.13 (1H, sa), 3.40 (1H, ma), 2.47 (2H, m), and l, 94 (2H, m).

DESCRIPTION 81 (±) - (2-S *, 3J ^) - 3- (3-Hydroxypropm-l-ü) -l- (fenümetoxicarbonü) -2-fenüpiperidin-3-ol Prepared from the compound of Description 80 according to with the procedure of Description 7.? NMR (250 MHz, CDCfe) d 7.56 (2H, d, J 6.0 Hz), 7.31 (8H, m), 5.66 (1H, s), 5.15 (1H, d, J12) , 5 Hz) ,. 5.09 (1H, d, J12.5 Hz), 4.12 (2H, s), 4.08 (1H, m), 3.55 (2H, sa), 3.20 (1H, m), 2.91 (1H, m) and 2.34-1.35 (3H, m).

DESCRIPTION 82 (±) - (5 /? *, 6-S *) - 3-Tributüestannü-6-fenü-l-oxa-7- (fenü? Netoxicarbonü) aza-espiror4,51dec-3-ene Prepared from the compound of Description 81 according to the procedure of Description 8.? NMR (250 MHz, CDCls) d 7.39-7.14 (10H, m), 5.91 (1H, t, J2.4 Hz), 5.15 (1H, d, J12.5 Hz) ,. 5.01 (1H, d, J12.5 Hz), 4.99 (1H, s), 4.60 (1H, dd, J12.8, 2.4 Hz), 4.22 (1H, m), 4.14 (1H, dd, J 12.8, 2.4 Hz), 3.31 (1H, m), 2.01-1.70 (4H, m) and 1.54-0.82 (27H) , m).

DESCRIPTION 83 (±) - (5i? *, 6 - ^ ^) - 3-Iodo-6-phene-l-oxa-7- (fenu-methoxycarbon) aza-spiro [4,5] dec-3-ene A solution of iodine (2.08 g, 8.2 mmol) in dichloromethane (100 ml) was added to a stirred solution of (±) - (5? *, 65 *) - 3-thibutylstannane-6-phene-1-oxa- 7- (fenumethoxycarbon) aza-spiro [4.5] dec-3-ene (Description 82, 5.0 g, 7.8 mmol) at -78 ° C. The mixture was stirred for 1 h. and quenched with saturated aqueous sodium sulfite solution (10 ml). After warming to room temperature, the mixture was washed with saturated sodium chloride solution (100 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was taken up in acetone (100 ml) and washed with hexane (3 x 100 ml). The hexane washes were extracted with acetonithia (3 x 50 ml). The combined acetonitrile fractions were evaporated under reduced pressure to give a yellow oil, which was triturated with hexane to give the title compound as a white solid (2.27 g, 61%). i H NMR (360 MHz, CDCl 3) d 7.40 (2H, d, J 7.4 Hz), 7.20-7.33 (8H, m), 6.36 (1H, t, J2.2 Hz) , 5.16 (1H, s), 5.12 (2H, s), 4.49 (1H, dd, J 2.2 and 12.6 Hz), 4.16 (1H, dd, J 2.2 and 12.6 Hz), 4.13-4.19 (1H, m), 3.08-3.18 (1H, m), 2.00-2.12 (1H, m), 1.70-1.84 (3H, m). m / z (ES +) 476 (M + 1).

DESCRIPTION 84 (±) - (5R * / 6 - ^) - 6-Fenü-l-oxa-7- (fenürnetoxicarbonü) aza-espiror4.51dec-3-ene A solution of (±) - (5i? *, 6- S *) - 3-iodo-6-phenyl-1-oxa-7- (phenylmethoxycarbonyl) aza-spiro [4.5] dec-3-ene (Description 83, 1.11 g, 2.34 mmol), a , a'-azo-isobutyronitrile (38 mg, 0.23 mmol) and tributyltin hydride (0.75 ml, 2.80 mmol) in toluene (10 ml) was heated at 100 ° C for 5 h, cooled and the solvent was evaporated under reduced pressure. The residue was taken up in acetonitrile (50 ml) and washed with hexane (3 x 50 ml). The hexane washes were extracted with acetonithy (50 ml). The acetonitrile fractions were combined and the solvent was evaporated under reduced pressure to give an oil which was chromatographed with 10% ethyl acetate in hexane to give the title compound as a colorless oil (665 mg, 81%). iH NMR (360 MHz, CDCls) d 7.45 (2H, d, J 7.2 Hz), 7.20-7.31 (8H, m), 6.00 (1H, dt, J6.2, 2 , 3 Hz), 5.87 (1H, day, J6.2 Hz), 5.15 (1H, s), 5.15 (1H, d, J12.5 Hz), 5.09 (1H, d, J 12.5 Hz), 4.61 (1H, dt, J 13.3, 1.9 Hz), 4.32 (1H, dt, J 13.2, 2.1 Hz), 4.16 (1H , dd, J 13, l, 5.7 Hz), 3.08-3.18 (1H, m), 2.00-2.10 (1H, m) and 1.70-1.90 (3H, m). m / z (ES +) 350 (M + l).

DESCRIPTION 85 Z- (2S ', 3i?) - l-ferc-Butoxycarbonii-3- (3-hydroxyprop-l-en-l-u) -2-phenylpiperidin-3-ol Palladium was added to calcium carbonate, poisoned with lead ( Lindlar catalyst, 2 g) to a solution of (2-S, 3Z?) - 1 -, grc-butoxycarbonyl-3- (3-hydroxypropyl-1-y) -2-phenylpiperidin-3-ol (Description 7; 32 g, 96.6 mmol) in ethyl acetate (300 ml) and the mixture was stirred under hydrogen (1 atm) for 4 h. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound as an oil (32 g, 100%). ? NMR (360 MHz, CDCls) d 7.42 (2H, d, J 7.6 Hz), 7.35-7.25 (3H, m), 5.83 (1H, d, 12.3 Hz), 5.68 (1H, dt, J12.3, 6.0 Hz), 5.06 (1H, s), 4.27 (1H, m), 4.12 (2H, m), 3.32 (1H , m), 3.13 (1H, s), 2.28 (1H, t, J5.9 Hz), 2.02 (1H, m), 1.92-1.78 (3H, m) and 1 , 32 (9H, s). m / z (ES +) 334 (M + 1).

DESCRIPTION 86 (5J?, 6-S -6-Fenu-l-oxa-7 - (- 'grc-butoxycarbonii) aza-spiro [4,5] dec-3-ene Drip to diethyl azodicarboxylate (18.2 ml, 115 mmol) in THF (100 ml) was added to a solution of Z- (2-S, 3i?) - l-fer-butoxycarbonyl-3- (3-Hdroxyprop-1-en-1-y) -2-phenylpiperidine- 3-ol (Description 85; 32 g, 96 mmol) and triphenylphosphine (30.2 g, 115 mmol) in THF (700 mL) The mixture was stirred at 0 ° C for 30 min and then at room temperature for 1 min. 5 h The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexane / EtOAc (95: 5 increasing to 80:20) to give the title compound as a colorless solid (23.4 g, 77%). * H NMR (CDCl 3) d 7.45 (2H, d, J 7.4 Hz), 7.27 (2H, t, J 7.4 Hz), 7.20 (1H, t, J 7.4), 6.03 (1H, dt, J 6.1, 2.0 Hz), 5.68 (1H, dt, J6, 1, 2.0 Hz). ), 5.06 (1H, s), 4.61 (1H, dt, J13, I, 2.0 Hz), 4.32 (1H, dt, J13, I, 2.0 Hz), 4.08 (1H, m), 3.05 (1H, m), 2.05 (1H, m), 1.75 (3H, m) and 1.37 (9H, s). m / z (ES +) 316 (M + l).

DESCRIPTION 87 (2S) -l-rgrc-Butoxycarbonii-2- (4-fluorofenu)? Iperidin-3-one Prepared from (2S, 3-S) -l-tert-butoxycarbonii-3-hydroxy-2- (4- fluorofenu) piperidine (prepared by the procedure described in International Patent Publication YJO 94/19323) in accordance with the procedure of Description 1.? NMR (360 MHz, CDCls) d 1.43 (9H, s), 1.99 (2H, m), 2.48 (2H, m) 3.31 (1H,), 4.05 (1H, sa) , 5.62 (1H, sa), 7.04 (2H, t, J7.4 Hz) and 7.21 (2H, dd, J7.5, 8.9 Hz).

DESCRIPTION 88 (2 .3J?) - l - * grc-Butoxycarbonyl-3- (3-hydroxypro? In-l-u) -2- (4-fluorophenyl) pi? Eridin-3-ol Prepared from the compound of Description 87 according to the procedure of Description 7. »H NMR (360 MHz, CDCl 3) d 1.40 (9H, s), 1.64 (1H, m), 2.04 (2H, m), 2 , 1 (1H, m), 2.75 (1H, td, J 13.4, 3.6 Hz), 3.03 (1 H, sa), 3.47 (1H, sa), 3.96 (1H, dd, J14.8, 4.7 Hz), 4.25 (2H, s), 5.58 (1H, s), 6.96 (2H, t, J6.7 Hz) and 7.53 (2H, dd, J8.5, 5.4 Hz).

DESCRIPTION 89 Z - (----), 3-R) -l- 'grc-Butoxycarbonyl-3- (3-hydroxyprop-l-en-l-ü) -2- (4-fluorofenü) piperidin-3-ol Prepared from the compound of Description 88 according to the procedure of Description 85. * H NMR (360 MHz, CDCls) d 1.34 (9H, s), 1.77 (1H, m), 1.90 (1H, m), 2.03 (1H, m), 3.19 (2H, dd, J11, 3, 5.9 Hz), 4.06 (1H, dd, J 13.7, 6.04 Hz), 4.18 (1H, dd, J5.73, 1.2 Hz), 4.30 (1H, dd, J14.0, 7.4 Hz), 5.10 (1H, s), 5.68 (1H, m), 5.85 (1H, dt, J 12.3, 1.3 Hz), 7.00 (2H, t, J 8.9 Hz) and 7.41 (2H, dd , J 8.71, 5.6 Hz).

DESCRIPTION 90 (5i?, 6-S) -6- (4-puorofenu) -l-oxa-7 - (- 'grc-butoxycarbonu) aza-spiro [4,51dec-3-ene Prepared from the compound of Description 89 according to the procedure of Description 86.? NMR (360 MHz, CDCb) d 1.37 (9H, s), 1.75 (3H, m), 1.99 (1H, m), 3.04 (1H, td, J11, 7 Hz), 4.08 (1H, dd, J 13.2 Hz), 4.27 (1H, dt, J 12.9 Hz), 4.60 (1H, dt, J13.2, 1.8 Hz), 5, 00 (1H, s), 5.87 (1H, d, J6.16 Hz), 5.99 (1H, d, J 8.6 Hz), 6.95 (2H, t, J8.7 Hz) and 7.40 (2H, dd, J8.7, 5.8 Hz).

DESCRIPTION 91 ^ - ^^ / - ^ - ^^ - (S-Methoxy-S-drifluorometoxDfen ^ -o-fenü- -oxa ^ -ffórc-butoxicarbon ^ aza-espiro [4,5] decan-3-ol added in portions 2-Bromo-4- (trifluoromethoxy) anisole (Description 12, 417 mg, 1.54 mmol) to magnesium (41 mg, 1.7 mmol) in diethyl ether (1 mL), under a nitrogen atmosphere and the mixture briefly heated to reflux after each addition. After the addition was complete, the mixture was heated to reflux for 30 min, during which time most of the magnesium was dissolved. The solution was cooled to room temperature and was added drop by drop to a cooled (0 ° C) solution of (5i?, 6-S) -3-keto-6-phenyl-1-oxa-7- (fer-butoxycarbon) ) aza-spiro [4.5] decane (Description 4, 212 mg, 0.64 mmol) in diethyl ether (10 ml). The mixture was stirred at 0 ° C for 10 r in. and at room temperature overnight. Saturated aqueous ammonium chloride (40 ml) was added and the mixture was extracted with ethyl acetate (2 x 40 ml). The combined organic fractions were washed with brine (20 ml), dried (MgSQt) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / hexane (1: 5) to give the title compound as a pale foam (240 mg, 72%). ? NMR (360 MHz, CDCl 3) d 1.47 (9H, s), 1.52-1.71 (3H, m), 2.17-2.22 (1H, m), 2.42 (1H, d) , J13.5 Hz), 2.56 (1H, d, J13.5 Hz), 2.77-2.84 (1H, m), 3.89 (3H, s), 3.96-4.00 (1H, m), 4.20 (1H, d, J9.5 Hz), 4.29 (1H, d, J9.5 Hz), 5.78 (1H, s), 6.90 (1H, d , J 8.9 Hz), 7.13-7.16 (1H, m), 7.21-7.25 (1H, m), 7.30-7.35 (1H, m) and 7.62 (2H,?, J 7.7 Hz). m / z (ES +) 524 (M + l).

DESCRIPTION 92 (S ^ or-Sl-S-fS-Methoxy-S-Cyti? UoromethoxyDennyl-or-phen-l-oxa-aza-spiro ^^ ldec ^ -eno and (5R, 6S) -3- (2-methoxy-5 - (trifluoromethoxy) fenu) -6-phene-1-oxa-7-aza-spiro [4.5] dec-3-ene Trifluoroacetic acid (1 ml) was added to a cooled (0 ° C) solution of (3-S ', 5i?, 6-S) -3- (2-methoxy-5- (thiifluoromethoxy) fenu) -6-phen-l-oxa-7- (tgrc-butoxycarbon) aza-spiro [4, 5] decan-3-ol (Description 91, 240 mg, 0.46 mmol) in dichloromethene (10 ml). The solution was stirred at 0 ° C for 10 min. and at room temperature for 1 h. The solvent was evaporated under reduced pressure and saturated aqueous potassium carbonate was added. The mixture was extracted with ethyl acetate (2 x 40 ml) and the combined organic fractions were washed with brine (20 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethene / methanol / ammonia (160: 8: 1) to give (5R, 6S) -3- (2-methoxy-5- (trifluoromethoxy) phenyl) - 6-phenyl-l-oxa-7-aza-spiro [4.5] dec-2-ene (29 mg, 16%), i H NMR (360 MHz, CDCl 3) d 1.56-1.65 (2H, m), 2.05-2.12 (1H, m), 2.22-2.26 (1H, m), 2.41 (1H, dd, J14.0, 1.6 Hz), 2, 76 (1H, dd, J14.0, 1.9 Hz), 2.87 (1H, dt, J12.2, 2.7 Hz), 3.23-3.28 (1H, m), 3 , 59 (1H, s), 3.79 (3H, s), 6.58 (1H, d, J2.7 Hz), 6.98 (1H, d, J8.9 Hz), 6.83-6 , 85 (1H, m), 7.13 (1H, s), 7.15-7.26 (3H, m) and 7.43-7.45 (2H, m), m / z (ES +) 506 (M + l) and (5R, 6S) -3- (2-methoxy-5- (trifluoromethoxy) phenyl) -6-phenyl-l-oxa-7-aza-spiro [4,5] dec-3-ene (69 mg, 37%), XH NMR (250 MHz, CDCl 3) d 7.45 (2H, d, J 7.2 Hz), 7.30-7.2 (3H, m), 7.13-7 , 09 (1H, dd, J 9.0 Hz), 6.89 (2H, s + d), 6.64 (1H, t, J2.04 Hz), 5.16 (1H, s), 4, 96 and 4.56 (2H, ABdd, J 12.1 and 2 Hz), 4.11 (1H, m), 3.86 (3H, s), 3.08 (1H, m), 2.1 ( 1H, m), 1.87-1.77 (3H, m) and 1.37 (9H, s), m / z (ES +) 506 ( M + l).

DESCRIPTION 93 3-Bromo-2-fenüprop-l-ene A mixture of 2-fenüprop-l-ene (14,16 g, 0,12 mol), N-bromosuccinimide (13,5 g, 72 mmoles), a'- azoisobutyronitrile (1.5 mg) in carbon tetrachloride (7.5 ml) was placed in an oil bath preheated to 170 ° C (the internal temperature was raised to 110 ° C). The suspension was stirred vigorously at this temperature for 2 h. and then allowed to cool to room temperature. The mixture was filtered, washed with carbon tetrachloride, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane to give the title compound as an oil (320 mg). iH NMR (250 MHz, CDC-b) d (7.85-7.81 (2H, m), 7.75-7.63 (3H, m), 5.89 (1H, s), 5.82. (1H, s) and 4.72 (2H, s).

DESCRIPTION 94 (2-S, 3-R) -l-ferc-Butoxycarborul-2-phenyl-3- (2-fer? Üprop-l-en-3-ü) piperidin-3-ol A Grignard reagent was prepared from 3-bromo-2-fenüprop-l-ene (Description 93, 150 mg, 0.76 mmol) and metal magnesium (24 mg, 1 mmol) in THF (4 ml). The solution was cooled to -30 ° C and a solution of (2S) -l-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Description 1, 161 mg, 0.59 mmol) in THF (1 ml) was added. . The mixture was stirred at room temperature for 16 h. and then saturated aqueous ammonium chloride (10 ml) was added. The mixture was extracted with ethyl acetate (2 x 20 ml) and the combined organic fractions were dried (Na 2 SO 4). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with hexane / ethyl acetate (85:15) to give the compound of the title in the form of an oil (52 mg). * H NMR (360 MHz, CDCI3) d 7.44-7.20 (10H, m), 5.43 (1H, s), 5.25 (1H, s), 5.12 (1H, s), 4.06-4.03 (1H, m), 3.34-3.30 (1H, m), 3.08-2.94 (3H, m), 2.47-2.43 (1H, m), 1.93-1.86 (2H, m), 1.70-1 , 64 (2H, m) and 1.38 (9H, s). m / z (ES +) 394 (M + 1).

DESCRIPTION 95 (2 i? 2, R) -3- (l-pho-Butoxycarbonii-3-hydroxy-2-phenylpiperidin-3-y) -2-phenylpropan-l-ol was dissolved (2S ', 3i?) - l- / grc-butoxycarbonyl-2-phenyl-3- (2-phenuprop-1-en-3-yl) piperidin-3-ol (Description 94, 46 mg, 0.12 mmol) in THF (5 ml) and The mixture was cooled to 0 ° C. It was added for 5 min. borane-tetiahydrofuran complex (solution 1, 0 M in THF, 0.36 ml, 0.36 mmol) and the resulting mixture was stirred at room temperature for 16 h. Aqueous sodium hydroxide (4 M, 0.5 ml) and aqueous hydrogen peroxide (30%, 0.5 ml) were added and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (10 ml) and extracted with ethyl acetate (15 ml). The organic layer was dried (Na 2 S 4) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica, eluting with hexane / ethyl acetate (75:25) to give the title compound as an oil (13 mg). ? NMR (250 MHz, CDC-b) d 7.51-7.48 (2H, m), 7.34-7.19 (8H, m), 5.29 (1H, s), 4.03-3 , 98 (1H, m), 3.83-3.70 (2H, m), 3.29-3.19 (1H, m), 3.15-3.03 (1H, m), 2.41 -2.30 (3H, m), 2.12-1.95 (2H, m), 1.78-1.73 (2H, m), 1.45-1.41 (1H, m) and 1 , 31 (9H, s). m / z (ES +) 412 (M + 1).

DESCRIPTION 96 (4-S-4-Benzyl-3- (2-methoxyphenyl) acetyl-l, 3-oxazolidin-2-one. Thionyl chloride (6.91 ml) was added slowly to a heated solution (50 ° C) of acid. 2-methoxy phenyl acetic (13.77 g, 0.083 mol) and dimethylformamide (0.1 ml) in toluene (50 ml) and the mixture was stirred at 50 ° C for 2 h.

The solvent was evaporated under reduced pressure and the residue was dissolved in tetiahydrofuran (50 ml). To a cooled solution (-20 ° C) of (4S) -4-benzyl oxazolidin-2-one (14.7 g, 83 mmol) in tetiahydrofuran (80 ml) was slowly added n-butyllithium (1.6 M) , 52 ml, 83 mmol) and the mixture was heated to CPC. To this solution was added slowly the solution of the acid chloride (above) in tetrahydrofuran for 20 min. The mixture was warmed to room temperature and stirred for 72 h. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water and brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with hexane / EtOAc (90:10 increasing to 50:50) to give the title compound (12.8 g) * H NMR (360 MHz, CDCls) d 7.37-7.15 (7H, m), 6.92 (2H, m), 4.71 (1H, m), 4.30 (1H, d, J 17.6 Hz), 4.26-4.17 (4H, m ), 3.82 (3H, s), 3.29 (1H, dd, J13.4, 3.1 Hz) and 2.81 (1H, dd, J13.3 9.4 Hz).

DESCRIPTION 97 (2, J?> 4) -4-Benzyl-3-r3-benzoxy-2- (2-methoxyphenyl) 1propionyl-1,3-oxazolidin-2-one Titanium tetrachloride in dichloromethane (1M, 37.2 ml. ) to a cooled solution (-80 ° C) of (45) -4-benzyl-3- (2-methox-ifenu) acetu-l, 3-oxazo-idin-2-one (Description 96, 12.1 g , 37.2 mmol) in dichloromethane (100 ml) and the mixture was warmed to room temperature. The mixture was cooled to -80 ° C and düsopropüetilamina was added. (7.0 ml, 39.4 mmol). The mixture was heated at 0 ° C for 1 h., Benzyl oxymethyl chloride (10.3 ml, 74.4 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was poured into saturated aqueous ammonium chloride and ethyl acetate and the organic phase was washed with water and brine and dried (MgSQi). The solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate / hexane to give the title compound (9.14 g). * H NMR (360 MHz, CDOb) d 7.36-7.21 (14H, m), 6.9-6.85 (2H, m), 5.80 (1H, dd J 9.33 Hz and 4.45 Hz), 4.69 (1H , m), 4.63 (2H, s), 4.16 ^, 06 (3H, m), 3.85 (3H, s), 3.74 (1H, dd J 9.3 and 4.5 Hz), 3.30 (1H, dd J 13.5 Hz and 3.14 Hz) and 2.83 (1H, dd J 13.5 Hz and 9.2 Hz).

DESCRIPTION 98 (2S) -3-Benzoxy-2- (2-methoxyphenyl) propan-1-ol Sodium borohydride (0.366 g, 16.8 mmol) was added to a solution of (2'i? 4S) -4-benzyl- 3- [3-benzyl-oxy-2- (2-methoxyphenyl)] propionyl-l, 3-oxazolidin-2-one (Description 97, 6.8 g, 15.3 mmol) in tetiahydrofuran (100 ml) and water (0 , 3 ml) and the mixture was stirred at room temperature for 2 h. Aqueous sodium hydroxide (1M, 100 ml) and ethyl acetate (200 ml) were added and the layers were separated. The organic phase was washed with water and brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (90:10 increasing to 80:20) to give the title compound as an oil (3.4 g). * H NMR (250 MHz, CDCl 3) d 7.38-7.13 (5H, m), 6.94-6.85 (2H, m), 4.56 (2H, s), 4.06-3 , 98 (1H, dd J 10.7 Hz and 7.03 Hz) and 3.90-3.52 (7H, m).

DESCRIPTION 99 (2 #) - 3-Benzyloxy-1-chloro-2- (2-methoxyphene) propane A solution of (2S) -3-benzyoxy-2- (2-methoxyphenyl) propan-1-ol (Description 98, 2 g , 7.4 mmol) and triphenylphosphine (2.12 g, 8.1 mmol) in carbon tetrachloride (10 ml) was heated in an oil bath at 100 ° C for 5 h. Methanol (1 ml) was carefully added, the mixture was cooled to room temperature and stirred for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (100: 0 increasing to 95: 5) to give the title compound (1.5 g). ? NMR (250 MHz, CDCls) d 7.37-7.2 (7H, m), 6.96-6.86 (2H, m), 4.54 (2H, s), 3.92 (2H, m) ) and 3.81-3.73 (7H, m).

DESCRIPTION 100 (2-S '> 3 ^ 2, / -) - l-rerc-Butoxycarbonii-3-hydroxy-3-r3-benzyl-oxy-2- (2-methoxy-tremol)? Ropi-2-phenylpiperidine A suspension of magnesium ( , 1 g, 4.2 mmol) in tetrahydrofuran (1 ml) was added with a solution of (2 /?) - 3-benzyloxy-l-chloro-2- (2-methoxy-phen) propane (Description 99, 0.45 g, 1.55 mmol) in tetrahydrofuran (1 mL) at 60 ° C for 3 h.

The mixture was cooled and (2S) -l- / grc-butoxycarbonyl-2-phenylpiperidin-2-one (Description 1) in tetiahydrofuran (1 ml) was added. The mixture was stirred at room temperature for 1 h, divided between ethyl acetate and saturated ammonium chloride solution and the organic phase was washed with water and saturated brine and dried (MgSO4). The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (95: 5) to give the title compound (0.115 g). iH NMR (360 MHz, COCk) d 7.48 (2H, d J 6.8 Hz), 7.36 (1H, d J 4.5 Hz), 7.30-7.16 (9H, m), 6.88 (1H, tJ7.4 Hz), 6.84 (1H, dJ8.0 Hz), 5.17 (1H, s), 4 , 53 (2H, s), 4.00 (1H, dd), 3.83-3.68 (5H, m), 3.67 (2H, m), 3.27 (1H, s), 3, 02 (1H, td J 3.0 Hz and 12.0 Hz), 2.35 (1H, dd J 14.7 Hz and 6.12 Hz), 2.20 (1H, dd J 14.6 Hz and 6.2 Hz), 2.04 (1H, m), 1.76 (2H, m) and 1.28 (9H, s). m / z (ES +) 532 (M + 1).

DESCRIPTION 101 (2-y, 3?, 2, i?) - 3- (l-Forc-Butoxycarbonii-3-hydroxy-2-phenyl? I? Eridin-3-y) -2- (2-methoxypheni) propan-l -ol A solution of (2S, 3R, 2'R) -l-tert-butoxycabonbon-3-idtoxy-3- [3-benzoxy-2- (2-methoxyphenyl) propu] -2-phenylpiperidine (Description 100, 0,115 g) was hydrogenated in the presence of 10% palladium hydroxide on carbon (50 mg) in ethyl acetate (10 ml) and methanol (10 ml) at 50 psi (344.737 kPa) for 1 h. The mixture was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (95: 5 increasing to 75:25) to give the title compound (0.073 g). ? NMR (360 MHz, CDOb) d 7.48 (2H, d J7.2Hz), 7.30-7.16 (5H, m), 6.91 (1H, t J7.5Hz), 6.86 (1H , d J7.9Hz), 5.19 (1H, s), 4.00 (1H, dd J 13.0Hz and 4.7Hz), 3.82 (3H, s), 3.79-3.62 ( 3H, m), 3.09 (1H, m), 2.69 (2H, vbs), 2.33 (1H, dd J 14.7 Hz and 5.6 Hz), 2.08 (1H, dd J 14.9 Hz and 6.4 Hz), 1.98 (1H, m), 1.73 (3H, m), 1.27 (9H, s). m / z (ES +) 442 (M + 1).

DESCRIPTION 102 2-Benzyloxy-5- (trifluoromethoxy) benzene Benzyl bromide (66.17 ml, 95.35 g, 0.56 mol) was added to a mixture of 4- (trifluoromethoxy) phenol (90.26 g, 0.51 moles) and potassium carbonate (140.97 g, 1.2 moles) in dimethylformamide (160 ml) and the mixture was stirred at room temperature for 72 h. The mixture was poured into water (1.5 l) and extracted with ethyl acetate (3 x 500 ml). The combined organic fractions were washed with aqueous sodium carbonate (saturated, 500 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (133.5 g, 99% ). ? NMR (360 MHz, CDOb) d 7.39 (5H, m), 7.14 (2H, d, J 9.0 Hz), 6.95 (2H, d, J 9.0 Hz) and 5.05 (2H, s).

DESCRIPTION 103 2-Benzyloxy-5- (trifluoromethoxy) iodobenzene. Iodine (71.96 g, 0.28 mol) in chloroform was added to a mixture of 2-benzyoxy-5- (thi-fluoromethoxy) benzene (Description 102, 73.06 g, 0.27 mol) and silver trifluoroacetate (71.57 g, 0.32 mol) in dichloromethane, and the mixture was stirred at room temperature for 18 h. The mixture was filtered through celite, washed with aqueous sodium thiosulfate (5%, 2 x 2 1), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane / EtOAc, to give the title compound as a colorless oil (108.03 g), which contained 11% of 2-benzoxy-5 - (trifluoromethoxy) iodobenzene which had not reacted. ? NMR (360 MHz, CDCl 3) d 7.67 (1H, d, J2.8 Hz), 7.40 (5H, m), 7.16 (1H, dd, J8.9, 2.8 Hz), 6 , 82 (1H, d, J8.9 Hz) and 5.14 (2H, s).

DESCRIPTION 104 l-Benzyloxy-4- (difluoromethoxy) benzene Ethyl chlorodifluoroacetate (25 ml, 0.20 mole) was added to 4- (benzyloxy) phenol (, 10 g, 0.10 mol) and potassium carbonate (41.90 g, 0.30 mol) in dimethylformamide (200 ml) and the mixture was stirred at 80 ° C for 18 h. Additional ethyl chlorodifluoroacetate (12.7 ml, 0.10 mole) and potassium carbonate (27.74 g, 0.20 mole) were added and the mixture was stirred at 80 ° C for 6 h. Additional ethyl chlorodifluoroacete (12.7 ml, 0.10 mole) and potassium carbonate (27.74 g, 0.20 mole) were added and the mixture was stirred at 120 ° C for 15 h. The mixture was cooled, poured into water (1000 ml) and extracted with ethyl acetate (500 ml). The organic fraction was washed with aqueous sodium hydroxide (1 M, 500 ml) and brine (500 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / CH2Cl2 (90:10) to give the title compound as a colorless solid (6.67 g, 27%). ? NMR (360 MHz, CDC-b) d 5.05 (2H, s), 6.42 (1H, t, J 74 Hz), 6.94 (2H, m), 7.06 (2H, m) and 7.31-7.44 (5H, m).

DESCRIPTION: 105 2-Benzyloxy-5- (difluoromethoxy) iodobenzene Prepared from the compound of Description 104 according to the procedure of Description 103. iH NMR (360 MHz, CDCl 3) d 5.13 (2H, s), 6.40 (1H, t, J 74 Hz), 6.80 (1H, d, J 8.9 Hz), 7.07 (1H, dd, J 8.9, 2.8 Hz), 7.33 (1H, m), 7.40 (2H, m), 7.48 (2H, m), 7.60 (1H, d, J2.8 Hz).

DESCRIPTION 106 -Fluoro-2-hydroxyiodobenzene Chloramine-T trihydrate (50 g, 178 mmol) was added to an agitated and cooled (0 ° C) solution of 4-fluorophenol (20 g, 178 mmol) and sodium iodide (26.7 g). 178 immoles) in dimethylformamide (250 ml). The mixture was stirred at 0 ° C for 1 h. and poured into water (1000 ml). The mixture was acidified with hydrochloric acid (1 M) and extracted with ether (4 x 200 ml). The combined organic fractions were washed with aqueous sodium thiosulfate (5%, 3 x 100 ml), water (2 x 50 ml) and brine (50 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane / CH2C12 to give the title compound as an off-white solid (7.8 g, 18%). i H NMR (360 MHz, CDCl 3) d 5.08 (1H, s), 6.90-7.01 (2H, m) and 7.37 (1H, dd, J7.6, 2.9 Hz).

DESCRIPTION 107 2-Benzyloxy-5-fluoroiodobenzene Prepared from the compound of Description 106 according to the procedure of Description 36. * H NMR (360 MHz, CDCl 3) d 5.10 (2H, s), 6.78 (1H , dd, J9.0, 4.6 Hz), 6.94-7.01 (1H, m) and 7.30-7.56 (6H, m).

DESCRIPTION 108 -Benzyoxy-2-isopropoxyinitrobenzene 2-Bromopropane (4.51 ml, 5.90 g, 48 mmol) was added to a mixture of 4-benzyoxy-2-nitrophenol (J. Biol. Chem., 1985, 260, 3440). , 2.94 g, 12 mmol) and potassium carbonate (9.95 g, 72 mmol) in dimethylformamide (20 ml) and the mixture was stirred at 50 ° C for 22 h. The mixture was cooled, ducted with water (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic fractions were washed with aqueous sodium hydroxide (1 M, 4 x 100 ml) and brine (100 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure to give the title compound as an orange oil (3.40 g, 99%)? NMR (360 MHz, CDCl 3) d 7.41-7.33 (6H, m), 7.12 (1H, dd, J9, 1, 3.1 Hz), 7.02 (1H, d, J 9, l Hz), 5.05 (2H, s), 4.52 (1H, hept., J6, l Hz) and 1.35 (6H, d, J 6.1 Hz).

DESCRIPTION 109 -Benzyl-oxy-2-iso? -oxybenzeneamine Titanium trichloride (10% solution in 20-30% hydrochloric acid, 50 ml) was added to a solution of 5-benzyoxy-2-isopropoxynithiobenzene (Description 108, 2, 78 g, 9.7 mmol) in acetic acid (50 ml) and the mixture was stirred at room temperature for 18 h. The mixture was poured into ice cold aqueous sodium hydroxide (4 M, 400 ml) and the mixture was extracted with dichloromethane (8 X 100 ml). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (2 x 200 ml), dried (MgSQt) and the solvent was evaporated under reduced pressure to give the title compound as a dark oil (1.74 g, 71%)? NMR (360 MHz, CDCl 3) d 7.42-7.25 (5H, m), 6.71 (1H, d, J 8.7 Hz), 6.41 (1H, d, J2.9 Hz), 6.30 (1H, dd, J8.7, 2.9 Hz), 4.97 (2H, s), 4.38 (1H, hept., J 6.0 Hz), 3.6 (2H, sa ) and 1.32 (6H, d, J6.0 Hz).

DESCRIPTION 110 -Benzyloxy-2-isopropoxyiobenzene Sodium nitrite (589 mg, 8.5 mmol) in water (2.5 ml) was added dropwise to an agitated and cooled suspension (0 ° C) of 5-benzyoxy-2-isopropoxybenzeneamine. (Description 109, 2.05 g, 8.4 mmol) in sulfuric acid (2M, 14 ml). The mixture was stirred at 0 ° C for 30 min. and then drop by drop was added to a stirred and cooled solution (0 ° of potassium iodide (2.50 g, 15.1 mmol) in water (10 ml) .The mixture was stirred at room temperature for 90 min. Water (50 ml) was added The mixture was extracted with ethyl acetate (3 x 50 ml) The combined organic fractions were washed with aqueous sodium thiosulfate (10%, 2 x 50 ml), hydrochloric acid (2M, 2 x). 50 ml), saturated aqueous sodium hydrogen carbonate (2 x 50 ml) and brine (50 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure, the residue was purified by flash column chromatography on silica gel, eluting with hexane / CH2C12 (80:20) to give the title compound as a cream solid (1.49 g, 48% μH NMR (360 MHz, CDCU) d 7.42- 7.30 ( 6H, m), 6.90 (1H, dd, J9.0, 2.9 Hz), 6.77 (1H, d, J 9.0 Hz), 4.98 (2H, s), 4.41 (1H, hept., J6, l Hz) and 1.35 (6H, d, J6, l Hz).

DESCRIPTION 111 (3-y, 5?, 6 ^ -3- [2- (l-Phenutiocycloprop-l-ü) oxy-5- (trifluorornetoxy) phenyl-6-phenyl-l-oxa-7- (fórc-butoxicarbonü) aza -spiror4,5] decane It was dissolved (3-S ', 5 - *, 6-S) -3- (2-hydroxy-5- (trifluoromethoxy) phen) -6-phen-1-oxa-7- (b) -butoxycarbonu) aza-spiro [4.5] decane (Example 212) (290 mg, 0.59 mmole) in toluene (5 ml) and silver carbonate (179 mg, 0.65 mmole) was added in one portion. Then, (1-yo-cycloprop-1-yl) phenylsulfide (Cohen T. and Matz J., J. Am. Chem. Soc. 1980, 102, 6902) (180 mg) was added for one minute at room temperature. 0.65 mmol) The mixture was stirred at 55 ° C for 4 h and then further portions of silver carbonate (179 mg, 0.65 mmol) and (1-iodocycloprop-1-yl) phenolsulfide ( 180 mg, 0.65 mmol) The mixture was stirred at 55 ° C for a further 3 h, cooled, filtered and the solvent was evaporated under reduced pressure.The residue was purified by column chromatography on silica gel, eluting with hexane / ethyl acetate (90:10 increasing to 80:20) to give the title compound as a colorless oil (120 mg, 32%). ? NMR (250 MHz, CDCl 3) d 7.55-7.44 (4H, m), 7.36-7.23 (7H, m), 7.13-7.02 (2H, m), 5.16 (1H, sa), 4.09 (1H, t, J6Hz), 4.03-3.92 (1H, m), 3.67-3.49 (2H, m), 2.94-2 , 79 (1H, m), 2.26 (1H, dd, J 7.9, 12.9 Hz), 2.15-2.01 (2H, m), 1.76-1.59 (3H, m), 1.53-1.45 (4H, m) and 1.36 (9H, s). m / z (ES +) 642 (M + 1).

DESCRIPTION 112 (3R.5J ?, 6S) -3-r2- (1-Phenylthiocycloprop-1-y) oxy-5 - (, trifluoromethoxy) phenyl] -6-phenyl-1-oxa-7- (chloro-butoxycarbonyl) aza- spiro [4.5] decane Prepared from (3i?, 5-β, 6S) -3- (2-hydroxy-5- (trifluoromethoxy) fenu) -6-phene-1-oxa-7- ( fórc-butoxicarbonü) aza-spiro [4.5] decane (Example 212) according to the procedure of Description 111.? NMR (360 MHz, CDCls) d 7.57 (2H, d ap., J 7.6 Hz), 7.45 (2H, d ap., J 7.7 Hz), 7.36-7.19 ( 7H, m), 7.16-7.06 (2H, m), 5.28 (1H, sa), 4.13 (1H, t ap., J 7.8 Hz), 3.96 (1H, day, J 13 Hz), 3.80-3.60 (2H, m), 2.79 (1H, ta , J 13 Hz), 2.50 (1H, ??, J 13, 7.9 Hz), 2.17 (lH, dt, J 13, 4.6 Hz), 1.80 (1H, dd, J 12, 9 , 8 Hz), 1.75-1.38 (7H, m) and 1.44 (9H, s). m / z (ES +) 642 (M + 1).

DESCRIPTION 113 (3-S'.5ig, 6-Sl) -3-r2- (l-Phenutiocycloprop-1-y) oxy-5- (thiifluoromethyl) phenyl] -6-phenyl-1-oxa-7 - (- ') -butoxycarbonu) aza-espirol4.5] decane Prepared from (3-S, 5-β, 6-S) -3- (2-hydroxy-5- (trifluorornetut) phenyl) -6-phen-1-oxa -7- (- 'grc-butoxycarbon) aza-spiro [4.5] decane (Example 216) according to the procedure of Description 111. W NMR (360 MHz, CDCk) d 7.53-7.22 ( 13H, m), 5.13 (1H, s), 4.11 (1H, m), 3.97 (1H, m), 3.59 (2H, m), 2.89 (1H, m), 2.28 (1H, dd, J 12.7, 7.6 Hz), 2.08 (2H, m), 1.68 (3H, m), 1.75-1.48 (4H, m) and 1.34 (9H, s). m / z (ES +) 626 (M + l).

DESCRIPTION 114 (3 / ?, 5?, 6-S) -3- [2- (l-Phenutiocycloprop-1-y) oxy-5- (difluoromethoxy) phenyl] -6-phenyl-1-oxa-7- (tert- butoxycarbon) aza-spiro [4.5] decane Prepared from the compound of Example 225 according to the procedure of Description 111. * H NMR (360 MHz, CDCl 3) d 7.57 (2H, d, J 7, 6 Hz), 7.46 (2H, d, J 7.2 Hz), 7.35-7.20 (7H, m), 7.03 (2H, m), 6.44 (1H, t, J 74.3 Hz), 5.27 (1H, s), 4.12 (1H, m), 3.96 (1H, m), 3.70 (2H, m), 2.80 (1H, m), 2.49 (1H, m) , 2.18 (1H, m), 1.82 (1H, m), 1.75-1.26 (7H, m) and 1.44 (9H, s). m / z (ES +) 624 (M + l).

DESCRIPTION 115 (3H5J ?, 6-S) -3- [2- (1-Phenutiocycloprop-1-y) oxy-5- (trifluorornetoxy) phenyl] -6- (4-fluorofenu) -l-oxa-7- ( ferd-butoxycarbon) aza-espiror4,51decano Prepared from the compound of Example 223 according to the procedure of Description 111. * H NMR (360 MHz, CDCl 3) d 1.42 (9H, s), 1.43- 1.65 (5H, m), 1.80 (1H, dd, J 12.5, 9.6 Hz), 2.12 (1H, m), 2.47 (1H, dd, J 7.8, 12.8 Hz), 2.77 (1H, td, J13.2, 9.5 Hz), 3.65 (1H, qn, J8.6 Hz), 3.73 (1H, t, J8.3 Hz ), 3.95 (1H, dd, J9.67 Hz), 4.10 (1H, m), 5.23 (1H, s), 7.00 (2H, t, J8.76 Hz), 7, 10 (2H, s), 7.29 (6H, m), 7.47 (2H, d, J8.5 Hz) and 7.53 (2H, dd, J8.9, 5.8 Hz).

DESCRIPTION 116 Tetiacyclopropyl tin Cyclopropyl bromide (3.3 ml) in tetiahydrofuran (18 ml) to magnesium (1 ml) was added drop by drop., 1 g) in tetiahydrofuran (2 ml) and the mixture heated until a self-sustained reflux was started. The mixture was stirred at 65 ° C for 1 h., Cooled to room temperature and tin gase (IV) (2.4 ml) was added dropwise. The mixture was stirred at 65 ° C for 16 h, cooled and diluted with aqueous ammonium chloride (saturated, 30 ml). The mixture was extracted with ether (3 x 20 ml) and the combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane, to give the title compound as a colorless oil. X H NMR (360 MHz, CDQ b) d -0.38 (4H, m), 0.37 (8H, m) and 0.57 (8H, m).

DESCRIPTION 117 3-Iodo-4- (4-methoxybenzoxy) benzonitrile Iodine (21 g, 84 mmol) was added to a solution of 4-cyanophenol (10.0 g, 84 mmol) and sodium hydrogen carbonate (7.06 g, 84 mmol) ) in water (100 ml) and the mixture was stirred at room temperature for 24 h. The solid was collected, washed with water and dried in vacuo. The solid was dissolved in tetiahydrofuran (100 ml) and triphenylphosphine (14.4 g, 55 mmol) and 4-methoxybenzyl alcohol (8.3 g, 60 mmol) were added. Slowly diethyl azodicarboxylate (8.5 ml, 55 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was poured into sodium hydrogen carbonate solution (saturated, 200 ml) and extracted with ethyl acetate (2 × 200 ml). The combined organic fractions were dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel to give the title compound (3.38 g). * H NMR (250 MHz, CDC-b) d 8.05 (1H, d, J 2.0 Hz), 7.57 (1H, dd, J 2.0, 8.5 Hz), 7.38 ( 2H, d, J 6.8 Hz), 6.79-6.96 (3H, m), 5.14 (2H, s) and 3.82 (3H, s).

DESCRIPTION 118 (, 3i?, 5ig, 6-S ^ -3-r5-Cyano-2- (4-methoxybenzeneoxy) phen-1 -6-phen-l-oxa-7 - (- 'grc-butoxycarbonu) aza-espiror4,51decano Prepared from Description 117 and (5?, 6-S) -6-phene-l-oxa-7- (tert; -butoxycarbon) aza-spiro [4.5] dec-3-ene (Description 86) of according to the procedure of Example 219.? NMR (250 MHz, CDCb) d 7.48-7.57 (4H, m), 7.20-7.34 (5H, m), 6.89-7.01 (3H, m), 5.29 (1H, s), 5.07 (1H, s), 4.22-4.32 (1H, m), 3.90-3.99 (1H, m), 3.81 (3H, s), 2.76 (1H, dt, J 12.0, 4.3 Hz), 2.50-2.57 (1H, m), 1.91 -2.23 (2H, m), 1.60-1.66 (5H, m) and 1.42 (9H, s).

DESCRIPTION 119 Q ^^ SR ^ -Sl-^ - ^ - Cyano ^ -farc-butoxycarbon ^ ox-ifenyl-or-phen-l-oxa ^ -fforc-butoxycarbon) aza-spiror4,5] decane Di (/ grc-butuo) (698 mg, 3.2 mmol) to a solution of (3i?, 5i?, 6-S) -3- (5-cyano-2-hydroxyphenyl) -6-phen-1-oxa-7 aza-spiro [4.5] decane (Example 274, 533 mg, 1.6 mmol) and dioxypropylethylamine (0.556 ml, 3.2 mmol) in dichloromethane (50 ml) and the mixture was stirred at room temperature for 16 h . The mixture was washed with sodium hydrogen carbonate solution (saturated, 50 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the title compound as a colorless solid (465 mg). ? NMR (250 MHz, CDCb) d 7.72 (1H, d, J 1.9 Hz), 7.54-7.60 (3H, m), 7.22-7.36 (4H, m), 5 , 33 (1H, m), 4.26 (1H, dd, 7.2, 8.7 Hz), 3.94-3.98 (1H, m), 3.81-3.88 (1H, m), 3.69-3.75 (1H, m), 2.77 (1H, dt, J 3.5, 12.6 Hz), 2.64 (1H, dd, J 8.3, 13.0 Hz), 2.25 (1H, dt, J8, l, 13.1 Hz), 1.89 (1H, dd, J 8 , 6, 13.0 Hz), 1.71-1.77 (3H, m), 1.56 (9H, s) and 1.46 (9H, s).

DESCRIPTION 120 (3J ^ 5i?, 6-S ^ -3- [2- (l-Phenutiocycloprop-l-ü) oxy-5- (fa-ifluorometü) fenül-6-fenü-l-oxa-7- (fórc-butoxicarbonü ) aza-spiro [4,5] decane Prepared from (3 /? 5i?, 6-S) -3- (2-hydroxy-5- (trifluoromethyl) fenu) -6-phen-1-oxa- 7- (tert-butoxycarbon) aza-spiro [4.5] decane (Example 216) according to the procedure of Description 111. * H NMR (360 MHz, CDCb) d 1.44 (9H, s), 1 , 40-1.72 (7H, m), 1.84 (1H, m), 2.16 (1H, m), 2.51 (1H, m), 2.80 (1H, m), 3, 71 (2H, m), 3.97 (1H, m), 4.15 (1H, m), 5.29 (1H, s) and 7.22-7.59 (13H, m). (ES +) 570 (M + l-QH8).

DESCRIPTION 121 6-Fluoro-2-methoxyiobenzene. Dripping to n-bufa lithium (1.6 M in hexanes, 26 ml, 42 mmol) was added to an agitated and cooled solution (-78 ° C) of 3-fluoroanisole (5.0 g, 40 mmol) in THF (150 ml) and the mixture was stirred at -78 ° C for 2.5 h. Iodine drop (11.1 g, 43 mmol) in THF (50 mL) was added dropwise and the mixture was allowed to warm to room temperature. Water (200 ml), saturated aqueous sodium thiosulfate (100 ml) and ether (300 ml) were added and the layers separated. The aqueous layer was extracted with ether (200 ml), the combined organic fractions were dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / EtOAc (99: 1) to give the title compound as a pale yellow oil (7.65 g, 77%). i H NMR (360 MHz, CDC b) d 7.27 (1 H, dt, J d 6.6 Hz, J t 8.2 Hz), 6.71 (1 H, t, J8.2 Hz), 6.62 (1 H, d, J8.2 Hz) and 3.90 (3H, s).

EXAMPLE 1 (5?, 6-S) -3- (2-Methoxy-5-trifluoromethoxy-phenyl) -6-phen-1-oxa-7- (tg / 'c-butoxycarbon) aza-spiro [4 > 5] dec-3-ene Degassed (5i?, 6 - ^ - 3-trünetüestarmü-6-fenü-l-oxa-7 - (- 'grc-butoxicarbonü) aza-spiro [4,5] dec-3 -ne (Description 6, 3.07g, 6.43 -mol), lithium chloride (0.163g), 2-bromo-4-trifluoromethoxyanisole (Description 12, 2.07g, 7.7mmol) in toluene (25 ml) ), before the addition of triphenylphosphine palladium (0) (0.37 g) The solution was thoroughly degassed before heating at 110 ° C. for 14 h.The solution was divided between water and ethyl acetate and the dry organic phase was purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate of 0% and 4%), to give the title compound.? RMN (250 MHz, CDCb) d 7 , 45 (2H, d, J7.2 Hz), 7.30-7.2 (3H, m), 7.13-7.09 (1H, dd, J9.0 Hz), 6.89 (2H, s + d), 6.64 (1H, t, J2.04 Hz), 5.16 (1H, s), 4.96 and 4.56 (2H, ABdd, J 12.1, 2 Hz), 4 , 11 (1H, m), 3.86 (3H, s), 3.08 (1H, m), 2.1 (1H, m), 1.87-1.77 (3H, m) and 1.37 (9H, s). m / z (ES +) 506 (M + 1).

EXAMPLE 2 (5?, 6S) -3- (2-Methoxy-5-trifluoromethoxy-phenyl) -6-phene-l-oxa-7-aza-spiro4,5] dec-3-ene was dissolved (5i?, 6-S) -3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7- (1-butoxycarbonyl) aza-spiro [4.5] dec-3-ene (Example 1; 2.7g) in dichloromethane (25 ml) and anhydrous trifluoroacetic acid (25 ml) was added over 10 min., before evaporation to dryness and purification by chromatography on a column containing silica gel (eluting with dichloromethane containing increasing proportions of methanol). aqueous ammonia (25: 1) between 0% and 5%) to give the title compound. * H NMR (360 MHz, CDCk) d 7.35 (2H, dd, J8.4, 1.58 Hz), 7.20-7.10 (3H, m), 7.00 (1H, dd, J 8.89, 1.89 Hz), 6.77 (1H, d, J 8.97 Hz), 6.64 (1H, d, J 2.58 Hz), 6.12 (1H, t, J 2 , ll Hz), 4.85 and 4.26 (2H, ABdd, J 11.91, 2.0 Hz), 3.75 (4H, s), 3.26. (1H, d a), 2.83 (1H, td, J 12.1, 2.75 Hz) and 2.06-1.63 (4H, m). m / z (ES +) 406 (M + 1). A sample of this material was crystallized from diethyl ether as the hydrochloride salt p.f. 278-286 ° C.

EXAMPLE 3 (3-S ', 5?, 6-y) -3- (2-Methoxy-5-trifl.uoromethoxy-phenyl) -6-phene-l-oxa-7-aza-spiro4,5] decane A mixture of (5R , 6-S) -3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene (Example 2, 1.4 g) 10% palladium hydroxide / carbon (0.25 g) in methanol (90 ml) containing acetic acid (9 ml) was hydrogenated at 50 psi (344.737 kPa) for 16 h. The solution was filtered, evaporated and the residue was crystallized twice from hexane to give the title compound, m.p. 91-104 ° C. * H NMR (250 MHz, CDCb) d 7.50-7.54 (2H, m), 7.33-7.36 (3H, m),), 6.90 (1H, dd, J8.9, 2.07 Hz), 6.68 (1H, d, J8.9 Hz), 6.17 (1H, d, J2.7 Hz), 4.08 (1H, t, J 7.8 Hz), 3 , 75 (1H, m), 3.69 (4H, s + d), 3.24 (1H, da), 3.12 (1H, dd, J10.3, 8.03 Hz), 2.82 ( 1H, td, J12.4, 2.6 Hz), 2.16-1.80 (6H, m) and 1.55-1.64 (2H, m). m / z (ES +) 408 (M + 1).

EXAMPLE 4 f ±) - (3 * -S ', 5j? * 6-S *) - 3- (2-Methoxy-5-thiifluoromethoxy-phenyl) -6-phene-l-oxa-7-aza-es? iro [4, 5] decane The title compound was prepared in a manner analogous to that of Examples 1, 2 and 3 using (5i2 *, 6-S *) - 3-thiimetüestannü-6-fenü-l-oxa-7 - (- racemic 'g' c-butoxycarbonii) aza-spiro [4.5] dec-3-ene (3.07 g, 0.419 mmol) as a starting material, this compound was prepared in a manner analogous to that of Descriptions 2-6 using (±) -l-fer-butoxycarbonyl-2-phenylpipericlin-3-one (Description 1) as starting material. ? NMR (250Mz) d 1.55-1.64 (2H, m), 1.85 (2H, d, J9.9 Hz), 2.10-2.14 (2H, m), 2.80 (1H , m), 3.10-3.28 (2H, m), 3.69 (1H, s), 3.76-3.86 (2H, m), 4.11 (1H, m), 6, 17 (1H, d, J2.7 Hz), 6.68 (1H, d, J 8.9 Hz), 6.89-6.94 (1H, m), 7.33-7.36 (3H, m) and 7.50-7.54 (2H, m). m / z (ES +) 408 (M + 1).

EXAMPLE 5 (3-S, 5i?, 6-Sl) -3- (2-Methoxy-5-trifluoromethoxy-phenyl) -6-phenyl-7- (1, 2,4-thiazole-3-methylene) -l-oxa- 7-aza-spiro [4,5] decane A tma solution of (3-S ,, 5i?, 65) -3- (2-methoxy-5-trifluoromethoxyphenyl) -6-phenyl-oxa-7-aza-spiro [4, 5] decane (Example 3, 0.15g, 0.369mmol) and K2CO3 (0.254g, 1.84mmol) in dimethylformamide (2ml), a solution of JV-formyl-2-chloro-amidrazone (0.055g) was added. 0.405 mmole) in dimethyl formamide (0.5 ml). The solution was stirred at room temperature for 2 h. and then it was heated in an oil bath at 140 ° C for 2 h. The cooled solution was poured into a mixture of ethyl acetate and water and the organic phase was washed with saturated brine and dried (MgSO). The solvent was removed in vacuo and the residue was purified on a column containing silica gel (eluting with dichloromethane containing 1-5% of a methanol-ammonia mixture (SG 0.88) (96: 4) to give the title compound.? NMR (360 MHz, CDOb) d 7.91 (1H, s), 7.55 (2H, sa), 7.34-7.33 (3H, m), 6.92 (1H , d, J8.8 Hz), 6.69 (1H, d, J8.9 Hz), 6.13 (1H, s), 4.09 (1H, t, 7.89 Hz), 3.84 ( 1H, s), 3.77 (1H, t, J9.15 Hz), 3.71 (3H, s), 3.48-3.39 (2H, m), 3.10-3.01 (2H , m), 2.36 (1H, t J 12.0 Hz), 2.17-2.06 (3H, m), 1.86 (2H, m) and 1.62 (2H, m). / z (ES +) 489 (M + 1).

EXAMPLE 6 (5 - ^, 6-S -3- (2-Isopropoxy-5-thiifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-ene Prepared from the compound of Description 13 and (5R, 6S) -3-trimethylstannü-6-phenyl-1-oxa-7- (tgr £. -butoxycarbonu) aza-spiro [4,5] dec-3-ene, according to the procedures of Examples 1 and 2. * H NMR (360 MHz, CDOb) d 1.25 (3H, d, J2.6 Hz), 1.27 (3H, d, J2.6 Hz), 1.66 (1H, m), 1.78 (1H, dd, J13.5, 4.5 Hz ), 1.96 (1H, m), 2.08 (1H, m), 2.83 (lH, dt, J 12.6, 2.8 Hz), 3.30 (1H, d, J10.4 Hz), 3, 79 (1H, s), 4.33 (1H, dd, J12, 2.1 Hz), 4.45 (1H, m), 4.86 (1H, dd, J12, 2 Hz), 6.10 (1H, t, 2.1 Hz), 6.69 (1H, d, J2.5 Hz), 6.73 (1H, d, J9, l Hz), 6.96 (1H, d, J8.6 Hz), 7.17 (3H , m) and 7.37 (2H, d, 6.4 Hz). m / z (ES +) 434 (M + 1).

EXAMPLE 7 (5?, 6 - ^ - 3- (2-A-Iloxy-5-trifluoromethoxy-phenyl) -6-phenyl-l-oxa-7-aza-spiro [4,5] dec-3-ene Hydrochloride Prepared to From the compound of Description 14 and (5i?, 6-S) -3-thiimetüestennü-6-fenü-l-oxa-7 - (- 'grc-butoxicarbonü) aza-spiro [4,5] dec-3- In accordance with the procedures of Examples 1 and 2, mp 234-245 ° C, * H NMR (360 MHz, DMSO-dβ) d 1.73 (1H, d, J 12.4 Hz), 1, 81 (1H, m), 1.92 (1H, dt, J 13, 3.9 Hz), 2.03 (lH, m), 2.43 (1H, dd, J 16.3, 5.9 Hz ), 2.60 (1H, dd, J16.6, 5.3 Hz), 3.02 (1H, m), 3.26 (1H, m), 3.89 (1H, d, J13.4 Hz), 4.34 (1H, d, J12.4 Hz), 4.43 (1H, m), 4.57 (1H, dd, J17, 1.6 Hz), 4.80 (1H, d, J10, l Hz), 5.34 (1H, m), 5.42 (1H, s), 7.36 (5H, m), 8.99 (1H, sa) and 9.68 (1H, sa) .

EXAMPLE 8 (5R, 6) -3- (5-Trifluoromethoxy-2,3-dihydrobenzofuran-7-ü) -6-fenü-l-oxa-7-aza-spiro [4,5] dec-3-ene Prepared from of the compound of Description 17 and (5R, 6_S) -3-tiimetüestannü-6-fenü-l-oxa-7 - (/ gr £ - butoxycarbonü) aza-spiro [4,5] dec-3-ene, of according to the procedures of Examples 1 and 2. XH NMR (250 MHz, CDCb) d 1.68 (1H, m), 1.80 (1H, dd, J 13.3, 4.33 Hz), 1, 95 (1H, m), 2.11 (1H, m), 2.80 (1H, td, J 12.5, 2.7 Hz), 3.17 (2H, t, J8.8 Hz), 3 , 28 (1H, m), 3.80 (1H, s), 4.32 (1H, dd, J 2.2, 12 Hz), 4.63 (2H, t, J8.8 Hz), 4, 80 (1H, dd, J12, 2.1 Hz), 6.23 (1H, t, J2, l Hz), 6.41 (1H, d, Jl, 61 Hz), 6.88 (1H, d, 1.2 Hz), 7.17 (3H, m) and 7.37 (2H, m). m / z (ES +) 418 (M + 1).

EXAMPLE 9 (5-R, 6-S ^ -3- (2-Methoxy-5- (2,2,2-thiifluoroethoxy) phenyl ') - 6-phenyl-l-oxa-7-aza-spiro4,51dec-3- eno Prepared from the compound of Description 21 and (5i?, 65) -3-trimetüesta? mü-6-fenü-l-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] dec-3 -eno, according to the procedures of Examples 1 and 2. H NMR (360 MHz, DMSO-dβ) d 1.64 (1H, m), 1.79 (1H, dt, J 13.4, 4, 2 Hz), 2.00 (2H, m), 2.82 (1H, dt, J 12.4, 2.8 Hz), 3.26 (1H, m), 3.70 (3H, s), 3.75 (1H, s), 4.21 (2H, dq, J 8.3, 2.5 Hz), 4.3 (1H, dd, J ll, 9, 2.2 Hz), 4.84 (1H, dd, J ll, 9, 2.1 Hz), 6.12 (1H, t, J 2, l Hz), 6.41 (1H, t, J l, 7 Hz), 6.72 ( 2H, d, Jl, 7 Hz), 7.15 (3H, m) and 7.35 (2H, m) m / z (ES +) 420 (M + 1).

EXAMPLE 10 (5i?, 6-S) -3- (2,5-Bis (2,2,2-trifluoroethoxy) fenu) -6-phene-1-oxa-7-aza-spiro [4,51dec-3-ene] Prepared from the compound of Description 22 and (5R, 6S) -3-tri-metüestannü-6-fenü-l-oxa-7 - (- 'grc-butoxicarbonü) aza-es? Iro [4,5] dec -3-ene, according to the procedures of Examples 1 and 2. JH NMR (250 MHz, CDCb) d 1.60 (1H, m), 1.80 (1H, dt, J 13.5 and 4, 3 Hz), 1.97 (1H, m), 2.02 (1H, m), 2.83 (1H, dt, J 12.4 and 2.7 Hz), 3.28 (1H, m), 3.78 (1H, s), 4.08 (2H, m), 4.22 (2H, q, J 8 Hz), 4.36 (1H, dd, Jll, 9 and 2.2 Hz), 4 , 84 (1H, dd, Jll, 9 and 1.9 Hz), 6.16 (1H, t, J2, l Hz), 6.45 (1H, t, 1.7 Hz), 6.72 (2H , d, J 1.7 Hz), 7.15 (3H, m) and 7.36 (2H, m). m / z (ES +) 488 (M + 1).

EXAMPLE 11 (5-R, 6-S) -3- (2-difluoromethoxy-5-thiifluorornetoxyphenyl) -6-phenyl-l-oxa-7-aza-spiro [4.5] dec-3-ene Prepared from the compound of Description 23 and (5i?, 65) -3-tri? netüestannü-6-fenü-l-oxa-7 - (- Igrc-butoxicarbonü) aza-spiro [4,5] dec-3-ene, in accordance with the procedures of Examples 1 and 2. * H NMR (360 MHz, DMSO-dβ) d 1.8-1.9 (1H, m), 1.9-2.1 (1H, m), 3, 04-3.12 (1H, m), 3.26-3.36 (1H, m), 4.33 (1H, d, J 12 Hz), 4.60 (1H, s), 4.91 ( 1H, d, J 12 Hz), 6.41 (1H, s), 7.08 (1H, d, J3 Hz), 7.16 (1H, t, J 7.3 Hz), 7.25-7 , 4 (5H, m) and 7.45-7.47 (2H, m). m / z (ES +) 442 (M + 1).

EXAMPLE 12 (5J?, 6- $ -3- (2- (2,2,2-Trifluoroethoxy) -5-trifluoromethoxypheni) -6-phenyl-l-oxa-7-aza-spiro [4,5] decoloride 3-ene Prepared from the compound of Description 24 and (5?, 6-S) -3-trirnetüestannü-6-fenü-l-oxa-7 - (/ grc-butoxicarbonü) aza-spiro [4,5] dec-3-ene, according to the procedures of Examples 1 and 2, m / z (ES +) 474 (M + l).

EXAMPLE 13 (3-S ', 5J?, 6-->) -3- (2-Isopropoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the compound of Example 6 according to the procedure of Example 3, mp. 85-88 ° C. H NMR (360 MHz, DMSO-d6) d 1.23 (6H, t, J6.4 Hz), 1.65 (1H, t, J 12.3 Hz), 1.80 (2H, d, J 11 , 7 Hz), 2.04 (3H, m), 3.06 (2H, q, J 9 Hz), 3.30 (1H, m), 3.79 (lH, m), 4.15 (1H , t, J 7.8 Hz), 4.49 (1H, s), 4.55 (1H, m), 6.12 (1H, s), 6.99 (1H, d, 9 Hz), 7 , 06 (1H, m), 7.46 (3H, m), 7.56 (2H, m), 9.0 (1H, sa) and 9.65 (1H, sa), m / z (ES +) 436 (M + l).

EXAMPLE 14 Chlorohydrate of ^ - ^^^^ - ^^ - (S-trifluoromethoxy-S ^ -dihvdrobenzofuran ^ -iD-ó-fenü-l-oxa-7-aza-spiro [4,5] decane Prepared from the compound of Example 8 according to the procedure of Example 3, mp 303-305 ° C.? NMR (360 MHz, DMSO-d6) d 1.81 (3H, m), 2.0 (3H, m), 3, 09 (3H, t, J8.9 Hz), 3.22 (2H, m), 3.57 (1H, m), 4.06 (1H, t, J 7.9 Hz), 4.35 (2H, dt, J8.9, 4 Hz), 4.46 (1H, s), 6.17 (1H, s), 7.03 (1H, s), 7.47 ( 3H, m) and 7.54 (2H, m). m / z (ES +) 420 (M + 1).

EXAMPLE 15 Hydrochloride of (3 ', 5J?, 65'j-3- (2-Methoxy-5- (2,2,2-trifluoroethoxy) fenu) -6-feml-l-oxa-7-aza-spiro [4, 5] decane Prepared from the compound of Example 9 according to the procedure of Example 3, mp 126-128 ° C.? NMR (360 MHz, DMSO-d6) d 1.77 (3H, m), 1.99 (3H, m), 3.17 (1H, t, J 10.2 Hz), 3.59 (3H, s), 4.09 (1H, t, J 7, 7 Hz), 4.47 (1H, q, J8.9 Hz), 6.05 (1H, s), 6.82 (2H, s), 7.47 (3H, m) and 7.57 (2H, m). m / z (ES +) 422 (M + l).

EXAMPLE 16 (-3-S, 5R, 6S) -3- (2,5-Bis (2,2,2-trifluoroethoxy) fenu) -6-phene-l-oxa-7-aza-spiro hydrochloride [4,5 ] decane Prepared from the compound of Example 10 according to the procedure of Example 3, mp. 210-212 ° C,? NMR (250 MHz, DMSO-d6) d 1.88 (1H, t, J 11, 7 Hz), 2.04 (2H, m), 2.27 (3H, m), 3.35 (2H, t, J9.9 Hz), 3.48 (1H, m), 3.96 (1H, m), 4.37 (1H, t, J 7.9 Hz), 4.73 (3H, q, J2.9 Hz), 7.09 (1H, dd, J9.0, 2.9 Hz), 7.23 (1H, d, 9.1 Hz), 7.67 (3H, m) and 7.77 (2H, m). m / z (ES +) 490 (M + l).

EXAMPLE 17 (3-S ', 5?, 6-S -3- (2-Difluoromethoxy-5-thiifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from Compound of Example 11 according to the procedure of Example 3.? NMR (360 MHz, DMSO-d6) d 1.67 (1H, t, J 12 Hz), 1.74-1.84 (2H, m), 2.00-2.18 (3H, m), 3.07 (1H, m), 3.14 (1H, t, J8 Hz), 3.3 (1H, m), 3.81 (1H, qn , J 9 Hz), 4,15 (1 H, t, J 8 Hz), 4,51 (1 H, s), 6,10 (1 H, s), 7,16 (1 H, t, J 7,3 Hz ), 7.23 (2H, s), 7.40-7.54 (3H, m) and 7.58-7.60 (2H, m) m / z (ES +) 444 (M + l).

EXAMPLE 18 (3-S ', 5R, 6-y) -3- (2- (2,2,2-Trifluoroethoxy) -5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-espir or [ 4,5] decane Prepared from the compound of Example 12 according to the procedure of Example 3, mp. 209-211 ° C. ? NMR (360 MHz, DMSO-d6) d 1.63-1.69 (1H, m), 1.70-1.88 (2H, m), 2.0-2.14 (3H, m), 3 , 06-3.12 (2H, m), 3.24-3.32 (1H, m), 3.77 (1H, m), 4.16 (1H, t, J8 Hz), 4.51 ( 1H, s), 4.74-4.78 (2H, m), 6.19 (1H, s), 7.11-7.20 (2H, m), 7.44-7.48 (3H, m) and 7.56-7.58 (2H, m). m / z (ES +) 476 (M + 1).

EXAMPLE 19 (3-P ', 5i?> 6-S) -3- (2- (2,2,2-Trifluoroethoxy) -5-fluorofenu) -6-phenyl-l-oxa-7-aza-spiro [4 , 5] decane Prepared from the compound of Description 25, according to the procedures of Examples 1, 2 and 3. * H NMR (360 MHz, CDCb) d 1.69 (1H, m), 1.81 (1H, dd, J8.5, 8 Hz), 1.92-2.07 (2H, m), 2.74 (1H, dt, J12, 2.7 Hz), 3.11 (1H, t) , 3.15 (1H, m), 3.58 (1H, s), 3.73 (1H, qn, J8 Hz), 4.02 (1H, t, J8 Hz), 4.16 (2H, q , J8 Hz), 5.95 (1H, dd, J9.6, 3 Hz), 6.56-6.69 (2H, m), 7.18-7.27 (3H, m) and 7.39 -7.41 (2H, m). m / z (ES +) 410 (M + 1). EXAMPLE 20 (5?, 6 - ^ - 3- (5-Methanesulfonyl-2-methoxyphenu) -6-phenyl-1-oxa-7- (chloro-butoxycarbonu) aza-spiro [4,5] dec-3-ene Prepared from the compound of the Description 28 and (5i?, 65) -3-trimetüestannü-ó-fenü-l-oxa ^ - ^ grc-butoxicarbonüJaza-spiro ^ SJdec-S-ene, according to the procedure of Example 1 . * H NMR (250Mz, CDCk) d 7.86-7.83 (1H, dd, J8.8, 2.4 Hz), 7.59-7.58 (1H, d, J2.4 Hz), 7.49-7.43 (2H, m), 7.31-7.20 (3H, m), 7.05-7.02 (1H, d, 8.8 Hz), 6.69-6.68 ( 1H, m), 5.17 (1H, s), 5.00-4.94 (1H, dd, J12, l, 2.06 Hz), 4.68-4.62 (1H, dd, J 12 , 1, 2.06 Hz), 4.15-4.11 (1H, m), 3.95 (3H, s), 3.18-3.01 (1H, m), 3. 03 (3H, s), 2.13-2.06 (1H, m), 1.92-1.79 (3H, m) and 1.37 (9H, s). m / z (ES +) 500 (M + l).

EXAMPLE 21 (5R, 6S) -3- (5-Methanesulfonyl-2-methoxy-7) -6-phenyl-1-oxa-7-aza-spiro [4/5] dec-3-ene Prepared from the compound of Example 20 of according to the procedure of Example 2.? NMR (250 MHz, CDCb) d 10.33 (1H, sa), 7.78-7.73 (1H, dd, J8.7, 2.4 Hz), 7.55-7.45 (2H, m) ), 7.32-7.31 (1H, d, J2.4 Hz), 7.28-7.21 (3H, m), 6.92-6.89 (1H, d, J8.7 Hz) , 6.05-6.03 (1H, m), 5.34 (1H, s), 4.91-4.86 (1H, m), 4.46-4.41 (1H, m), 4 , 16-4.12 (1H, m), 3.82 (3H, s), 3.53-3.49 (1H, m), 2.97 (3H, s), 2.56-2.50 (1H, m) and 2.1-1.95 (3H, m). m / z (ES +) 400 (M + l).

EXAMPLE 22 (3-S ', 5?, 6-S -3- (5-Methenesulfonyl-2-n-ethoxypheni) -6-phen-1-oxa-7-az-a-spiro [4> 5] decane Prepared to from the compound of Example 21 according to the procedure of Example 3. * H NMR (250 MHz, CDOb) d 7.72-7.67 (1H, dd, J8.7, 2.3 Hz), 7.54 -7.50 (2H, m), 7.39-7.29 (3H, m), 7.06-7.05 (1H, d, J2.3 Hz), 6.85-6.82 (1H , d, J 8.7 Hz), 4.13 ^, 07 (1H, m), 3.86-3.74 (1H, m), 3.74 (3H, s), 3.70 (1H, s), 3.27-3.22 (1H, m), 3.19-3.11 (1H, m), 2.87 (3H, m), 2.88-2.78 (1H, m) and 2.14-1.56 (6H, m) .m / z (ES +) 402 (M + 1).

EXAMPLE 23 (5i?, 6-S) -3- [2- (Trifluoromethoxy) phenyl] -6-phenyl-1-oxa-7 - (? Grc-butoxycarbonu) aza-spiro [4,5] dec-3-ene Prepared from 2- (trifluoromethoxy) iodobenzene and (5R, 6-S) -3-tri? netüesta-nnü-6-fenü-l-oxa-7 - (- 'grc.-butoxycarbonu) aza-spiro [4, 5] dec-3-ene, according to the procedure of Example 1. * H NMR (250 MHz, CDCb) d 7.56-7.43 (3H, m), 7.34-7.17 (6H, m), 6.51-6.49 (1H, m), 5.14 (1H, s), 4.95-4.89 (1H, dd, J 12.2, 2.0 Hz), 4, 61 ^, 55 (1H, dd, J 12.2, 2.0 Hz), 4.18-4.11 (1H, m), 3.20-3.15 (1H, m), 2.12- 2.08 (1H, m), 1.90-1.78 (3H, m) and 1.35 (9H). m / z (ES +) 420 (M + 1 H).

EXAMPLE 24 (5?, 6-S -3- [2- (Trifluoromethoxy) phenyl] -6-phe n-l-oxa-7-aza-spiro [4.5] dec-3-ene Prepared from the compound of Example 23 , according to the procedure of Example 2.? NMR (250 MHz, CDCb) d 7.39-7.35 (2H, m), 7.25-7.06 (6H, m), 6.90-6 , 87 (1H, m), 6.04-6.03 (1H, m), 4.87-4.82 (1H, dd, J 12.0, 2.0 Hz), 4.38-4, 33 (1H, dd, J 12.0, 2.0 Hz), 3.79 (1H, s), 3.31-3.25 (1H, m), 3.05-2.95 (1H, sa ), 2.85-2.75 (1H, m), 2.14-1.94 (2H, m) and 1.85-1.64 (2H, m) m / z (ES +) 376 (M) + l) EXAMPLE 25 (3-S, 5?, 6-S ^ -3- [2- (Trifluoromethoxy) fenu] -6-phenyl-l-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the compound of Example 24 according to the procedure of Example 3. iH NMR (360 MHz, DMSO-d6) d 9.76 (1H, sa), 9.04 (1H, sa), 7.62-7.51 (5H , m), 7.27-7.25 (2H, m), 7.12-7.07 (1H, m), 6.23-6.21 (1H, d, J7.5 Hz), 4, 52 (1H, s), 4.15-4.11 (1H, m), 3.80-3.74 (1H, m), 3.39-3.26 (1H, m), 3.22- 3.17 (1H, m), 3.10-3.04 (1H, m), 2.14-2.08 (3H, m) and 1.83-1.67 (3H, m). z (ES +) 378 (M + 1).

EXAMPLE 26 (5J?, 6-S -3-r2-Cyclobutoxy-5 - ('thiifluoromethoxy) phenyl-6-phenyl-l-oxa-7- (ferc-butoxycarbon) aza-spiro [4,5] dec-3-ene Prepared from the compound of Description 29 and (5 - / ?, 6S) -3-tiimetüestannü-6-fenü-l-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] dec-3- ene, according to the procedure of Example 1.? NMR (360 MHz, CDCI3) d 7.47-7.45 (2H, m), 7.28-7.20 (3H, m), 7.06- 7.02 (1H, m), 6.96-6.94 (1H, m), 6.70-6.67 (1H, d, J 8.9 Hz), 6.64-6.63 (1H , m), 5.15 (1H, s), 5.00-4.94 (1H, m), 4.66-4.59 (2H, m), 4.15-4.11 (2H, m ), 3.10-3.08 (1H, m), 2.48-2.44 (2H, m), 2.20-2.10 (3H, m), 1.88-1.67 (4H , m) and 1.36 (9H, s).

EXAMPLE 27 (S / ^^^ - S - ^ - Cyclobutoxy-S-drifluoromethoxyfennyl-or-phen-1-oxa-aza-spiro ^^ ldec-S-ene Prepared from the compound of Example 26 according to the procedure of Example 2. NMR (250 MHz, CDCb) d 7.38-7.34 (2H, m), 7.23-7.10 (3H, m), 6.97-6.92 (1H, m) , 6.68-6.67 (1H, d, J2.3 Hz), 6.60-6.56 (1H, d, J 9.0 Hz), 6.16-6.14 (1H, m) , 4.90-4.85 (1H, dd, J 12.0, 2.1 Hz), 4.60-4.49 (1H, m), 4.33-4.27 (1H, dd, J 12.0, 2.1 Hz), 3.76 (1H, s), 3.31-3.24 (1H, m), 2.87-2.76 (1H, m), 2.48-2 , 36 (2H, m) and 2.19-1.62 (8H, m) m / z (ES +) 446 (M + l).

EXAMPLE 28 (3-S, 5R, 6-S ^ -3-r2-Cyclobutoxy-5- (trifluorornetoxy) fenu] -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from of the compound of Example 27 according to the procedure of Example 3. iH NMR (360 MHz, DMSO-d6) d 9.69 (1H, sa), 9.00 (1H, sa), 7.58-7.57 (2H, m), 7.48-7.43 (3H, m), 7.07-7.05 (1H, m), 6.81-6.79 (1H, d, J9.0 Hz), 6.13 (1H, s), 4.67-4.63 (1H, m), 4.51-4.48 (1H, m), 4.19-4.15 (1H, m), 3, 82-3.78 (1H, m), 3.41-3.36 (1H, m), 3.09-3.04 (2H, m), 2.40-2.36 (2H, m), 2.12-1.96 (5H, m) and 1.80-1.60 (5H, m) m / z (ES +) 448 (M + l).

EXAMPLE 29 (5J?, 6-S) -3 - ('2 - (, 2-Fluoroethoxy) -5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7 - (- erc-butoxycarbon) aza-spiro [4,5] dec-3-ene Prepared from the compound of Description 31 and (5R, 65) -3-tri? Netüestennü-6-fenü-l-oxa-7- (te c-butoxicarbonü) aza- spiro [4.5] dec-3-ene, according to the procedure of Example 1. W NMR (360 MHz, CDCls) d 1.36 (9H, s), 1.84 (3H, m), 2, 09 (1H, m), 3.12 (1H, dt, J 12 Hz, J5, l Hz), 4.11 (1H, m), 4.18 (1H, q, J4.6 Hz), 4, 27 (1H, q, J4.7 Hz), 4.60 (1H, dd, J 12.2 Hz, J 2.1 Hz), 4.69 (1H, m), 4.82 (1H, m) , 4.95 (1H, dd, J 12.3 Hz, J 2.1 Hz), 5.14 (1H, s), 6.65 (1H, t, J 2.1 Hz), 6.85 ( 1H, d, J9 Hz), 6.95 (1H, d, J2.4 Hz), 7.09 (1H, d, J8, l Hz), 7.24 (3H, m) and 7.45 (2H , d, J7.5 Hz).

EXAMPLE 30 Hydrochloride of (5-R, 6-S -3- (2- (2-Fluoroethoxy) -5- (thiifluoromethoxy) fenu) -6-phen-l -oxa-7-aza-spiro [4,5] dec- 3-ene The compound of Example 29 was stirred in 1 N methanolic HCl at room temperature for 15 h.The solvent was evaporated in vacuo and the residue partitioned between saturated aqueous potassium carbonate (50 ml) and ethyl acetate (3x50 ml). The combined organic fractions were washed with brine (50 ml), dried (MgSO 4) and evaporated in vacuo Purification on silica, eluting with 10% methanol in dichloromethane, gave the title compound as an solid white (180 mg, 68%). NMR (360 MHz, CDCl 3) d 1.86 (2H, m), 2.02 (2H, m), 3.14 (1H, m), 3.40 ( 1H, m), 4.21 (1H, m), 4.28 (1H, m), 4.33 (1H, d, J 12.5 Hz), 4.58 (1H, d, J 11.7 Hz), 4.71 (1H, m), 4.84 (1H, m), 4.94 (1H, d, J 12.4 Hz), 6.44 (1H, s), 6.94 (1H , d, J2.5 Hz), 7.08 (1H, d, J 9.1 Hz), 7.30 (3H, m), 7.45 (2H, d, J6.6 Hz), 9.07 (1H, broad s) and 9 70 (1H, broad s), m / z (ES +) 438 (M + l).

EXAMPLE 31 (IS ,, 5?, 6-S 3- (2- (2-Fluoroethoxy) -5- (trifluoromethoxy) -6-phenyl-l-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared to from the compound of Example 30 according to the procedure of Example 3. iH NMR (500 MHz, DMSO-d6300K) d 1.70 (1H, m), 1.80 (2H, m), 1.95 (1H, m), 2.09 (2H, m), 3.07 (2H, m), 3.73 (1H, d, J 12.8 Hz), 3.82 (1H, m), 4.17 (1H , m), 4.22 (1H, m), 4.33 (1H, d, Jll, 3 Hz), 4.51 (1H, d, Jll, 6 Hz), 4.65 (1H, m), 4.75 (1H, m), 7.01 (1H, d, J9 Hz), 7.12 (1H, d, J 10.8 Hz), 7.18 (2H, m), 7.39 (1H , m), 7.46 (2H, m), 7.55 (1H, d, J7.4 Hz), 8.93 (1H, m) and 9.53 (1H, m). m / z (ES + ) 440 (M + l).

EXAMPLE 32 (5i?, 6 - ^ - 3- (2- (Eten-l-ü) -5- (trifluorornetoxy) fenu) -6-phen-l-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5] dec-3-ene Prepared from the compound of Description 33 and (5R, 6S) -3-tiimetüestennü-6-fenü-l-oxa-7- (férc. -butoxicarbonü) aza-spiro [ 4.5] dec-3-ene, according to the procedure of Example 1.? NMR (250 MHz, CDCb) d 1.36 (9H, s), 1.86 (2H, m), 2.12 ( 1H, m), 3.22 (1H, m), 4.12 (1H, q, J 7.1 Hz), 4.18 (1H, m), 4.37 (1H, dd, J12.6 Hz , J2.2 Hz), 4.7 (1H, dd, J12.6 Hz, J2.0 Hz), 5.1 (1H, s), 5.28 (1H, d, J 11.1 Hz), 5.61 (1H, d, J17.4 Hz), 6.03 (1H, t, J2, l Hz), 6.66 (1H, m), 6.85 (1H, m), 7.11 (1H, m), 7.28 (3H, m), 7.46 (2H, m) and 7.50 (1H, d, J8.6 Hz).

EXAMPLE 33 (5i?, 6-S) -3- (2- (Eten-l-ü) -5- (thiouluoromethoxy) fenu) -6-phen-l-oxa-7-aza-spiro [4,51dec-3-] Was prepared from the compound of Example 32 according to the procedure of Example 30.? NMR (360 MHz, CDCb) d 1.67 (1H, m), 1.81 (2H, m), 2.83 (1H, dt, J 3 Hz, J 12.3 Hz), 3.26 (1H , m), 3.74 (1H, s), 4.28 (1H, dd, J 2.4 Hz, J 12.6 Hz), 4.68 (1H, dd, J 2.2 Hz, J 12 , 4 Hz), 5.06 (1H, dd, J 1.2 Hz, J 11 Hz), 5.47 (1H, dd, Jl, l Hz, J17.3 Hz), 5.57 (1H, t , J2.2 Hz), 5.92 (1H, m), 6.60 (1H, s), 7.01 (1H, d, J 8.6 Hz), 7.28 (4H, m) and 7 , 40 (2H, m).

EXAMPLE 34 (3lS, y5-R> 6-S) -3- (2-Etii-5- (trifluoromethoxy) fenu) -6-phenyl-l-oxa-7-aza-spiro [4.5] decane Prepared from of the compound of Example 33 according to the procedure of Example 3. i H NMR (250 MHz, CDCl 3) d 1.12 (3 H, t, J 7.5 Hz), 1.61 (2 H, m), 1.90 (2H, m), 2.12 (2H, m), 2.58 (2H, q, J 7.6 Hz), 2.77 (1H, dt, J 2.5 Hz, J 12.2 Hz) , 3.16 (1H, m), 3.27 (1H, m), 3.61 (1H, m), 3.73 (1H, s), 4.05 (1H, t, J8, l Hz) , 4.56 (1H, broad s), 5.88 (1H, d, J l, 63 Hz), 6.85 (1H, dd, J l, 2 Hz, J 8.3 Hz), 7.03 (1H, d, J 8.4 Hz), 7.36 (3H, m) and 7.54 (2H, m). m / z (ES +) 406 (M + 1).

EXAMPLE 35 (5i?, 6-S) -3- (2-Benzoxy-5- (thiouluoromethoxy) fenu) -6-phen-1-oxa-7- (rgrc-butoxycarbon) aza-spiro [4,5] dec-3 -eno Prepared from the compound of Description 34 and (5R, 65) -3-tri? netüestannü-6-fenü-l-oxa-7 - (- 'grc-butoxicarbonü) aza-spiro [4,5] dec -3-ene, according to the procedure of Example 1. XH NMR (360 MHz, CDCb) d 1.33 (9H, s), 1.65 (1H, m), 1.76 (2H, m), 2.08 (1H, m), 3.11 (1H, m), 4.08 (1H, m), 4.60 (1H, dd, J 12.2 Hz, J 2 Hz), 4.92 ( 1H, dd, J 12.1 Hz, J 1.8 Hz), 5.08 (1H, s), 5.1 (2H, q, J 11.5 Hz), 6.65 (1H, s), 6.94 (2H, d, J8.9 Hz), 7.08 (1H, d, J9 Hz), 7.18 (2H, t, J8, l Hz), 7.25 (3H, m), 7 , 38 (5H, m).

EXAMPLE 36 (5 ^, 6.S) -3- (2-Benzoxy-5- (trucoromethoxy) fenu) -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene Prepared to from the compound of Example 35 according to the procedure of Example 30.? NMR (250 MHz, CDCls) d 1.70 (2H, m), 1.94 (1H, m), 2.05 (1H, m), 2.77 (1H, td, J 12.5 Hz, J 2.8 Hz), 2.93 (1H, broad s), 3.25 (1H, m), 3.70 (1H, s), 4.34 (1H, dd, J14.5 Hz, J2 Hz), 4.99 (1H, s), 6.14 (1H, t, J2 Hz), 6.67 (1H, d, J 2.7 Hz), 6.80 (1H, d, J 9 Hz), 6.98 (1H, dd, J 9 Hz, J 2 Hz), 7.17 (3H, m) and 7.26-7.47 (7H, m). m / z (ES +) 482 (M + 1).

EXAMPLE 37 Hydrochloride of (J-S ', 5? .6-S) -3- (2-Hydroxy-5- (trifluoromethoxy) fenu) -6-phenyl-l-oxa-7-aza-spiro [4,5] decane Prepared from the compound of Example 36 according to the procedure of Example 3. iH NMR (360 MHz, DMSO-d6) d 1.67 (1H, t, J 12.1 Hz), 1.80 (2H, d , Jll, 5 Hz), 2.05 (3H, m), 3.06 (2H, t, J8, l Hz), 3.30 (1H, m), 3.77 (1H, m), 4, 13 (1H, t, J7.8 Hz), 4.48 (1H, m), 6.03 (1H, d), 6.80 (1H, d, J8.8 Hz), 6.92 (1H, dd, J 8.9 Hz), 7.45 (3H, m) and 7.56 (2H, m). m / z (ES-) 394 (M + 1).

EXAMPLE 38 (3-S ', 5i?, 6-S) -3- (2-Hydroxy-5 - (' trifluoromethoxy) fenu) -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5] decane To a solution of (3-S, 5?, 6-S) -3- (2-hydroxy-5- (thiifluoromethoxy) phenyl) -6-phenyl-1-oxa-7 hydrochloride aza-spiro [4.5] decane (Example 37, 290 mg, 0.7 mmol) in water (3 ml), solid sodium carbonate was added until pH 10. To this was added dichloromethane (2 ml) followed by dicarbonate of di-tert-butyl (170 mg, 0.8 mmol) and the reaction was stirred at room temperature for 16 h. The reaction was diluted with water (40 ml) and the organic layer was separated. The organic layer was washed with brine (50 ml), dried (MgSO 4) and evaporated in vacuo to give the title compound as a white solid, (320 mg, 96%). ? NMR (360 MHz, CDCb) d 1.38 (9H, s), 1.73 (2H, m), 1.81 (1H, m), 2.18 (2H, m), 2.50 (1H, m), 2.81 (1H, m), 3.62 (1H, t, J7.2 Hz), 3.92 (1H, m), 3.98 (1H, d, J13.2 Hz), 4 , 23 (1H, m), 5.33 (1H, s), 6.75 (1H, d, J 8.5 Hz), 6.94 (2H, m), 7.25 (1H, m), 7.31 (2H, m) and 7.55 (2H, d, J7.8 Hz).

EXAMPLE 39 (^ d ^^ or-S ^ -S-fS-fEten-l- ^ - S-ftrifluoromethoxDfen-o-phen-l-oxa ^ -grt-butoxycarbonii) aza-spiro [4, 5] decane Prepared from the compound of Example 144 and vinyl tributyl tin according to the procedure of Description 33. XH NMR (250 MHz, CDCb) d 1.76 (2H, m), 2.10 (2H, m), 2.43 (1H, m), 2.90 (1H, m), 3.69 (2H, m), 4.0 (1H, d, J13.5 Hz), 4.12 (1H, d, J7, l Hz), 4.22 (1H, m), 5.18 (IR, s), 5.38 (IR, dd, J 10.9 Hz, J 1.2 Hz), 5.59 (1H, dd, J17.2 Hz, Jl, 2 Hz), 6.96 (1H, m), 7.04 (1H, m), 7.15 (1H, m), 7.32 (3H, m ), 7.45 (1H, d, J 8.2 Hz) and 7.56 (2H, m).

EXAMPLE 40 (3-S, 5-R> 6-S) -3- (2- (Eten-l-ü) -5- (trifluoromethoxy) fenu) -6-phene-l-oxa-7-aza-spiro [4,5] decane Prepared from the compound of Example 39 according to the procedure of Example 2.? NMR (250 MHz, CDCb) d 1.62 (2H, d, J 11.1 Hz), 1.88 (2H, d, J9.5 Hz), 2.10 (2H, m), 2.78 ( 1H, dt, J12.2 Hz, J2.5 Hz), 3.17 (1H, m), 3.25 (1H, dt, J9.9 Hz, J2, l Hz), 3.66 (1H, m ), 3.72 (1H, s), 4.06 (1H, d, J8 Hz), 5.29 (1H, dd, J 10.9 Hz, J 1.3 Hz), 5.49 (1H, dd, J 17.2 Hz, J 1.3 Hz), 6.04 (1H, d, J 1.5 Hz), 6.83 (1H, m), 6.92 (1H, d, J7.6 Hz), 7.36 (4H, m) and 7.50 (2H, m). m / z (ES +) 404 (M + l).

EXAMPLE 41 (5i?, 6-S ^ -3- (2-Methoxiferdl) -6-phen-l-oxa-7 - (- 'grc-butoxycarbonu) aza-spiro [4,5] dec-3-ene Prepared from of 2-methoxychlorobenzene and (5R, 6S) -3-trimeti-istannü-6-phene-l-oxa-7 - (- 'grc-butoxycarbonu) aza-es? iro [4,5] dec-3-ene, in accordance with the procedure of Example 1.? NMR (360 MHz, CDCb) d 1.27 (9H, s), 1.75-1.90 (3H, m), 2.09-2.12 (1H, m) , 3.07-3.14 (1H, m), 3.86 (3H, s), 4.11-4.15 (1H, m), 4.61 (1H, dd, J12.0 and 2, 1 Hz), 4.97 (1H, dd, J 12.0 and 2.1 Hz), 5.16 (1H, s), 6.19 (1H, s), 6.88-6.92 (2H) , m), 7.04 (1H, d, J8, l Hz), 7.16-7.27 (4H, m) and 7.46 (2H, d, J7.4 Hz).

EXAMPLE 42 (5i?, 6-S ^ -3- (2-Methoxypheni) -6-phen-l-oxa-7-aza-spiro [4.5] dec-3-ene Prepared from the compound of Example 41 in accordance with the procedure of Example 2.? NMR (360 MHz, CDCls) d 2.02-2.23 (4H, m), 3.27 (1H, t, J 12.7 Hz), 3.57-3, 60 (1H, m), 3.77 (3H, s), 4.49 (1H, s), 4.51 (1H, d, J 12.3 Hz), 4.93 (1H, d, J12, 3 Hz), 6.31 (1H, s), 6.89 (2H, d, J4.4 Hz), 6.99 (1H, d, J8.3 Hz), 7.26-7.38 (4H , m) and 7.46 (2H, d, 7.4 Hz).

EXAMPLE 43 (3-S ', 5J?, 6-S) -3- (2-Methoxyphene) -6-phene-l-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the Compound of Example 42 according to the procedure of Example 3. * H NMR (360 MHz, D20) d 1.87-1.95 (3H, m), 2.07-2.20 (3H, m), 3.23 ( 1H, t, J 12.6 Hz), 3.33-3.38 (1H, m), 3.49-3.53 (1H, m), 3.67 (3H, s), 4.14 ( 1H, t, J7.8 Hz), 4.42 (1H, s), 6.49 (1H, á, J7.7 Hz), 6.79 (1H, t, J7.4 Hz), 6.95 (1H, d, J 7.4 Hz), 7.19 (1H, t, J8.7 Hz) and 7.48-7.54 (5H, m).

EXAMPLE 44 (3-Sl, 5R, 6S -3- (2-Hydroxy-5- (thiifluoromethoxy) fenu) -6-phen-1-oxa-7 - (? Grc-butoxycarbon) aza-spiro [4.5] decane dissolved (5i?, 6-S) -3- (2-benzuboxy-5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7 - (-, grc-butoxycarbon) aza-spiro [4,5] dec-3-ene (Example 35) (3.88 g) in ethyl acetate (15 ml) and methanol (15 ml) Palladium hydroxide on carbon (1.00 g) was added and the suspension was stirred under a hydrogen atmosphere (50 psi) for 72 h.The mixture was filtered and the solvent was evaporated under reduced pressure.The residue was purified by medium pressure chromatography on silica gel, eluting with hexane / ethyl acetate ( 75:25) to give (3R, 5R, 6S) -3- (2-hydroxy-5- (trifluoromethoxy) phenyl) -6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4, 5] decane (191 mg),? NMR (250 MHz, CDC13) d 7.70 (2H, d, J 7.3 Hz), 7.33 (2H, t, J 7.3 Hz), 7.26 (1H, d, J 7.3 Hz), 7.05 (1H, sa), 6.96 (2H, m), 6.82 (1H, d, J 9.4 Hz), 5.43 (1H , s), 4.27 (1H, m), 4.01 (1H, m), 3.95 (1H, m), 3.73 (1H, m), 2.73 (2H, m), 2.33 (1H, m), 1.87-1.58 (4H, m); and 1.50 (9H, s); and (3S, 5R, 6S) -3- (2-hydroxy-5- (trifluoromethoxy) phenyl) -6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4, d-decade (2,3 g),? NMR (360 MHz, CDCla) d 1.38 (9H, s), 1.73 (2H, m), 1.81 (1H, m), 2.18 (2H, m), 2.50 (1H, m), 2.81 (1H, m), 3.62 (1H, t, J 7.2 Hz), 3.92 (1H, m), 3.98 (1H, d, J 13.2 Hz) , 4.23 (1H, m), 5.33 (1H, s), 6.75 (1H, d, J8.5 Hz), 6.94 (2H, m), 7.25 (1H, m) , 7.31 (2H, m) and 7.55 (2H, d, J7.8 Hz).

EXAMPLE 45 (5i?, 6-S) -3- (2-Benzyl-oxy-5- (trucluoromethyl) fenu) -7 - (; 'grc-butoxycarbonu) -6-phen-1-oxa-7-aza-spiro [4, 5] dec-3-ene Prepared from the compound of Description 36 and (5 / Z, 6-S) -3-tributüestannü-6-fenü-l-oxa-7- (ig-butoxycarbon) aza-spiro [ 4.5] dec-3-ene, according to the procedure of Example 1.? NMR (360 MHz, CDCb) d 1.33 (9H, s), 1.72-1.83 (3H, m), 2.03-2.11 (1H, m), 3.06-3.15 (1H, m), 4.07-4.11 (1H, m), 4.64 (1H, dd, J 11, 5, 15.5 Hz), 4.96 (1H, dd, J 2, 12 Hz), 5.09 (1H, s), 5.16 (2H, dd, J 11, 5, 15.5 Hz), 6.66 (1H, t, J2 Hz), 7.02 (1H, d , 8.5 Hz), 7.16-7.27 (3H, m), 7.32 (1H, d, J 2 Hz) and 7.34-7.49 (8H, m). m / z (ES +) 566 (M + 1).

EXAMPLE 46 (3-S, 5R, 6S) -3- (2-Hydroxy-5- (trifluoromethyl) phenyl) -6-phenyl-1-oxa-7 - (/ g / -c-butoxycarbon) aza-is-iror4 , 5] decane Prepared from the compound of Example 45 according to the procedure of Example 44. (3R, 5R, 6S) -3- (2-Hydroxy-5- (trifluoromethyl) phenyl) -6-phenyl-1- oxa-7- (tert-butoxycarbonyl) aza-spiro [4,5] decane,? NMR (250 MHz, CDCb) d 1.51 (9H, s), 1.58-1.75 (2H, m), 1.82-1.88 (2H, m), 2.33 (1H, dt , J4, 13 Hz), 2.70 (1H, dd, J8.6, 13 Hz), 2.79 (1H, dt, J3, 13 Hz), 3.84 (1H, qn), 3.93- 3.97 (2H, m), 4.31 (1H, t, J9 Hz), 5.44 (1H, s,), 6.89 (1H, d, J 9 Hz), 7.23-7, 35 (5H, m) and 7.58-7.60 (2H, m). m / z (ES +) 478 (M + 1). (3S, 5R, 6S) -3- (2-Hydroxy-5- (trifluoromethyl) phenyl) -6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4.5] decane,? NMR (360 MHz, CDCb) d 1.34 (9H, s), 1.72-1.82 (3H, m), 2.10-2.21 (2H, m), 2.53 (1H, dd) , J 9, 13 Hz), 2.79-2.88 (1H, m), 3.65 (1H, qn, J8.6 Hz), 3.94-3.98 (2H, m), 4, 24 (1H, dd, J 7, 9 Hz), 5.33 (1H, s,), 6.83 (1H, d, J9 Hz), 7.01 (1H, s), 7.23-7.34 (5H, m) and 7.55 (2H, d, J7.5 Hz). m / z (ES +) 478 (M + 1).

EXAMPLE 47 (5?, 6-S) -3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene Trifluoroacetic acid (1 ml) to a cooled solution (0 ° C) of (35 ', 5?, 6-S) -3- (2-methoxy-5-thiifluoromethoxy-phenyl) -6-phene-1-oxa-7 - (-' g. -butoxycarbonu) aza-spiro [4.5] decan-3-ol (Description 37, 240 mg, 0.46 mmole) in dichloromethane (10 ml). The solution was stirred at 0 ° C for 10 min. and at room temperature for 1 h. The solvent was evaporated under reduced pressure and saturated aqueous potassium carbonate was added. The mixture was extracted with ethyl acetate (2x40 ml) and the combined organic fractions were washed with brine (20 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane / methanol / ammonia (160: 8: 1) to give (5R, 6S) -3- (2-methoxy-5-trifluoromethoxyphenyl) -6-phenyl -l-oxa-7-aza-spiro [4, 5] dec-2-ene (29mg, 16%), iH NMR (360 MHz, CDCb) d 1.56-1.65 (2H, m), 2 , 05-2.12 (1H, m), 2.22-2.26 (1H, m), 2.41 (1H, dd, J14.0, 1.6 Hz), 2.76 (1H, dd, J 14.0, 1.9 Hz), 2.87 (1H, dt, J 12.2, 2.7 Hz), 3.23-3.28 (1H, m), 3.59 (1H , s), 3.79 (3H, s), 6.58 (1H, d, J2.7 Hz), 6.98 (1H, d, J8.9 Hz), 6.83-6.85 (1H , m), 7.13 (1H, s), 7.15-7.26 (3H, m) and 7.43-7.45 (2H, m), m / z (ES +) 506 (M + l ); and (5R, 6S) -3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-ene (69 mg, 37%), * H NMR (250 MHz, CDOb) d 7.45 (2H, d, J 7.2 Hz), 7.30-7.2 (3H, m), 7.13-7.09 (1H, dd, J9.0 Hz), 6.89 (2H, s + d), 6.64 (1H, t, J2.04 Hz), 5.16 (1H, s), 4.96 and 4.56 (2H, ABdd, J 12.1 and 2 Hz), 4.11 (1H, m), 3.86 (3H, s), 3.08 (1H, m), 2.1 (1H, m), 1.87 -1.77 (3H, m) and 1.37 (9H, s), m / z (ES +) 506 (M + 1).

EXAMPLE 48 (5R, 6S) -3- (2-Methoxy-5-thiifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-is-iro [4,5] dec-3-ene and (3S, 5R, 6-S ^ -3- (2-methoxy-5-thiifluorornetoxyphenyl) -6-phene-l-oxa-7-aza-spiro [4.5] decane Triethyl succinate (100 1, 0.6 mmol) was added to a solution of (5i?, 65) -3- (2-methoxy-5-thiifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spOO [4,5] dec-2-ene (Example 47, 14 mg, 0.03 mmole) in trifluoroacetic acid (1 ml) and the mixture was stirred at room temperature for 2 hrs. More thiietiusane (100 1, 0.6 mmole) was added and the mixture was stirred at room temperature for 15 h. The solvent was evaporated under reduced pressure and the residue made azeotropic with toluene (2 x 10 ml) Saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane (3x10 ml) The combined organic fractions were washed with brine ( 20 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure The residue was purified by preparative thin-layer chromatography on silica gel, and with chloromethane / methanol / ammonia (120: 8: 1) to give a gum (6 mg). HPLC analysis of the gum [HIPRB column (250 x 4.6 mm); 40% MeCN in 25 mM KH2P04, 0.2% thiothiumamine. pH 3.1, 210 nm] showed that it consisted of a mixture of (5R, 6S) -3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] dec -3-ene, (3S, 5R, 6S) -3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4, 5] decane and (3R, 5R, 6S) -3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane (ratio: 1.5: 2.5: 1).

EXAMPLE 49 O ^ S ^^ - S ^ -S-fS-Methoxy-S-trifluoromethoxyphene-5-phenyl-1-oxa-aza-spiro ^ SIdecano Thiietiusane (252.1, 1.6 mmol) was added to a solution of (5R, 6S) -3- (2-methoxy-5-thiifluoromethoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene (Example 47, 32 mg, 0, 08 mmole) in trifluoroacetic acid (2 ml) and the solution was stirred at 50 ° C for 16 h. The solvent was evaporated under reduced pressure and the residue azeotyped with toluene (2 x 10 ml). Saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane (4 x 20 ml). The combined organic fractions were washed with brine (20 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel, eluting with dichloromethane / methanol / ammonia (120: 8: 1) to give a gum (6 mg). HPLC analysis of the gum [HIPRB column (250 x 4.6 mm); 40% MeCN in 25 mM KH2P04, 0.2% triethylamine. pH 3.1, 210 nm] showed that it consisted of a mixture of (3S, 5R, 6S) -3- (2-methoxy-5-trifluoromethoxyphenyl) -6-phenyl-l-oxa-7-aza-spiro [4 , 5] decane and (3R, 5R, 6S) -3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4, 5] decane (ratio: 2: 1) ).

EXAMPLE 50 (3-S '> 5J?> 6-Sl) -3- (2-Methoxyphene) -6-phene-l-oxa-7- (fórc-butoxicarbonü) a2-a-spiro [4,5] decane Mephanosulfonyl chloride (10 ml, 0.14 mmol) was added to a stirred solution of triethylamine (42 ml, 0.3 mmol) and the product of the 39 (19 mg, 0.043 mmol) in dichloromethane (2 ml) at 0 ° C. The mixture was allowed to warm to room temperature, stirred for 18 h, dyed with dichloromethane (20 ml), washed with hydrochloric acid (2 M, 10 ml) and saturated aqueous sodium carbonate (10 ml), dried ( MgSO 4) and the solvent was evaporated under reduced pressure. The residue was taken up in tetiahydrofuran (3 ml) and heated with sodium hydride (60% dispersion in oil, 100 mg) under reflux for 18 h, cooled, poured into hydrochloric acid solution (2 M, 20 ml ) and was extracted with ethyl acetate (2x20 ml). The combined organic fractions were washed with saturated aqueous sodium chloride (10 ml), dried (MgS?) And the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with hexane / ethyl acetate (80:20) to give the title compound as a 1: 3 mixture with the 3R and 3S epimers (8 mg, 44%). iH NMR (360 MHz, CDC-b) d 7.61 (2H, d, J 7.6 Hz, 3R isomer), 7.57 (2H, d, J 7.5 Hz, 3S isomer), 7.05 -7.34 (5H, m, 3R and 3S isomers), 6.80-6.98 (2H, m, 3R and 3S isomers), 5.37 (1H, s, 3R isomer), 5.25 (1H) , s, 3S isomer), 4.31 (1H, t, J 7.4 Hz, 3R isomer), 4.21 (1H, t, J 7.2 Hz, 3S isomer), 3.95-4.04 (1H, m, 3R and 3S isomers), 3.82 (3H, s, 3R isomer), 3.81 (3H, s, 3S isomer), 3.64-3.81 (2H, m, 3R isomers and 3S), 2.85 (1H, dt, J5.9 and 12.1 Hz, 3S isomer), 2.67 (1H, dt, J4.9, 12.7 Hz, 3R isomer), 2.59 (1H , dd, J 7.3 and 12.7 Hz, 3R isomer), 2.37 (1H, dd, J 8.0 and 12.6 Hz, 3S isomer), 2.21 (1H, dd, J9, l , 12.6 Hz, 3S isomer), 2.08-2.23 (1H, m, 3R and 3S isomers), 1.93 (1H, dd, J10.4, 12.4 Hz, 3R isomer), 1 , 64-1.78 (3H, m, 3R and 3S isomers), 1.47 (9H, s, 3R isomer) and 1.38 (9H, s, 3S isomer). m / z (ES +) 424 (M + 1).

EXAMPLE 51 (3-S'.5J?> 6S) -3- (2-Methoxypheni) -6-phen-l-oxa-7-aza-es? Iro [4,5] decane Prepared from the compound of Example 50 according to the procedure of Example 2, in the form of a mixture of (3-S, 5-R, 6-S) -3- (2-methoxy-phenyl) -6-phen-1-oxa-7-aza-es ? iro [4,5] decane and (3?, 5R, 6-S) -3- (2-methoxyphenu) -6-phene-l-oxa-7-aza-spiro [4.5] decane. ? NMR (360 MHz, CDCl 3) d 7.51-7.59 (2H, m, 3R and 3S isomers), 7.32-7.45 (3H, m, 3R and 3S isomers), 7.05-7, 13 (1H, m, 3R and 3S isomers), 6.97 (1H, d, J 7.6 Hz, 3R isomer), 6.81 (1H, t, J7.5 Hz, 3R isomer), 6.71 -6.82 (1H, m, 3R and 3S isomers), 6.69 (1H, t, J 7.5 Hz, 3S isomer), 6.43 (1H, d, J 7.6 Hz, 3S isomer) , 4.09 (1H, t, J 7.8 Hz, 3S isomer), 3.94 (1H, t, J 7.6 Hz, 3R isomer), 3.67-3.87 (1H, m, isomers) 3R and 3S), 3.68 (4H, s, 3S isomer), 3.63 (3H, s, 3R isomer), 3.53 (1H, s, 3R isomer), 3.17-3.25 (1H , m, 3R and 3S isomers), 2.75-2.84 (1H, m, 3R and 3S isomer) and 1.55-2.37 (8H, m, 3R and 3S isomers). m / z (ES +) 324 (M + 1).

EXAMPLE 52 (5?, 6-S) -3- (2-Methoxy-5-thiifluoromethoxyuene) -6-phen-1-oxa-7 - (- '-butoxycarbon) aza-spiro [4,5] dec- 3-en-2-one A mixture of (5 - / ?, 6 »S) -7 - 'g. Butoxycarbonyl-6-phenyl-3-thibutyl-tenn-l-oxa-7-aza-spiro [4, 5] dec-3-en-2-one (Description 10, 538 mg, 0.87 mmol), 2-bromo-4-trifluoromethoxyanisole (Description 12, 244 mg, 0.90 mmol) and lithium chloride (230 mg , 5.4 mmol) in toluene (10 ml), was degassed with nitrogen at 60 ° C for 30 min. Tetrakis (triphenylphosphine) palladium (0) (100 mg) was added and the mixture was refluxed under nitrogen for 16 h. The mixture was cooled, filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile (50 ml), washed with hexane (4 x 20 ml) and then treated with 10% solution of methanolic potassium fluoride. The mixture was stirred for 30 min., Filtered and the solvent was evaporated under reduced pressure. The residue was then partitioned between saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (50 ml). The organic phase was dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound as a gum (200 mg, 0.39 mmol, 44%). * H NMR (250 MHz, CDCl 3) d 8.60 (1H, s), 8.02 (1H, d), 7.40 (2H, m), 7.26 (4H, m), 6.93 ( 1H, d, .79.11 Hz), 5.28 (1H, s), 4.20 (1H, m), 3.91 (3H, s), 3.18 (1H, m), 2.32 (1H, m), 1.89 (3H, m) and 1.39 (9H, s).

EXAMPLE 53 (3, S ', 5R, 6S) -3- (2-Methoxy-5-trifluoromethoxy-phenyl) -6-phen-1-oxa-7 - (? G / -c-butoxycarbon) aza-spiro [4,5] decan-2-one A mixture of (5i?, 65) -3- (2-methoxy-5-thifluoromethoxy-phenyl) -6-phene-l-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] dec-3-en-2-one (Example 52, 100 mg, 0.19 mmol) and palladium acetate (10 mg) in N, N -dimethylformamide (1 ml) was degassed with nitrogen for 30 min. Potassium formate (42 mg, 0.50 mmol) was added and the mixture was heated at 80 ° C for 16 h. The mixture was poured into water (10 ml) and extracted with ethyl acetate (2 x 10 ml). The combined organic fractions were dried (Na 2 SO 3) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound as a colorless solid (44 mg, 0.08 mmol, 44%). XH NMR was shown to be a 1: 1 mixture of the diastereomers (3S, 5R, 6S) and (3R, 5R, 6S), which were separated by preparative liquid chromatography using a KR60 column and eluting with 5% ethene / hexane containing 0.1% DEA, to give (3R, 5R, 6S) -3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [ 4,5] decan-2-one,? NMR (250 MHz, CDCb) d 7.50-7.53 (2H, m), 7.26-7.39 (3H, m), 7.14 (1H, dd, J 2.59, 8.96 Hz), 7.02 (1H, d, J 2.59 Hz), 6.88 (1H, d, J8.96 Hz), 5.35 (1H, s), 4.00-4.05 (1H , m), 3.85 (3H, s), 3.70 (1H, t, J 11.02 Hz), 2.70-2.97 (2H, m), 2.38-2.50 (1H , m), 2.22 (1H, dd, J 11.32, 12.97 Hz), 1.72-1.92 (3H, m) and 1.46 (9H, s); and the title compound (3S, 5R, 6S) -3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4,5] decan- 2-one, XH NMR (250 MHz, CDCb) d 7.50-7.53 (2H, m), 7.26-7.39 (3H, m), 7.13 (1H, dd, J 2, 91, 8.97 Hz), 6.90 (1H, d, J2.91 Hz), 6.83 (1H, d, J 8.97 Hz), 5.31 (1H, sa), 4.02- 4.10 (1H, m), 3.92 (1H, t, J 10.56 Hz), 3.64 (3H, s), 2.91-3.02 (1H, m), 2.67 ( 1H, dd, J 10.04, 12.98 Hz), 2.29-2.52 (2H, m), 1.80-1.87 (3H, m) and 1.36 (9H, s).

EXAMPLE 54 (3-S, 5j?, 6S) -3- (2-Methoxy-5- (trifluoromethoxy) fenu) -6-phenyl-l-oxa-7-aza-spiro [4,5] decan-2 hydrochloride -one Prepared from the compound of Example 53 according to the procedure of Example 2, mp 248-250 ° C. ? NMR (360 MHz, DMSO-d6) d 9.90 (1H, sa), 9.30 (1H, sa), 7.42-7.60 (5H, m), 7.19 (1H, d, J 7.17 Hz), 6.93 (1H, d, J 7.17 Hz), 4.70 (1H, sa), 4.42-4.48 (1H, m), 3.30-3.33 (1H, m), 3.11-3.15 (1H, m), 2.29-2.36 (1H, m) and 1.94-2.03 (5H, m). m / z (ES +) 422 (M + 1). Found: C, 55.94; H, 5.06; N, 3.06, C22H22F3N04.HC1.H20 requires: C, 55.53; H, 5.30; N, 2.94%.

EXAMPLE 55 (5-R, 6 ^ -N- (4-Methoxy-3- [6-phenyl-1-oxa-7- (fórc-butoxicarbonü) aza-spiro [4,5] dec-3-en-3-üjfenültrifluoroacetemida Prepared from the compound of Description 47 and (5R, 6S) -3-tributüestaru-? Ü-6-fenü-l-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] dec-3- ene, according to the procedure of Example 1. iH NMR (250 MHz, CDOb) d 7.83 (1H, sa), 7.53 (1H, dd, J 8.9, 2.7 Hz), 7, 47 (2H, m), 7.23 (3H, m), 7.13 (1H, d, J 2.7 Hz), 6.97 (1H, d, J 8.9 Hz), 6.67 (1H, t, J2, l Hz), 5.15 (1H, s), 4.94 (1H, dd, J 12, 2.1 Hz), 4,58 (1H, dd, J 12, 2.1 Hz), 4.12 (1H, m), 3.87 (3H, s), 3.11 (1H, m), 2.11 (1H, m), 1.88-1.82 (3H, m) and 1.36 (9H, s). m / z (ES +) 533 (M + 1).

EXAMPLE 56 (, 5J?> 6S) -N- [4-Methoxy-3 - (, 6-phenyl-1-oxa-7-aza-spiro-4,51dec-3-en-3-ü) phenyltiifluoroacetemide Prepared from the compound of Example 55 according to the procedure of Example 2. * H NMR (250 MHz, CDCb) d 7.94 (1H, sa), 7.41 (1H, dd, J8.9, 2.7 Hz), , 36 (2H, m), 6.91 (1H, d, J2.7 Hz), 6.80 (1H, d, J8.9 Hz), 6.18 (1H, t, J2.0 Hz), 4.83 (1H, dd, .711.8, 2.0 Hz), 4.32 (1H, dd, .711.8, 2.0 Hz), 3.78 (3H, s), 3.77 (1H, m), 3.27 (1H, m), 2.81 (1H, m), 2.20-1.95 (2H, m), 1.88-1.79 (2H, m) and 1.69 (1H, m). m / z (ES +) 433 (M + 1).

EXAMPLE 57 (3-S.5i?, 6) -N-r4-Methoxy-3- (6-phenyl-1-oxa-7-aza-spfro [4,51decan-3-ü) phenyl] trifluoroacetemide Prepared from the compound of Example 56 according to the procedure of Example 3. iH NMR (360 MHz, DMSO-d6) d 7.44 (2H, m), 7.32 (1H, dd, J8.8, 2.5 Hz), 7.27-7.16 (5H, m), 6.87 (1H, d, J8.8 Hz), 6.78 (1H, d, J 2.5 Hz), 3.97 (1H, t, J7.5 Hz), 3.64 (3H, s), 3.63 (1H, m), 3.01 (1H, m), 2.93 (1H, m), 1.89-1.73 ( 3H, m) and 1.59-1.48 (2H, m). m / z (ES +) 435 (M + 1).

EXAMPLE 58 (5i?, 6-S -3- (5-Amino-2-methoxyphenu) -6-phen-l-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5] dec-3-ene Prepared from the compound of Description 43 and (5R, 6S) -3-tributylstannane-6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5] dec-3-ene , according to the procedure of Example 1.? NMR (250 MHz, CDCb) d 7.46 (2H, m), 7.23 (3H, m), 6.79 (1H, d, J 8.7 Hz ), 6.64 (2H, m), 6.43 (1H, d, J2.8 Hz), 5.13 (1H, s), 4.92 (1H, dd, J12.0, 2.0 Hz ), 4.56 (1H, dd, J12.0, 2.0 Hz), 4.12 (1H, m), 3.78 (3H, s), 3.12 (1H, m), 1.87 -1.81 (4H, m) and 1.36 (9H, s) m / z (ES +) 437 (M + l).

EXAMPLE 59 (S ^ SR ^ -S ^ -S-fS-A ino ^ -nietoxifen ^ -ó-fenü-l-oxa ^ -fter-butoxycarbon ^ aza-spiro [4,5] decane Prepared from the compound of Example 58 according to the procedure of Example 3. H NMR (360 MHz, CDCb) d 7.52 (2H, m), 7.27 (3H, m), 6.68 (1H, d, J8.4 Hz), 6.55 (1H, d, J2.7 Hz), 6.52 (1H, dd, J8.4, 2.7), 5.25 (1H , s), 4.18 (1H, m), 4.00 (1H, m), 3.77 (1H, m), 3.74 (3H, s), 3.67 (1H, m), 2.91 (1H, m) , 2.35 (1H, m), 2.38-2.32 (2H, m), 2.20-2.09 (3H, m) and 1.38 (9H, s). m / z (ES +) 439 (M + 1).

EXAMPLE 60 (3-Sl, 5R, 6-S) -N-. { 4-Methoxy-3- [6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4,5] decan-3-methyl-methylcarbamate Potassium carbonate (200 mg, 1.4 mmol) was added. and methyl chloroformate (70 μL, 86 mg, 0.9 mmol) to a solution of (37?, 57?, 6-S) -3- (5-amino-2-methoxyphen) -6-phen-l- oxa-7- (tert-butoxycarbon) aza-spiro [4.5] decane (Example 59, 100 mg, 0.23 mmol) in acetone (4 ml) and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and water (50 ml) was added. The mixture was extracted with ethyl acetate, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting hexane / EtOAc (80:20) to give the title compound as a solid (80 mg, 70%). ? NMR (250 MHz, CDCb) d 7.56 (2H, m), 7.35-7.21 (4H, m), 7.01 (1H, d, J2.5 Hz), 6.79 (1H, d, J8.8 Hz), 6.60 (1H, sa), 5.27 (1H, s), 4.22 (1H, m), 4.00 (1H, m), 3.79 (3H, s), 3.74 (3H, s), 3.81-3.66 (2H, m), 2.89 (1H, m), 2.39-2.06 (3H, m), 1.37 (3H, m) and 1.38 (9H, s). m / z (ES +) 497 (M + 1).

EXAMPLE 61 (3-S'.5J? 6- $ l) -N-4-Methoxy-3- [6-phenyl-1-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] decan-3 -ii] METHYL Phenuí-N- (methü) carbamate Sodium hydride (60% dispersion in mineral oil, 16 mg, 0.4 mmol) was added to a solution of (3-S, 572.6-S) -N- { 4-methoxy-3- [6-phen-1-oxa-7- (tert-butoxycarbonyl) a-za-spiro [4,5] decan-3-ü] phen} methyl carbamate (Example 60, 80 mg, 0.16 mmol) in DMF (8 ml) and the mixture was stirred at room temperature for 30 min. Iodomethane (50 μL, 114 mg, 0.8 mmol) was added and the mixture was stirred for 3 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography, eluting with hexane / EtOAc (70:30) to give the title compound as a colorless foam (67 mg, 83%). ? NMR (360 MHz, CDCb) d 7.56 (2H, m), 7.32-7.21 (4H, m), 7.02 (1H, sa), 6.81 (1H, d, J 9, 2 Hz), 5.02 (1H, s), 4.20 (1H, m), 4.00 (1H, m), 3.81 (3H, s), 3.77-3.67 (2H, m), 3.62 (3H, sa), 3.2 (3H, s), 2 , 87 (1H, m), 2.35 (1H, m), 2.22-2.08 (2H, m), 1.74 (3H, m) and 1.36 (9H, s). m / z (ES +) 511 (M + 1).

EXAMPLE 62 (3 .5-R, 6 - ^ - N- [4-Methoxy-3- (6-phenyl-1-oxa-7-aza-spiro4,5] decan-3-ü) phenyl-N- (methylP-carbamate) METHOD Prepared from the compound of Example 61 according to the procedure of Example 2. * H NMR (360 MHz, CDCl 3) d 7.49 (2H, m), 7.33-7.26 (3H, m), 6.91 (1H, sa), 6.69 (1H, d, J8.7 Hz), 6.15 (1H, m), 4.09 (1H, m), 3.79 (1H, m), 3.69 (3H, s), 3.68 (1H, s), 3.64 (3H, sa), 3.25-3.15 (2H, m), 3.08 (3H, s), 2 , 28 (1H, m), 2.15-2.02 (2H, m), 1.90-1.83 (2H, m), 1.62-1.55 (2H, m), 1.26 (1H, m).) M / z (ES +) 411 (M + l).

EXAMPLE 63 (5R, 6S) -N- | 4-Methoxy-3- [6-phenyl-1-oxa-7- (fórc-butoxicarbonü) aza-spiro [4,51dec-3-en-3-ü] fenü} -N- (methü) thiifluoroacetemide Prepared from the compound of Description 52 and (5?, 6_S) -3-tributüestannü-6-fenü-l-oxa-7 - (- 'gr £. -butoxicarbonü) aza-spiro [4,5] dec-3-ene according to the procedure of Example 1.? NMR (250 MHz, CDCb) d 7.49-7.20 (5H, m), 7.12 (1H, dd, J8.7, 2.0 Hz), 6.91 (1H, d, J8.7 Hz), 6.89 (1H, d, J2.0 Hz), 6.63 (1H, s), 5.16 (1H, s), 4.93 (1H, d, J 12.0 Hz), 4.57 (1H, d, J 12.0 Hz), 4.12 (1H, m), 3.89 (3H, s), 3.31 (3H, s), 3.11 (1H, m) , 2.13 (1H, m), 1.82 (3H, m) and 1.36 (9H, s). m / z (ES +) 547 (M + 1).

EXAMPLE 64 (5-R, 6-S) -N- [4-methoxy-3- (6-phenyl-1-oxa-7-aza-spiro [4,5] dec-3-en-3-yl) hydrochloride fenu] -N- (meth) thiifluoroacetamide Prepared from the compound of Example 63 according to the procedure of Example 2. W NMR (250 MHz, CD3OD) d 7.47 (2H, d, J 7.5 Hz), 7.34 (3H, m), 7.19 (1H, dd, J8.9, 2.0 Hz), 6.99 (1H, d, J8.9 Hz), 6.85 (1H, d, J 2.0 Hz), 6.26 (1H, t, J 1.9 Hz), 4.95 (1H, dd, J 12.3, 1.9 Hz), 4.51 (1H, dd, J 12 , 3, 1.9 Hz), 4.47 (1H, s), 3.82 (3H, s), 3.44 (1H, m), 3.24 (3H, s), 3.23 (1H , m) and 2.34-1.95 (4H, m). m / z (ES +) 447 (M + 1). Found: C, .59.47; H, 5.43; N, 5.80, C 24 H 25 F 3 N 2 O 3. HCl requires: C, 59.69; H, 5.43; N, 5.80%.

EXAMPLE 65 Hydrochloride of OS.S ^^ - ^ - N- ^ methoxy-S-Co-phenyl-l-oxa ^ -za-spiro ^^ ldecan-S-ü) fenü] -N- (meth) thiifluoroacetemide Prepared from Compound of Example 64 according to the procedure of Example 3. iH NMR (360 MHz, DzO) d 1.80-2.00 (3H, m), 2.10-2.20 (3H, m), 3, 17 (3H, s), 3.22-3.33 (2H, m), 3.48-3.60 (1H, m), 3.75 (3H, s), 3.97 (1H, t, J9.2 Hz), 4.15 (1H, t, J 8.3 Hz), 4.41 (1H, s), 5.79 (1H, m), 6.96 (1H, d, J 8, 8 Hz), 7.15 (1H, dd, J8.8, 2.4 Hz) and 7.50-7.56 (5H, m). m / z (ES +) 449 (M + 1).

EXAMPLE 66 (5 / ?, 6-S ^ -N-f4-Isopropoxy-3- [6-phen-l-oxa-7 - (- 'grc-butoxycarbonyl) aza-spiror4,5] dec-3-en-3 ü] feml.}. -N- (methyl) trUluoroacetamide Prepared from the compound of Description 53 and (5 /? 6-S) -3-thibutylstannane-6-phenyl-l-oxa-7 - (- ' grc-butoxycarbon) aza-spiro [4.5] dec-3-ene, according to the procedure of Example 1. * H NMR (250 MHz, CDCls) d 7.46 (2H, d, J7.4 Hz) , 7.24 (3H, m), 7.08 (1H, dd, J8.8, 2.5 Hz), 6.95 (1H, d, J2.5 Hz), 6.88 (1H, d, J 8.8 Hz), 6.60 (1H, s), 5.15 (1H, s), 4.94 (1H, d, .712.3 Hz), 4.61 (2H, m), 4 , 12 (1H, m), 3.31 (3H, s), 3.12 (1H, m), 2.10 (1H, m?, 84 (3H, m) and 1.36 (15H, m) m / z (ES +) 575 (M + l).

EXAMPLE 67 (5R, 6S) -N-r4-Iso? Ro? Oxi-3- (6-phenyl-l-oxa-7-aza-es? Iro [4,5] dec-3-en-3-ü) fenü ] -N- (meth) trifluoroacetamide Prepared from the compound of Example 66 according to the procedure of Example 2? NMR (360 MHz, CDCb) d 7.36 (2H, d, J6.6 Hz), 7.17 (3H, m), 6.97 (1H, dd, J8.8, 2.6 Hz), 6 , 77 (1H, d, J8.8 Hz), 6.66 (1H, d, J2.6 Hz), 6.11 (1H, t, J2, l Hz), 4.86 (1H, dd, J12 , 0, 2.1 Hz), 4.51 (1H, sept., J6.0 Hz), 4.30 (1H, dd, J 12.0, 2.1 Hz), 3.77 (1H, s ), 3.31 (1H, m), 3.25 (3H, s), 2.83 (1H, m), 2.14-1.64 (5H, m) and 1.31 (6H, d, J6.0 Hz). m / z (ES +) 475 (M + 1).

EXAMPLE 68 Hydrochloride of (35.5j?, 6S) -N- [4-isopropoxy-3- (6-phen-l-oxa-7-aza-spiro [4,5] decan-3-ü) fenül-N- (methyl) ) trifluoroacetemide Prepared from the compound of Example 67 according to the procedure of Example 3.? NMR (360 MHz, CD3OD) d 7.63-7.44 (5H, m), 7.05 (1H, dd, J8.8, 2.5 Hz), 6.93 (1H, d, J8.8 Hz), 5.98 (1H, d, J2.5 Hz), 4.89 (2H, sa), 4.59 (1H, sept., J5.8 Hz), 4.43 (1H, s), 4.23 (1H, m), 3.98 (1H, m), 3.44 (1H, m), 3.21 (2H, m), 3.15 (3H, s), 2.32-1 , 76 (6H, m), 1.30 (3H, d, J5.8 Hz) and 1.29 (3H, d, J5.8 Hz). m / z (ES +) 477 (M + 1). Found: C, 60.61; H, 6.14; N, 5.46, C26H31F3N2O3.HCl requires: C, 60.87; H, 6.29; N, 5.46%.

EXAMPLE 69 (5 / ?, 6-S) -N-f4- (Difluoromethoxy) -3- [6-phen-l-oxa-7- (tert-butoxycarbon) aza-esp-jo [4,5] dec-3- en-3-ülfenü} -N- (methü) thiifluoroacetemide Prepared from Description 54 and (5i?, 6-S) -3-tributylstannane-6-phene-1-oxa-7 - (- "erc-butoxycarbon) aza-spiro [4] , 5] dec-3-ene according to the procedure of Example 1.? NMR (360 MHz, CDCl3) d 7.45 (2H, d, J 7.4 Hz), 7.29-7.17 (5H , m), 7.03 (1H, s), 6.59 (1H, s), 6.52 (1H, t, J 73.0 Hz), 5.15 (1H, s), 4.91 ( 1H, d, J12.2 Hz), 4.56 (1H, d, J 12.2 Hz), 4.12 (1H, m), 3.33 (3H, s), 2.12 (1H, m ), 1.84 (3H, m) and 1.36 (9H, s) m / z (ES +) 583 (M + l).

EXAMPLE 70 (5 / ?, 6-Sl) -N- [4- (Difluoromethoxy) -3- (6-feml-l-oxa-7-aza-spiro [4,5] dec-3-en-3-infenü] -N- (meth) thiifluoroacefamide Prepared from the compound of Example 69 according to the procedure of Example 2. * H NMR (360 MHz, CDCb) d 1.65-1.69 (1H, m), 1.80 -2.05 (4H, m), 2.80-2.87 (1H, m), 3.27 (3H, s), 3.41 (1H, s), 4.29-4.32 (1H , m), 4.81-4.85 (1H, m), 6.14 (1H, s), 6.23 (1H, t, J 73 Hz), 6.74 (1H, s), 7, 08 (2H, s), 7.15-7.22 (3H, m) and 7.37 (2H, d, J6.5 Hz) m / z (ES +) 483 (M + 1).

EXAMPLE 71 (3 £ 5-ft, 6-SVN- [4- (D-fluoromethoxy) -3- (6-phenyl-l-oxa-7-aza-esp or4,5] decan-3-ü) fenü] hydrochloride -N- (meth) thiifluoroacetamide Prepared from the compound of Example 70 according to the procedure of Example 3.? NMR (360 MHz, D20) d 1.83-1.96 (3H, m), 2.14- 2.30 (3H, m), 3.18 (3H, s), 3.23-3.35 (2H, m), 3.50-3.54 (1H, m), 4.00 (1H, quint., J 9.3 Hz), 4.19 (1H, t, and 8.5 Hz), 4.42 (1H, s), 5.70 (1H, s), 6.75 (1H, t .773 Hz), 7.19 (2H, s) and 7.50-7.57 (5H, m) m / z (ES +) 485 (M + l).

EXAMPLE 72 (57 → 6-S) -N- [4-Methoxy-3- (6-phen-1-oxa-7- (fór-butoxycarbonü) aza-spiro [4,5] dec-3-en-3 -ii) fenu] -N- (2,2,2-thiifluoroe1) acetamide Prepared from the compound of Description 57 and (57?, 6-S) -3-thibutylstannane-6-phene-1-oxa-7 - (- 'g. butoxycarbon) aza-spiro [4.5] dec-3-ene according to the procedure of Example 1. * H NMR (360 MHz, CDCb) d 7.47 (2H, d, J7 , 5 Hz), 7.24 (3H, m), 7.12 (1H, dd, J8.7, 2.6 Hz), 6.93 (1H, d, J8.7 Hz), 6.87 ( 1H, d, J 2.6 Hz), 6.64 (1H, t, J 2.0 Hz), 5.17 (1H, s), 4.94 (1H, dd, J 12.0, 2, 0 Hz), 4.58 (1H, d, J 12.0, 2.0 Hz), 4.29 (2H, m), 4.13 (1H, m), 3.90 (3H, s), 3.10 (1H, m), 2.12 (1H, m), 1.87 (3H, s), 1.82 (3H, m) and 1.37 (9H, s). m / z (ES +) 561 (M + 1).

EXAMPLE 73 (5R, 6-S ') - N-r4-Methoxy-3- (6-phenyl-1-oxa-7-aza-spiro-4,51dec-3-en-3-y) phen-1-N- (2.2 , 2-thiifluoroetu) acefamide Prepared from the compound of Example 72 according to the procedure of Example 2. * H NMR (360 MHz, CDCb) d 7.37 (2H, d, J6.8 Hz), 7.16 (3H, m), 7.01 (1H, dd, -78.7, 2.6 Hz), 6.81 (1H, d, J8.7 Hz), 6.60 (1H, d, J 2, 6 Hz), 6.08 (1H, t, J2, l Hz), 4.85 (1H, dd, J 12.0, 2.1 Hz), 4.23 (3H, m), 4.29 ( 2H, m), 3.80 (3H, s), 3.77 (1H, s), 3.29 (1H, m), 2.83 (1H, m), 2.06-1.65 (5H , m) and 1.79 (3H, s). m / z (ES-) 461 (M + 1).

EXAMPLE 74 (3-S, .57?, 6-$ ') - N-r4-Methoxy-3- (6-phenyl-l-oxa-7-aza-spiro [4.5] decan-3-ü) fenül-N- (2,2,2-thiifluoroethal) acetamide Prepared from the compound of Example 73 according to the procedure of Example 3.? NMR (360 MHz, CD3OD) d 7.64 (2H, m), 7.52 (3H, m), 7.12 (1H, dd, J8.8, 2.5 Hz), 6.98 (1H, d, J8.8 Hz), 6.24 (1H, d, J2.5 Hz), 4.88 (2H, sa), 4.47 (1H, s), 4.36-4.22 (3H, m), 4.02 (1H, m), 3.78 (3H, s), 3.47 (1H, m), 3.39 (1H, m), 3.23 (1H, m), 2, 35-1.86 (6H, m) and 1.70 (3H, s). m / z (ES +) 463 (M + 1). Found: C, 60.39; H, 5.99; N, 5.63, C25H &F3N2O3.HCl requires: C, 60.18; H, 6.06; N, 5.61%.

EXAMPLE 75 (3-S.5J?, 6-S ^ -N- [4-Methoxy-3- (6-phen-1-oxa-7 - (? Grc-butoxycarbon)) aza-spiro [4.5] decan-3 -ii) fenu] benzamide Benzoyl chloride (40 μl, 0.34 mmol) was added to an agitated and cooled (0 ° C) solution of (3S, 5R, 6-S) -3- (5-amino-2) -methoxypheni) -6-phen-1-oxa-7 - (/ grc-butoxycarbon) aza-spiro [4.5] decane (Example 59, 98 mg, 0.22 mmol) and pyridine (200 μl, 2.47 mmoles) in dichloromethane (3 ml) The mixture was stirred for 15 min and then water (20 ml) and ether (30 ml) were added.The layers were separated and the aqueous layer was extracted with ether (10 ml). The combined organic fractions were washed with aqueous copper (II) sulfate (0.5 M, 2 x 20 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL), dried (MgSO4) and the solvent was evaporated under pressure The residue was purified by column chromatography on silica gel, eluting with hexane / EtOAc (75:25) to give the title compound as a colorless glass (102 mg, 84%). MHz, CDCl 3) d 8.07 (1H, sa), 8.0-7.85 (2H, m), 7.65-7.18 (10H, m), 6.84 (1H, d, J8, 8 Hz), 5.43 (1H, sa), 4.28 (1H, t, J 7.8 Hz), 4.03-3.68 (3H, m), 3.82 (3H, s), 2.94-2.79 (1H, m), 2.30-2.05 (2H, m), 1.80-1.60 (4H, m) and 1.38 (9H, s). m / z (ES +) 543 (M + 1).

EXAMPLE 76 (3-S 5 / ?, 6-S) -N-r4-Methoxy-3- (6-phenyl-1-oxa-7- (ferc-butoxycarbon) aza-spiro4,5] decan-3-ü) fenü ] -N- (meth) benzamide was added (SS.S ^ or - ^ - - ^ methoxy-S-1-phenyl-1-oxa ^ - ^ rc-butoxycarbonii) aza-spiro [4.5] decan-3 -ii) fenu] benzamide (Example 75, 100 mg, 0.18 mmol) to an agitated and cooled suspension (0 ° C) of sodium hydride (dispersion at 60% in mineral oil, 22 mg, 0.55 mmol) in DMF (3 ml). Methyl iodide (79 mg, 0.55 mmol) was then added and the mixture was stirred at room temperature for 1 h. Water (10 ml) was added and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic fractions were washed with water (3 x 10 mL) and brine (10 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / EtOAc (2: 1) to give the title compound as a colorless cristel (95 mg, 93%). iH NMR (250 MHz, CDCls) d 7.59-7.50 (2H, m), 7.38-7.05 (8H, m), 6.90-6.75 (2H, m), 6, 64 (1H, d, J9.6 Hz), 5.15 (1H, sa), 4.07-3.92 (2H, m), 3.75 (3H, s), 3.75- 3.60 (1H, m), 3.41 (3H, s), 3.40-3.25 (1H, m), 2.98-2.82 (1H, m), 2.27 (1H, dd, J 13, 9 Hz), 2.11-1.96 (1H, m), 1.78-1.60 (4H, m) and 1.38 (9H, s). m / z (ES +) 557 (M + 1).

EXAMPLE 77 Hydrochloride of (35.5-R, 6-S-N- [4-methoxy-3- (6-phenyl-1-oxa-7-aza-spiro [4,5] decan-3-ü) phenyl] -N- (methi) benzamide Prepared from the compound of Example 76 according to the procedure of Example 2, mp 275-280 ° C. * H NMR (360 MHz, CD3OD) d 7.62-7.52 (5H, m) , 7.28-7.02 (5H, m), 6.91 (1H, da, J8.6 Hz), 6.74 (1H, d, J8.6 Hz), 5.98 (1H, sa) , 4.40 (1H, s), 4.01 (1H, t, J8.0 Hz), 3.82 (1H, quint.ap., J9.8 Hz), 3.64 (3H, s), 3.41 (1H, dd, J 12, 4.2 Hz), 3.28 (3H, s), 3.19 (1H, dt, J 13, 3.2 Hz), 3.13-3.05 (1H, m), 2.30-2.08 (2H, m) and 1.96-1.65 (4H, m) m / z (ES +) 457 (M + l). Recognized: C, 69 80, H, 6.75, N, 5.45, C2 H32N203.HC1 requires: C, 70.60, H, 6.75, N, 5.68%.

EXAMPLE 78 (5J?, 6 - ^ - 3- [5-Methano-nino-2- (trifluorornetoxy) fenu] -6-phen-1-oxa-7- (te / -c-butoxycarbon) aza-spiro [4 , 5] dec-3-ene Prepared from Description 51 and (57?, 6-S) -3-tiibutüestannü-6-fenü-l-oxa-7- (tew-butoxycarbonü) aza-spiro [4, 5] dec-3-ene according to the procedure of Example 1. * H NMR (250 MHz, CDCb) d 7.50-7.40 (2H, m), 7.31-7.20 (3H, m ), 7.09 (1H, dq, J8.8, 1.5 Hz), 6.55 (1H, dd, J 8.8, 2.9 Hz), 6.44 (1H, t, J 2, l Hz), 6.38 (1H, d, J2.9 Hz), 5.13 (1H, sa), 4.88 (1H, dd, J12, 2.1 Hz), 4.55 (1H, dd , J12, 2.2 Hz), 4.17-4.08 (1H, m), 3.20-3.05 (1H, m), 2.83 (3H, s), 1.90-1, 50 (5H, m) and 1.35 (9H, s).

EXAMPLE 79 (57?, 6-S) -3- [5-Methano? Nino-2- (trifluorom.etoxy) fenu] -6-phene-1-oxa-7-aza-spiro [4r51dec-3-ene Prepared from of the compound of Example 78 according to the procedure of Example 2. * H NMR (250 MHz, CDCb) d 7.42-7.30 (2H, m), 7.25-7.13 (3H, m), 6.98 (1H, dq, J8.8, 1.4 Hz), 6.38 (1H, dd, J8.8, 2.9 Hz), 5.99-5.97 (2H, m), 4 , 80 (1H, dd, J 13, 2.1 Hz), 4.31 (1H, dd, J 13, 2.3 Hz), 3.78 (1H, s), 3.68 (1H, sa) , 3.33- 3.20 (1H, m), 2.82 (1H, dd, J 12, 3.0 Hz), 2.75 (3H, s), 2.15-1.60 and (5H) , m). m / z (ES +) 405 (M + l).

EXAMPLE 80 (35.57 ?, 6-S -3- [5-Methylamino-2- (trifluoromethoxy) phenyl-6-phenyl-1-oxa-7-aza-spiro [4.5] decane Prepared from the compound of Example 79 according to the procedure of Example 3. NMR (250 MHz, CDCb) d 7.60-7.50 (2H, m), 7.40-7.35 (3H, m), 6.91 (1H, da, J7.5 Hz), 6.30 (1H, dd, J8.8, 2.8 Hz), 5.28 (1H, d, J2.9 Hz), 4.10 (1H, t, J 8 , 0 Hz), 3.98 (1H, s), 3.82-3.72 (1H, m), 3.40-2.85 (5H, m), 2.57 (3H, s) and 2 30-1.55 (6H, m) m / z (ES +) 407 (M + l).

EXAMPLE 81 (5J?, 6-->) -N-Methyl-N-3- [6-phen-1-oxa-7- (rgrc-butoxycarbon) aza-spiro [4,51dec-3-en-3-ü ] -4- (thiifluoromethoxy) fenü} thiifluoroacetemide Prepared from Description 55 and (5i?, 65) -3-tributylstannane-6-phene-l-oxa-7- (fer-butoxycarbon) aza-es? iro [4,5] dec-3-ene according to the procedure of Example 1.? NMR (250 MHz, CDC-b) d 7.50-7.40 (2H, m), 7.35-7.15 (5H, m), 7.06 (1H, sa), 6.54 (1H , t, J2 Hz), 5.16 (1H, sa), 4.90 (1H, day, J 12 Hz), 4.55 (1H, day, J12 Hz), 4.18-4.08 (1H , m), 3.35 (3H, s), 3.20-3.04 (1H, m), 2.20-2.05 (1H, m), 1.95-1.70 (3H, m ) and 1.35 (9H, s).

EXAMPLE 82 (5?, 6-) -N-Methyl-N- [3- (6-phen-1-oxa-7-aza-esp-o [4,51dec-3-en-3-ü) -4- ( trifluorornetoxy) phenyltrifluoroaceteride Prepared from the compound of Example 81 according to the procedure of Example 2. * H NMR (250 MHz, CDC-b) d 7.40-7.30 (2H, m), 7.25-7 , 05 (5H, m), 6.73 (1H, sa), 6.08 (1H, t, J2, l Hz), 4.81 (1H, dd, J2,0, 12 Hz), 4.30 (1H, dd, J 12, 2.0 Hz), 3.80 (1H, s), 3.28 (3H, s), 2.83 (1H, dt, J 12, 2.9 Hz) and 2 , 25-1.60 (6H, m). m / z (ES +) 501 (M + 1).

EXAMPLE 83 Hydrochloride of (3, 5-R, 6-S) -N-metü-N- [3- (6-phene-l-oxa-7-aza-spiro [4,5] decan-3-ü) -4 - (trifluoromethoxy) fenu] trifluoroacetamide Prepared from the compound of Example 82 according to the procedure of Example 3.? NMR (250 MHz, CD3OD) d 7.65-7.40 (5H, m), 7.28 (1H, dd, J6, 1, 1.0 Hz), 7.22 (1H, da, J6, 1). Hz), 5.89 (1H, sa), 4.44 (1H, s), 4.22 (1H, t, J 5.8 Hz), 3.93 (1H, quin. Ap., J6,5 Hz), 3.42 (1H, dd, J8.8, 2.7 Hz), 3.35 (1H, t, J6.2 Hz), 3.22 (1H, dd, J 9.0, 2, 2 Hz), 3.16 (3H, s), 2.26-2.15 (3H, m) and 1.95-1.75 (3H, m). m / z (ES +) 503 (M + 1). Found: C, 53.10; H, 4.69; N, 5.06, C24H24F6N203.HC1 requires: C, 53.50; H, 4.68; N, 5.20%.

EXAMPLE 84 (57? .6-S ^ -3-r2-Ethoxy-5- (trifluorornetoxy)) phenyl1-6-phen-1-oxa-7 - (- 'erc-butoxycarbon) aza-spiro [4.5] dec- 3-ene Prepared from the compound of Description 58 and (5i?, 6S) -3-tributylstannu-or-phen-1-oxa ^ - ^ erc-butoxycarbon ^ aza-spiro ^ SJdec-S-ene of according to the procedure of Example 1. * H NMR (250 MHz, CDCb) d 1.36 (9H, s), 1.45 (3H, t, J 7.0 Hz), 1.73-1.93 ( 3H, m), 2.06-2.16 (1H, m), 3.05-3.18 (1H, m), 3.98-4.19 (3H, m), 4.61 (1H, dd, J 12.2, 2.2 Hz), 4.97 (1H, dd, J 12.2, 2.2 Hz), 5.15 (1H, s), 6.64 (1H, t, J2 , l Hz), 6.84 (1H, d, J 9.0 Hz), 6.93 (1H, d, J 2.7 Hz), 7.07 (1H, da, J 8.15 Hz), 7.18-7.32 (3H, m) and 7.44-7.51 (2H, m) m / z (ES +) 520 (M + 1).

EXAMPLE 85 (57?, 6- $ -3- [2-Ethoxy-5- (thiifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4y5] dec-3-ene Prepared from the compound of Example 84 according to the procedure of Example 2. NMR (360 MHz, CDCl 3) d 1.39 (3H, t, J 7.0 Hz), 1.67 (1H, da, J 15.3 Hz), 1.78 (1H, td, J 13.4.4.3 Hz), 1.93-2.16 (2H, m), 2.83 (1H, td, J 12.6, 2.9 Hz) , 3.27 (1H, day, J 12.4 Hz), 3.83 (1H, s), 3.94 (2H, q, J 7.0 Hz), 4.34 (1H, dd, J 12 , 0, 2.2 Hz), 4.89 (1H, dd, J 12.0, 2.2 Hz), 6.12 (1H, t, J 2.1 Hz), 6.67 (1H, d , J 3.0 Hz), 6.73 (1H, d, J9.0 Hz), 6.98 (1H, d, J8.8 Hz), 7.10-7.23 (3H, m) and 7 32-7.39 (2H, m) m / z (ES +) 420 (M + 1).

EXAMPLE 86 (35.5J?, 6> S) -3- [2-ethoxy-5- (thiifluoromethoxy) fenu] -6-phenyl-l-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from of the compound of Example 85 according to the procedure of Example 3.? NMR (360 MHz, DMSO-d6) d 1.27 (3H, t, J 7.0 Hz), 1.66-1.84 (3H, m), 2.01-2.10 (3H, m) , 3.03-3.12 (2H, m), 3.24-3.32 (1H, m), 3.79 (1H, q), 3.96 (2H, q, J7.0 Hz), 4.14 (1H, t, J 8.0 Hz), 4.48 (1H, sa), 6.17 (1H, sa), 6.95 (1H, d, J 9.0 Hz), 7, 08 (1H, da, J 9.0 Hz), 7.41-7.49 (3H, m) and 7.54-7.59 (2H, m). m / z (ES +) 422 (M + 1).

EXAMPLE 87 (5 /? 65) -3- [2- (Trifluoromethotthio) fenu] -6-phene-l-oxa-7- (tgrc-butoxycarbon) aza-spiro4,5] dec-3-ene Prepared from the compound of Description 59 and (5i?, 65) -3-tiibutüestannü-6-fenü-l-oxa-7- (ig-butoxycarbon) aza-spiro [4,5] dec-3-ene according to the process of Example 1, m / z (ES +) 492 (M + 1).

EXAMPLE 88 (57?, 65) -3- [2- (Trifluoromethylthio) phenyl] -6-phe n-l-oxa-7-aza-spiro [4.5] dec-3-ene Prepared from the compound of Example 87 of according to the procedure of Example 2.? NMR (360 MHz, CDCb) d 1.66 (1H, m), 1.76-1.86 (lH, m), 1.96-2.11 (2H, m), 2.82 (1H, td , J 12, 3 Hz), 3.26 (1H, da, J 10.3 Hz), 3.75 (1H, s), 4.30 (1H, dd, J12.3, 2.2 Hz), 4.81 (1H, dd, J12.3, 2.2 Hz), 5.66 (1H, t, J 2.0 Hz), 6.70 (1H, dd, J7.3, 1.8 Hz), 7.18-7.32 (4H, m), 7.39 (1H, dd, J5.8, 1.5 Hz) and 7.58 ( 1H, d, J7.4 Hz). m / z (ES +) 392 (M + 1).

EXAMPLE 89 (35.5J?, 65) -3- [2- (Trifluoromethylthio ') phenyl] -6-phene-1-oxa-7-aza-spiro [4,51decano Prepared from the compound of Example 88 according to procedure of Example 3. iH NMR (360 MHz, CDCls) d 1.54-1.64 (2H, m), 1.81-2.21 (5H, m), 2.81 (1H, td, J 12 , 2, 2.5 Hz), 3.21-3.32 (2H, m), 3.66 (1H, s), 4.07 (1H, t, J 8.2 Hz), 4.20-4.32 (1H, m), 6.20 (1H, dd, J7.6, 2.0 Hz), 7.08-7.18 (2H, m), 7.30-7.43 (3H, m) and 7.48-7.62 (3H, m). m / z (ES +) 394 (M + 1).

EXAMPLE 90 (5-R, 6-S -3- [2- (2,2,2-Trifluoroethoxy) -5- (trifluoromethyl) phenyl) -6-phen-1-oxa-7- (te / -c-butoxycarbonyl) aza-spiro [4,5] dec-3-ene Prepared from the compound of Description 60 and (57?, 65) -3-tributüestannü-6-fenü-l-oxa-7- (ig-butoxycarbon) aza -spiro [4.5] dec-3-ene according to the procedure of Example 1. * H NMR (250 MHz, CDCb) d 1.36 (9H, s), 1.86 (3H, m), 2 , 10 (1H, m), 3.18 (1H, m), 4.11 (1H, m), 4.43 (2H, dq, J 7.8, 3.9 Hz), 4.64 (1H , dd, J12.2, 2.2 Hz), 4.96 (1H, dd, J12.2, 2.0 Hz), 5.15 (1H, s), 6.67 (1H, t, J2, l Hz), 6.90 (1H, d, J8.6 Hz), 7.27 (4H, m), 7.36 (1H, d, J 2.1 Hz), 7.45 (1H, d, J 7.3 Hz) and 7.55 (lH, d, J8.8 Hz) EXAMPLE 91 (5R, 65) -3- [2- (2,2,2-Trifluoroethoxy) -5- (trifluoromethyl) fenu) -6-phen-1-oxa-7-aza-spiro [4,5] dec-3 -ne Prepared from the compound of Example 90 according to the procedure of Example 2. * H NMR (250 MHz, CDCb) d 1.79 (2H, m), 1.90 (1H, m), 2.24 (1H, m), 2.83 (1H, td, J12.6, 2.6 Hz), 3.47 (1H, d, J 10.7 Hz), 3.93 (1H, s), 4, 33 (2H, q, J7.9 Hz), 4.40 (1H, dd, J 12.2, 2.2 Hz), 4.90 (1H, dd, J12.2, 2.0 Hz), 6 , 16 (1H, t, J2.0 Hz), 6.81 (1H, d, J 8.6 Hz), 7.01 (1H, d, J 2.0 Hz), 7.18 (3H, m ) and 7.74 (3H, m). m / z (ES +) 458 (M + 1).

EXAMPLE 92 Hydrochloride of (35.5 /? 6-S) -3- [2- (2,2,2-Trifluoroethoxy) -5- (trifluoromeru) phenu) -6-phen-l-oxa-7-aza-es? Iro [4,51decano Prepared from the compound of Example 91 according to the procedure of Example 3.? NMR (250 MHz, DMSO-d *.) D 1.72 (3H, m), 2.10 (3H, m), 3.11 (1H, t, J8.4 Hz), 3.80 (1H, m), 4.15 (1H, t, J8.0 Hz), 4.49 (1H, s), 4.83 (2H, dq, J8.8, 4.9 Hz), 6.58 (1H, s), 7.21 (1H, d, J8.7 Hz), 7.44 (3H, m) and 7.56 (4H, m). m / z (ES +) 460 (M + l).

EXAMPLE 93 (5i?, 65) -3-r2-Ispoxy-5- (thiifluoromethy) phenyl] -6-phenyl-l-oxa-7- (f6-c-butoxycarbon) aza-spiro [4,51dec-3-ene Prepared from the compound of Description 61 and (5R, 65) -3-tributüestannü-ó-fenü-l-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] dec-3-ene according to the procedure of Example 1.? NMR (250 MHz, CDCl 3) d 0.93 (2H, m), 1.31 (15H, m), 1.83 (2H, m), 2.30 (1H, m), 3.14 (1H, m), 4.61 (2H, m), 4.98 (1H, dd, J12.3, 2.0 Hz), 5.15 (1H, s), 6.78 (1H, d, J2, l Hz), 7.22 (1H, d, J8.4 Hz), 7.44 (2H, m) and 7.55 (5H, m).

EXAMPLE 94 (5i?> 65) -3- [2-ispoxy-5- (trifluoromethyl) phenyl] -6-phenyl-l-oxa-7-aza-spiro [4,5] dec-3-ene Hydrochloride Prepared to from the compound of Example 93 according to the procedure of Example 2.? NMR (360 MHz, DMSO-d6) d 1.25 (6H, dd, J 8.8 Hz), 1.85 (2H, m), 2.01 (2H, m), 3.12 (1H, m ), 3.33 (1H, m), 4.37 (1H, d, J14.2 Hz), 4.60 (1H, s), 4.72 (1H, septete, J 6.0 Hz), 4 , 94 (1H, d, J 12.3 Hz), 6.41 (1H, t), 7.17 (2H, m), 7.30 (3H, m), 7.47 (2H, d, J 6.4 Hz) and 7.53 (1H, d, J 8.5 Hz).

EXAMPLE 95 Hydrochloride of (35, 57?, 65) -3- [2-isopropoxy-5- (thiifluoromethy) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Prepared from the compound of Example 94 according to the procedure of Example 3. iH NMR (360 MHz, DMSO-dβ) d 1.23 (6H, dd, J8.8, 5.9 Hz), 1.79 (2H, m), 2.06 (2H, m), 3.07 (2H, t, J 10.2 Hz), 3.81 (1H, qn), 4.14 (1H, t, J 7.9 Hz), 4, 46 (1H, s), 4.66 (1H, septete, J 6.0 Hz), 6.52 (1H, s), 7.09 (1H, d, J 8.6 Hz), 7.44 ( 5H, m) and 7.56 (2H, d, J6.5 Hz).

EXAMPLE 96 (35.5i?, 65) -3- [2-Cyclopropyl-5- (tr: luoromethoxy) fenu] -6-phen-1-oxa-7 - (- 'erc-butoxycarbonyl) aza-spiro [4,5] Dean Magnesium filings (128 mg) were placed in a dry flask and covered with a minimum amount of tetiahydrofuran. Dibromoethane (0.1 ml) was added and the reaction was heated. After observation of the effervescence, a solution of cyclopropyl bromide (0.4 ml) in tetrahydrofuran (10 ml) was added drop by drop until steady state reflux was maintained. The reaction was then heated at 65 ° C for 1 h. The mixture was allowed to cool to room temperature and a solution of zinc bromide (1.6 g) in tetiahydrofuran (5 ml) was added causing the formation of a white precipitate. The reaction was stirred at room temperature for 2 h. [1, 1-bis (diphenylphosphino) ferrocene] dichloropalacle (11) (50 mg) was added and the reaction was stirred for 5 min. (-? 5,5R, 65) -3- (5- (trifluoromethoxy) -2- (trifluoromethylsulfonumoxy) fenu) -6-phen-1-oxa-7 - (- 'erc-butsxicarbonu) aza spiro [ 4.5] decane (Example 144, 300 mg) and the solution was stirred at room temperature for 16 h. and then at 65 ° C for 1 h. The mixture was cooled, diluted with saturated aqueous ammonium chloride (20 ml) and extracted with dichloromethene (3 x 20 ml).

The organic fractions were washed with brine, dried (MgS?) And the solvent was evaporated under reduced pressure. The residue was purified by medium pressure liquid chromatography on silica gel, eluting with hexane / EtOAc (80:20) to give the title compound as an oil (121 mg). * H NMR (250 MHz, CDCl 3) d 0.64 (2H, m), 0.97 (2H, dt, J 8, 1, 1.4 Hz), 1.36 (9H, s), 1.78 (1H, m), 1.92 ( 1H, m), 2.16 (1H, m), 2.48 (1H, m), 3.66 (1H, t, J 8.6 Hz), 4.07 (3H, m), 4.22 (1H, t, J 6, 9 Hz), 5.22 (1H, s), 6.99 (3H, m), 7.30 (3H, m) and 7.56 (2H, d, J 7.5 Hz).

EXAMPLE 97 Hydrochloride of (35, 5J?, 6 - ^ - 3- [2-cyclopropyl-5- (trifluoro? Netoxy) phenyl-6-phene-l-oxa-7-aza-spiro [4,5] decane Prepared to from the compound of Example 96 according to the procedure of Example 2. * H NMR (360 MHz, DMSO-de) d 0.56 (2H, m), 0.88 (2H, d, J 8, 1 Hz) , 1.72 (1H, m), 1.80 (2H, m), 1.94 (1H, m), 2.14 (3H, m), 3.15 (2H, t, J 8.2 Hz ), 4.18 (2H, m), 4.51 (1H, s), 5.92 (1H, s), 7.02 (2H, m), 7.51 (3H, m) and 7.60 (2H, d, J 6.3 Hz).

EXAMPLE 98 (57?, 65) -3- (2-Benzyl-oxyphenyl) -6-phenyl-1-oxa-7- (chloro-butoxycarbon) -saza-spiro [4/5] dec-3-ene Prepared from the compound of the Description 62 and (5?, 65) -3-tiibutüestannü-6-fenü-l-oxa-7- (rg? -c-butoxicarbonü) aza-spiro [4,5] dec-3-ene according to the procedure of Example 1. * H NMR (250 MHz, CDCb) d 7.43-6.90 (14H, m), 6.65 (1H, t, J2, 1 Hz), 5.15 (1H, d,. 711.5 Hz), 5.09 (1H, d, Jll, 5 Hz), 5.07 (1H, s), 4.95 (1H, dd, 12.0, 2.1 Hz), 4.648 (1H , dd, .712.0, 2.1 Hz), 4.10 (1H, m), 3.13 (1H, m), 2.04 (1H, m), 1.76 (3H, m) and 1.32 (9H, s). m / z (ES +) 498 (M + 1).

EXAMPLE 99 (35, 5R, 6-S) -3- (2-Hydroxyphenyl) -6-phenyl-1-oxa-7- (rgrc-butoxycarbon) aza-spiro [4,5] decane Prepared from the compound of Example 98 according to the procedure of Example 3.? NMR (360 MHz, CDCb) d 7.58 (2H, d, J 7.5 Hz), 7.32 (2H, t, J7.5 Hz), 7.24 (1H, t, J7.5 Hz) , 7.13 (1H, d, J7.7 Hz), 7.08 (1H, t, J7.7 Hz), 6.85 (1H, t, J7.7 Hz), 6.76 (1H, d , J 7.7 Hz), 5.79 (1H, s), 5.36 (1H, s), 4.24 (1H, dd, J8.9, 7.1 Hz), 3.96 (1H, s), m), 3.92 (1H, dd, J8.9, 7.2 Hz), 3.68 (1H, m), 2.83 (1H, m), 2.47 (1H, m), 2, 22 (1H, m), 2.09 (1H, m), 1.75 (3H, m) and 1.36 (9H, s). m / z (ES +) 410 (M + 1).

EXAMPLE 100 (35.5R, 65) -3- (5-Bromo-2-hydroxyurea) -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-espiror4, 5] decane Tetiabutylammonium perbromide (118 mg) was added over 10 min. to a solution of (35.5 [beta], 65) -3- (2-hydroxyphenyl) -6-phenyl-1-oxa-7- (1-butocarboxy) aza-spiro [4.5] decane (Example 99, 100 mg, 0.24 mmol) in dichloromethane (3 ml) / methanol (2 ml) and the mixture was stirred at room temperature for 10 min. The residue was poured into water and extracted with ethyl acetate. The combined organic fractions were dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane / EtOAc (80:20) to give the title compound as a foam (76 mg, 64%). ? NMR (360 MHz, CDCl 3) d 7.56 (2H, d, J7.5 Hz), 7.33 (2H, t, J7.5 Hz), 7.26 (1H, t, 7.5 Hz), 7.21 (1H, d, J2.4 Hz), 7.17 (1H, dd, J8.4, 2.4 Hz), 6.66 (1H, d, 8.4 Hz), 6.20 ( 1H, sa), 5.33 (1H, s), 4.21 (1H, dd, and 9.1, 7.1 Hz), 3.98 (1H, m), 3.91 (1H, dd, and 9.1, 6.6 Hz), 3.59 (1H, m), 2.84 (1H, m), 2.48 (1H, m), 2.14 (2H, m), 1.74 (3H, m) and 1.36 (9H, s). m / z (ES +) 488, 490 (M + 1).

EXAMPLE 101 (35.57 → 65) -3- (5-Bromo-2-isopropoxyphenyl) -6-phenyl-1-oxa-7- ('' -butoxycarbonyl) aza-spiro-4,5] decane 2-Bromopropane (0.053) ml) to a mixture of (35.5R, 65) -3- (5-bromo-2-hydroxyurea) -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4.5 ] decane (Example 100, 69 mg, 0.14 mmol) and potassium carbonate (157 mg) in DMF (5 ml) and the mixture was stirred at 50 ° C for 3 days. The mixture was cooled, poured into water and extracted with ethyl acetate (2 x). The combined organic fractions were washed with water, dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane / EtOAc (85:15) to give the title compound as an oil (68 mg, 91%). iH NMR (360 MHz, CDCb) d 7.56 (2H, d, and 7.4 Hz), 7.34-7.23 (5H, m), 6.72 (1H, d, and 8.5 Hz), 5.20 (1H, s), 4.50 (1H, hept., And 6.2 Hz), 4.23 (1H, t, J 8.2 Hz ), 4.00 (1H, m), 3.73 (1H, m), 3.63 (1H, t, J 8.2 Hz), 2.89 (1H, m), 2.38 (1H, m), 2.15 (2H, m), 1.74 (3H, m), 1.40 (9H, s), 1.34 (3H, d, J 6.2 Hz) and 1.32 (3H, d, J 6.2 Hz). m / z (ES +) 530, 532 (M + l).

EXAMPLE 102 (35.5-R> 65) -3- (5-Bromo-2-isopropoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane Prepared from the compound of Example 101 according to the procedure of Example 2. W NMR (360 MHz, CDCl 3) d 7.49-7.47 (2H, m), 7.37-7.31 (3H, m), 7.12-7, 09 (1H, dd, and 8.6, 2.4 Hz), 6.62-6.60 (1H, d, and 8.6 Hz), 6.35-6.34 (1H, d, and 2) , 4 Hz), 4.42-4.36 (1H, m), 4.09-4.04 (1H, t, J 7.9 Hz), 3.84-3.73 (1H, m), 3.65 (1H, s), 3.24-3.21 (1H, m), 3.10-3.06 (1H, m), 2.85-2.78 (1H, m), 2, 14-1,% (2H, m), 1.87-1.76 (3H, m), 1.63-1.55 (2H, m) and 1.28-1.24 (6H, m). m / z (ES +) 430, 432 (M + 1).

EXAMPLE 103 (35.5R, 65) -3- (5-Cyano-2-isopropoxypheni) -6-phen-1-oxa-7- (grc-butoxycarbon) aza-spiro [4.5] decane A solution of (35, 5i ?, 6S) -3- (5-bromo-2-isopropoxyphenyl) -6-phenyl-l-oxa-7- (tert-butoxycarbonyl) aza-spiro [4.5] decane (Example 101; 226 mg, , 43 mmol) and copper (I) cyanide (227 mg, 2.54 mmol) in DMF (4 mL) was heated under reflux for 17 h. The mixture was allowed to cool, poured into aqueous ethylene diamine (10%, 50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic fractions were washed with aqueous ethylenediamine (10%, 50 ml) and brine (50 ml), combined, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (4 ml), treated with di-tert-butyl dicarbonate (110 mg, 0.50 mol) and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by tdtiarchap chromatography on silica gel, eluting with hexane / EtOAc (80:20 increasing to 70:30), to give the title compound (92 mg, 45%). m / z (ES +) 477 (M + 1).

EXAMPLE 104 (35.5R, 65) -3- (5-Cyano-2-isopropoxyphenyl) -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the compound of Example 103 of according to the procedure of Example 3, pf 230-234 ° C (dec.). ? NMR (360 MHz, DzO) d 1.27 (6H, m), 1.73-1.97 (3H, m), 2.19 (3H, m), 3.23 (1H, m), 3, 39 (1H, m), 3.53 (1H, m), 3.76 (1H, m), 4.17 (1H, t, and 8.1 Hz), 4.39 (1H, s), 4 , 61 (1H, p, and 6.0 Hz), 6.49 (1H, s), 6.88 (1H, d, and 8.7 Hz), 7.32 (1H, m) and 7.47 ( 5H, m); m / z (ES +) 377 (M + 1). Found: C, 66.59; H, 6.80; N, 6.51, C2 H-8N-O2.HClH2O requires: C, 66.89; H, 7.25; N, 6.50%.

EXAMPLE 105 (5J?> 65) -4- (Difluoromethoxy) -3- [6-phen-l-oxa-7- (fer-butoxycarbon) aza-spiro [4,5] dec-3-en-3-ü] Methoxy benzoate Prepared from Description 65 and (5 / ?, 65) -3-Thiibutüestennü-6-fenü-l-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] dec-3- ene according to the procedure of Example 1. iR NMR (250 MHz, CDCl3) d 7.98 (1H, dd, J 2.1, 8.6 Hz), 7.85 (1H, d, and 2.1 Hz), 7.47 (2H, m), 7.25 (4H, m), 6.62 (1H, t, and 2.1 Hz), 6.55 (1H, t, and 73 Hz), 5 , 16 (1H, s), 4.97 (1H, dd, J 2"12.3 Hz), 4.62 (1H,? D, J 2.1, 12.3 Hz), 4.13 (1H , m), 3.92 (3H, s), 3.18 (1H, m), 2.12 (1H, m), 1.85 (3H, m) and 1.37 (9H, s).

EXAMPLE 106 (5R, 65) -3- [6-Fenü-l-oxa-7 - (- grc-butoxycarbon) aza-spiro [4,5] dec-3-en-3-ü] -4- (2, 2,2-thiifluoroethoxymethoate Methioate Prepared from Description 66 and (5i?, 6-S) -3-tributylstannane-6-phene-1-oxa-7- (1-butoxycarbon) aza-spiro [4 , 5] dec-3-ene according to the procedure of Example 1.? NMR (250 MHz, CDCb) d 7.97 (1H, dd, J 8.67, 2.14 Hz), 7.80 (1H , d, and 2.1 Hz), 7.44 (2H, m), 7.17-7.30 (3H, m), 6.85 (1H, d, and 8.7 Hz), 6.67 (1H, t, and 2.1 Hz), 5.15 (1H, s), 4.98 (1H, dd, and 2.0, 12.2 Hz), 4.67 (1H, dd, J 2"12.2 Hz), 4.36-4.51 (2H, m), 4.13 (1H, m), 3.90 (3H, s), 3.14 (1H, m), 2.08 (1H, m), 1.79-1.89 (3H, m) and 1.36 (9H, s) EXAMPLE 107 (35.57 ?, 65) -4- (Difluoromethoxy) -3- [6-phenyl-1-oxa-7 - (- 'grc-butoxycarbonyl) aza-spiro [4.5] decan-3-yl] benzoate of methyl prepared from the compound of Example 105 according to the procedure of Example 3.? NMR (250 MHz, CDOb) d 7.96 (2H, m), 7.56 (2H, m), 7.30 (3H, m), 7.13 (1H, d, and 5.9 Hz), 6.59 (1H, t, J73 Hz), 5.22 (1H, s), 4.23 (1H, m), 3.98 (1H, m), 3.89 (3H, s), 3, 77 (2H, m), 2.89 (1H, m), 2.47 (1H, m), 2.19 (2H, m), 1.75 (3H, m) and 1.37 (9H, s) ).

EXAMPLE 108 (35.5i ?, 65) -3-r6-Fenu-l-oxa-7 - (- grc-butoxycarbon) aza-spiro [4.5] decan-3-u1-4- (2,2,2- trifluoroethoxy'-methylbenzoate Prepared from the compound of Example 106 according to the procedure of Example 3. NMR (250 MHz, CDCb) d 7.96 (1H, m), 7.83 (2H, m), 7.22-7.36 (4H, m), 6.82 (1H, d, J 8.4 Hz), 5.22 (1H, s), 4.38-4.52 (2H, m), 3.94 (1H, m), 3.88 (3H, s), 3.74 (1H, m), 2.85-2.93 (1H, m), 2.46-2.54 (1H, m), 2.10-2.22 (1H, m), 1.76-1.81 (3H, m) and 1.38 (9H, s).

EXAMPLE 109 (35.57?, 65) -. { 4- (Difluoromethoxy) -3- [6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4.5] decan-3-u] phen} carboxamide A cooled solution (0 ° C) of (35.5i?, 65) -4- (difluoromethoxy) -3- [6-phenyl-1-oxa-7- (fer-butoxycarbon) aza-spiro [4,5 ] decan-3-ü] methylbenzoate (Example 107, 730 mg, 1.41 mmol) in methanol (100 ml) was saturated with ammonia gas and then heated at 80 ° C in a tube for 16 h. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / EtOAc (50:50) to give the title compound as a colorless solid (410 mg, 58%). * H NMR (250 MHz, CDCl 3) d 8.25 (1H, sa), 8.00 (1H, dd, and 2.1, 8.6 Hz), 7.64 (2H, m), 7.30 (3H, m), 7.15 (1H, d, and 8.6 Hz), 6.57 (1H, t, J 73 Hz), 5.78 (1H, sa), 5.53 (1H, sa ), 4.34 (1H, t, J 8.8 Hz), 4.10 (2H, m), 3.68 (1H, t, J 8.8 Hz), 2.75 (1H, m), 2.30 (3H, m), 1.65 (3H, m) and 1.47 (9H, s).

EXAMPLE 110 (35.57 ?, 65) -i3- [6-Phen-1-oxa-7- (tert-butoxycarbon) aza-spiro4,51decan-3-ü] -4- (2,2,2-trifluoroethoxy) phenol } carboxamide Prepared from the compound of Example 108, according to the procedure of Example 109. m / z (ES +) 535 (M + 1).

EXAMPLE 111 (35.5-R, 65) -3- [5-Cyano-2- (difluoromethoxy) phenyl-6-phen-1-oxa-7 - (/ g /, c-butoxycarbon) aza-spiro4 and 5] decane was added drop to trifluoroacetic anhydride (252 μl, 1.8 mmol) to a solution of (35.5 μl, 65) -. { 4- (difluoromethoxy) -3- [6-phenyl-1-oxa-7- (ig-butoxycarbonyl) aza-spiro [4,5] decan-3-y] phen} carboxamide (Example 109, 410 mg, 0.82 mmol) and pyridine (332 μl, 4.1 mmol) in 1,4-dioxane (20 ml) and the mixture was stirred at room temperature for lh. The mixture was poured into saturated aqueous sodium bicarbonate (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic fractions were dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / EtOAc (75:25) to give the title compound as a gum (347 mg, 87%). i H NMR (250 MHz, CDC b) d 7.50 (4 H, m), 7.25 (4 H, m), 7.15 (1 H, d, J 8.6 Hz), 6.60 (1 H, t, J 73 Hz), 5.13 (1H, sa), 4.16 (1H, m), 4.03 (1H, m), 3.67 (2H, m), 2.94 (1H, m), 2.42 (1H, m), 2.13 (2H, m), 1.75 (3H, m) and 1.47 (9H, s).

EXAMPLE 112 (35.5J?, 6- $ l) -3- [5-Cyano-2- (2,2,2-trifluoroethoxy) phenyl-6-phenyl-1-oxa-7- (ferc-butoxycarbon) aza-spiro [ 4,5] decane Prepared from the compound of Example 110 according to the procedure of Example 111.? NMR (250 MHz, CDCb) d 7.48-7.56 (4H, m), 7.22-7.36 (3H, m), 6.84 (1H, d, J 8.5 Hz), 5 , 14 (1H, s), 4.42 (2H, q, J 7.8 Hz), 4.25 (1H, m), 4.00 (1H, m), 3.67-3.84 (2H , m), 2.84-3.00 (1H, m), 2.40-2.56 (1H, m), 2.02-2.18 (2H, m), 1.64-1.75 (3H, m) and 1.37 (9H, s).

EXAMPLE 113 (35, 57?, 65) -3- [5-Cyano-2- (difluoromethoxy) fenu] -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the compound of Example 111 according to the procedure of Example 2.? NMR (360 MHz, DMSO-d6) d 9.78 (1H, sa), 9.05 (1H, sa), 7.70 (1H, dd, J 2.0, 8.5 Hz), 7.50 (5H, m), 7.31 (1H, t, J 73 Hz), 7.20 (1H, d, J 8.5 Hz), 6.58 (1H, d, and 2.0 Hz), 4.51 (1H, sa), 4.14 (1H, t, and 8.1 Hz), 3.78 (1H, m) , 3.28 (1H, m), 3.07 (1H, m), 2.09 (3H, m) and 1.70 (3H, m). m / z (ES +) 385 (M + l).

EXAMPLE 114 (35.5i ?, 65) -3- [5-Cyano-2- (2,2 > 2-thiifluoroethoxy) phenyl-1-6-phene-1-oxa-7-aza-spiro [4,5] decane Prepared from the compound of Example 112 according to the procedure of Example 2. iH NMR (360 MHz, DMSO-d6) d 9.60 (1H, sa), 8,% (1H, sa), 7.66 (1H , dd, and 6.7, 1.9 Hz), 7.44-7.54 (5H, m), 7.18 (1H, d, and 8.7 Hz), 6.66 (1H, d, and 1.9 Hz), 4.81-4.88 (2H, m), 4.50 (1H, m), 4.16 (1H, t, J 8.0.0 Hz), 3.72 (1H, m ), 3.26 (2H, m), 3.06 (1H, ma), 1.99-2.17 (3H, m) and 1.60-1.81 (3H, m). m / z (ES +) 417 (M + l).

EXAMPLE 115 (57?, 65) -. { 4- (Cyclobutyloxy) -3- [6-phen-1-oxa-7- (tgrc-butoxycarbon) aza-spiro [4,5] dec-3-en-3-ülfenü} carboxamide Prepared from Description 68 and (57?, 65) -3-tributylstannane-6-phenyl-1-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] dec-3-ene according to with the procedure of Example 1.? NMR (CDCb) d 1.37 (9H, s), 1.70-1.93 (4H, m), 2.14-2.21 (3H, m), 2.42-2.34 (3H, m), 3.07-3.20 (1H, m), 4.09-4.18 (1H, m), 4.66-4.75 (2H, m), 5.00 (1H, dd, J 12.3, 2.0 Hz), 5.16 (1H, sa), 6.20 (2H, sa), 6.67 (1H, sa), 6.74 (2H, d, J 8.5 Hz), 7.20-7.29 (3H, m), 7.47 (2H, d, J 8.0 Hz), 7.60 (1H, d, J 2.2 Hz) and 7.64 ( 1H, dd, J 8.5, 2.2 Hz).

EXAMPLE 116 (35.5 / ?, 65) -f4- (Cyclobutyloxy) -3- [6-phenyl-1-oxa-7- (fór-butoxycarbonü) aza-espfro [4,5] decan-3-ü] fenü} carboxamide Trifluoroacetic acid (0.5 ml) was added to a solution of (57?, 65) -. { 4- (Cyclobutyloxy) -3- [6-phen-1-oxa-7 - (- 1-rub-butoxycarbon) -zapray [4,5] dec-3-en-3-yl] phen} carboxamide (Example 115, 0.5g) in dichloromethane (15 ml) and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with dichloromethene / methanol / ammonia (90: 10: 1). The residue was dissolved in a mixture of methanol (25 ml) and acetic acid (0.5 ml), palladium hydroxide on carbon (50 mg) was added and the mixture was stirred for two days under a hydrogen atmosphere at 50 psi. (344,737 kPa). The mixture was filtered, a further portion of palladium hydroxide on carbon (50 mg) was added and the mixture was stirred for 24 h. under a hydrogen atmosphere at 50 psi (344.737 kPa). The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (15 ml), triethylamine (0.14 ml) and di-tert-butyl dicarbonate (130 mg) were added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate / hexane to give the title compound as a gum (210 mg). ? NMR (CDCb) d (CDCb) d 1.46 (9H, s), 1.64-1.93 (5H, m), 2.08-2.27 (4H, m), 2.39-2.48 (3H, m), 2.74-2.80 (1H, m), 3.64 (1H, t ap., And 9.0 Hz), 3.93 (1H, da, and 12.7 Hz), 3.98-4.09 (1H, m), 4.35 (1H, t ap, and 8.6 Hz) 4.69 (1H, pent. Ap., J 7.0 Hz), 5.68 (1H, sa), 6.73 (1H, d, J 8.6 Hz), 7.21-7.25 (1H, m), 7.30-7.34 (2H, m), 7.62 (2H, d, and 7.7 Hz), 7.90 (1H, d, J 8.5 Hz) and 8.06 (1H, s a).

EXAMPLE 117 (35.5 - / ?, 65) -3-f5-Cyano-2- (cyclobutyloxy) fenu] -6-phenyl-1-oxa-7- (chloro-butoxycarbon) aza-spiro [4,51decano Prepared from of the compound of Example 116 according to the procedure of Example 111. iH NMR (CDCb) d 1.38 (9H, s), 1.67-1.81 (4H, m), 1.86-1.95 ( 1H, m), 2.09-2.22 (4H, m), 2.41 (1H, dd, J 12.9, 8.3 Hz), 2.44-2.54 (2H, m), 2.87-2.95 (1H, m), 3.65 (1H, t ap., And 8.4 Hz), 3.68-3.76 (1H, m), 4.01 (1H da, J 13.1 Hz), 4.26 (1H, t ap., And 8.4 Hz), 4.68 (1H, pent. Ap., And 7.1 Hz), 5.16 (1H, sa) , 6.71 (2H, d, and 8.5 Hz), 7.23-7.27 (1H, m), 7.33 (2H, t ap., And 7.1 Hz), 7.42 ( 1H, d, J 1.9 Hz), 7.45 (1H, dd, J 8.4, 1.9 Hz) and 7.54 (2H, d, J 7.7 Hz). m / z (ES +) 489 (M + 1).

EXAMPLE 118 (35, 57?, 65) -3- [5-Cyano-2- (cyclobutyloxy) fenu] -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the compound of Example 117 according to the procedure of Example 2. pf (MeOH / tert-butyl methyl ether) 252-254 ° C. * H NMR (D20) d 1.59-1.82 (3H, m), 1.87-1.96 (3H, m), 2.04-2.23 (3H, m), 2.26- 2.41 (2H, m), 3.11-3.24 (1H, m), 3.24-3.37 (2H, m), 3.47 (1H, da, and 10.3 Hz), 3.74 (1H, pent.ap, and 8.6 Hz), 4.14 (1H, t ap., And 8.2 Hz), 4.34 (1H, s), 4.60 (1H, pent . ap., and 7.1 Hz), 6.40 (1H, d, J 1.9 Hz), 6.66 (1H, d, J 8.7 Hz), 7.27 (1H, dd, J 8.6, 1.9 Hz) and 7.35-7.52 (5H, m). m / z (ES +) 389 (M + 1). Found: C, 66.82; H, 7.01; N, 6.38, C25H25N2? 2.HCl.l, 25H20 requires: C, 67.10; H, 7.10; N, 6.26%.

EXAMPLE 119 (57?, 65) -3- [2-Cyano-5- (trifluoromethoxy) fenu] -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5] dec-3 -eno Prepared from the compound of Description 69 and (5R, 65) -3-tributy-cistannu-6-phene-l-oxa-7- (ig-butoxycarbon) aza-spiro [4,5] dec-3-ene according to the procedure of Example 2. * H NMR (360 MHz, CDCl 3) d 1.34 (9H, s), 1.82-1.94 (3H, m), 2.12-2.16 (1H , m), 3.18-3.24 (1H, m), 4.13-4.16 (1H, m), 4.48 (1H, d, and 11.7 Hz), 4.91 (1H , d, J 11.7 Hz), 5.13 (1H, s), 6.85 (1H, s), 6.89 (1H, s), 7.20-7.29 (4H, m), 7.43 (2H, d, J 7.2 Hz) and 7.74 (1H, d, and 8.6 Hz).

EXAMPLE 120 (5 / ?, 65) -3- [2-Cyano-5- (trifluoromethoxy) fenu] -6-phenyl-l-oxa-7-aza-spiro [4,5] dec-3-ene Hydrochloride Prepared to from the compound of Example 119 according to the procedure of Example 2.? NMR (360 MHz, D20) d 1.96-2.18 (3H, m), 3.19-3.29 (1H, m), 3.49-3.56 (1H, m), 4.49 (1H, d, and 12.5 Hz), 4.91 (1H, d, J 12.5 Hz), 6.44, 1H, s), 6.81 (1H, s), 7.17-7 , 19 (1H, m), 7.33-7.38 (4H, m), 7.42-7.45 (2H, m) and 7.61 (1H, d, J 8.7 Hz).

EXAMPLE 121 (35.5R, 6-S ^ -3- [2- (Cyclopropyl? Neoxy) -5- (thiifluorornetoxy) fenu] -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro4, 5] decane Cyclopropylmethyl bromide (0.078 ml, 0.8 mmol) was added to a mixture of (35.5 - /? 6-S) -3- [2-hydroxy-5- (trifluorornetoxy) fenu] -6 -phen-1-oxa-7 - (/ grc-butoxycarbon) aza-spiro [4.5] decane (Example 44, 330 mg, 0.67 mmol) and potassium carbonate (103 mg, 0.75 mmol) in DMF (5 ml) and the mixture was stirred at room temperature for 48 hrs Water (20 ml) was added and the mixture was extracted with ethyl acetate (2 x 20 ml) The combined organic fractions were dried and the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography on silica, eluting with hexane / EtOAc (90:10), to give the title compound (150 mg). * H NMR (360 MHz, CDCl 3) d 0, 31-0.35 (2H, m), 0.61-0.65 (2H, m), 1.20-1.29 (1H, m), 1.37 (9H, s), 1.72- 1.84 (3H, m), 2.09-2.18 (2H, m), 2.41-2.47 (1H, m), 2.83-2.91 (1H, m), 3, 39 (1H, sa ), 3.62-3.68 (1H, m), 3.77-3.84 (2H, m), 3.98-4.02 (1H, m), 4.27-4.32 (1H) , m), 5.21 (1H, s), 6.74-6.77 (1H, m), 6.99-7.04 (2H, m), 7.21-7.33 (3H, m ) Y 7.56 (lH, d, and 7.5 Hz).

EXAMPLE 122 Hydrochloride of (35, 5 j?, 65) -3- [2- (cyclopropi-methyloxy) -5- (thifluoromethoxy) phenin-6-phene-l-oxa-7-aza-spiro [4,5] decane Prepared from the compound of Example 121 according to the procedure of Example 2. * H NMR (360 MHz, D20) d 0.29-0.28 (2H, m), 0.56-0.58 (2H, m), 1.14-1.18 (1H, m), 1.78-2.02 (2H, m), 2.16-2.26 (3H, m), 3.18-3.28 ( 2H, m), 3.48-3.55 (1H, m), 3.74-3.79 (2H, m), 4.18-4.22 (1H, m), 4.40 (1H, s), 6.20 (1H, s), 6.92 (1H, d, and 9.0 Hz), 7.02-7.06 (1H, m) and 7.45-7.53 (6H, m).

EXAMPLE 123 (35.5J?, 65) -3- [2-Methoxy-5- (trifluoromethyl) phenyl-1-6-phene-1-oxa-7- (tert-butoxycarbon) aza-spiro [4,51 dekane Sodium hydride (dispersion 60% in mineral oil, 10 mg) to a solution of (35.5i?, 6-S) -3- (2-hydroxy-5- (thiifluoromethyl) phen) -6-phen-1-oxa-7 (-'grc-butoxycarbonii) a2-a-spiro [4.5] decane (Example 46, 100 mg) in dimethylformamide (2 ml). The mixture was stirred at room temperature until effervescence ceased, methyl iodide (0.4 ml) was added and the mixture was stirred at room temperature for 1 h. Water (10 ml) was added and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (102 mg). m / z (ES +) 492 (M + 1).

EXAMPLE 124 (35.5 μg, 65) -3- [2-Methoxy-5- (trifluoromethyl) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane Prepared from the compound of Example 123 according to the procedure of Example 2.? NMR (250 MHz, CDCb) d 1.18 (2H, s), 1.54 (2H, d, J 11.1 Hz), 1.87 (1H, d, J 12.2 Hz), 2.04 (2H, d, J 12.0 Hz), 2.73 (1H, t, J 12.4 Hz) , 3.10 (1H, dd, and 8.0, 10.4 Hz), 3.18 (1H, d, J 11.7 Hz), 3.65 (3H, s), 4.02 (1H, t, J 7.6 Hz), 6.52 (1H, d, and 2.1 Hz), 6.69 (1H, d, J 8.6 Hz), 7.25 (4H, m) and 7.43 (3H, m).

EXAMPLE 125 (35.5i?, 65) -3- [2-Methoxy-5- (trifluoromethyl) phenyl-6-phenyl-1-oxa-7- (1, 2,4-thiazole-3-methyl) -7-aza-spiro [4,5] decane Prepared from the compound of Example 124 according to the procedure of Example 5. iH NMR (500 MHz, CDCls) d 0.9 (2H, t, J 7.3 Hz), 1.29 (2H, s), 1.35 (1H, q, and 7.35 Hz), 1.54 (1H, dt, and 9.8, 4 Hz), 1.62 (2H, m), 2.00 (2H, m), 2.15 (1H, d, and 12.3 Hz), 3.11 (1H, m), 3.74 (3H, s), 3.82 (1H, m), 4, 08 (1H, t, J 8.0 Hz), 6.52 (1H, s), 6.77 (1H, d, and 8.6 Hz), 7.25 (1H, s), 7.35 (4H, m), 7.58 (1H, m) and 8.13 (1H, s).

EXAMPLE 126 (5J?, 65) -3- (2-Methanesulfonyl-phenyl) -6-phenyl-1-oxa-7- (ferc-butoxycarbon) aza-spiro [4.5] dec-3-ene Prepared from the compound of the Description 71 and (5R, 6S) -3-tiibutüestannü-6-fenü-l-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] dec-3-ene, according to the procedure of Example 1 . * H NMR (360 MHz, CDCb) d 8.14 (1H, dd, and 7.7, 1.34 Hz), 7.61-7.47 (4H, m), 7.36-7.26 (3H, m), 7.10 (1H, dd, and 7.33, 1.51 Hz), 6.16 (1H, t, and 2.15 Hz), 5.19 (1H, s), 4 , 90 (1H, dd, and 12.5, 2.1 Hz), 4.56 (1H, dd, and 12.5, 2.2 Hz), 4.11 (1H, dt, and 12.3 Hz ), 3.20 (1H, m), 3.07 (3H, s), 2.17 (1H, m), 1.90 (3H, m) and 1.35 (9H, s). m / z (ES +) 470 (M + 1).

EXAMPLE 127 (5-R, 65) -3- (2-Methenesulfonuchen) -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene Prepared from the compound of Example 126 in accordance with the procedure of Example 2. iH NMR (250 MHz, CD3OD) d 7.89 (1H, m), 7.50-7.22 (8H, m), 6.33 (1H, m), 5.71 ( 1H, t, and 2.1 Hz), 4.87 (1H, dd, and 12.5, 2.2 Hz), 4.76 (5H, sa), 4.39 (1H, dd, and 12, 5, 2.2 Hz), 4.28 (1H, s), 3.38 (1H, broad d, and 11.7 Hz), 3.13 (1H, td, J 10.2, 2.5 Hz ), 2.71 (3H, s) and 2.27-1.87 (4H, m). m / z (ES +) 370 (M + 1).

EXAMPLE 128 (35.5J?, 65) -3- (2-Methanesulfonuchen) -6-phen-1-oxa-7-aza-spiro [4.5] decane Prepared from the compound of Example 127 according to the procedure of Example 3.? NMR (360 MHz, CDCl 3) d 7.9 (1H, dd, J 7.7, 1.99 Hz), 7.55 (2H, day), 7.38 (3H, m), 7.21 (2H) , m), 6.16 (1H, d, J 7.3 Hz), 5.01 (2H, sa), 4.39 (1H, q, and 8.9 Hz), 4.17 (1H, t , J 8.3 Hz), 3.88 (1H, s), 3.47 (1H, m), 3.33 (1H, dm, J 13.2 Hz), 3.04 (3H, s), 2.88 (1H, td, and 12.61 Hz), 2.17 (3H, m), 1.86 (1H, dd, and 12.7, 10.3 Hz) and 1.60 (2H, m ). m / z (ES +) 372 (M + 1).

EXAMPLE 129 (57?, 65) -. { 4-Hydroxy-3- [6-phenyl-1-oxa-7- (fórc-butoxicarbonü) aza-spiro [4 > 5] dec-3-en-3-ülfenüjetanoato metüo Prepared from the compound of Description 73 and (5 / ?, 65) -3-tributüestannü-6-fenü-l-oxa-7- (grc-butoxicarbonü) aza-es? iro [4,5] dec-3-ene, according to the procedure of Example 1. * H NMR (250 MHz, CDCb) d 7.50-7.53 (2H, m), 7, 18-7.32 (3H, m), 7.05 (1H, dd, and 2.27, 8.31 Hz), 6.86 (1H, d, J 2.27 Hz), 6.82 (1H , d, and 8.31 Hz), 6.51 (1H, t, J 2.06 Hz), 6.33 (1H, sa), 5.24 (1H, sa), 4.98 (1H, dd , J 2.01, 12.44 Hz), 4.62 (1H, dd, and 2.01, 12.44 Hz), 4.03-4.10 (1H, m), 3.68 (3H, s), 3.51 (2H, s), 3.02-3.10 (1H, m), 2.11-2.18 (1H, m), 1.75-1.88 (3H, m) and 1.42 (9H, s).

EXAMPLE 130 (57?, 65) - [4-Hydroxy-3- (6-phenyl-1-oxa-7-aza-spiro [4,5] dec-3-en-3-ü) phenyl] ethanoate methylated Prepared to from the compound of Example 129 according to the procedure of Example 2.? NMR (250 MHz, CDCl 3) d 7.37-, 7.42 (2H, m), 7.16-7.30 (3H, m), 6,% (1H, dd, and 2.18, 8, 40 Hz), 6.70 (1H, d, J 2.18 Hz), 6.68 (1H, d, J 8.40 Hz), 5.87 (1H, t, and 2.18 Hz), 4 , 82 (1H, dd, and 2.06, 12.54 Hz), 4.30 (1H, dd, and 2.06, 12.54 Hz), 3.78 (1H, s), 3.65 ( 3H, s), 3.44 (2H, s), 3.25-3.36 (1H, m), 2.82 (1H, dt, and 2.83, 12.39 Hz), 1.97- 2.09 (2H, m) and 1.65-1.84 (2H, m).

EXAMPLE 131 (35.5R, 65) - [4-Hydroxy-3- (6-phenyl-1-oxa-7-aza-es? Iro [4,5] decan-3-ü) methylated phenethiolate Prepared from the compound of Example 130 according to the procedure of Example 3.? NMR (250 MHz, DMSO-dβ) d 9.33 (1H, sa), 7.50-7.54 (2H, m), 7.35-7.44 (3H, m), 6.80 (1H , dd, and 2.11, 8.18 Hz), 6.65 (1H, d, J 8.18 Hz), 5.99 (1H, d, and 2.11 Hz), 3.89-4, 04 (2H, m), 3.64-3.72 (1H, m), 3.60 (3H, s), 3.30 (2H, s), 3.11-3.16 (1H, m) , 2.94 (1H, dd, J 7.84, 10.36 Hz), 2.78-2.87 (1H, m) and 1.62-2.06 (6H, m) EXAMPLE 132 (35.5 ^, 65) -. { 4-Hydroxy-3- [6-phenyl-1-oxa-7- (fer-butoxycarbonyl) aza-spiro [4,5] decan-3-ylmethyl methanoate N-ethyl düsopropyamine (0.324 ml, 1.9 mmoles) to a mixture of (35, 5R, 65) - [4-hydroxy-3- (6-phenyl-1-oxa-7-aza-spiro [4.5] decan-3-yl) phen] -ethenoate of methylene (Example 131, 309 mg, 0.81 mmol) and di-ferric-butyl dicarbonate (400 mg, 1.83 mmol) in tetiahydrofuran (100 ml) and the mixture was stirred at room temperature for 4 h. Additional N-ethyl diisopropyamine (0.324 ml, 1.9 mmol) was added and the mixture was stirred at room temperature for 16 h, poured into saturated aqueous sodium hydrogen carbonate (100 ml) and extracted with ethyl acetate (2 ml). x 100 ml). The combined organic fractions were dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound as a colorless solid (259 mg, 66%). JH NMR (250 MHz, CDCl 3) d 7.55-7.58 (2H, m), 7.24-7.35 (3H, m), 6.98-7.01 (2H, m), 6, 71 (1H, d, and 8.75 Hz), 5.99 (1H, sa), 5.35 (1H, sa), 4.22 (1H, dd, and 7.13, 8.95 Hz), 3.90-3.98 (2H, m), 3.66 (3H, s), 3.51 (2H, s), 2.84-2.88 (1H, m), 2.48 (1H, dd, and 8.84, 12.87 Hz), 2.05-2.24 (3H, m), 1.72-1.82 (3H, m) and 1.35 (9H, s).

EXAMPLE 133 (35.57?, 65) -. { 4-Methoxy-3-r6-phenyl-1-oxa-7 - (/ grc-butoxycarbonii) a2-a-spiro [4.5] decan-3-ülfenyl methoxide methode Iodomethane (0.051 ml, 0.81 mmol) was added ) to a mixture of (35.5R, 65) -. { 4-hydroxy-3- [6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4.5] decan-3-ü] phen} methyl ethanoate (Example 132, 259 mg, 0.54 mmol) and potassium carbonate (149 mg, 1.08 mmol) in acetone (10 ml) and the mixture was refluxed for 16 h.

The mixture was cooled, filtered and the solvent was evaporated under reduced pressure. Aqueous saturated sodium bicarbonate solution (20 ml) was added and the mixture was extracted with ethyl acetate (2 x 20 ml). The combined organic fractions were dried (Na? S? 4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound as a gum (179 mg, 67%). W NMR (250 MHz, CDCb) d 7.55-7.58 (2H, m), 7.20-7.35 (3H, m), 7.10 (1H, dd, and 2.25, 8, 28 Hz), 7.04 (1H, d, J 2.25 Hz), 6.80 (1H, d, J 8.28 Hz), 5.21 (1H, sa), 4.16-4.20 (1H, m), 3.96-4.02 (1H, m), 3.80 (3H, s), 3.69-3.72 (2H, m), 3.64 (3H, s), 3.52 (2H, s), 2.82-2.94 (1H, m), 2.34-2.42 (1H, m), 2.08-2.24 (2H, m), 1, 72-1.78 (3H, m) and 1.37 (9H, s).

EXAMPLE 134 (35.57?, 65) -. { 4-Methoxy-3- [6-phenyl-1-oxa-7 - (- 'grc-butoxycarbonyl) aza-spiro-4,5] decan-3-yl-eningenylidene Prepared from the compound of Example 133 according to the procedure of Example 109.? NMR (250 MHz, CDCfe) d 7.54-7.57 (2H, m), 7.23-7.34 (4H, m), 7.13 (1H, dd, and 8.27, 2.24) Hz), 6.81 (1H, d J 8.27 Hz), 5.31 (1H, sa), 5.17 (1H, sa), 4.25 (1H, dd, and 6.84, 14, 75 Hz), 3.93-4.00 (1H, m), 3.81 (3H, s), 3.47 (2H, s), 3.00 (1H, t, and 7.07 Hz), 2.80-2.84 (1H, m), 2.27-2.31 (2H, m), 2.12-2.16 (1H, m), 1.66-1.73 (3H, m ) and 1.39 (9H, s).

EXAMPLE 135 (35.5J?, 65) -3- [5- (Cyanomethyl) -2-methoxyenu] -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5] decane Prepared from the compound of Example 134 according to the procedure of Example 111.? NMR (250 MHz, CDCl 3) d 7.54-7.57 (2H, m), 7.24-7.36 (3H, m), 7.17 (1H, dd, and 2.34, 8.36) Hz), 7.05 (1H, d, J 2.34 Hz), 6.83 (1H, d, and 8.36 Hz), 5.21 (1H, sa), 4.20 (1H, t, J 6.84 Hz), 3.96-4.02 (1H, m), 3.82 (3H, s), 3.68-3.79 (2H, m), 3.63 (2H, s) , 2.84-2.96 (1H, m), 2.32-2.41 (1H, m), 2.06-2.23 (2H, m), 1.73-1.78 (3H, m) and 1.37 (9H, s) EXAMPLE 136 Hydrochloride of (35.5 / ?, 65) -3- [5- (Cyanomethyl) -2-methoxy: en-1-phenyl-1-oxa-7-aza-spiro [4,5] decane Prepared from the compound of Example 135 according to the procedure of Example 111.? NMR (360 MHz, DMSO-d6) d 9.56 (1H, da), 8.84 (1H, da), 7.55-7.58 (2H, m), 7.48-7.51 (3H , m), 7.09 (1H, d, and 8.52 Hz), 6.87 (1H, d, J 8.52 Hz), 6.34 (1H, s), 4.47-4.50 (1H, m), 4.09 (1H, t, J 7.63 Hz), 3.72 (2H, s), 3.59 (3H, s), 3.08-3.30 (4H, m ), 1.96-2.07 (3H, m) and 1.77-1.85 (3H, m). m / z (ES +) 363 (M + 1).

EXAMPLE 137 (5i?, 65) - (4-Methoxy-3- [6-phen-1-oxa-7 - (- 'grc-butoxycarbonu) aza-spiro [4,51dec-3-en-3-ü] fenü) carboxamide Prepared from the compound of Description 63 and (5 / ?, 65) -3-thibutylstannane-6-phenyl-1-oxa-7 - (- ') -butoxycarbonyl) aza-spiro [4,5] dec- 3-ene according to the procedure of Example 1.? NMR (250 MHz, CDCb) d 1.36 (9H, s), 1.81-2.11 (4H, m), 3.02-3.16 (1H, m), 3.86 (3H, s) ), 4.10-4.16 (1H, m), 4.62-4.67 (1H, dd, and 2, 12 Hz), 4.95-5.01 (1H, dd, and 2, 12 Hz), 5.16 (1H, s), 6.66 (1H, m), 6.91-6.95 (2H, m), 7.19-7.58 (5H, m) and 7.59 (1H, d, y2.2 Hz). m / z (ES +) 465 (M + l).

EXAMPLE 138 (5 ^, 6--> - [4-Methoxy-3- (6-phen-1-oxa-7-aza-spiro [4,51dec-3-en-3-ü) phenolcarboxar-ida Prepared from of the compound of Example 137 according to the procedure of Example 2. NMR (250 MHz, DMSO-dβ) d 1.51-1.63 (1H, m), 1.86-1.96 (3H, m) , 2.58-2.72 (1H, m), 3.10-3.15 (1H, m), 3.81 (1H, s), 3.87 (3H, s), 4.20-4 , 25 (1H, dd, and 2, 12 Hz), 4.77-4.83 (1H, dd, J 1, 12 Hz), 6.43 (1H, s), 7.04-7.39 ( 7H, m) and 7.77-7.81 (1H, dd, y2, 8.6 Hz).

EXAMPLE 139 (35.5 / ?, 6 - ^ - r4-Methoxy-3- (6-phene-1-oxa-7-a2a-spiro4,5] decan-3-ü) phenolcarboxa-mida Prepared from the compound of Example 138 according to the procedure of Example 3.? NMR (360 MHz, DMSO-dβ) d 1.78-1.85 (3H, m), 1.97-2.08 (3H, m), 3, 00-3.08 (1H, m), 3.21-3.31 (2H, m), 3.61 (3H, s), 3.63-3.88 (1H, m), 4.11- 4.15 (1H, m), 4.47-4.51 (1H, m), 6.90 (1H, d, J 8.60 Hz), 7.08 (1H, s), 7.21 ( 1H, d, J 2.04 Hz), 7.41-7.48 (3H, m), 7.54-7.56 (2H, m), 7.66-7.69 (2H, m), 8.93 (1H, sa) and 9.55 (1H, sa), m / z (ES +) 367 (M + 1).

EXAMPLE 140 (35.5J?, 65) -3- (5-Cyano-2-methoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] decane Potassium carbonate (250 mg) was added to a solution of (35, 5R, 6S) -3- (5-cyano-2-methoxy-phenyl) -6-phenyl-1-oxa-7- (trifluoroacetyl) aza-es-iro [4,5] decane (Description 72, 160 mg) in methanol (10 ml) and water (1 ml) and the mixture was heated to reflux for 2 h. The mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate, the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 / MeOH (97.5: 2.5 increasing to 92.5: 7.5), to give the title compound. i H NMR (250 MHz, DMSO-dβ) d 1.72-1.79 (3H, m), 2.01-2.09 (3H, m), 3.06-3.12 (1H, m), 3.23-3.28 (2H, m), 3.66, (3H, s), 3.71-3.76 (1H, m), 4.08-4.12 (1H, m), 4 , 47-4.50 (1H, m), 6.67 (1H, d, J 2.0 Hz), 6.99 (1H, and 8.7 Hz) and 7.47-7.63 (5H, m). m / z (ES +) 349 (M + 1).

EXAMPLE 141 (5i?, 65) -. { 4-Methoxy-3- [6-phenyl-1-oxa-7- (chlor-butoxycarbonyl) aza-spiro [4,5] dec-3-en-3-ylmethylene methoxide Prepared from the compound of Description 74 and (57?, 65) -3-tiibutüestar? nü-6-phenyl-1-oxa-7 - (- 'grc-butoxycarbonu) aza-spiro [4,5] dec-3-ene, according to the procedure of Example 1. * H NMR (360 MHz, CDCl 3) d 7.47 (2H, d, J 7.3 Hz), 7.26 (2H, t, J 7.3 Hz), 7.19 (1H, t, J 7.3 Hz), 7.16 (1H, dd, and 8.4, 2.3 Hz), 6.94 (1H, d, and 2.3 Hz), 6.86 (1H, d , and 8.4 Hz), 6.61 (1H, t, and 2.1 Hz), 5.15 (1H, s), 4.96 (1H, dd, and 12.0, 2.1 Hz) , 4.63 (1H, dd, and 12.0, 2.1 Hz), 4.14 (1H, m), 3.84 (3H, s), 3.68 (3H, s), 3.54 (2H, s), 3.11 (1H, m), 2.10 (1H, m), 1.95-1.74 (3H, m) and 1.37 (9H, s).

EXAMPLE 142 (5i?, 65) - [4-Methoxy-3- (6-phene-1-oxa-7-aza-spiro [4,5] dec-3-en-3-ü) phenyl] ethanoate methylated Prepared to from the compound of Example 141 according to the procedure of Example 2.? NMR (360 MHz, CDCb) d 7.37 (2H, d, J 6.9 Hz), 7.16 (3H, m), 7.07 (1H, dd, and 8.4, 2.2 Hz), 6.76 (1H, d, and 8.4 Hz), 6.70 (1H, d, J 2 , 2 Hz), 6.10 (1H, t, and 2.1 Hz), 4.86 (1H, dd, J 11.9, 2.1 Hz), 4.33 (1H, dd, J 11, 9, 2.1 Hz), 3.76 (1H, s), 3.74 (3H, s), 3.66 (3H, s), 3.46 (2H, s), 3.27 (1H, m), 2.81 (1H, m), and 2.10-1 , 61 (5H, m). m / z (ES +) 394 (M + 1).

EXAMPLE 143 (35.57?, 65) - [4-Methoxy-3- (6-phenyl-1-oxa-7-aza-spiro [4,5] decan-3-ü) phenyl] methoxyethoate Prepared from Compound of Example 142 according to the procedure of Example 3. iH NMR (360 MHz, DzO) d 7.52 (5H, m), 7.01 (1H, dd, J 8.4, 2.1 Hz), 6.87 (1H, d, and 8.4 Hz), 6.03 (1H, d, J 2.1 Hz), 4.74 (2H, sa), 4.39 (1H, s), 4, 10 (1H, m), 3.87 (1H, m), 3.69 (3H, s), 3.68 (3H, s), 3.51 (1H, m), 3.42 (2H, s) ), 3.34-3.18 (2H, m) and 2.21-1.80 (6H, m). m / z (ES +) 396 (M + 1).

EXAMPLE 144 (35 J-, 65) -3- (5- (Trifluorornetoxy) -2- (thiifluoro-methylsu-fonyloxy) fenu) -6-phenyl-1-oxa-7- (fe c -butoxycarbonii) aza-spiro [ 4.5] decane To a cooled (0 ° C) solution of (55.5?, 65) -3- (2-hydroxy-5- (trifluoromethoxyJphenyl) -or-phenyl-1-oxa-3-butoxycarbonyl-Jaza- Sodium (example 38, 320 mg, 0.65 mmol) in pyridine (2 ml), trifluoromethenesulfonic anhydride (0.12 ml, 0.71 mmol) was added and the reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated copper (II) sulfate (80 ml) and the residue was taken up in ethyl acetate (3 × 60 ml) The combined organic fractions were washed with water (80 ml) and brine (80 ml), dried (MgSO 4). ) and evaporated in vacuo Purification on silica, eluting with 25% ethyl acetate in hexane gave the title compound as a yellow oil (160 mg). * H NMR (250 MHz, CDCb) d 1, 36 (9H, s), 1.75 (3H, m), 2.11 (2H, m), 2.53 (1H, m), 2.95 (1H, m), 3.66 (1H, q , and 7.9 Hz), 3.72 (1H, m), 4.0 (1H, m), 4.23 (1H, t, J 6.5 Hz), 5.18 (1H, s), 7.16 (2H, m), 7.30 (4H, m) and 7.53 (2H, d, J 7.1 Hz).

EXAMPLE 145 (35.5 / ?, 6 - ^ ^ - 3- (5- (Trifluoromethoxy) -2- (trifluoromethylsulfonyloxy) fenu) -6-phenyl-1-oxa-7-aza-spirof4,5] decane Hydrochloride Prepared to from the compound of Example 144 according to the procedure of Example 2.? NMR (360 MHz, D20) d 1.78-2.00 (3H, m), 2.07-2.36 (3H, m), 3.42-3.50 (2H, m), 3.77-3.89 (1H, m), 4.16-4.24 (1H, m), 4.44 1H, s), 6.09 (1H, s), 7.16-7.20 (1H, m), 7.36 (1H, d, J 9.2 Hz) and 7.50-7.55 (6H, m).

EXAMPLE 146 Dihydrochloride of (35.5 ^, 6 - ^ - 7-ir5- (dimethylaminomethyl) -lH-ri> 2,3] triazol-4-ü] methyl.}. -3- [2-isopropoxy-5- (thiifluorometü) fenü] -6-fenü-l-oxa-7-aza-spiro [4,5] decane Dimethylamine was bubbled through a solution of (35,57?, 65) -7- (4-azidobut-2-in) -l-ü) -3- [2-isopropoxy-5- (trucluoromethyl) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane (description 76, 98 mg) in dioxane ( 3 ml) for 10 min.The mixture was heated at 80 ° C overnight in a sealed tube.The mixture was cooled and the solvent was evaporated under reduced pressure.The mixture was diluted with water (20 ml) and exfoliated with ethyl acetate (3 x 5 ml) The combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure The residue was purified by chromatography on silica gel, eluting with CH 2 Cl 2 / MeOH / NH 3 (Ac.) (98: 2: 0 increasing to 90: 10: 1) The residue was dissolved in ether and treated with excess ethereal hydrogen chloride. evaporated under reduced pressure and the residue was crystallized from ethanol / ethyl acetate. The solid was collected and dried in vacuo to give the title compound as a colorless solid. ? NMR (360 MHz, DMSO-dβ) d 1.24 (6H, t, J 6.2 Hz), 1.62 (1H, m), 1.68-1.92 (2H, m), 2.04 -2.26 (3H, m), 2.68 (6H, s), 3.07 (1H, m), 3.36 (1H, m), 3.58-3.72 (1H, m), 3.74-3.96 (2H, m), 4.10-4.39 (4H, m), 4.66 (1H, q, J 6.0 Hz), 4.6 (1H, sa), 6.45 (1H, s), 7.09 (1H, d, and 8.6 Hz), 7.36-7.68 (5H, m) and 8.00-8.10 (1H, m). m / z (ES +) m / z 558 (M + 1).

EXAMPLE 147 (35.5i?, 6 - $) - 3- [5-puoro-2- (2,2,2-trifluoroethoxy) fenu) -6-phenyl-1-oxa-7- (1, 2,4-thiazo-yl) 3-metii) -7-aza-spiro [4.5] decane Prepared from the compound of Example 19 according to the procedure of Example 5.? NMR (360 MHz, CDCb) d 1.54 (1H, dt, J 13, 4 Hz), 1.58-1.64 (1H, m), 1.77 (1H, t, J 12 Hz), 1 , 94 (1H, dd, J 12, 12 Hz), 2.00-2.22 (2H, m), 2.37 (1H, m), 3.00-3.10 (1H, m), 3.13 (1H, t, J 8 Hz), 3.38-3.52 (2H, m), 3, 74-3.92 (2H, m), 4.11 (1H, t, and 8 Hz), 4.22 (2H, q, J 8 Hz), 5.95 (1H, dd, and 9, 3 Hz ), 6.66 (1H, dd, and 9, 4.5 Hz), 6.76 (1H, dt, and 9, 3 Hz), 7.30-7.37 (3H, m), 7.56 (2H, sa, ArH) and 7.92 (1H , s). m / z (ES +) m / z 491 (M + l). Found: C, 60.76; H, 5.28; N, 11.15, requires: C, 61.22; H, 5.34; N, 11.42%.

EXAMPLE 148 (5-R> 65) -3- [2-Dimetüamino-5- (thiifluorornetoxy) fenu] -6-phen-1-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] dec-3 -ne Prepared from the compound of Description 78 and (5 / ?, 65) -3-tributyl-tin? u-6-phenyl-l-oxa-7- (g-butoxycarbon) aza-es? iro [4, 5] dec-3-ene according to the procedure of Example 1. * H NMR (360 MHz, CDCb) d 7.47 (2H, d, J 7.4 Hz), 7.29-6.94 (6H , m), 6.36 (1H, t, J 2.1 Hz), 5.12 (1H, s), 4.92 (1H, dd, J 12.6, 2.1 Hz), 4.61 (1H, dd, and 12.6, 2.1 Hz), 4.13 (1H, m), 3.14 (1H, m), 2.57 (6H, s), 2.05 (1H, m ), 1.85 (3H, m) and 1.35 (9H, s).

EXAMPLE 149 (57?, 65 -3- [2-Di? Netüamino-5- (triforuom.etoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4,51dec-3-ene Prepared from compound of Example 148 according to the procedure of Example 2.

EXAMPLE 150 (35.5-R, 65 ^ -3- [2-Din et? Aino-5- (thiifluorornetoxy) fenu1-6-fenu-l-oxa-7-aza-es? Iro [4,5] decane Prepared to from the compound of Example 149 according to the procedure of Example 3. m / z (ES +) m / z 421 (M + 1).

EXAMPLE 151 (+) - (3R *, 5i? * > 65 *) - 3- (2-Methoxypheni) -6-phen-l-oxa-7- (fenumethoxycarbon) aza-spiro [4,5] decane Acid was added formic acid (35 ml, 0.95 mmol) to an agitated and degassed solution of (±) - (5R *, 65 *) - 6-phene-1-oxa-7- (fenümetoxicarbonü) aza-spiro [4,5] dec-3-ene (Description 84, 125 mg, 0.36 mmol), palladium (II) acetate (8.3 mg, 0.036 mmol), tri-o-tolylphosphine (21 mg, 0.071 mmol), tributuin ina ( 282 mL, 1.23 mmol) and 2-iodoanisole (112 mL, 0.87 mmol) in iV, -V-dimethylformamide (2 mL) at room temperature and the resulting mixture was heated at 100 ° C for 2 h. A second equivalent of palladium (II) acetate, tri-o-tolylphosphine, tributylamine and 2-iodoanisole were added and the mixture was stirred at 90 ° C for 18 h. The mixture was cooled, filtered, diluted with diethyl ether (15 ml), washed with water (5 ml), hydrochloric acid (2M, 10 ml) and saturated aqueous sodium chloride (10 ml), dried (MgSO) and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with hexane / ethyl acetate (80:20) to give the title compound as a yellow oil (28 mg, 17%). ? NMR (360 MHz, CDCls) d 7.60 (2H, d, J 7.8 Hz), 7.18-7.32 (10H, m), 6.92 (1H, t, J7.5Hz), 6.85 (1H, d, J 8.7 Hz), 5.42 (1H, s), 5.19 (1H, d, J 12.4 Hz), 5.16 (1H, d, and 12, 6 Hz), 4.31 (1H, t, and 6.6 Hz), 4.02-4.10 (1H, m), 3.80-3.90 (2H, m), 3.79 (3H , s), 2.87 (1H, dt, and 4.4, 12.7 Hz), 2.54 (1H, dd, J 7.2, 12.7 Hz), 2.23 (1H, dt, J 5.5, 12.5 Hz), 1.95 (1H, dd, and 10.4, 12.6 Hz) and 1.64-1.84 (3H, m). m / z (ES +) 458 (M + 1).

EXAMPLE 152 (±) - (3J? *, 5J? *, 65 *) - 3- (2-Methoxyphene) -6-phene-l-oxa-7-aza-spiro [4.5] decane Palladium on carbon ( 10%, 10 mg) to an agitated solution of (±) - (3R *, 5R *, 65i) -3- (2-methoxy: enu) -6-phen-1-oxa-7- (fenumethoxycarbon) aza- spiro [4.5] decane (Example 151, 17 mg, 0.037 mmol) and cyclohexane (2 ml) in ethanol (10 ml) and the resulting suspension was heated to reflux for 5 h. The mixture was cooled, filtered and the solvent was evaporated under reduced pressure. The residue was purified by preparative layer chromatography on silica gel, eluting with dichloromethane / methanol / ammonia (95: 5: 1) to give the title compound as an orange oil (4 mg, 33%). * H NMR (360 MHz, CDCb) d 7.47 (2H, dd, J 1.9, 7.9Hz), 7.27-7.35 (3H, m), 7.10 (1H, dt, and 1.7, 7.8 Hz), 6.97 (1H, d, J 7.6 Hz), 6.81 (1H, t, and 7.5Hz), 6.72 (1H, d, J 8, 2 Hz), 3.94 (1H, t, J 7.6 Hz), 3.68 (1H, dd, and 7.9, 10.6 Hz), 3.63 (3H, s), 3.53 (3H, s), 3.16-3.26 (1H, m), 2.78 (1H, dt, and 2.7, 12.3 Hz), 2.28-2.38 (1H, m) , 2.15 (1H, dd, and 8.0, 12.4 Hz), 1.92-2.10 (2H, m) and 1.56-1.70 (4H, m). m / z (ES +) 324 (M + 1).

EXAMPLE 153 (3-R, 5R> 65) -3- (2-Methoxy-5- (trifluoromethoxy) fenu) -6-phene-l-oxa-7-aza-spiro4,5] decane Triethyl succinate (0.1 ml, 0.6 mmol) to a solution of (5R, 6S) -3- (2-methoxy-5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7-aza-spiro [4,5] dec-2-ene (Description 92, 14 mg, 0.03 mmol) in trifluoroacetic acid (1 ml) and the mixture was stirred at room temperature for 2 h. More triethyl sucsan (0.1 ml, 0.6 mmol) was added and the mixture was stirred at room temperature for 15 h. The solvent was evaporated under reduced pressure and the residue azeotyped with toluene (2 x 10 ml). Saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane (3 x 10 ml). The combined organic fractions were washed with brine (20 ml), dried (MgSQt) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel, eluting with dichloromethane / methanol / ammonia (120: 8: 1) to give a gum (6 mg).

HPLC analysis of the gum [HIPRB column (250 x 4.6 mm); MeCN at 40% in mM KH2P04, 0.2% thiiethylamine. pH 3.1, 210 nm] showed that it consisted of (5R6SJ-3- (2-methoxy-5- (trifluoromethoxy) phenyl) -6-phenyl-1-oxa-7-aza-spiro [4, 5] dec- 3-ene, (3S, 5R, 6SJ-3- (2-methoxy-5- (trifluoromethoxy) phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane and (3R5R6S) - 3- (2-methoxy-5- (trifluoromethoxy) phenyl) -6-phenyl-1-oxa-7-aza-spiro [4, 5] decane (ratio: 1.5: 2.5: 1).

EXAMPLE 154 (3-R, 57?, 65) -3- (2-Methoxy-5- (trifluoromethoxy) fenu) -6-phene-1-oxa-7-aza-spiro [4.5] decane Triethyl succinate ( , 25 ml, 1.6 mmol) to a solution of (5R, 65) -3- (2-methoxy-5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7-aza-spiro [4, 5] dec-3-ene (Description 92, 32 mg, 0.08 mmol) in trifluoroacetic acid (2 ml) and the solution was stirred at 50 ° C for 16 h. The solvent was evaporated under reduced pressure and the residue azeotyped with toluene (2 x 10 ml). Saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane (4 x 20 ml). The combined organic fractions were washed with brine (20 ml), dried (MgSQt) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel, eluting with dichloromethane / mefanol / ammonia (120: 8: 1) to give a gum (6 mg). HPLC analysis of the gum [HIPRB column (250 x 4.6 mm); 40% MeCN in 25 mM KH2PO4, 0.2% triethylamine. pH 3.1, 210 nm] showed that it consisted of a mixture of (3S, 5R, 6S) -3- (2-methoxy-5- (trifluoromethoxy) phenyl) -6-phenyl-1-oxa-7-aza -spiro [4,5] decane and (3R, 5R, 6S) -3- (2-methoxy-5- (trifluoromethoxy) phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane ( ratio, 2: 1).

EXAMPLE 155 (37?, 57?, 65) -3,6-Bis (fenu) -l-oxa-7 - (- 'grc-butoxycarbonu) aza-is? Iror4,51decano It was dissolved (25.37?, 2'R ) -3- (1-g-butoxycarbonyl-3-hydroxy-2-phenylpiperidin-3-yl) -2-phenupropan-1-ol (Description 95, 13 mg, 0.03 mmol) in dichloromethane (1 ml). Pyridine (0.038 ml, 0.045 mmol) was added, followed by methanesulfonyl chloride (3.2 ml, 0.039 mmol) and the mixture was stirred at room temperature for 72 h. Dichloromethene (10 ml) was added and the mixture was washed with water (10 ml), dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica, eluting with ethyl acetate / hexane (25:75) to give the title compound as an oil (6.4 mg). iH NMR (360 MHz, CDCk) d 7.61-7.59 (2H, m), 7.35-7.30 (4H, m), 7.27-7.22 (4H, m), 5, 34 (1H, s), 4.31 (1H, t, and 8.1 Hz), 4.00-3.96 (1H, m), 3.89 (1H, t, J 8.9 Hz), 3.62-3.54 (1H, m), 2.80-2.72 (1H, m), 2.70-2.65 (1H, m), 2.29-2.21 (1H, m ), 1.92-1.85 (1H, m), 1.81-1.78 (1H, m), 1.70-1.54 (3H, m) and 1.47 (9H, s). m / z (ES +) 394 (M + 1).

EXAMPLE 156 (3i ?, 5R, 65) -3,6-Bis (fenu) -l-oxa-7-aza-spiro [4,51decano] Prepared from the compound of Example 155 according to the procedure of Example 181.? NMR (360 MHz, CDCb) d 7.51-7.48 (2H, m), 7.35-7.33 (3H, m), 7.21-7.13 (3H, m), 6.91 -6.88 (2H, m), 4.04-3.99 (1H, t, J 7.9Hz), 3.66 (1H, s), 3.66-3.60 (1H, m), 3.26-3.22 (1H, m), 2.85-2.79 (1H, m), 2.75 (1H, sa), 2.24-2.11 (2H, m), 2, 03-1.94 (2H, m) and 1.73-1.61 (3H, m). m / z (ES +) 294 (M + l).

EXAMPLE 157 (3R, 5R, 65) -3- (2-Methoxyphene) -6-phene-1-oxa-7- (fg-c-butoxycarbon) aza-spiro [4,5] decane Methanesulfonyl chloride (10 ml) , 0.14 mmol) to an agitated solution of triethylamine (42 ml, 0.3 mmol) and the product of Description 39 (19 mg, 0.043 mmol) in dichloromethane (2 ml) at 0 ° C. The mixture was allowed to warm to room temperature, stirred for 18 h, dyed with dichloromethane (20 ml), washed with hydrochloric acid (2 M, 10 ml) and saturated aqueous sodium carbonate (10 ml), dried ( MgS?) And the solvent was evaporated under reduced pressure. The residue was taken up in tetrahydrofuran (3 ml) and heated with sodium hydroxide (60% dispersion in oil, 100 mg) at reflux for 18 h, cooled, poured into hydrochloric acid solution (2 M, 20 ml. ) and was extirpated with ethyl acetate (2 x 20 ml). The combined organic fractions were washed with saturated aqueous sodium chloride (10 ml), dried (MgSOé) and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with hexane / ethyl acetate (80:20) to give (3R, 5R, 6S) -3- (2-methoxyphenyl) -6-phenyl-1-oxa-7- ( tert-butoxycarbonyl) aza-spiro [4.5] decane and (3S, 5R, 6S) -3- (2-methoxyphenyl) -6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4 , 5] decane in the form of a 1: 3 mixture (8 mg, 44%). i H NMR (360 MHz, CDC b) d 7.61 (2 H, d, J 7.6 Hz, isomer 3R), 7.57 (2H, d, J 7.5, 3S isomer), 7.05-7.34 (5H, m, 3R and 3S isomers), 6.80-6.98 (2H, m, 3R and 3S isomers), 5.37 (1H, s, 3R isomer), 5.25 (1H, s, 3S isomer), 4.31 (1H, t, and 7.4 Hz, isomer 3R), 4.21 (1H, t, J 7.2Hz, 3S isomer), 3.95-4.04 (1H, m, isomers) 3R and 3S), 3.82 (3H, s, 3R isomer), 3.81 (3H, s, 3S isomer), 3.64-3.81 (2H, m, isomers 3R and 3S), 2.85 (1H, dt, and 5.9 and 12.1 Hz, 3S isomer), 2.67 (1H, dt, 4.9, 12.7 Hz, isomer 3R), 2.59 (1H, dd, and 7.3 and 12.7 Hz, 3R isomer), 2.37 (1H, dd, and 8.0 and 12.6 Hz, isomer 3S), 2.21 (1H, dd, and 9.1, 12.6 Hz, 3S isomer), 2.08-2.23 (1H, m, 3R and 3S isomers), 1.93 (1H, dd , and 10.4, 12.4 Hz, 3R isomer), 1.64-1.78 (3H, m, 3R and 3S isomers), 1.47 (9H, s, 3R isomer) and 1.38 (9H , s, 3S isomer). m / z (ES +) 424 (M + 1).

EXAMPLE 158 (3-R, 5J?, 65) -3- (2-Methoxyben) -6-phen-1-oxa-7-aza-spiro [4,51decano Prepared as a mixture of (3R, 5R, 6S) -3 - (2-methoxyphenyl) -6-phenyl-1-oxa-7-aza-spiro [4,5] decane and (3S, 5R, 6S) -3- (2-methoxyphenyl) -6-phenyl-1-oxa -7-aza-spiro [4.5] decane from the compound of Example 157 according to the procedure of Example 181. iH NMR (360 MHz, CDCls) d 7.51-7.59 (2H, m, isomers 3R and 3S), 7.32-7.45 (3H, m, 3R and 3S isomers), 7.05-7.13 (1H, m, 3R and 3S isomers), 6.97 (1H, d, J 7.6 Hz, 3R isomer), 6.81 (1H, t, J 7.5, 3R isomer), 6.71-6.82 (1H, m, 3R and 3S isomers), 6.69 (1H, t, J 7.5 Hz, 3S isomer), 6.43 (1H, d, J 7.6 Hz, 3S isomer), 4.09 (1H, t, J 7.8 Hz, 3S isomer), 3.94 (1H, t, J 7.6 Hz, 3R isomer), 3.67-3.87 (1H, m, 3R and 3S isomers), 3.68 (4H, s, 3S isomer), 3.63 (3H) , s, 3R isomer), 3.53 (1H, s, 3R isomer), 3.17-3.25 (1H, m, 3R and 3S isomers), 2.75-2.84 (1H, m, 3R and 3S isomer) and 1.55-2.37 (8H, m, 3R and 3S isomers). m / z (ES +) 324 (M + 1).

EXAMPLE 159 (37?, 57?, 65) -3- (2-Methoxypheni) -6-phen-1-oxa-7- (tert-butoxycarbon) -za-spiro [4,5] decane A tma solution of (25, 3R, 2'i?) - 3- (l- 'grc-butoxycarbonii-3-hydroxy-2-phenylpiperidin-3-y) -2- (2-methoxyphen)? Ropan-l-ol (Description 101, 0.073 g, 0.166 mmol) in dichloromethane (1 ml) and anhydrous pyridine (0.067 ml) was added methanesulfonyl chloride (0.015 ml, 0.2 mmol). The solution was stirred at room temperature for 16 h, then pyridine (1 ml) was added and the solution was heated in an oil bath at 80 ° C for 2 h. plus. The solvent was evaporated under reduced pressure and the residue was dissolved in dilute aqueous copper sulfate solution and ethyl acetate. The organic phase was washed with water and saturated brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (95: 5) to give the title compound (0.55 mg). i H NMR (360 MHz, CDCl 3) d 7.56 (2 H, d J 7.9 Hz), 7.25 (2 H, t J 7.1 Hz), 7.20-7.17 (1 H, m), 6, 88 (1H, td J 7.5 Hz and 1 Hz), 6.79 (1H, d J 7.8 Hz), 5.30 (1H, s), 4.24 (1H, t and 7.4 Hz), 3.90-3.79 (3H, m), 3.75 (3H, s), 2.67 (1H, td J 12.0 Hz and 4.5 Hz), 2.53 (1H, dd J 12 , 6 Hz and 7.2 Hz), 2.14 (1H, td, J 12.5 Hz and 5.7 Hz), 1.85 (1H, dd J 12.4 Hz and 10.4 Hz), l, 65 (1H, broad d and 12.8 Hz), 1.63-1.47 (2H, m) and 1.40 (9H, s). m / z (ES +) 424 (M + 1).

EXAMPLE 160 (3J?, 5R, 65) -3- (2-Methoxypheni) -6-phenyl-1-oxa-7-aza-spiro [4,51 decano] Hydrochloride Prepared from the compound of Example 159 according to the procedure of Example 188, pf 243-253 ° C. ? NMR (360 MHz, CD3OD) d 7.57 (2H, m), 7.53 (3H, m), 7.11 (1H, t and 8, l Hz), 6.95 (1H, d H 7.7 Hz), 6.80 (2H, m) , 4.27 (1H, s), 4.02 (1H, t and 7.64), 3.77 (1H, dd J 10.5 Hz and 8.3 Hz), 3.63 (3H, s), 3.40 ( 1H, broad d), 3.18 (1H, broad t), 2.34-2.21 (3H, m), 2.07 (1H, m) and 1.96-1.83 (3H, m) .

EXAMPLE 161 (37?, 5J?, 65) -3- (2-Methoxy-5- (trifluoromethoxy) fenu) -6-phenyl-1-oxa-7- (fórc-butoxicarbonü) aza-spiro [4,5] decan- 2-one A mixture of (5i?, 65) -3- (2-methoxy-5- (trifluoromethoxy) phenyl) -6-phene-l-oxa-7- (férc-butoxicarbonü) aza-spiro [4,5 ] dec-3-en-2-one (Example 52, 100 mg, 0.19 mmol) and palladium acetate (10 mg) in N, N -dimethylformamide (1 ml) was degassed with nitrogen for 30 min. Potassium formate (42 mg, 0.50 mmol) was added and the mixture was heated at 80 ° C for 16 h. The mixture was poured into water (10 ml) and extracted with ethyl acetate (2 x 10 ml). The combined organic fractions were dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound as a colorless solid (44 mg, 0.08 mmol, 44%). The * H NMR showed that it was a 1: 1 mixture of diastereoisomers (3S, 5R, 6S) and (3R, 5R, 6S) that were separated by preparative liquid chromatography using a KR60 column, eluting with 5% acetonol aj / hexane which contained 0.1% DEA. to give (3 §R, 6S) -3- (2-methoxy-5- (trifluoromethoxy) phenyl) -6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4,5] decan- 2-one,? NMR (250 MHz, CDCb) d 7.50-7.53 (2H, m), 7.26-7.39 (3H, m), 7.14 (1H, dd, J 2.59, 8.96 Hz), 7.02 (1H, d, J 2.59 Hz), 6.88 (1H, d, and 8.96 Hz), 5.35 (1H, s), 4.00-4.05 (1H, m), 3.85 (3H, s), 3.70 ( 1H, t, J 11.02 Hz), 2.70-2.97 (2H, m), 2 ^ 8-2.50 (1H, m), 2.22 (1H, dd, J 11.32, 12.97 Hz), 1, 72-1.92 (3H, m) and 1.46 (9H, s); and (3S, 5R, 6S) -3- (2-methoxy-5- (trifluoromethoxy) phenyl) -6-phenol-oxa-7- (tert-butoxycarbonyl) aza-esp? ro [4,5] decan -2-ona,? NMR (250 MHz, CDCb) d 7.50-7.53 (2H, m), 7.26-7.39 (3H, m), 7.13 (1H, dd, and 2.91, 8.97 Hz), 6.90 (1H, d, and 2.91 Hz), 6.83 (1H, d, and 8.97 Hz), 5.31 (1H, sa), 4.02-4.10 (1H, m), 3.92 (1H, t, and 10.56 Hz), 3 , 64 (3H, s), 2.91-3.02 (1H, m), 2.67 (1H, dd, and 10.04, 12.98 Hz), 2.29-2.52 (2H, m), 1.80-1 , 87 (3H, m) and 1.36 (9H, s).

EXAMPLE 162 (3-?, 5i?, 65) -3- (2-Methoxy-5- (trifluoromethoxy) fenu) -6-phenyl-l-oxa-7-aza-spiro [4,5] decan-2-hydrochloride ona Prepared from the compound of Example 161 according to the procedure of Example 181. pf 244-245 ° C. ? NMR (360 MHz, DMSO-dβ) d 10.20 (1H, sa), 9.40 (1H, sa), 7.60-7.62 (2H, m), 7.52-7.54 (3H , m), 7.23 (1H, dd, and 2.61, 9.03 Hz), 7.04 (1H, d, and 9.03 Hz), 6.88 (1H, d, and2.61 Hz ), 4.67 (1H, sa), 3.73 (3H, s), 3.34-3.38 (1H, m), 3.10-3.12 (1H, m), 2.61 ( 1H, dd, J 9.78, 12.65 Hz) and 1.93-2.20 (6H, m). m / z (ES +) 422 (M + 1).

EXAMPLE 163 (3R, 5R, 6S) - and (35.5R, 65) -3- (2-Hydroxy-5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7 - (- ') -butoxycarbonyl) aza -spiro [4.5] decane (5 / ?, 65) -3- (2-benzyl-oxy-5- (thiouluoromethoxy) fenu) -6-phen-1-oxa-7- (tert-butoxycarbon) aza- spiro [4.5] dec-3-ene (Example 35, 3.88 g) in ethyl acetate (15 ml) and methanol (15 ml). Palladium hydroxide on carbon (1.00 g) was added and the suspension was stirred under a hydrogen atmosphere (50 psi) for 72 h. The mixture was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by medium pressure chromatography on silica gel, eluting with hexane / ethyl acetate (75:25) to give (3R5R, 6S) -3- (2-hydroxy-5- (trifluoromethoxy) phenyl) -6 phenyl-l-oxa-7- (tert-butoxycarbonyl) aza-spiro [4.5] decane (191 mg), 1 H NMR (250 MHz, CDCl 3) d 7.70 (2H, d, and 7.3 Hz) ), 7.33 (2H, t, J 7.3 Hz), 7.26 (1H, d, J 7.3 Hz), 7.05 (1H, sa), 6.96 (2H, m), 6.82 (1H, d, J 9.4 Hz), 5.43 (1H, s), 4.27 (1H, m), 4.01 (1H, m), 3.95 (1H, m) , 3.73 (1H, m), 2.73 (2H, m), 2.33 (1H, m), 1.87-1.58 (4H, m); and 1.50 (9H, s) .and (3S, 5R, 6S) -3- (2-hydroxy-5- (trifluoromethoxy) phenyl) -6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza. -spiro [4.5] decane (2.3 g), iH NMR (360 MHz, CDCb) d 1.38 (9H, s), 1.73 (2H, m), 1.81 (1H, m) , 2.18 (2H, m), 2.50 (1H, m), 2.81 (1H, m), 3.62 (1H, t, J 7.2 Hz), 3.92 (1H, m ), 3.98 (1H, d, and 13.2 Hz), 4.23 (1H, m), 5.33 (1H, s), 6.75 (1H, d, J 8.5 Hz), 6.94 (2H, m), 7.25 (1H, m), 7.31 (2H, m) and 7.55 (2H, d, J 7.8 Hz).

EXAMPLE 164 (3 / ?, 5i?, 65) -3- (2-Methoxy-5- (trifluoromethoxy) fenu) -6-phen-l-oxa-7- (fórc-butoxicarbonü) aza-espiro [4,5] dean It was dissolved (37?, 57?, 65) -3- (2-hydroxy-5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] decane (Example 163, 180 mg) in dimethylformamide (2 ml) and sodium hydride (60% dispersion in mineral oil, 23 mg) was added. After cessation of effervescence, methyl iodide (0.1 ml) was added and the mixture was stirred at room temperature for 3 h. Water was added dropwise (5 ml) to the reaction solution. The mixture was ducted with water (20 ml) and extracted with ethyl acetate (3 x 10 ml). The combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure to give the title compound as an oil (235 mg). * H NMR (250 MHz, CDCb) d 7.61 (2H, d, J 7.9 Hz), 7.36-7.24 (3H, m), 7.09 (2H, m), 6.82 (1H, d, J 8.7 Hz), 5.35 (1H, s), 4.30 (1H, m), 3.98 (1H, m), 3.89-3.78 (2H, m ), 3.83 (3H, s), 2.77 (1H, m), 2.59 (1H, m), 2.22 (1H, m), 1.90-1.66 (4H, m) and 1.47 (9H, s).

EXAMPLE 165 (3R, 5R> 65) -3- (2-methoxy-5- (trifluoromethoxy) fenu) -6-phenyl-1-oxa-7-aza-spiro [4,51-decano] Hydrochloride Prepared from the compound of Example 164 according to the procedure of Example 181.? NMR (500 MHz, CD3OD) d 1.88 (1H, dd, J12.6, 10.9 Hz), 1.99 (2H, m), 2.13 (1H, d, J 15.4 Hz), 2.34 (2H, m), 2.39 (1H, m), 3.25 (1H, dt, and 15.8, 3.3 Hz), 3.45 (1H, m), 3.72 ( 3H, s), 3.79 (1H, dd, J 8.3, 1.2 Hz), 4.09 (1H, t, J7.5Hz), 4.48 (1H, s), 6.94 (2H, m), 7.10 (1H, d, and 8.9 Hz), 7.58 (3H, t, J 2.6 Hz) and 7.64 (2H, t, and 3.6 Hz).

EXAMPLE 166 (3?, 5R, 65) -7-Benzyl-3- (2-methoxy-5- (thiifluoromethoxy) fenu) -6-phenyl-1-oxa-7-aza-espir or [4,51-decane dissolved (3i?, 5i?, 65) -3- (2-methoxy-5- (trifluoromethoxy) fenu) -6-phene-1-oxa-7-aza-spiro [4,5] decane hydrochloride (Example 165) , 100 mg, 0.2 mmol) and potassium carbonate (38 mg) in dimethyl formamide (0.5 ml). Benzyl bromide (0.3 ml) was added and the mixture was stirred at room temperature overnight and then at 60 ° C for 3 h. The mixture was cooled, ducted with water (10 ml) and extracted into ether (3 x 10 ml). The combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (5 ml) and ethereal hydrogen chloride (1 M, 1 ml) was added. The solid was collected and dried in vacuo to give the title compound as a crystalline solid (19 mg). ? NMR (360 MHz, dß-DMSO) d 1.75 (3H, m), 2.01 (2H, m), 2.22 (2H, m), 2.96 (1H, m), 3.63 ( 3H, s), 3.67 (1H, m), 3.92 (1H, m), 4.01 (1H, m), 4.41 (1H, d, and 9.74 Hz), 6.92 (1H, d, J 8.9 Hz), 7.05 (1H, s), 7.13 (1H, d, J 8.65 Hz), 7.31 (2H, d, and 6.53 Hz) , 7.42 (3H, m), 7.60 (4H, m) and 7.91 (1H, m).

EXAMPLE 167 (3R, 5R, 6S) - and (35.5 / ?, 65) -3- (2-Hydroxy-5- (thiifluoromethyl) fenu) -6-phen-l-oxa-7- (tert-butoxycarbon) aza -spiro [4,5] decane Prepared from the compound of Example 45 according to the procedure of Example 163, (3R, 5R, 6S) -3- (2-Hydroxy-5- (trifluoromethyl) phenyl) -6- phenyl-l-oxa-7- (tert-butoxycarbonyl) aza-spiro [4.5] decane, * H NMR (250 MHz, CDCb) d 1.51 (9H, s), 1.58-1.75 ( 2H, m), 1.82-1.88 (2H, m), 2.33 (1H, dt, and 4, 13 Hz), 2.70 (1H, dd, and 8.6, 13 Hz), 2.79 (1H, dt, and 3, 13 Hz), 3.84 (1H, qn), 3.93-3.97 (2H, m), 4.31 (1H, t, J 9 Hz), 5.44 (1H, s,), 6.89 (1H, d, J 9 Hz), 7.23-7.35 (5H, m) and 7.58-7.60 (2H, m). m / z (ES +) 478 (M + 1). (3S, 5R, 6S) -3- (2-Hydroxy-5- (trifluoromethyl) phenyl) -6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4.5] decane, * H NMR (360 MHz, CDCl 3) d 1.34 (9H, s), 1.72-1.82 (3H, m), 2.10-2.21 (2H, m), 2.53 (1H, dd , and 9, 13 Hz), 2.79-2.88 (1H, m), 3.65 (1H, qn, and 8.6 Hz), 3.94-3.98 (2H, m), 4 , 24 (1H, dd, and 7, 9 Hz), 5.33 (1H, s,), 6.83 (1H, d, J 9 Hz), 7.01 (1H, s), 7.23- 7.34 (5H, m) and 7.55 (2H, d, and 7.5 Hz). m / z (ES +) 478 (M + 1).

EXAMPLE 168 (3i?, 5-R, 65) -3- (2-Methoxy-5- (thiifluoromethy) phenyl) -6-phene-l-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,51decano Prepared from (3 /? 5 / ?, 65) -3- (2-hydroxy-5- (trifluoromethyl) fenu) -6-phen-1-oxa-7- (tert-butoxycarbon) aza-spiro [ 4.5] decane (Example 167) according to the procedure of Example 164. m / z (ES +) 492 (M + 1).

EXAMPLE 169 (3J? > 5 /? 65) -3- (2-Methoxy-5- (trifluoromethyl) fenu) -6-phene-l-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared to from the compound of Example 168 according to the procedure of Example 181.? NMR (500 MHz, CDCl 3 + CD 3 OD) d 1.71-1.78 (3H, m), 1.94-1.98 (1H, m), 2.13-2.24 (3H, m), 3 , 00 (1H, dt, and 3, 12 Hz), 3.42 (1H, dd, and 4, 12 Hz), 3.61 (3H, s), 3.67 (1H, dd, and 8, 14 Hz), 3.96-4.01 (2H, m), 6.71 (1H, d, J 8 Hz), 7.04 (1H, d, and 2 Hz), 7.32 (1H, dd, and 2, 8 Hz), 7.38-7.36 (3H, m) and 7.42-7.44 (2H, m). m / z (ES +) 392 (M + 1).

EXAMPLE 170 (3R, 5R, 65) -3- (2-Benzyloxy-5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4y5] decane A mixture of 2-benzuboxy-5- (trifluoromethoxy) iodobenzene (Description 103, 21.8 g, 55.2 mmol), (5i?, 6-S) -6-phenyl-1-oxa-7 - (- "grc-butoxycarbon) ) aza-spiro [4.5] dec-3-ene (Description 86, 7.0 g, 22.1 mmol), tetra-n-butylammonium chloride (6.18 g, 22.2 mmol), Lithium (9.35 g, 0.22 mol) and potassium formate (5.64 g, 67.0 mmol) in dimethylformamide (100 ml) were degassed with an iron pyrite valve (5 x). palladium (491 mg, 2.2 mmol) and the mixture was degassed with an iron pyrite valve (5 x) .The mixture was stirred at 60 ° C for 15 h and then more 2-benzyoxy-5- was added. (trifluoromethoxy) iodobenzene (Description 103, 4.32 g, 11.0 mmol), potassium formate (2.78 g, 33.5 mmol) and palladium acetate (260 mg, 1.1 mmol). The mixture was stirred at 60 ° C for 22 h, cooled and filtered. Evaporated under reduced pressure, water (600 ml) was added and the mixture was extracted with ethyl acetate (2 x 300 ml). The combined organic fractions were washed with brine (300 ml), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane / CH2Cl2 (75:25 increasing to 0: 100) and then with CH2Cl2 / EtOAc (95: 5), to give the title compound (9, 42 g, 73%). * H NMR (360 MHz, CDCb) d 7.56 (2H, d, J 7.7 Hz), 7.40-7.20 (8H, m), 7.14 (1H, d, and 2.0 Hz), 7.00 (1H, dd, and 8.9, 2.0 Hz), 6.88 (1H, d, and 8.9 Hz), 5.30 (1H, s), 5.08 (2H, s), 4.27 (1H, m), 3.97 (1H , m), 3.87 (2H, m), 2.78 (1H, m), 2.56 (1H, m), 2.15 (1H, m), 1.96 (1H, m), 1 , 67 (3H, m) and 1.42 (9H, s).

EXAMPLE 171 (3J ?, 5J ?, 65) -3- (2-Hydroxy-5- (trifluoromethoxy) fenu) -6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4,5] decane added palladium on carbon (10%, 0.59 g) to a solution of (3?, 5i2.65) -3- (2-benzuoxy-5- (thiouluoromethoxy) fenu) -6-phene-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4.5] decane (Example 170, 6.10 g, 10.5-mmol) in methanol-water (99: 1, 200 ml) and the mixture was stirred under hydrogen (50 psi) (344.737 kPa) for 72 h. The mixture was washed, washed with ethanol and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2C12 / EtOAc (99: 1 increasing to 90:10) to give the title compound, NMR (360 MHz, CDCb) d 7.70 (2H, d, J 7.3 Hz), 7.33 (2H, t, J 7.3 Hz), 7.26 (1H, d, J 7.3 Hz), 7.05 (1H, sa), 6, 96 (2H, m), 6.82 (1H, d, J 9.4 Hz), 5.43 (1H, s), 4.27 (1H, m), 4.01 (1H, m), 3 , 95 (1H, m), 3.73 (1H, m), 2.73 (2H, m), 2.33 (1H, m), 1.87-1.58 (4H, m) and 1, 50 (9H, s).

EXAMPLE 172 (3i?, 5i?, 65) -3- [2-Hydroxy-5- (trifluoromethoxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from compound of Example 171 according to the procedure of Example 181.? NMR (360 MHz, D20) d 1.83-2.35 (7H, m), 3.20 (1H, m), 3.50 (1H, m), 3.73 (1H, m), 4, 05 (1H, t, and 8.0 Hz), 4.29 (1H, s), 6.79 (1H, d, and 9.4 Hz), 7.02 (2H, m) and 7.54 ( 5H, sa), m / z (ES +) 394 (M + 1).

EXAMPLE 173 (3 / ?, 5i ?, 65) -3- (2-Benzuoxy-5- (trifluoromethoxy) fenu) -6- (4-fluorofenu) -l-oxa-7 - (/ grc-butoxycarbon) aza-spiro [ 4,51decano Prepared from Description 103 and (5 / ?, 65) -6- (4-fluorofenü) -l-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] dec-3- eno (Description 90) according to the procedure of Example 170.? NMR (360 MHz, CDCb) d 7.54-6.80 (12H, m), 5.25 (1H, m), 5.28 (1H, s), 5.08 (2H, s), 4.26 (1H, m), 97 (1H, m), 3.86 (2H, m), 2.76 (1H, m), 2.53 (1H, m), 2.10 (1H, m), 1.97 (1H, m ), 1.66 (3H, m) and 1.42 (9H, s). m / z (ES +) 546 (M + 1-QHg).

EXAMPLE 174 (3R, 5-R, 65) -3- (2-Hydroxy-5- (trifluoromethoxy) fenu) -6- (4-fluorofenu) -l-oxa-7- (rgrc-butoxycarbon) aza-spiro [4, 5] decane Prepared from the compound of Example 173 according to the procedure of Example 171. iH NMR (360 MHz, CDCls) d 1.49 (9H, s), 1.72 (1H, m), 1.83 (3H, m), 2.25 (1H, td, and 12.5, 4.8 Hz), 2.69 (2H, m), 3.72 (1H, qn), 3.98 (1H, m ), 4.01 (1H, dd, and 9.4, 5.4 Hz), 4.25 (1H, dd, and 9.3, 7.4 Hz), 5.39 (1H, s), 6 , 81 (1H, d, J 9.4 Hz), 6.98 (4H, m) and 7.57 (2H, dd, and 8.7, 5.6 Hz).

EXAMPLE 175 (3 / ?, 5R, 65) -3- [2-Benzuoxy-5- (ducluoromethoxy) fenu] -6-phen-1-oxa-7 - (- grc-butoxycarbon) aza-spiro [4,5] decane Prepared from the compound of Description 105 and (5R, 6S) -6-phen-1-oxa-7- (tert-butoxycarbon) aza-spiro [4.5] dec-3-ene (Description 86) of according to the procedure of Example 170.? NMR (360 MHz, CDCb) d 1.42 (9H, s), 1.65 (3H, m), 1.98 (1H, m), 2.15 (1H, m), 3.85 (2H, m), 3.97 (1H, m), 4.28 (1H, m), 5.07 (2H, m), 5.30 (1H, s), 6.42 (1H, t, and 74 Hz ), 6.85 (1H, d, and 8.8 Hz), 6.95 (1H, dd, and 8.8, 2.8 Hz), 7.07 (1H, d, and 2.8 Hz) , 7.22-7.39 (8H, m) and 7.56 (2H, m). m / z (ES +) 566 (M + 1).

EXAMPLE 176 (3 / ?, 5 / ?, 65) -3- [5- (Difluoromethoxy) -2-hydroxyphenyl] -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-es? Iro [4 , 5] decane Prepared from the compound of Example 175 according to the procedure of Example 171. H NMR (360 MHz, CDCb) d 1.50 (9H, s), 1.64 (1H, m), 1, 70 (1H, m), 1.83 (2H, m), 2.33 (1H, dt, and 4.8, 13.0 Hz), 2.72 (2H, m), 3.71 (1H, m), 3.94 (1H, m), 4.02 (1H, dd, J 9.4, 5.3 Hz), 4.27 (1H, dd, and 9.4, 7.4 Hz), 5.43 (1H, s), 6.40 (1H, t, and 74 Hz), 6.80 (1H, m), 6.89 (2H, m), 7.27 (1H, m), 7 , 33 (2H, m) and 7.60 (2H, m). m / z (ES +) 476 (M + 1).

EXAMPLE 177 (3J?, 5j?, 65) -3- (2-Benzoxy-5-fluorofenu) -6-phene-1-oxa-7- (forn-butoxycarbon) aza-spiro [4,5] decane Prepared from Description 107 and (5 - / ?, 6-S) -6-phenyl-1-oxa-7- (ferc-butoxycarbonyl) aza-es? iro [4,5] dec-3-ene (Description 86) of according to the procedure of Example 170, 7.56 (2H, d, J 7.4 Hz), 7.39-7.21 (8H, m), 7.01 (1H, dd, and 9.4, 2 , 7 Hz), 6.84 (2H, m), 5.30 (1H, s), 5.05 (2H, s), 4.27 (1H, m), 3.97 (1H, m), 3.84 (2H, m), 2.78 (1H, m), 2.56 (1H, m), 2.17 (1H, m), 1.95 (1H, m), 1.66 (3H , m) and 1.42 (9H, s). m / z (ES +) 518 (M + 1).

EXAMPLE 178 (3i?, 5 / ?, 65) -3- (5-Fluoro-2-hydroxyuii) -6-phen-l-oxa-7 - (- 'grc-butoxycarbonii) aza-spiro [4,5] decane Prepared from the compound of Example 177 according to the procedure of Example 171.? NMR (360 MHz, CDCb) d 1.49 (9H, s), 1.59-1.69 (2H, m), 1.80-1.86 (2H, m), 2.31 (1H, dt) , J 13.0, 4.9 Hz), 2.67-2.79 (2H, m), 3.70-3.74 (1H, m), 3.93-4.01 (2H, m) , 4.24-4.29 (1H, m), 5.42 (1H, s), 6.73-6.85 (3H, m), 7.23-7.35 (3H, m) and 7 , 60 (2H, d, J 7.5 Hz). m / z (ES +) 428 (M + 1).

EXAMPLE 179 (3 / ?, 5J?, 65) -3- (5-Benzyoxy-2-isopropoxyfen) -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5] decane Prepared from Description 110 and (5 /? 65) -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4.5] dec-3-ene (Description 86) of according to the procedure of Example 170.? NMR (360 MHz, CDCb) d 7.60 (2H, d, J 7.9 Hz), 7.53-7.21 (8H, m), 6.91 (1H, d, J 1.9 Hz) , 6.78 (2H, m), 5.32 (1H, s), 5.01 (2H, s), 4.43 (1H, hept., And 6.0 Hz), 4.29 (1H, m), 3.97 (1H, m), 3.82 (2H, m), 2.78 (1H, m), 2.54 (1H, m), 2.20 (1H, m), 1, 90 (1H, m), 1.77-1.65 (3H, m), 1.45 (9H, s) and 1.31 (6H, d, J 6.0 Hz). m / z (ES +) 558 (M + 1).

EXAMPLE 180 (3 / ?, 5i?, 65) -3- (5-Hydroxy-2-isopropoxypheni) -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5] decane Prepared from the compound of Example 179 according to the procedure of Example 171. * H NMR (360 MHz, CDCb) d 7.60 (2H, d, J 7.5 Hz), 7.32 (2H, t, y 7.5 Hz), 7.24 (1H, t, J 7.5 Hz), 6.76 (1H, d, and 3.0 Hz), 6.73 (1H, d, and 8.7 Hz) , 6.63 (1H, dd, J 8.7, 3.0 Hz), 5.32 (1H, s), 4.77 (1H, s), 4.41 (1H, hept., J 6, 0 Hz), 4.28 (1H, m), 3.98 (1H, m), 3.82 (2H, m), 2.78 (1H, m), 2.55 (1H, m), 2 , 21 (1H, m), 1.91 (1H, m), 1.79-1.62 (3H, m), 1.45 (9H, s) and 1.36 (6H, d, 6.0 Hz). m / z (ES +) 468 (M + 1).

EXAMPLE 181 (3-R, 5-R, 65) -3- (5-Hydroxy-2-isopropoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Hydrogen chloride was added ethanolic (5 M, 4 mL) to a stirred and cooled solution (0 ° C) of (3?, 5i?, 65) -3- (5-hydroxy-2-iso? ropoxypheni) -6-phen-l- oxa-7- (chlor-butoxycarbon) aza-spiro [4.5] decane (Example 180, 43 mg, 0.09 mmol) in ethenol (2 ml) and the mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the residue was crystallized from ether-ethanol. The solid was collected and dried in vacuo to give the title compound as a colorless solid (34 mg, 92%). p.f. 175-178 ° C. ? NMR (360 MHz, CD3OD) d 7.63 (2H, m), 7.56 (3H, m), 6.70 (1H, d, and 8.6 Hz), 6.57 (1H, dd, and 8.6, 2.9 Hz), 6.52 (1H, d, J 2.9 Hz), 4.88 (2H, sa), 4.60 (1H, s), 4.32 (1H, s ), 4.27 (1H, hept., J 6.0 Hz), 4.11 (1H, m), 3.71 (1H, m), 3.44 (1H, m), 3.22 (1H , m), 2.50 (1H, m), 2.29 (2H, m), 2.14 (1H, m), 2.02-1.84 (3H, m), 1.14 (3H, d, J 6.0 Hz) and 1.36 (3H, d, J 6.0 Hz). m / z (ES +) 368 (M + 1).

Found: C, 67.24; H, 7.59; N, 3.43, C23H29NO3.HCLO H2O requires: C, 67.19; H, 7.55; N, 3.41%.

EXAMPLE 182 (3J?, 5J?, 65) -3- [2,4-Bis (methoxy) phenyl-6-phenyl-l-oxa-7- (fórc-butoxicarbonü) aza-spiro [4,5] decane Prepared from of 2,4 ~ (dimethoxy) iodobenzene and (5?, 65) -6-phenyl-1-oxa-urea-butoxycarbonii-Jaza-spiro ^ SJdec-S-ene (Description 86) according to the procedure of Example 170. i H NMR (360 MHz, CDC b) d 7.60 (2 H, d, J 8 Hz), 7.36-7.20 (3 H, m), 7.14 (1 H, d, J 9 Hz), 6, 50-6.42 (2H, m), 5.35 (1H, s), 4.32-4.24 (1H, m), 3.97 (1H, da, and 12 Hz), 3.85- 3.75 (2H, m), 3.80 (6H, s), 2.73 (1H, dt, J 12, 4.5 Hz), 2.55 (1H, dd, and 12, 6.5 Hz) ), 2.20 (1H, dt, and 12, 5.6 Hz), 1.94-1.84 (1H, m), 1.80-1.60 (3H, m) and 1.47 (9H) , s). m / z (ES +) 454 (M + 1).

EXAMPLE 183 (3 /? 5 /? 65) -3- [2,4-Bis (methoxy) fenu] -6-phenyl-l-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from of the compound of Example 182 according to the procedure of Example 181. * H NMR (360 MHz, CD3OD) d 7.60-7.40 (5H, m), 6.84 (1H, da, and 9 Hz), 6.40-6.32 (2H, m), 4.26 (1H, s), 3.98 (1H, t, J 7.7 Hz), 3.78-3.70 (1H, m), 3.70 (3H, s), 3.61 (3H, s), 3.40 (1H, dd, and 12, 4 Hz), 3.17 (1H, dt, and 11, 3 Hz), 2, 40-2.15 (3H, m), 2.07 (1H, da, J 13 Hz) and 1.96-1.78 (3H, m). m / z (ES +) 354 (M + 1).

EXAMPLE 184 (3?, 5 / ?, 65) -3- [2-Difluoromethoxy-5- (trifluoromethoxy) fenu] -6-phene-l-oxa-7- (fórc-butoxicarbonü) aza-spiro [4,5] dean Ethyl chlorodifluoroacetate (0.86 ml) was added dropwise to an agitated and heated mixture (110 ° C) of (3-R, 5R, 65) -3- (2-hydroxy-5- (trifluoromethoxy) - O-phenol-1-oxa-3-hydroxy-butoxycarbonyl-spiro-S-decano (Example 171, 1.5 g) and potassium carbonate (1.4 g) in dimethylformamide (10 ml). The mixture was heated at 110 ° C for 2 h until gas evolution ceased The mixture was cooled and diluted with water (150 ml) The mixture was extracted with ether (3 x 20 ml) and the organic fractions they were washed with brine, dried (MgSQi) and the solvent was evaporated under reduced pressure.The residue was purified by MPLC on silica gel, eluting with hexane / EtOAc (90:10) to give the title compound as a colorless oil (800 mg) aH NMR (250 MHz, CDCl 3) d 1.46 (9H, s), 1.63-1.72 (4H, m), 2.26 (1H, dt, J 12.5, 5.0 Hz), 2.63-2.82 (2H, m), 3.81-4.04 (3H, m), 4.23-4.36 ( 1H, m), 5.34 (1H, s), 6.53 (1H, t, J 73 Hz), 7.12-7.36 (6H, m) and 7.58-7.61 (2H, m). m / z (ES +) 544 (M + 1).

EXAMPLE 185 Oig ^^ o-S -S- ^ - Difluoromethoxy-S-drifluorometoxDfenül-ó-fenü-l-oxa ^ -aza-spiro [4,5] decane Prepared from the compound of Example 184 according to the procedure of Example 181. i H NMR (500 MHz, CDCl 3) d 1.58-1.71 (3H, m), 1.93-2.00 (1H, m), 2.12-2.19 (2H, m), 2.35-2.43 (1H, m), 2.80 (1H, m), 3.34-3.37 (1H, m), 3.55 (1H, t, and 9 Hz), 3, 82 (1H, t, J 10 Hz), 3.96 (1H, t, J 7.5 Hz), 6.10 (1H, t, J 7.3 Hz), 6.83 (1H, s), 6.90-6.95 (2H, m), 7.25-7.35 (3H, m), 7.53 (2H, sa), 9.18 (1H, sa) and 10.16 (1H, sa), m / z (ES +) 444 (M + 1).

EXAMPLE 186 (3i?, 5i?, 6- $ l) -3- [2-Isopropoxy-5- (thiifluoromethoxy) fenu] -6-phen-l-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4 , 5] decane Prepared from the compound of Example 171 according to the procedure of Description 108. * H NMR (360 MHz, CDCb) d 1.33-1.35 (6H, m), 1.45 (9H , s), 1.87-1.93 (1H, m), 2.17-2.33 (4H, m), 2.5-2.59 (1H, m), 2.74-2.82 (1H, m), 3.80-3.83 (2H, m), 3.96-4.00 (1H, m), 4.30 (1H, m), 4.50-4.57 (1H , m), 5.35 (5.33 (1H, s), 6.81 (1H, d, and 8.9 Hz), 6.95-7.02 (1H, m), 7.09 (1H , m), 7.22-7.26 (1H, m), 7.30-7.34 (2H, m) and 7.60 (2H, d, and 7.9 Hz) m / z (ES + ) 434 (M + l- X-yBu).

EXAMPLE 187 (3J?, 5J?, 65) -3- [2-isopropoxy-5- (thiifluoromethoxy) fenu] -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from Compound of Example 186 according to the procedure of Example 181. H NMR (360 MHz, D20) d 1.01 (3H, d, and 6.0 Hz), 1.07 (3H, d, and 6.0 Hz ), 1.78 (1H, m), 2.00-2.10 (3H, m), 2.20-2.40 (3H, m), 3.30-3.40 (1H, m), 3.50-3.58 (1H, m), 3.62-3.68 (1H, m), 4.02-4.10 (1H, m), 4.10-4.18 (1H, m ), 4.39 (1H, s), 6.61 (1H, d, and 9.2 Hz), 6.86-6.89 (1H, m), 6.93 (1H, s), 7, 56-7.58 (3H, m) and 7.66 (2H, m). m / z (ES +) 436 (M + 1).

EXAMPLE 188 (i-, 5J?, 65 -3- [5- (Trifluoromethoxy) -2- (trifluoro? net? sulphonoxy) phenyl-6-phene-l-oxa-7 - (- * grc-butoxycarbon) aza-spiro4.5] decane Trifluoromethanesulfonic anhydride (0.68 ml) was added dropwise to an agitated and cooled (0 ° C) solution of (3i? 5i? 65) -3- (2-hydroxy-5- (trifluoromethoxy) fenu) -6-Phen-l-oxa-7- (tgrg-butoxycarbon) aza-spiro [4.5] decane (Example 171, 1 g) in pyridine (4 ml) The mixture was allowed to warm to room temperature and stirred for 16 h, more trifluoromethanesulfonic anhydride (0.34 ml) was added and the mixture was stirred at room temperature for 2 hrs. Aqueous copper (II) sulfate was added and the mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic fractions were washed with brine, dried (MS) and the solvent was evaporated under reduced pressure.The residue was purified by MPLC on silica gel, eluting with hexane / EtOAc (80:20) to give the Compound of the title as a colorless oil.? NMR (360 MHz, CDCb) d 1.43 (9H, s), 1.78 (3H, m), 2.25 (2H, m), 2.78 (2H, m), 3.85 (2H, m), 4, 02 (1H, dd, J 13.7 Hz), 4.27 (1H, dd, J 8.7, 6.9 Hz), 5.30 (1H, s), 7.27 (1H, m), 7.31 (5H, m) and 7.57 (2H, d, J 7.6 Hz).

EXAMPLE 189 (^^^^ - ^^ - ^ - (Eten-l-ül-S-ftrifluorometoxüfenüI-ó-fenü-l-oxa ^ -ferc-butoxicarbonü) aza-spiro [4,5] decane A mixture of (5? , 5?, 65) -3- [5- (trifluoromethoxy) -2- (tr uoromethystuTonuoxi) fenu] -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5] decane (Example 188, 200 mg), vinyltribututan (0.11 ml), lithium chloride (80 mg) and tetrakis (thifenuphosphine) palladium (0) (50 mg) in dioxane (5 ml), was degassed using a control valve. iron pyrite (x 5) The mixture was heated at 110 ° C for 2 h, cooled and filtered, the solvent was evaporated under reduced pressure and the residue was dissolved in acetonitrile.The mixture was washed with hexane (30 ml). ml) The mixture was extracted with ethyl acetate (3 x 30 ml) and the combined organic fractions were washed with brine, dried (MgS) and the solvent was evaporated under reduced pressure.The residue was purified by MPLC on gel. of silica, eluting with hexane / EtOAc (85:15) to give the title compound as an oil. JH NMR (360 MHz, CDCb) d 1.47 (9H, s), 1.62 (3H, m), 1.83 (1H, m), 2.25 (1H, td), 2.63 (1H, dd, and 7.5 Hz) , 2.76 (1H, td), 3.82 (1H, qn), 3.90 (1H, t, J 8.3 Hz), 3.98 (1H, dd), 4.24 (1H, t , J 7.3 Hz), 5.36 (2H, m), 5.57 (1H, d, J 16.7 Hz), 6.97 (1H, dd, and 11.0, 16.9 Hz) , 7.15 (1H, d), 7.25 (1H, s), 7.33 (1H, m), 7.35 (2H, m), 7.76 (1H, d, and 8.5 Hz) and 7.60 (2H, d, and 7.6 Hz).

EXAMPLE 190 (3 /? 5i?, 65) -3- [2- (Eten-l-ü) -5- (trifluoromethoxy) fenu] -6-phenyl-l-oxa-7-aza-spiro hydrochloride [4, 5] decane Prepared from the compound of Example 189 according to the procedure of Example 181.? NMR (360 MHz, CD3OD) d 0.53 (1H, t, J 15.1 Hz), 0.72 (1H, t, and 11.9 Hz), 0.90 (1H, m), 1.09 (3H, m), 1.95 (1H, td, J 12.4 Hz), 2.16 (1H, dd, and 12.8 Hz), 2.52 (1H, t, J 9.7 Hz) , 2.78 (1H, t, J 7.9 Hz), 3.08 (1H, s), 3.92 (1H, d, J 11.04 Hz), 4.18 (1H, d, and 17 , 2 Hz), 4.83 (1H, dd, and 17,2, 10.9 Hz), 5.83 (2H, m), 6.16 (1H, d, J 8.5 Hz) and 6, 37 (5H, m).

EXAMPLE 191 (3 /? 5R, 65) -3-r2- (2,2,2-Trifluoroethoxy) -5- (trifluoromethyl) phenyl) -6-phene-1-oxa-7 - (? Er-butoxycarbon) aza- spiro [4.5] decane 5 Prepared from the compound of Example 167 according to the procedure of Example 201. H NMR (360 MHz, CDCb) d 1.44 (9H, s), 1.64-1.80 (3H, m), 1.96 (1H, dd, J 13.0, 8.3 Hz), 2.21 (1H, dt, J 13.0, 5.4 Hz), 2.62 (1H, dd, J 12.2, 7.0 Hz), 2.88 (1H, dt, and 13.3, 4.0 Hz), 3.82-3.90 (2H, m), 3.98-4 , 05 (lH, m), 4.29-4.31 (1H, m), 4.42 (2H, q, J 7.9 Hz), 5.32 (1H, s), 6.88 (1H , d, J 8.6 Hz), 7.22-7.36 (3H, m), 7.51 10 (1H, d, and 8.6 Hz) and 7.54-7.63 (3H, m ). m / z (ES +) 560 (M + l). • EXAMPLE 192 (3J?, 5 / ?, 65) -3-r2- (2,2,2-Trifluoroethoxy) -5- (trifluoromethyl) phenyl] -6-fenfl-l-oxa-7-aza-15 spiro [4, 5] decane Prepared from the compound of Example 191 according to the procedure of Example 181. * H NMR (360 MHz, CDCls) d 1.60-1.74 (3H, m), 1.96-2.02 (1H, m), 2.12 (1H, dt, J 13.0, 4.3 Hz), 2.20-2.38 (3H, m), 2.77 (1H, dt, J 12.4 , 3.0 Hz), 3.24 (1H, dt, and 12.4, 4.0 Hz), 3.62 (1H, dd, and 9.7, 8.3 Hz), 4.07 (1H , t, J 7.1 Hz), 6.72 (1H, t, and 7.3 Hz), 7.24-7.34 (4H, m), 7.39 (1H, d, and 8.6 Hz) and 7.42-7.48 (2H, m). m / z (ES +) 460 (M + l).

EXAMPLE 193 (3i?, 5i?, 65) -3- [2,5-Bis (difluoromethoxy) fenu] -6-phen-l-oxa-7 - (/ grc-butoxycarbonu) aza-espiror4,5] decane Prepared from of the compound of Example 176 according to the procedure of Example 184.? NMR (360 MHz, CDCb) d 7.60 (2H, d, ./ 7.5 Hz), 7.33 (2H, t, and 7.5 Hz), 7.25 (1H, t, and7.5 Hz), 7.15 (1H, d, y2.8 Hz), 7.12 (1H, d, .78.8 Hz), 7.00 (1H, dd, and 8.8, 2.8 Hz) , 6.50 (1H, t, J 73.3 Hz), 6.48 (1H, t, J 73.5 Hz), 5.34 (1H, s), 4.28 (1H, m), 3 , 97 (1H, m), 3.84 (2H, m), 2.77 (1H, m), 2.66 (1H, m), 2.26 (1H, m), 1.84-1, 65 (4H, m) and 1.46 (9H, s). m / z (ES +) 526 (M + l).

EXAMPLE 194 (3 5i?, 65) -3- [2,5-Bis (difluoromethoxy) fenu] -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the Compound of Example 193 according to the procedure of Example 181. W NMR (360 MHz, D20) d 1.83 (1H, m), 1.98 (2H, m), 2.08-2.36 (4H, m), 3.20 (1H, m), 3.52 (1H, m), 3.70 (1H, m), 4.05 (1H, m), 4.30 (1H, s), 6.46 (1H , t, and 73 Hz), 6.73 (1H, t, J 74 Hz), 7.05 (3H, m, ArH) and 7.55 (5H, sa), m / z (ES +) 426 (M + l) Found: C, 56.8; H, 5.0; N, 3.3, C22H23F4NO3.HCl requires: C, 57.2; H, 5.2; N, 3.0%.

EXAMPLE 195 (3-R, 5i?, 65) -3- [5-Fluoro-2- (difluoromethoxy) fenu] -6-phen-1-oxa-7- (tert-butoxycarbon) aza-spiro [4,5] decane Prepared from the compound of Example 178 according to the procedure of Example 184.? NMR (360 MHz, CDCl 3) d 1.45 (9H, s), 1.64-1.83 (4H, m), 2.26 (1H, dd, J 12.8, 7.6 Hz), 2 , 63-2.80 (2H, m), 3.81-3.89 (2H, m), 3.96-4.00 (1H, m), 4.26-4.29 (1H, m) , 5.33 (1H, s), 6.47 (1H, t, 73.4 Hz), 6.89-6.94 (1H, m), 7.07-7.11 (1H, m), 7.22-7.27 (lH, m), 7.32 (2H, m), 7.59 (2H, d, J 7.9 Hz). m / z (ES +) 478 (M + 1).

EXAMPLE 196 (3-R, 5R, 6-S -3- [5-fluoro-2- (difluorom.etoxy) fenu] -6-phenyl-l-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the compound of Example 195 according to the procedure of Example 181.? NMR (360 MHz, D2O) d 1.42-2.00 (7H, m), 2.82-2.93 (1H, m) , 3.16-3.26 (1H, m), 3.32-3.39 (1H, m), 3.68-3.75 (1H, m), 3.97 (1H, s), 6 , 11 (1H, t, and 73.3 Hz), 6.58-6.74 (3H, m) and 7.58-7.61 (5H, s). M / z (ES +) 378 (M + l).

EXAMPLE 197 (3 ^, 5J?, 6 - ^ - 3- [5-Fluoro-2- (2,2,2-trifluoroethoxy) phenyl-6-phene-1-oxa-7 ^ grc-butoxycarbon) aza-spiro [ 4,5] decane Prepared from the compound of Example 178 according to the procedure of Example 201. iH NMR (360 MHz, CDCb) d 1.45 (9H, s), 1.57-1.76 (4H, m), 1.86-1.95 (1H, m), 2.18-2.23 (1H, m), 2.56-2.65 (1H, m), 2.72-2.85 ( 1H, m), 3.81-3.88 (1H, m), 3.94-4.03 (1H, m), 4.24-4.38 (3H, m), 5.30 (1H, s), 6.74-6.79 (1H, m), 6.89 (lH, dt, and 12.9, 4.4 Hz), 7.05 (1H, dd, and 13.6, 74, 3 Hz), 7.25-7.35 (3H, m) and 7.59 (2H, d, J 10.9 Hz). m / z (ES +) 454 (M + 1-QHβ).

EXAMPLE 198 (3R, 5R, 65) -3-r5-fluoro-2- (2,2,2-trifluoroethoxy) ferun-6-phenyl-1-oxa-7-aza-spiro-4,5-decane Hydrochloride Prepared from Compound of Example 197 according to the procedure of Example 181. * H NMR (360 MHz, D20) d 1.88-1.97 (3H, m), 2.08-2.13 (1H, m), 2 , 26-2.37 (3H, m), 3.15-3.21 (1H, m), 3.38-3.41 (1H, m), 3.70 (1H, dd, J 10.3 , 8.3 Hz), 4.13 (1H, t, J 7.5 Hz), 4.29-4.47 (3H, m), 6.83-6.89 (3H, m), 7, 48-7.50 (3H, m) and 6.29 (2H, m). m / z (ES +) 410 (M + 1).

EXAMPLE 199 (3 / ?, 5J?, 65) -3- (5-Fluoro-2-isopropoxypheni) -6-phenyl-1-oxa-7- (fórc-butoxicarbonü) aza-spiro [4,5] decane Prepared from of the compound of Example 178 according to the procedure of Description 108. * H NMR (360 MHz, CDCb) d 1.30-1.33 (6H, m), 1.45 (9H, s), 1.63 -1.78 (2H, m), 1.86-1.89 (1H, m), 2.18-2.27 (1H, m), 2.54-2.60 (1H, m), 2 , 77 (1H, dt, and 12.5, 4.0 Hz), 3.77-3.87 (2H, m), 3.96-4.01 (1H, m), 4.29 (1H, t, J 7.1 Hz), 4.43-4.51 (1H, m), 5.33 (1H, s), 6.76-6.80 (1H, m), 6.82-6, 88 (1H, m), 6.96 (1H, dd, and 9.6, 3.0 Hz), 7.22-7.25 (1H, m), 7.32 (2H, m) and 7, 60 (2H, d, J 7.9 Hz). m / z (ES +) 470 (M + 1).

EXAMPLE 200 Hydrochloride of (3 /? 5R, 65) -3- (5-fluoro-2-isopropoxyphene) -6-phene-1-oxa-7-aza-spiro [4,5] decane Prepared from the compound of Example 199 according to the procedure of Example 181. H NMR (360 MHz, D20) d 1.00 (3H, d, J 6.0 Hz), 1.04 (3H, d, and 6.0 Hz) , 1.81 (1H, t, J 12.6 Hz), 1.96-2.00 (2H, m), 2.10-2.14 (2H, m), 2.26-2.32 ( 1H, m), 2.40-2.43 (1H, m), 3.18-3.23 (1H, m), 3.47-3.53 (1H, m), 3.64 (1H, dd, and 10.8, 8.3 Hz), 4.09 (1H, t, and 8.0 Hz), 4.24-4.28 (2H, m), 6.90-6.99 (3H , m) and 7.56 (1H, s). m / z (ES +) 370 (M + 1).

EXAMPLE 201 (3 /? 5i?, 65) -3- [2-Isopropoxy-5- (2,2,2-trifluoroethoxy) fenu] -6-phen-l-oxa-7- (tgrc-butoxycarbon) aza-spiro [4,51decano 2,2,2-trifluoroethyl trichloromethanesulfonate (127 mg, 0.45 mmol) was added to a mixture of (3R, 5R, 65) -3- (5-hydroxy-2-isopropoxyphenyl) -6-phenol. -l-oxa-7 - (/ gr.-butoxycarbon) aza-spiro [4.5] decane (Example 180, 140 mg, 0.3 mmol) and potassium carbonate (104 mg, 0.75 mmol) in DMF (3 ml) and the mixture was heated to 60 ° C, adding further 2,2,2-thiifluoroeti trichloromethanesulfonate (338 mg, 1.2 mmol) and potassium carbonate (166 mg, 1.2 mmol) after 4 h. and 22 h. After 46 h, the mixture was cooled, poured into aqueous citric acid (10%, 20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic fractions were washed with aqueous citric acid (10%, 2 x 20 mL) and brine (20 mL), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2C12 / EtOAc (85:15 increasing to 80:20) to give the title compound (138 mg, 84%). ? NMR (250 MHz, CDCb) d 1.31 (6H, d, and 6.0 Hz), 1.45 (9H, s), 1.60-1.80 (3H, m), 1.87-1 , 92 (1H, m), 2.18-2.24 (1H, m), 2.52-2.59 (1H, m), 2.71-2.81 (1H, m), 3.77 -4.00 (3H, m), 4.25-4.35 (3H, m), 4.42-4.49 (1H, m), 5.38 (1H, s), 6.70-6 , 82 (2H, m), 6.90 (1H, d, J 2.9 Hz), 7.24-7.35 (3H, m) and 7.61 (2H, d, and 7.6 Hz) . m / z (ES +) 550 (M + 1).

EXAMPLE 202 (3R, 5R, 65) -3- [2-isopropoxy-5- (2> 2,2-thiifluoroethoxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro hydrochloride [4,5] decane Prepared from the compound of Example 201 according to the procedure of Example 181.? NMR (360 MHz, D20) d 0.99 (3H, d, J 6.0 Hz), 1.04 (3H, d, and 6.0 Hz), 1.77-1.84 (1H, m) , 1.98-2.05 (3H, m), 2.20-2.32 (2H, m), 2.38-2.48 (1H, m), 3.20-3.32 (1H, m), 3.50-3.63 (2H, m), 4.02-4.10 (1H, m), 4.12-4.20 (lH, m), 4.32 (1H, s) , 4.43 (2H, dd, J 16.8, 8.4 Hz), 6.74-6.80 (3H, m) and 7.58-7.61 (5H, m). m / z (ES +) 450 (M + 1).

EXAMPLE 203 (3i?, 5 / ?, 65) -3- [2,5-Bis (isopropoxy) fenu] -6-phene-l-oxa-7 - (.'-grc-butoxycarbonu) aza-espiror4,51decano Prepared from of the compound of Example 180 according to the procedure of Description 108.? NMR (360 MHz, CDCl 3) d 7.60 (2H, d, J 7.7 Hz), 7.32 (2H, t, and 7.7 Hz), 7.23 (1H, t, and 7.7) Hz), 6.82 (1H, d, and 2.9 Hz), 6.77 (1H, d, and 8.9 Hz), 6.69 (1H, dd, and 8.9, 2.9 Hz) ), 5.32 (1H, s), 4.43 (1H, hept., And 6.0 Hz), 4.29 (1H, m), 3.98 (1H, m), 3.83 (2H) , m), 2.78 (1H, m), 2.55 (1H, m), 2.21 (1H, m), 1.93 (1H, m), 1.79-1.63 (3H, m), 1.45 (9H, s) and 1.30 (12H, d, and 6.0 Hz). m / z (ES +) 510 (M + 1).

EXAMPLE 204 (3J?, 5i?, 65) -3- [2,5-bis (isopropoxy) fenu] -6-phenyl-l-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the compound of Example 203 according to the procedure of Example 181, mp 233-236 ° C * H NMR (360 MHz, CD3OD) d 7.68 (2H, m), 7.62 (3H, m), 6.82 (1H, d, and 8.9 Hz), 6, 75 (1H, dd, and 8.9, 2.7 Hz), 6.65 (1H, d, J 1.7 Hz), 4.88 (2H, sa), 4.49 (1H, hept., and 6.0 Hz), 4.38 (1H, hept., and 6.0 Hz), 4.37 (1H, s), 4.16 (1H, m), 3.77 (1H, m), 3.49 (1H, m), 3.27 (1H, m), 2.53 (1H, m), 2.34 (2H, m), 2.20 (1H, m), 2.09-1 , 90 (3H, m), 1.32 (6H, d, and 6.0 Hz), 1.21 (3H, d, J 6.0 Hz) and 1.15 (3H, d, J 6.0 Hz). m / z (ES +) 410 (M + 1).

EXAMPLE 205 (3?, 5R, 65) -3- (5-Chloro-2-methoxy-phen) -6-phen-1-oxa-7- (ferc-butoxycarbon) aza-spiro [4.5] decane Prepared from 5-chloro -2-methoxyiodobenzene and (5i?, 65) -6-phene-l-oxa-7- (g-butoxycarbon) aza-spiro [4.5] dec-3-ene (Description 86) according to the process of Example 170.? NMR (360 MHz, CDCb) d 1.40 (9H, s), 1.59-1.83 (3H, s), 2.12-2.22 (1H, m), 2.48-2.53 (1H, m), 2.64-2.72 (1H, m), 3.71-3.83 (2H, m), 3.73 (3H, s), 4.20-4.24 (1H, m), 5.28 (1H, s), 6.69-6.71 (1H, d, J 8.6 Hz), 7.07 -7.27 (5H, m) and 7.53-7.55 (2H, m). m / z (ES +) 458 (M + 1).

EXAMPLE 206 (3-R, 5R, 65) -3- (5-Chloro-2-methoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the Compound of Example 205 according to the procedure of Example 181. iH NMR (360 MHz, D20) d 1.78-2.29 (7H, m), 3.22 (1H, m), 3.51-3.57 (1H , m), 3.61 (3H, s), 3.68-3.74 (1H, m), 3.99-4.03 (1H, m), 4.29 (1H, s), 6, 85-6.88 (1H, d, J 8.8 Hz), 7.13-7.14 (1H, d, and 2.5 Hz), 7.17-7.21 (1H,? D, J 2.5, 8.8 Hz) and 7.56-7.59 (5H, m). m / z (ES +) 358 (M + 1).

EXAMPLE 207 (3 / ?, 5J?, 6 - $ ^ - 3-r2- (2,2,2-Tr uoroethoxy) -5- (ti] -fluoromethoxy-phenyl] -6-phenyl-l-oxa-7 - (/ grc -butoxycarbonu) aza-spiro [4.5] decane Prepared from the compound of Example 171 according to the procedure of Example 201. iH NMR (360 MHz, CDCb) d 1.37 (9H, s), 1.61 -1.67 (1H, s), 1.80-1.87 (1H, m), 2.09-2.13 (1H, m), 2.52-2.57 (1H, m), 2 , 71-2.77 (1H, m), 3.72-3.80 (2H, m), 3.89-4.00 (1H, m), 4.21 (1H, m), 4.26 -4.33 (2H, q, J 8 Hz), 5.23 (1H, s), 6.73-6.75 (1H, d, and 8.9 Hz), 7.01-7.03 ( 1H, m), 7.11 (1H, m), 7.17-7.27 (3H, m) and 7.50-7.52 (2H, m) m / z (ES +) 576 (M + l).

EXAMPLE 208 (3R.5 6-SV3- [2- (2,2,2-trifluoroethoxy) -5- (thifluoromethoxy) phenyl-6-phenyl-l-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the compound of Example 207 according to the procedure of Example 181.? NMR (360 MHz, D20) d 1.83-1.89 (1H, m), 1.90-2.04 (3H, m) , 2.25-2.33 (3H, m), 3.21-3.35 (1H, m), 3.58-3.68 (2H, m), 4.07-4.12 (1H, m), 4.27-4.31 (2H, q, and 8.5 Hz), 4.35 (1H, s), 6.81-6.84 (1H, d, J 8.9 Hz), 6.99-7.05 (2H, m) and 7.54-7.61 (5H, m) m / z (ES +) 476 (M + 1).

EXAMPLE 209 (3J ?, 5R, 65) -3- [2- (Cyclopromethoxy) -5- (thiifluoromethoxy) fenu] -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4 5] decane Cyclopropylmethyl bromide (112 mg) was added to a mixture of (3-R, 5-ß, 65) -3- (2-hydroxy-5- (thiifluoromethoxy) fenu) -6-phenyl-l-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4, 5] decane (Example 171, 274 mg) and potassium carbonate (192 mg) in dimethylformamide (5 ml). The mixture was stirred at 60 ° C for 18 h, poured into water (100 ml) and extracted with ethyl acetate (2 x 25 ml). The combined organic fractions were washed with brine (2 x) and water, dried (MgS?) And the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (95: 5 increasing to 90:10), to give the title compound as an oil (178 mg). ? NMR (360 MHz, CDCb) d 0.23-0.28 (2H, m), 0.54-0.59 (2H, m), 0.81 (1H, m), 1.18 (2H, m) ), 1.38 (9H, s), 1.63-1.72 (3H, m), 1.89-1.95 (1H, m), 2.12-2.16 (1H, m), 2.48-2.53 (1H, m), 2.69-2.75 (1H, m), 3.68-3.79 (3H, m), 3.89-3.93 (1H, m) ), 4.27 (1H, m), 5.27 (1H, s), 6.68-6.71 (1H, d, and 8.89 Hz), 6.95-6.97 (1H, m) ), 7.03 (1H, m) and 7.52-7.54 (2H, m). m / z (ES +) 548 (M + 1).

EXAMPLE 210 (3R, 5 - ?, 6-S ^ -3- [2- (cyclopropyrnetoxy) -5- (trifluorornetoxy) phenyl] -6-phenyl-l-oxa-7-aza-spiro [4,51decano] -hydrochloride Prepared to from the compound of Example 209 according to the procedure of Example 181. JH NMR (360 MHz, D20) d -0.01-0.00 (2H, m), 0.57-0.59 (2H, m) , 0.94 (1H, m), 1.76 (1H, m), 1.95 (2H, m), 2.21 (2H, m), 3.19-3.23 (2H, m), 3.53 (1 H, m), 3.61 (1H, m), 3.99 (1H, m), 4.35 (1H, m), 6.28-6.30 (1H, d, and 9.0 Hz), 6.67-6.68 (1H, m), 6.75 (1H, m), 7.46-7.52 (3H, m) and 7.61-7.63 (2H , m). m / z (ES +) 448 (M + 1).

EXAMPLE 211 (3R.5 / ?, 65) -3- [2-benzuboxy-5- (thiifluoromethoxy) fenin-6-phenyl-l-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the compound of Example 170 according to the procedure of Example 181. iH NMR (360 MHz, DzO) d 1.83-1.91 (4H, m), 2.08-2.24 (2H, m), 3.10 -3.22 (1H, m), 3.31 (3H, m), 3.42-3.48 (1H, m), 3.58-3.64 (1H, m), 4.01 (1H, m), 4.21 (1H, s), 6.86-6.89 (1H, m), 6.93 (1H, m), 7.00-7.04 (1H, m), 7.24 -7.25 (2H, m), 7.32-7.34 (3H, m) and 7.44-7.46 (5H, m). m / z (ES +) 484 (M + 1).

EXAMPLE 212 (3R.5R, 65) -3- [5- (Difluoromethoxy) -2- (2,2,2-trifluoroethoxy) phenyl] -6-phenyl-1-oxa-7- (fórc-butoxicarbonü) aza-spiro [ 4,5] decane Prepared from the compound of Example 176 according to the procedure of Example 201.? NMR (360 MHz, CDCb) d 1.37 (9H, s), 1.55-1.68 (3H, m), 1.82-1.88 (1H, m), 2.09-2.16 (1H, m), 2.50-2.56 (1H, m), 2.69-2.78 (1H, m), 3.73-3.81 (2H, m), 3.89-3 , 93 (1H, m), 4.17-4.20 (1H, m), 4.24-4.31 (2H, q, J 8.0 Hz), 5.22 (1H, s), 6 , 38 (1H, t, and 74 Hz), 6.72 (1H, d, J 8.8 Hz), 6.91-6.93 (1H, dd, and 2.8, 8.8 Hz), 7.03 (1H, d, and 2.8 Hz), 7.15-7.27 (3H, m) and 7.50-7.52 (2H, m). m / z (ES +) 558 (M + 1).

EXAMPLE 213 (3R 5R, 65) -3-r5- (d-fluoro-methoxy) -2- (2,2,2-thiifluoroethoxy ') phenyl] -6-phenyl-1-oxa-7-aza-spiro hydrochloride [4,5] Dean Prepared from the compound of Example 212 according to the procedure of Example 181.? NMR (360 MHz, DzO) d 1.89-2.32 (7H, m), 3.20 (1H, m), 3.49 (1H, m), 3.65-3.71 (1H, m) ), 4.08-4.12 (1H, m), 4.29 (1H, s), 4.29-4.37 (2H, q, and 8.5 Hz), 6.67 (1H, t , J 74 Hz), 6.87-7.02 (3H, m) and 7.54 (5H, s). m / z (ES +) 458 (M + 1).

EXAMPLE 214 (3R.5R, 65) -3-r2- (2,2-Difluoroethoxy) -5- (difluoromethoxy) fenu] -6-phenyl-l-oxa-7 - (? Grc-butoxycarbon) aza-spiro [4, 5] decane 2,2-difluoroethyl bromide (120 mg) was added to a mixture of (3i?, 5i?, 65) -3- [5- (difluoromethoxy) -2-hydroxyphenyl] -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5] decane (Example 176, 200 mg) and potassium carbonate (145 mg) in dimethylformamide (4 ml). The mixture was stirred at 50 ° C for 2 h., Poured into brine and extracted with ethyl acetate. The combined organic fractions were washed with water (3 x), dried (M S?) And the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (90:10 increasing to 80:20), to give the title compound as an oil (178 mg). ? NMR (360 MHz, CDCb) d 1.45 (9H, s), 1.62-1.76 (3H, m), 1.86-1.93 (1H, m), 2.18-2.23 (1H, m), 2.57-2.62 (1H, m), 2.74-2.82 (1H, m), 3.83-3.84 (1H, m), 3.96-3 , 99 (1H, m), 4.11-4.24 (2H, td, J 8.9, 12.9 Hz), 4.27 (1H, m), 5.33 (1H, s), 6 , 12 (1H, tt, and 55 Hz, 4 Hz), 6.43 (1H, t, J 74 Hz), 6.77-6.80 (1H, d, J 8.8 Hz), 6.97 -6.98 (1H, m), 7.07 (1H, m), 7.22-7.34 (3H, m) and 7.58-7.60 (2H, m). m / z (ES +) 484 (M + 1 H).

EXAMPLE 215 (37? 5 /? 65) -3- [2- (2,2-difluoroethoxy) -5- (difluoromethoxy) fenin-6-phene-1-oxa-7-aza-spiro hydrochloride [4,5 ] decane Prepared from the compound of Example 214 according to the procedure of Example 181. iH NMR (360 MHz, D20) d 1.88-2.33 (7H, m), 3.18-3.22 (1H , m), 3.47-3.55 (1H, m), 3.68-3.73 (1H, m), 4.04-4.13 (3H, m), 4.29 (1H, s) ), 6.06 (1H, tt, and 55, 4 Hz), 6.66 (1H, t, J 74 Hz), 6.67-7.03 (3H, m) and 7.55 (5H, s) ). m / z (ES +) 440 (M + l).

EXAMPLE 216 (3R, 5R, 65) -3- [2- (Cyclobutoxy) -5- (thiouluoromethoxy) fenu] -6-phene-l-oxa-7 - (- grc-butoxycarbon) aza-spiro F4.5] decane Cyclobutyl bromide (143 mg) was added to a mixture of (3 /? 5i?, 65) -3- (2-hydroxy-5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7- ( - * grg-butoxycarbon) aza-spiro [4.5] decane (Example 171, 181 mg) and potassium carbonate (126 mg) in dimethylformamide (10 ml). The mixture was stirred at 60 ° C for 18 h, poured into brine and extracted with ethyl acetate (2 x). The combined organic fractions were washed with water (3 x), dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (95: 5), to give the title compound (96 mg). ? NMR (360 MHz, CDCb) d 1.39 (9H, s), 1.58-1.87 (6H, m), 2.07-2.16 (3H, m), 2.34-2.40 (2H, m), 2.48-2.53 (1H, m), 2.66-2.75 (1H, m), 3.73-3.76 (2H, m), 3.89-3 , 93 (1H, m), 4.24 (1H, m), 4.52-4.56 (1H, m), 5.27 (1H, s), 6.56-6.59 (1H, d) , J 8.9 Hz), 6.92-6.95 (1H, m), 7.01 (1H, m), 7.15-7.17 (1H, m), 7.23-7.27 (2H, m) and 7.52-7.55 (2H, m). m / z (ES +) 548 (M + 1).

EXAMPLE 217 (3i ?, 5R, 65) -3- [2- (Cyclobutoxy) -5- (thiifluoromethoxy) phenyl-6-phenyl-1-oxa-7-aza-spiro [4.5] decane Prepared from the compound of Example 216 according to the procedure of Example 181. iH NMR (360 MHz, CDCb) d 1.50-1.77 (5H, m), 1.90-1.99 (4H, m), 2.08- 2.14 (1H, m), 2.24-2.36 (3H, m), 2.68-2.74 (1H, m), 3.13-3.16 (1H, m), 3, 46 (1H, s), 3.51-3.56 (1H, m), 3.91-3.95 (1H, m), 4.35-4.39 (1H, m), 6.42- 6.45 (1H, d, J 8.8 Hz), 6.75 (1H, m), 6.81-6.83 (1H, m) and 7.22-7.43 (5H, m). m / z (ES +) 448 (M + 1).

EXAMPLE 218 (3R, 5R, 65) -3-r2- (2-Methoxyethoxy) -5- (trifluoromethoxy) phenyl] -6-phenyl-1-oxa-7- (f6-c-butoxycarbon) aza-spiro [4,5 ] decane 2-Bromoethyl methyl ether (52 mg) was added to a mixture of (3R, 5R, 65) -3- (2-hydroxy-5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7 (/ 'g' c-butoxycarbon) aza-spiro [4.5] decane (Example 171, 150 mg) and potassium carbonate (92 mg) in dimethyl-Jf ormamide (2 ml). The mixture was stirred at 60 ° C for 20 h, poured into water and extracted with ethyl acetate. The combined organic fractions were washed with brine and water, dried (M S?) And the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane / EtOAc (80:20), to give the title compound (105 mg). H NMR (360 MHz, CDCb) d 1.45 (9H, s), 1.71-1.77 (3H, m), 1.94-2.00 (1H, m), 2.18-2, 21 (1H, m), 2.54-2.59 (1H, m), 2.77-2.83 (1H, m), 3.42 (3H, s), 3.48-3.87 ( 4H, m), 3.95-3.99 (1H, m), 4.10-4.13 (2H, t, and 4.90 Hz), 4.29 (1H, m), 5.32 ( 1H, s), 6.82-6.84 (1H, d, and 8.9 Hz), 7.03-7.06 (1H, m), 7.11 (1H, m), 7.24- 7.34 (3H, m) and 7.58-7.60 (2H, m). m / z (ES +) 552 (M + 1).

EXAMPLE 219 (3i?, 5i?, 65) -3- [2- (2-Methoxyethoxy) -5- (trifluoromethoxy) phenyl] -6-phenyl-l-oxa-7-aza-es? Iro hydrochloride [4,5 ] decane Prepared from the compound of Example 218 according to the procedure of Example 181. JH NMR (360 MHz, D20) d 1.91-2.31 (7H, m), 3.21 (1H, m), 3.43 (3H, s), 3.49-3.53 (1H, m), 3.66-3.72 (3H, m), 3.93-3.95 (2H, m), 4, 11 (1H, m), 4.29 (1H, m), 6.88-6.91 (1H, d, J 8.9 Hz), 7.04 (1H, m), 7.11 (1H, m) and 7.56 (5H, s). m / z (ES +) 452 (M + 1).

EXAMPLE 200 (IR, 5R, 65) -3- [5- (trifluoromethoxy) -2- (trifluoromethylsulfonuoxy) fenin-6-phene-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the compound of Example 188 according to the procedure of Example 181, mp > 250 ° C (EtOAc). ? NMR (400 MHz, D20) d 7.56 (5H, sa), 7.38 (2H, d, J 10.4 Hz), 7.30 (1H, d, J 8.8 Hz), 4.34 (1H, s), 4.22 (1H, t, J 7.9 Hz), 3.74 (1H, t, and 9.4 Hz), 3.52 (1H, da, and 9.8 Hz) , 3.23 (1H, ta, J 11.4 Hz), 2.43-2.53 (2H, m), 2.17-2.28 (2H, m) and 1.95-2.02 ( 3H, m). m / z (ES +) 526 (M + l). Found: C, 47.19; H, 3.58; N, 2.69, C22H21F6NO5S.HCl requires: C, 47.02; H, 3.95; N, 2.49%.

EXAMPLE 221 (3R, 5R, 65) -3- [2- (2,2-Difluoroethoxy) -5- (trifluoromethoxy) phenyl] -6-phenyl-1-oxa-7 - (- 1 g / -c-butoxycarbonyl) aza- spiro [4.5] decane 2-Bromo-l, 1-difluoroethane (100 mg, 0.69 mmol) was added to a mixture of (3?, 5i?, 65) -3- (2-hydroxy-5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5] decane (Example 171, 159 mg, 0.32 mmol) and potassium carbonate (110 mg , 0.8 mmol) in DMF (5 ml) and the mixture was stirred at 40 ° C for 72 h. Water (100 ml) was added and the mixture was streaked with ethyl acetate (2 x 100 ml). The combined organic fractions were dried (MgSOi) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane / EtOAc (75:25), to give the title compound (148 mg, 82%). ? NMR (360 MHz, CDCb) d 1.42 (9H, s), 1.58-1.76 (1H, m), 1.84-1.94 (2H, m), 2.10-2.26 (1H, m), 2.56-2.62 (1H, m), 2.74-2.82 (1H, m), 3.60-3.72 (2H, m), 3.78-3 , 92 (2H, m), 3.92-4.00 (1H, m), 4.06-4.32 (2H, m), 5.34 (1H, s), 6.14 (1H, m) ), 6.80 (1H, d, and 8.9 Hz), 7.06-7.10 (1H, m), 7.16 (1H, m), 7.20-7.36 (3H, m ) and 7.56-7.62 (2H, m). m / z (ES +) 558 (M + 1).

EXAMPLE 222 (3fl, 5R, 65) -3-r2- (2,2-difluoroethoxy) -5- (thiifluoromethoxy) phenyl-6-phenyl-l-oxa-7-aza-spiro hydrochloride [4,51 decane Prepared from of the compound of Example 221 according to the procedure of Example 181. i H NMR (360 MHz, D 20) d 1.89-2.42 (7H, m), 3.18- 3.26 (1H, m), 3 , 46-3.58 (1H, m), 3.72-3.78 (lH, m), 4.10-4.20 (4H, m), 6.10 (1H, d, J 9.05 Hz), 7.06-7.10 (2H, m) and 7.58 (5H, s). m / z (ES +) 458 (M + 1).

EXAMPLE 223 (3R, 5R, 65) -3- [2-Cyclopropyl-5- (trifluoromethoxy) fenu] -6-phenyl-1-oxa-7 - (- 'grc-butoxycarbonyl) aza-spiro [4,5] decane One mixture of (ii?, 5 / ?, 65) -3- [5- (trifluoromethoxy) -2- (thiifluoromethylsulfoxy) phenyl] -6-phenyl-l-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5] decane (Example 188, 200 mg), tetracyclopropyl tin (Description 116, 108 mg), lithium chloride (80 mg) and tetiache (thifeniphosphine)? Aladium (0) (50 mg) in dioxane (5 ml. ) was degassed with an iron pyrite valve (3 x) and stirred at 110 ° C for 16 h. The mixture was cooled, filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile (20 ml) and washed with hexane (20 ml). The hexane fraction was extracted with acetonitrile (2 x 20 ml) and the combined acetonitrile fractions were treated with methanolic potassium fluoride (5%, 5 ml). The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane / EtOAc (85:15), to give the title compound as a yellow oil. ? NMR (360 MHz, CDCb) d 0.63 (2H, dm, J 12.5 Hz), 0.98 (2H, d, J 8.5 Hz), 1.45 (9H, s), 1.67 (4H, m), 1.81 (1H, dd, J 12.8, 9.7 Hz), 2.04 (1H, m), 2.26 (1H, td, and 8.4, 5.1) Hz), 2.70 (1H, dd, and 12.7, 7.8 Hz), 2.78 (1H, td, and 12.5 Hz), 3.91 (1H, t, J 8.3 Hz) ), 3.96 (1H, dd), 4.14 (1H, qn), 4.29 (1H, t, J 7.6 Hz), 5.37 (1H, s), 6.99 (1H, m), 7.04 (1H, d, J 8.5 Hz), 7.25 (1H, d, J 3.6 Hz), 7.3 (1H, m), 7.33 (1H, t, J 7.1 Hz) and 7.61 (2H, d, J 7.7 Hz). m / z (ES +) 462 (M + 1-QH8).

EXAMPLE 224 (3-R, 5R, 65) -3- [2-cyclopropyl-5- (thiifluoromethoxy) fenu] -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from Compound of Example 223 according to the procedure of Example 181. iH NMR (360 MHz, CDCb) d 0.3 (2H, dm, and 16.8 Hz), 0.57 (2H, dd, and 6.6 Hz ), 1.10 (1H, m), 1.69 (3H, m), 2.06 (1H, m), 2.24 (1H, dd, J 13.0, 7.9 Hz), 2, 46 (1H, m), 2.62 (1H, qn), 2.87 (1H, t), 3.45 (1H, d, J 7.1 Hz), 3.59 (1H, t, J 8 , 8 Hz), 3.90 (1H, s), 4.09 (1H, t, J 7.7 Hz), 6.88 (3H, s), 7.33 (3H, m) and 7.63 (2H, sa), m / z (ES +) 418 (M + 1).

EXAMPLE 225 (3i?> 5i?, 65) -3- (5-Cyano-2-hydroxyphenyl) -6-phen-1-oxa-7-aza-spiro [4,5] decane Prepared from Description 118 of according to the procedure of Example 181. iH NMR (250 MHz, DMSO-dβ) d 7.15-7.47 (7H, m), 6.71 (1H, d, and 8.4 Hz), 3.83 (1H, t, J 7.1 Hz), 3.62 (1H, s), 3.46 (1H, t, and 8.8 Hz), 3.00-3.05 (1H, m), 2 , 62-2.71 (1H, m), 2.07-2.16 (2H, m), 1.83-1.96 (2H, m) and 1.49-1.68 (3H, m) .

EXAMPLE 226 (3i?, 5j?, 65) -3- (5-Cyano-2-hydroxyuii) -6-phen-l-oxa-7 - (- 'grc-butoxycarbonu) aza-spiro 14.51 decane Water ( 50 ml) to a solution of (3R, 5R, 65) -3- [5-cyano-2- (tert-butoxycarbonyl) ox-phenyl] -6-phenyl-1-oxa-7- (1-carbo-butoxycarbon) aza Spray [4.5] decane (Description 119, 427 mg) in tetiahydrofuran (50 ml) and the mixture was refluxed for 16 h. The mixture was cooled, ammonium chloride solution (saturated, 50 ml) was added and the mixture was extracted with ethyl acetate (2 x 100 ml). The combined organic fractions were dried (MgSO 4) and the solvent was evaporated under reduced pressure to give the title compound as a gum (337 mg). JH NMR (250 MHz, CDCb) d 7.56-7.59 (2H, m), 7.26-7.42 (5H, m), 6.90 (1H, d, J 9.0 Hz), 5.43 (1H, s), 4.29 (1H, dd, y9.5, 7.4 Hz), 3.92-3.98 (2H, m), 3.80-3.82 (1H, m), 2.67-2.81 (2H) , m), 2.31-2.37 (1H, m), 1.59-1.88 (4H, m) and 1.51 (9H, s).

EXAMPLE 227 (3?, 5R, 65) -3-r5-Cyano-2- (2,2,2-thiifluoroethoxy) phenyl] -6-phene-l-oxa-7- (fe / -c-butoxycarbon) aza-spiro [4,5] decane Prepared from the compound of Example 226 according to the procedure of Example 201.? NMR (250 MHz, CDCb) d 7.55-7.63 (4H, m), 7.25-7.36 (3H, m), 6.87 (1H, d, and 8.5 Hz), 5 , 32 (1H, s), 4.43 (2H, q, J 7.8 Hz), 4.28-4.30 (1H, m), 3.95-3.96 (1H, m), 3 , 83-3.85 (2H, m), 2.79-2.81 (1H, m), 2.58-2.66 (1H, m), 2.19-2.24 (1H, m), 1.88-1.97 (1H, m), 1.70-1.69 (3H, m) and 1.45 (9H, s).

EXAMPLE 228 (3J?, 5R, 65) -3- [5-Cyano-2- (2,2,2-trifluoroethoxy) phenyl-6-phene-l-oxa-7-aza-spiro [4,5] decane hydrochloride Prepared from the compound of Example 227 according to the procedure of Example 181. pf 258-260 ° C. iH NMR (360 MHz, DMSO-dβ) d 9.50 (1H, sa), 8.90 (1H, sa), 7.73 (1H, dd, J 2.0, 8.7 Hz), 7, 64 (1H, d, J 2.0 Hz), 7.54-7.55 (2H, m), 7.44-7.46 (3H, m), 7.13 (1H, d J 8.7 Hz), 4.74 (2H, q, J 8.7 Hz), 4, 40 (1H, s), 4.01 (1H, t, and 7.6 Hz), 3.61 (1H, dd, and 8.3, 10.3 Hz), 3.24-3.26 (1H, m), 3.06 -3.08 (1H, m), 2.21-2.27 (1H, m) and 1.86-2.14 (6H, m). m / z (ES +) 417 (M + l).

EXAMPLE 229 (3R, 5 / ?, 65) -3- (5-Cyano-2-isopropoxypheni) -6-phenyl-l-oxa-7- (rg->, c-butoxycarbon) aza-spiro [4,5] decane Prepared from the compound of Example 226 according to the procedure of Description 108. iH NMR (250 MHz, CDCb) d 7.48-7.62 (4H, m), 7.26-7.33 (3H , m), 6.87 (1H, d, J 8.4 Hz), 5.35 (1H, s), 4.64 (1H, sept., and 6.1 Hz), 3.95-4, 00 (1H, m), 3.75-3.79 (2H, m), 2.64-2.68 (1H, m), 2.56-2.60 (1H, m), 2.23- 2.27 (1H, m), 1.90-1.94 (1H, m), 1.70-1.74 (4H, m), 1.46 (9H, s) and 1.37 (6H, d, J 6.0 Hz).

EXAMPLE 230 (3R, 5 /? 65) -3- (5-Cyano-2-isopropoxyphenyl) -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the compound of Example 229 according to the procedure of Example 181. pf 256-258 ° C. ? NMR (360 MHz, DMSO-dβ) d 7.76-7.82 (4H,), 7.68-7.69 (3H, m), 7.24 (1H, d, J 8.7 Hz), 4.82 (1H, sept., And 6.0 Hz), 4.58 (1H, sa), 4.16 (1H, t, J 7.5 Hz), 3.79 (1H, dd, and 8 , 0.10.7 Hz), 3.45-3.47 (lH, .m), 3.23-3.27 (1H, m), 2.41-2.46 (1H, m), 2 , 24-2.33 (3H, m), 1.99-2.09 (3H, m) and 1.34 (6H, dd, and 6.0, 10.5 Hz). m / z (ES +) 377 (M + 1).

EXAMPLE 231 (^, 5?, 65) -3- [2- (Eten-l-ü) -5- (thiifluoromethoxy) fenu] -6-phenyl-l-oxa-7- (fórc-butoxicarbonü) aza-spiro [4 , 5] decane A mixture of (-3R, 5i-, 6-S) -3- [5- (thiifluoromethoxy) -2- (trifluoromethylsulfonyl) phenyl] -6-phene-l-oxa-7- (tert-butoxycarbon) ) aza-spiro [4.5] decane (Example 188, 700 mg), vinyltinuene tin (0.4 ml), lithium chloride (290 mg) and tetiakis (tiiienilphosphine) palladium (0) (50 mg) in dioxane ( 10 ml) was degassed with an iron pyrite valve (3 x) and stirred at 110 ° C for 16 h. The mixture was cooled, filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in acetone (10 ml) and washed with hexane (15 ml). The hexane fraction was extracted in acetonitrile (3 x 10 ml) and the combined acetonitrile fractions were treated with methanol (5%, 2 ml) potassium fluoride. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane / EtOAc (90:10), to give the title compound as an oil. * H NMR (360 MHz, CDCb) d 1.47 (9H, s), 1.77 (3H, m), 1.84 (1H, m), 2.25 (1H, td), 2.64 ( 1H, dd, J 12.8, 7.7 Hz), 2.76 (1H, td), 3.79 (1H, qn), 3.90 (1H, t, J 8.5 Hz), 3, 96 (1H, dd), 4.24 (1H, t, J 8.0 Hz), 5.34 (1H, s), 5.37 (1H, d, and 11.1 Hz), 5.59 ( 1H, d, J 17.2 Hz), 6.98 (1H, dd, J 17.2, 10.9 Hz), 7.08 (1H, d), 7.15 (1H, s), 7, 25 (1H, m), 7.33 (2H, t, J 7.4), 7.45 (1H, d, J 8.6 Hz) and 7.60 (2H,?, J7.5 Hz) .

EXAMPLE 232 (3 -, 5 / ?, 65) -3- [2- (eten-l-ü) -5- (trifluoromethoxy) phenyl] -6-phenyl-l-oxa-7-aza-spiro hydrochloride [4 , 51decano Prepared from the compound of Example 231 according to the procedure of Example 181.? NMR (360 MHz, CD3OD) d 0.53 (1H, t, J 15.1 Hz), 0.73 (2H, m), 0.89 (1H, m), 1.09 (3H, m), 1.96 (1H, td, J 12.4 Hz), 2.16 (1H, dd, J 12.8 Hz), 2.52 (1H, t, 9.7 Hz), 2.78 (1H, t, J 7.1 Hz), 3.08 (1H, s), 3.90 (1H, d, J 11.0 Hz), 4.18 (1H, d, and 17.2 Hz), 4, 83 (1H, dd, J 17.2, 10.9 Hz), 5.83 (2H, m), 6.17 (1H, d, J 8.5 Hz) and 6.34 (5H, m). m / z (ES +) 404 (M + l).

EXAMPLE 233 (-? R, 5 / ?, 65) -3-F2-Acetyl-5- (trifluoromethoxy) phenyl] -6-phene-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4,5 ] decane A mixture of (iR, 5R, 65) -3- [5- (thiifluoromethoxy) -2- (trucluoromethylsulfonyl) phenyl] -6-phenyl-1-oxa-7 - (- 'g' c-butoxycarbon) aza -spiro [4, 5] decane (Example 188, 270 mg), (l-ethoxyvinyl) tributyl tin (0.15 ml), lithium chloride (108 mg) and tetrakis (triphenylphosphine) α-aladium (0) (50 mg) in dioxane ( 2 ml), was degassed with an iron pyrite valve (3 x) and stirred at 110 ° C for 16 h. The mixture was cooled, filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile (10 ml) and washed with hexane (15 ml). The hexane fraction was extracted with acetonitrile (3 x 10 ml) and the combined fractions of acetonithium were added with methanolic potassium fluoride (5%, 2 ml). The mixture was made and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 ml) and aqueous hydrochloric acid (6 M, 2 ml) was added. The mixture was stirred at room temperature for 4 h, basified with aqueous sodium hydrogen carbonate (saturated) and extracted with dichloromethene (3 x 10 ml). The combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by medium pressure liquid chromatography on silica gel, eluting with hexane / EtOAc (85:15), to give the title compound as an oil. ? NMR (360 MHz, CDCb) d 1.47 (9H, s), 1.72 (3H, m), 1.81 (1H, dd, J 12.9, 8.3 Hz), 2.22 (1H, td), 2.58 (3H, s), 2.72 (1H, dd, J 12.9, 8.3 Hz), 2.76 (1H, td, 12.6 Hz), 3.86 (1H, dd, J 8.8, 6.6 Hz), 4.00 (1H, dd), 4.09 (1H, qn) , 4.24 (1H, dd, and 8.8, 7.3 Hz), 5.29 (1H, s), 7.14 (1H, d, J 8.6 Hz), 7.25 (1H, m), 7.34 (3H, m), 7.58 (2H, d, and 7.8 Hz) and 7.61 (1H, d, and 8.6 Hz).

EXAMPLE 234 (3R, 5J?, 65) -3- [2-Acetyl-5- (trifluoromethoxy) fenu] -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the compound of Example 233 according to the procedure of Example 181. i H NMR (360 MHz, CDC b) d 1.69 (3 H, m), 1.99 (1 H, m), 2.24 (3 H, s), 2, 29 (1H, dd, J 13.1, 8.3 Hz), 2.45 (2H, m), 2.84 (1H, t), 3.39 (1H, d), 3.67 (1H, t, and 8.9 Hz), 3.87 (1H, s), 3.99 (1H, t, J 7.6 Hz), 7.05 (1H, d, J 8.4 Hz), 7, 08 (1H, s), 7.37 (4H, m) and 7.59 (2H, d, J 7.1 Hz). m / z (ES +) 420 (M + 1).

EXAMPLE 235 (3 / ?, 5 / ?, 65) -3- [2-Formyl-5- (trifluoromethoxy) phenyl] -6-phen-1-oxa-7 - (- 'grc-butoxycarbon) aza-spiro [4, 5] decane A stirred and cooled mixture (-78 ° C) of (iR, 5R, 65) -3- [2- (ethe-l-yl) -5- (trifluoromethoxy) fenu] -6-phen-l- oxa-7 - (? grc-butoxycarbon) aza-spiro [4.5] decane (Example 231, 420 mg) and methanol (4 ml) in dichloromethane (10 ml) was purged with nitrogen and then a stationary stream of ozone through the mixture for 1 h. The mixture was purged with oxygen for 15 min. and then with nitrogen for 15 min. Dimethyl sulphide (0.3 ml) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with hexane / EtOAc (85:15), to give the title compound as an oil. ? NMR (360 MHz, CDCb) d 1.48 (9H, s), 1.55 (2H, m), 1.72 (1H, d, J 9.5 Hz), 1.85 (1H, dd, J 13.0, 8.4 Hz), 2.25 (1H, m), 2.77 (2H, m), 3.97 (2H, m), 4.27 (1H, dd, J 9.0, 7.2 Hz), 4.53 (1H, qn, and 7.2 Hz), 5.36 (1H, s), 7.26 (2H, m), 7.34 (2H, m), 7, 59 (1H, d, and 7.6 Hz), 7.87 (1H, d, J 8.5 Hz) and 10.26 (1H, s). m / z (ES +) 450 (M + 1-QHβ).

EXAMPLE 236 (iR, 5R, 6-γ -3- [2-Formu-5- (ti-ifluoromethoxy) phenyl-6-phenyl-1-oxa-7-aza-spiro [4.5] decane Prepared from the compound of Example 235 according to the procedure of Example 181.? NMR (360 MHz, CDCb) d 1.59 (3H, m), 2.20 (3H, m), 2.25 (1H, dd, and 12, 7 Hz), 2.80 (2H, m), 3.56 (1H, s), 3.72 (1H, t, and 9.8 Hz), 3.97 (1H, t, and 7.8 Hz ), 7.10 (2H, s), 7.38 (3H, m), 7.50 (2H, dd, J 7.7, 3.0 Hz), 7.78 (1H, d, J 9, 3 Hz) and 9.53 (1H, s) m / z (ES +) 406 (M + l).

EXAMPLE 237 (3?, 5i?, 65) -3- (3-Fluoro-2-methoxy-5- (thiifluoromethoxy) fenu) -6-phene-l-oxa-7aza-es? Iro [4,5] decane was added Selectfluor ™ (630 mg) to a solution of (3i?, 5R, 65) -3- (2-methoxy-5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7- (tert-butoxycarbon) aza Spray [4.5] decane (Example 164, 208 mg) in acetonitrile (15 ml) and the mixture was refluxed for 36 h. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by medium pressure liquid chromatography on silica gel, eluting with CH2? 2 / MeOH (92: 8), to give the title compound as a light brown oil (15 mg). JH NMR (360 MHz, CDCb) d 1.46-1.56 (1H, m), 1.0-1.75 (3H, m), 1.98-2.02 (1H, m), 2, 16-2.37 (3H, m), 2.86 (1H, t, J 12.6 Hz), 3.20-3.24 (1H, m), 3.49 (3H, s), 3, 56 (1H, s), 3.98 (1H, t, and 7.6 Hz), 6.64 (1H, s), 6.28 (1H, d, J 11 Hz) and 7.25-7, 60 (5H, m). m / z (ES +) 426 (M + 1).

EXAMPLE 238 (3R, 5R, 65) -3- [2-Cyano-5- (trifluoromethoxy) fenu] -6-phen-1-oxa-7 - (- 'g / -c-butoxycarbon) aza-spiro [4,5 ] decane A mixture of (K, 5 / ?, 65) -3- [5- (trifluoromethoxy) -2- (trifluoromethylsulfoxy) phenyl] -6-phenyl-1-oxa-7- (1-carboethoxycarbon) aza - spiro [4.5] decane (Example 188, 230 mg), zinc cyanide (26 mg), thiis (dibenzidene acetone) di? ally (0) (10 mg) and 1, 1-bis (diphenylphosphino) ferrocene (16 mg) in DMF (1 ml) was degassed with an iron pyrite valve (x 5) and stirred at 110 ° C for 4 h. The mixture was cooled, ducted with water and extracted with ethyl acetate (3 x 5 ml). The combined organic fractions were washed with brine, dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by medium pressure liquid chromatography on silica gel, eluting with hexane / EtOAc (90:10), to give the title compound as a colorless oil (60 mg). * H NMR (360 MHz, CDCb) d 1.48 (9H, s), 1.56-1.68 (1H, m), 1.70-1.80 (2H, m), 1.88 (1H , dd, J 13.2, 8.0 Hz), 2.26 (1H, dt, J 13.0, 5.0 Hz), 2.76-2.85 (2H, m), 3.93- 4.01 (3H, m), 4.28-4.35 (1H, m), 5.34 (1H, s), 7.10-7.20 (1H, m), 7.24-7, 3 (1H, m), 7.31-7.36 (3H, m), 7.57-7.60 (2H, m) and 7.68 (1H, d, J 8.6 Hz). m / z (ES +) 447 (M + 1-QH8).

EXAMPLE 239 (3R.5R, 65) -3-r2-Cyano-5- (thiifluoromethoxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro4,5] decane Prepared from the compound of Example 238 in accordance with the procedure of Example 181. iH NMR (360 MHz, CDCb) d 1.60-1.73 (2H, m), 1.86 (2H, me), 1.98-2.07 (1H, m), 2.36-2.54 (2H, m), 2.79 (1H, t, J 12 Hz), 3.19-3.25 (1H, m), 3.56 (1H, s), 3.71 (1H, t, J 9.0 Hz), 4.03 (1H, t, J 8.0 Hz), 7.00-7.1 (2H, m ), 7.30-7.40 (3H, m), 7.46-7.51 (2H, m) and 7.55 (1H, d, J 8.5 Hz). m / z (ES +) 403 (M + 1).

EXAMPLE 240 (3R, 5R, 65) -3- [2-Etii-5- (thiouluoromethoxy) fenu1-6-fenu-l-oxa-7 - (- 'grc-butoxycarbonu) aza-spiro [4.5] decane was added a suspension of palladium hydroxide on carbon (100 mg) in methanol (2 ml) to a solution of (5 /? 5 /? 65) -3- [2- (eten-l-u) -5- ( thiifluoromethoxy) phenyl] -6-phene-1-oxa-7- (1 g / "c-butoxycarbon) aza-spiro [4.5] decane (example 231, 200 mg) in ethyl acetate (10 ml) and the mixture was stirred under hydrogen (50 psi) overnight, the mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound as an oil.? NMR (CDCb, 360 MHz), d 1.20 (3H, t, J 7.6 Hz), 1.46 (9H, s), 1.63 (2H, m), 1.79 (2H, m), 2.27 (1H, td, J 7.6, 5.1 Hz), 2.67 (3H, m), 2.76 (1H, td, and 9.3, 3.9 Hz), 3.72 (1H, qn, J 8, 0 Hz), 3.89 (1H, t, and 8.6 Hz), 3.97 (1H, dd, and 13.1 Hz), 4.24 (1H, t, J 7.8 Hz), 5 , 35 (1H, s), 7.01 (1H, d, and 8.7 Hz), 7.17 (2H, m), 7.25 (1H, m), 7.33 (2H, t, J 7.1 Hz), 7.60 (2H, d, J 7.7 Hz) m / z (ES +) 450 (M + 1-Hβ) .

EXAMPLE 241 (3j?, 5R, 65) -3- [2-Ethyl-5- (thiifluorom.etoxy) fenu] -6-phenyl-l-oxa-7-aza-es? Iro [4,5] decane Prepared from of the compound of Example 240 according to the procedure of Example 181.? NMR (360 MHz, CDCl 3) d 0.78 (3H, t, J 7.6 Hz), 1.53 (1H, m), 1.34 (3H, m), 1.71 (1H, td, and 12.2, 4.5 Hz), 2.02 (2H, q, J 7.6 Hz), 2.18 (2H, m), 2.80 (1H, t, and 12.3 Hz), 3 , 22 (1H, d), 3.53 (1H, s), 3.60 (1H, t, J 10.3 Hz), 3.91 (1H, t, J 7.7 Hz), 6.89 (2H, m), 6.99 (1H, d, J 8.4 Hz), 7.30 (3H, m) and 7.47 (2H, m). m / z (ES +) 406 (M + 1).

EXAMPLE 242 (3R, 5R, 65) -3- (6-Fluoro-2-methoxyphenyl) -6-phen-1-oxa-7 - (-, grc-butoxycarbonyl) aza-spiro [4,5] decane Prepared from Description 121 and (5R, 65) -6-phene-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4.5] dec-3-ene (Description 86) according to the procedure of Example 170 .? NMR (360 MHz, CDCb) d 7.63 (2H, d, J 7.8 Hz), 7.32-7.11 (6H, m), 5.36 (1H, s), 4.18-3 , 96 (4H, m), 3.83 (3H, s), 2.80 (1H, m), 2.42 (1H, m), 2.23 (2H, m), 1.88-1, 64 (3H, m) and 1.48 (9H, s). m / z (ES +) 442 (M + 1).

EXAMPLE 243 (3i?, 5i?, 65) -3- (6-Fluoro-2-methoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4y5] decane Prepared from the compound of Example 242 in accordance with the procedure of Example 181. iH NMR (360 MHz, CDCb) d 7.47 (2H, m), 7.34 (3H, m), 7.02 (1H, dt, Jd 6.4 Hz, y, 8 , 3 Hz), 6.52 (2H, m), 3.99 (1H, m), 3.77 (1H, m), 3.63 (3H, s), 3.55 (1H, s), 3.22 (1H, m), 2.78 (1H, m), 2.70 (1H, sa), 2.06 (1H, m) and 2.12 (6H, m). m / z (ES-) 342 (M + 1).

EXAMPLE 244 (35.5i ?, 65) -3- [2-Cyclopropoxy-5- (trifluoromethoxy) fenu] -6-phen-1-oxa-7- (< 'g / -c-butoxycarbonyl) aza-es piro [ 4.5] decane Naphthelene (120 mg, 0.936 mmol) was dissolved in THF (1.5 ml) under nitrogen and freshly cut lithium methanol (7.0 mg, 0.94 mmol) was added. The mixture is then sonicated at room temperature for 20 min. to produce a dark green solution of lithium naphthalenide. This solution was cooled to -78 ° C, then (35, d ^ or - ^ - Sp-1-phenylthiocyclopropyl-1-xi-S- ^ O-uoromethoxy-phenyl-or-phenyl-1-oxa-7 was added. (/ grc-butoxycarbon) aza-spiro [4.5] decane (Description 111) (120 mg, 0.187 mmol) in THF (0.5 ml) for 1 minute The reaction mixture was stirred for 30 min. Water (5 ml) and ether (10 ml) were added The layers were separated and the aqueous layer was extracted with ether (10 ml) The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / ethyl acetate (90:10 increasing to 80:20) to give the title compound as a colorless oil (58.6 mg, 59% ). ? NMR (250 MHz, CDCb) d 7.58-7.52 (2H, m), 7.36-7.17 (4H, m), 7.10-7.01 (2H, m), 5.18 (1H, sa), 4.20 (1H, t, J 6.7 Hz), 4.05-3.95 (1H, m), 3.76-3.55 (3H, m), 2.92-2.79 (1H, m), 2.37 (1H, dd, J 12.9, 7.8 Hz), 2.18-2.06 (2H, m) , 1.80-1.67 (3H, m), 1.38 (9H, s) and 0.86-0.73 (4H, m). m / z (ES +) 534 (M + 1).

EXAMPLE 245 Hydrochloride of (35, 5 - / ?, 65) -3- [2-cyclopropoxy-5- (thiifluoromethoxy) fenu] -6-phene-l-oxa-7-aza-spiro [4,5] decane was added Trifluoroacetic acid (2.5 ml) was added dropwise to a stirred and cooled (0 ° C) solution of (35.5 [beta], 65) -3- [2-cyclopropoxy-5- (trifluoromethoxy) phen] -6-phenol. l-oxa-7- (tert-butoxycarbon) aza-spiro [4.5] decane (Example 244, 492 mg, 0.92 mmol) in dichloromethane (25 ml) and the mixture was stirred at room temperature for 3 h. The mixture was poured into water (50 ml), the pH was adjusted to 10.0 with aqueous sodium hydroxide (4 M) and the mixture was extracted with dichloromethene (3 x 50 ml). The combined organic fractions were dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2C / MeOH / NH3 (Ac) (96: 4: 0.4 increasing to 94: 6: 0.6). The residue was dissolved in ethanol (20 ml), cooled on ice and ethereal hydrogen chloride (1 M, 1.8 ml, 1.8 mmol) was added dropwise. The mixture was stirred at 0 ° C for 5 min. and then the solvent was evaporated under reduced pressure. The residue was crystallized from ether (20 ml) / ethenol (0.5 ml) and the solid was collected and dried in vacuo to give the title compound as a colorless solid (354 mg, 89%). p.f. 214-216 ° C,? NMR (500 MHz, CD3OD) d 7.59 (2H, m), 7.52 (3H, m), 7.26 (1H, d, J 8.9 Hz), 7.03 (1H, dd, and 8.9, 2.2 Hz), 6.20 (1H, d, J 1.1 Hz), 4.85 (2H, sa), 4.43 (1H, s), 4.19 (1H, t , and 8.0 Hz), 3.87 (1H, quin, J 8.0 Hz), 3.76 (1H, m), 3.44 (1H, m), 3.25 (2H, m) 2 , 29-1.78 (6H, m), 0.80 (2H, m) and 0.66 (2H, m). m / z (ES +) 434 (M + 1). Found: C, 61.41; H, .51; N, 3.08, C? ßFsNOs.HCl requires: C, 61.34; H, 5.79; N, 2.98%.

EXAMPLE 246 (3R, 5R, 65) -3- [2-Cyclopropoxy-5- (trifluoromethoxy) fenu] -6-phene-1-oxa-7- (forte-butoxycarbon) aza-spiro [4,5] decane Naphthalene was dissolved (120 mg, 0.936 mmol) in THF (1.5 ml) under nitrogen and freshly cut lithium metal (7.0 mg, 0.94 mmol) was added. Then, the mixture is sonic at room temperature for 20 min. to produce a dark green solution of lithium naphthalenide. A solution of (3R, 5R, 65) -3- [2- (1-phenylthiocycloprop-1-y) oxy-5- (thiouluoromethoxy) phenyl] -6-phenyl-1-oxa-7 (1-g / -c) -butoxycarbonu) aza-spiro [4.5] decane (Description 112, 135 mg, 0.21 mmol) in THF (2 ml) under nitrogen was cooled to -78 ° C and added drop by drop to the naphthelenide solution of lithium in THF until the intense green color persisted. Then, the reaction was stirred for one minute, water (5 ml) was added and the mixture was warmed to room temperature. Ether (10 ml) was added and the layers separated. The aqueous phase was extracted with an additional portion of ether (10 ml), the combined organic phases were dried (MgSO 4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / ethyl acetate (50:50) to give the title compound as a colorless oil (87 mg, 78%). ? NMR (360 MHz, CDCb) d 7.59 (2H, d ap., J 7.6 Hz), 7.32 (2H, t ap., And 7.6 Hz), 7.27-7.18 (2H, m), 7.11-7.03 (2H, m), 5.32 (1H, sa), 4 , 29-4.21 (1H, m), 3.97 (1H, á a, J13 Hz), 3.83-3.68 (3H, m), 2.76 (1H, dt, J 13, 4 , 1 Hz), 2.55 (1H, dd, J 13, 7.2 Hz), 2.22 (1H, dt, J 12, 5.2 Hz), 1.85 (1H, dd, J 13, 9.9 Hz), 1.80-1.63 ( 3H, m), 1.46 (9H, s) and 0.82-0.76 (4H, m). m / z (ES +) 534 (M + 1).

EXAMPLE 247 (3i? .5 / ?, 65) -3- [2-Cyclopropoxy-5- (trifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4, 5] decane Prepared from the compound of Example 246 according to the procedure of Example 245. iH NMR (360 MHz, CDCb) d 7.50-7.42 (2H, m), 7.36-7.26 (3H, m), 7.03 (1H, d, J 8.9 Hz), 6.95 (1H, day, J 8.9 Hz), 6.81 (1H, sa), 3.92 (1H , t, J 7.4 Hz), 3.62-3.53 (2H, m), 3.50 (1H, s), 3.20 (1H, dd, J 12, 4.2 Hz), 2 , 77 (1H, dt, J 12, 2.8 Hz), 2.30-1.93 (4H, m), 1.87 (1H, sa), 1.71-1.49 (3H, m) , 0.76-0.65 (2H, m) and 0.65-0.54 (2H, m). m / z (ES +) 434 (M + 1).

EXAMPLE 248 (35.5R, 65) -3- [2-Cyclopropoxy-5- (thifluoromethyl) phenyl] -6-phenyl-1-oxa-7- (tew-butoxycarbon) aza-spiro [4,5] decane Prepared from of the compound of Description 113 according to the procedure of Example 246. i H NMR (360 MHz, CDC b) d 7.54 (2 H, d, J 7.7 Hz), 7.46 (1 H, d, and 8, 2 Hz), 7.40 (1H, s), 7.33-7.24 (4H, m), 5.17 (1H, s), 4.20 (1H, t, J 7.2 Hz), 4.00 (1H, m), 3.78-3.60 (3H, m), 2.88 (1H, m), 2.39 (1H, dd, and 12.9, 7.8 Hz), 2.16 (2H, m), 1.73 (3H, m), 1.36 (9H, s) and 0.82 (4H, m).

EXAMPLE 249 (35.5 / ?, 65) -3- [2-Cyclopropoxy-5- (trifluoromethyl) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane Prepared from the compound of Example 248 according to the procedure of Example 245. iH NMR (360 MHz, CDCb) d 7.48-7.30 (6H, m), 7.16 (1H, d, and 8.5 Hz), 6, 53 (1H, s), 4.05 (1H, t, J 7.9 Hz), 3.78-3.66 (3H, m), 3.24 (1H, m), 3.06 (1H, dd, and 10.4, 8.2 Hz), 2.83 (1H, m), 2.6 (1H, sa), 2.08 (2H, m), 1.84 (2H, m), 1 , 61 (2H, m) and 0.74 (4H, m). m / z (ES +) 418 (M + 1).

EXAMPLE 250 (3 / ?, 5i?, 65) -3- [2-Cyclopropoxy-5- (difluoromethoxy) fenu] -6-phene-1-oxa-7- (fórc-butoxicarbonü) aza-es? Iro [4,5 ] decane Prepared from the compound of Description 114 according to the procedure of Example 246. * H NMR (360 MHz, CDCb) d 7.60 (2H, d, J 7.5 Hz), 7.32 (2H , t, and 7.5 Hz), 7.24 (1H, t, J 7.5 Hz), 7.18 (1H, d, and 8.7 Hz), 7.02 (1H, d, and 2 , 8 Hz), 6.98 (1H, dd, and 8.7, 2.8 Hz), 6.43 (1H, t, J 74.4 Hz), 5.32 (1H, s), 4, 25 (1H, m), 3.97 (1H, m), 3.81-3.69 (3H, m), 2.75 (1H, m), 2.54 (1H, m), 2, 22 (1H, m), 1.89-1.62 (4H, m), 1.46 (9H, s) and 0.77 (4H, m). m / z (ES +) 516 (M + 1).

EXAMPLE 251 (3R 5R, 65) -3- [2-Cyclopropoxy-5- (difluoromethoxy) fenu] -6-phenyl-1-oxa-7-aza-spiro [4,5] decane Hydrochloride Prepared from the Compound of Example 250 according to the procedure of Example 245, (360 MHz, D20) d 0.51 (2H, m), 0.72 (2H, m), 1.79 (1H, m), 1.90-2, 28 (6H, m), 3.21 (1H, m), 3.50 (1H, m), 3.65 (2H, m), 4.00 (1H, m), 4.26 (1H, s) ), 6.66 (1H, t, and 74 Hz), 6.93 (1H, d, J 1.7 Hz), 7.01 (1H, dd, and 8.9, 2.7 Hz), 7, 18 (1H, d, J 8.9 Hz) and 7.55 (5H, m). m / z (ES +) 416 (M + 1). Found: C, 62.2; H, 6.2; N, 3.1, C24H27F2N? 3.HC1.0.5H2O requires: C, 62.5; H, 6.3; N, 3.0%.

EXAMPLE 252 (3-R.5R, 65) -3- [2-Cyclopropoxy-5- (thiifluoromethoxy) fenu] -6- (4-fluorofenu) -l-oxa-7 - (- 'grc-butoxycarbonu) aza-spiro [ 4,5] decane Prepared from the compound of Description 115 according to the procedure of Example 246.? NMR (360 MHz, CDCb) d 0.79 (2H, m), 0.86 (2H, m), 1.46 (9H, s), 1.68 (3H, m), 1.87 (1H, dd, and 9.9 Hz), 2.14 (1H, td), 2.53 (1H, dd, J 12.6 Hz), 3.77 (3H, m), 3.98 (1H, dd) , 4.24 (1H, s), 5.20 (1H, s), 7.00 (2H, t, J 8.8 Hz), 7.08 (2H, s), 7.23 (2H, d) , J 9.5 Hz) and 7.55 (2H, dd, and 8.7, 5.6 Hz).

EXAMPLE 253 (3R, 5 - ^, 65) -3- [2-Cyclopropoxy-5- (trifluoromethoxy) fenu] -6- (4-fluorophenyl) -l-oxa-7-aza-es? Iro hydrochloride [4,5 ] dean Prepared from the compound of Example 252 according to the procedure of Example 245.? NMR (400 MHz, CDCb) d 0.59 (2H, s), 0.74 (2H, d, and 6.28 Hz), 1.68 (3H, m), 2.05 (2H, m), 2.21 (1H, m), 2.42 (1H, dd, and 13.4 Hz), 2.87 (1H, dd, and 9.2 Hz), 3.39 (1H, d, J 10, 2 Hz), 3.59 (2H, m), 3.87 (1H, d, J 10.4 Hz), 4.00 (1H, t, J 7.7 Hz), 6.77 (1H, s ), 7.03 (4H, m), 7.61 (2H, s), 9.21 (1H, s) and 10.24 (1H, s).

EXAMPLE 254 (3R, 5R, 65) -3- [2-Cyclopropoxy-5- (thiifluoromethy) phenyl] -6-phenyl-1-oxa-7- (fórc-butoxicarbonü) aza-spiro [4,5] decane Prepared from of the compound of Description 120 according to the procedure of Example 246. i H NMR (360 MHz, CDCl 3) d 0.83-0.91 (4H, m), 1.46 (9H, s), 1.55- 1.8 (3H, m), 1.86-1.92 (1H, m), 2.22 (1H, dt, and 13.0, 5.0 Hz), 2.56 (1H, dd, and 12.0, 6.5 Hz), 2.76 (1H, me), 3.77-3.80 (3H, m), 3.97 (1H, me), 4.27 (1H, me), 5.33 (1H, s), 7.24-7.34 (4H, m), 7.45-7.50 (2H, m) and 7.58-7.62 (2H, m). m / z (ES +) 462 (M + l- EXAMPLE 255 (3 / ?, 5R, 65) -3- [2-Cyclopropoxy-5- (thiifluoromethyl) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane Prepared from the compound of Example 254 according to the procedure of Example 245. iH NMR (360 MHz, CDCb) d 0.56-0.70 (2H, m), 0.70-0.80 (2H, m), 1.62- 1.72 (3H, m), 1.96-2.04 (1H, m), 2.08-2.28 (3H, m), 2.81 (1H, t, J 12.0 Hz), 3.14-3.22 (1H, m), 3.58-3.68 (2H, m), 3.76 (1H, s), 4.00 (1H, t, J 7.5 Hz), 7.10-7.20 (2H, m), 7.26-7.42 (4H, m) and 7.42-7.54 (2H, m). m / z (ES +) 418 (M + 1).

Claims (22)

NOVELTY OF THE INVENTION CLAIMS; •

1. - A compound of the formula (I): (1. in which: R1 represents hydrogen, hydroxy, Ci-ß alkyl, C2-β alkenyl, C3-7 cycloalkyl, Cj-7-alkyl cycloalkyl, alkoxy-β, fluoro-alkoxy-β, alkoxy-β- C1-4 alley, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4-fluoro-alkoxy-C 1-4 alkyl, C 2-6 alkenyloxy, C 3-7 cycloalkoxy, C 3-7 cycloalkyl-C 1-4 alkoxy, phenoxy, benzyloxy, cyano, halogen, NR * Rb, SR ", SOR", S02Ra, OS02Ra, NRaCORi *, COR ", C02R" or CONR "R>, where each R" and Ri > independently represents hydrogen, alkyl 4 or fluoro-C 1-4 alkyl; R2 represents hydrogen, halogen, alkyl-β or Ci-β alkoxy; or when R2 is adjacent to R1, 15 can be linked together in such a way that a saturated or unsaturated 5 or 6-member ring is formed, which contains one or two atoms selected from nitrogen, oxygen and sulfur, which is optionally substituted by a group selected from alkyl C ? -4, CF3, = 0 or = S; R3 represents hydrogen, halogen, O-β alkyl, fluoro-alkyl-β, alkoxy O-β, fluoro-alkoxy Ci-β, cycloalkyl C3-7, cycloalkyl C3-7- 20 alky1-4, cyano, SR ", SOR ", SO2R", NR "Rb, NR" COR ", COR", CO2R ", CONR" Rb or C ¼ -4 alkyl substituted by cyano, C? 2Ra or CONRaRb, where Ra and Rb are as previously defined; R4 represents hydrogen, halogen, Ci-β alkyl, Ci-β alkoxy, CF3, OCF3, NO2, CN, SRa, SOR ", S02Ra, COzRa, CONRaRb, C2-β alkenyl, C2-β alkyne or C1-4 alkyi substituted by C1-4 alkoxy, where Ra and Rb are as previously defined; represents hydrogen, halogen, Ci-ß alkyl, CF3 or Ci-β alkoxy substituted by C1-4 alkoxy, R6 represents hydrogen, CORa, C02Ra, COCONRaRb, COC02R, alkyl-β optionally substituted by a group selected from (C02Ra, CONR "R, hydroxy, CN, COR", NRaR, C (NOH) NRaRb, CONHfenü (alkyl) Cw), COCOzRa, CONHNRaR, C (S) NRaRb, CONRaalquio C? -6R12, CONR ^ alkenuo C2-6, CONRiSalquinüo C2-ß, COCONR "R, CONRaC (NR) NRaR, CONR" heteroaru and phenol optionally substituted by one , two or three substituents selected from the Ci-ß alkyl, Ci-β alkoxy, halogen and trifluoromethyl); or R6 represents a group of the formula -CH2C = CCH2NR7R8 where R7 and R8 are as defined above; or R6 represents Q-β alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by = 0 or = S and optionally substituted by a group of the ZNR7R8 formula wherein: Z is Ci-β alkyne or C3-6 cycloalkyl; R7 is hydrogen or C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl or C2-4 alkyl substituted by C1-4 alkoxy or hydroxyl; R8 is hydrogen or alkyl -4, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyloxy or C2-4 alkyi substituted by C1-4 alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring, containing one or two heteroatoms selected from N, O, and S; or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring having from 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or C1-4 alkoxy, optionally substituted by a C1-alkoxy group -4 or hydroxy and optionally containing a double bond, annulus which may optionally contain an oxygen or sulfur atom in the ring, a group S (O) or S (0) 2, or a second nitrogen atom which will form part of an NH or NRC radical, where R c is C 1-4 alky optionally substituted by hydroxy or Cu alkoxy; or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 atoms in the ring; or Z, R7 and the nitrogen atom to which they are attached, form heteroaliphatic ring with from 4 to 7 atoms in the ring, which may optionally contain an oxygen atom in the ring; each of R9 and R10 represents, independently, hydrogen, halogen, alkyl Ci-β, CH2ORe, oxo, C02Ra or CONR "Rb, where Ra and Rb are as previously defined and Re represents hydrogen, alkyl O-ß or phenol; R12 represents ORa, CONRaRb or heteroaryl; R13 represents hydrogen or C1-6 alkyl; R 14 represents alkyl Ci-β, alkoxy Ci-β, fluoro-alkyl-6 or phenyl; X is an oxygen atom or two hydrogen atoms; and the line of thiazos represents an optional double bond; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R1 is hydroxy, alkyl-β, C2-β alkenyl, alkoxy-6, fluoro-alkoxy Ci-β, alkenoxy C2-6, cycloalkoxy C3-7, cycloalkyl C-7-C 1-4 -alkoxy, Ci-mo, NRaRb, SRa, OS02Ra, or R 1 together with the group R 2 form a 5-membered saturated ring containing an oxygen atom.

3. A compound according to claim 1 or claim 2, wherein R2 is a fluorine or chlorine atom.

4. A compound according to any one of claims 1 to 3, wherein R3 is hydrogen, halogen, fluoroalkyl C? -6, fluoro-alkoxy C? -6, cyano, NRaR, or NR "COR *4.

5. - A compound according to any one of claims 1 to 4, wherein R 4 is a hydrogen atom or a fluorine atom.

6. A compound according to any one of claims 1 to 5, wherein R5 is a hydrogen atom.

7. A compound according to any one of claims 1 to 6, wherein R6 is a hydrogen atom or a Ci-β alkyl group, substituted by a 5-membered heterocyclic group containing 2 or 3 carbon atoms. nitrogen, as defined in claim 1.

8. A compound according to any one of the 10 claims 1 to 7, wherein one of R9 and R10 is hydrogen.

9. A compound according to any one of claims 1 to 8, wherein X represents two hydrogen atoms.

10. A compound according to any one of claims 1 to 9, wherein the double bond represented by the line of thiazos 15 is absent.

11. A compound of the formula (Ia) or a pharmaceutically acceptable salt thereof: (la) wherein R1, R2, R3, R4 and the broken line are as defined in claim 1.

12. A compound according to claim 1, wherein R1 represents hydrogen, hydroxy, O-βalkyl, C2-6alkenyl, C3-7 cycloalkyl, C-cycloalkylC4alkyl, Q-βalkoxy, fluoro-alkoxy Q-β, alkoxy O-β-C1- alkyl 4, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4-fluoro-alkoxy-C 1-4 alkyl, C 2-7 alkenyloxy, cycloalkoxy C3-7, C3-7 cycloalkyl-C1-4 alkoxy, phenoxy, benzyloxy, cyano, halogen, NRaRb, SRa, SORa, S02Ra, OS02R ", NR" COR14, COR ", C02Ra or CONR" R, wherein each Ra and Rb independently represents hydrogen, C1-4alkyl or fluoroalkyl4-4; R2 represents hydrogen or halogen; or when R2 is adjacent to R1, they can be joined together in such a way that a 5-membered unsaturated ring containing an oxygen atom is formed; R 3 represents hydrogen, halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkoxy, C 1-6 fluoro-alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alky, cyano, SR a, SOR ", S02R", NRaRb, NR "CORw, COR", C02R ", CONR" Rb or C1-4 alky substituted by cyano, CO2R "or CONR" Rb, where Ra and Rb are as previously defined; R4 represents hydrogen or halogen; R5 represents hydrogen; R6 represents hydrogen or R6 represents Ci-β, substituted by a 5-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms and optionally substituted by a group of the formula ZNR7R8; R7 is hydrogen or C1-4 alkyl; R8 is hydrogen or C1-4 alkyl; each of R9 and R10 represents, independently, hydrogen; R 14 represents alkyl-β, C 1-6 alkoxy, C 1-6 fluoro-alkyl or phenol; X is an oxygen atom or two hydrogen atoms; Z is alkylene C, -, and the dotted line represents an optional double bond, or a pharmaceutically acceptable salt thereof.

13. - A compound selected from: 5R, 6S) -3- (2-methoxy-5-trifluoromethoxyuene) -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- (2-methoxy-5-thiifluoromethoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phenyl-7- (1, 2,4-thiazole-3-methylene) -l-oxa-7-aza-is? iro [4,5] dean; (5R, 6S) -3- (2-isopropoxy-5-trifluoromethoxyuene) -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene; (5R, 6S) -3- (2-alyloxy-5-thiifluoromethoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene; (5R, 6S) -3- (5-Trifluoromethoxy-2,3-dihydrobenzofuran-7-yl) -6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-ene; (5R, 6S) -3- (2-methoxy-5- (2,2,2-thiifluoroethoxy) fenu) -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene; (5R, 6S) -3- (2,5-bis (2,2,2-trifluoroethoxy) phen) -6-phenol-oxa-7-aza-spiro [4.5] dec-3-ene; (5R, 6S) -3- (2-difluoromethoxy-5-thiifluoromethoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) -3- (2- (2,2,2-trifluoroethoxy) -5-trifluoromethoxy-phenyl) -6-phene-1-oxa-7-aza-spiro [4,5] dec-3-ene; (3S, 5R, 6S) -3- (2-isopropoxy-5-thiifluoromethoxyuene) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- (5-Ti-fluoro-methoxy-2,3-d-idrobenzofuran-7-ü) -6-phe-l-oxa-7-aza-spiro [4,5] dean; (3S, 5R, 6S) -3- (2-methoxy-5- (2,2,2-thiifluoroethoxy) fenu) -6-phenyl-1-oxa-7-aza-spiroespiro [4,5] decane; (3S, 5R, 6S) -3- (2,5-bis (2,2,2-thiifluoroethoxy) fenu) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- (2-difluoromethoxy-5-trifluoromethoxyuene) -6-phenyl-1-oxa-7-aza-es-iro [4,5] decane; (3S, 5R, 6S) -3- (2- (2,2,2-trifluoroethoxy) -5-trifluoromethoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- (2- (2,2,2-thiifluoroethoxy) -5-fluorophenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) -3- (5-methanesulfonyl-2-methoxy: enu) -6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- (5-methanesulfonyl-2-methoxy: enu) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) -3- [2- (trifluoromethoxy) phenyl] -6-phenyl-l-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- [2- (Rifluoromethoxy) fenu] -6-phenyl-1-oxa-7-aza-es-iro [4,5] decane; (5R, 6S) -3- [2-cyclobutoxy-5- (trifluoromethoxy) phen] -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- [2-cyclobutoxy-5- (thiifluoromethoxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) -3- (2- (2-Fluoroethoxy) -5- (thiifluoromethoxy) fenu) -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- (2- (2-fluoroethoxy) -5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) -3- (2- (eten-l-ü) -5- (thiifluoromethoxy) fenu) -6-phene-l-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- (2-eti-5- (thiifluoromethoxy) fenu) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) -3- (2-Benzoxy-5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- (2-hydroxy-5- (thiifluoromethoxy) fenu) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- (2- (eten-1-ü) -5- (trifluoromethoxy) phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) -3- (2-methoxyphenyl) -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- (2-methoxyuene) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- (2-methoxy-5- (trifluoromethoxy) fenu) -6-phen-1-oxa-7-aza-spiro [4.5] decan-2-one; (5R, 6S) -N- [4-methoxy-3- (6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-en-3-yl) phenyl] -trifluoroacetamide; (3S, 5R, 6S) -N- [4-methoxy-3- (6-phenyl-1-oxa-7-aza-spiro [4.5] decan-3-yl) phenyl] -trifluoroacetamide; (3S, 5R, 6S) -N- [4-methoxy-3- (6-phen-1-oxa-7-aza-spiro [4.5] decan-3-ü) phen] -N- (metü) methylated carbamate; (5R, 6S) -N- [4-methoxy-3- (6-phen-1-oxa-7-aza-spiro [4,5] dec-3-en-3-ü) fenü] -N- ( metii) thiifluoroacetemide; (3S, 5R, 6S) -N- [4-methoxy-3- (6-phen-1-oxa-7-aza-spiro [4.5] decan-3-ü) phen] -N- (metü) trifluoroacetemide; (5R, 6S) -N- [4-isopropoxy-3- (6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-en-3-ü) phenyl] -N- ( metii) trifluoroacetemide; (3S, 5R, 6S) -N- [4-isopropoxy-3- (6-phenyl-1-oxa-7-aza-spiro [4,5] decan-3-ü) phenyl] -N- (meth) thiifluoroacetamide; (5R, 6S) -N- [4- (difluoromethoxy) -3- (6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-en-3-ü) phenyl] -N - (metü) tiü: Iuoroacetemida; (3S, 5R, 6S) -N- [4- (difluoromethoxy) -3- (6-phen-1-oxa-7-aza-spiro [4.5] decan-3-ü) phen] -N- ( metii) thiifluoroacetemide; (5R, 6S) -N- [4-methoxy-3- (6-phen-1-oxa-7-aza-spiro [4,5] dec-3-en-3-ü) fenü] -N- ( 2,2,2-tirfluoroetu) acetemide; (3S, 5R, 6S) -N- [4-methoxy-3- (6-phen-1-oxa-7-aza-spiro [4.5] decan-3-ü) phen] -N- (2, 2,2-thiifluoroeti) acetemide; (3S, 5R, 6S) -N- [4-methoxy-3- (6-phenyl-1-oxa-7-aza-spiro [4,5] decan-3-ü) phenyl] -N- (metü) benzamide; (5R, 6S) -3- [5-methylamino-2- (thiifluoromethoxy) fenu] -6-phenyl-1-oxa-7-aza-spiO [4.5] dec-3-ene; (3S, 5R, 6S) -3- [5-methylamino-2- (thiifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) -N-metii-N- [3- (6-phen-1-oxa-7-aza-spiro [4.5] dec-3-en-3-ü) -4- (trifluoromethoxy) fenu] trifluoroacetemide; (3S, 5R, 6S) -N-metii-N- [3- (6-phene-1-oxa-7-aza-spiro [4.5] decan-3-y) -4- (trifluoromethoxy) phenyl] thiifluoroacetemide; (5R, 6S) -3- [2-ethoxy-5- (thiifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- [2-ethoxy-5- (trifluoromethoxy) phen] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) -3- [2- (thi-fluoromethio) phenyl] -6-phe n-l-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- [2- (thiifluoromethotthio) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) -3- [2- (2,2,2-trifluoroethoxy) -5- (thiouluoromethyl) phenyl) -6-phenyl-1-oxa-7-aza-spiro [4,5] dec-3 -one; (3S, 5R, 6S) -3- [2- (2,2,2-trifluoroethoxy) -5- (thiouluoromethyl) phenyl) -6-phene-l-oxa-7-aza-spiro [4,5] decane; (5R, 6S) -3- [2-isopro-oxy-5- (trifluoromethyl) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- [2-isopropoxy-5- (trifluoromethyl) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [2-cyclopropyl-5- (trifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- (5-bromo-2-isopropoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- (5-Cyano-2-isopropoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [5-Cyano-2- (difluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [5-Cyano-2- (2,2,2-trifluoroethoxy) phen] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [5-Cyano-2- (cyclobutyloxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) -3- [2-cyano-5- (thiifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- [2- (Cyclopropyr-methyloxy) -5- (trifluoromethoxy) phenyl] -6-phenyl-1-oxa-7-aza-es-iro [4,5] decane; (3S, 5R, 6S) -3- [2-methoxy-5- (trifluoromethyl) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [2-methoxy-5- (trifluoromethyl) phenyl] -6-phenyl-1-oxa-7- (1, 2,4-triazol-3-methyl) -7-aza -spüO [4,5] dean; (5R, 6S) -3- (2-7-aza-spiro [4.5] decane; (5R, 6S) -3- [2-isopropoxy-5- (trifluoromethyl) phenyl] -6-phenyl-1- oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- [2-isopropoxy-5- (trifluoromethyl) phenyl] -6-phenyl-1-oxa-7 -aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [2-cyclopropyl-5- (trifluoromethoxy) phenyl] -6-phenyl-l-oxa-7-aza-spiro [4, 5] decane; (3S, 5R, 6S) -3- (5-bromo-2-isopropoxyphenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- (5-cyano-2-isopropoxyphenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [5-Cyano-2- (difluoromethoxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [5-Cyano-2- (2,2,2-trifluoroethoxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [5-Cyano-2- (cyclobutyloxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) -3- [2-cyano-5- (trifluoromethoxy) f-enyl] -6-f-enyl-1 -oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- [2- (cyclopropylmethyloxy) -5- (trifluoromethoxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [2-methoxy-5- (trifluoromethyl) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [2-methoxy-5- (trifluoromethyl) phenyl] -6-phenyl-l-oxa-7- (l, 2,4-triazolyl-3-methyl) -7-aza -spiro [4,5] dean; (5R, 6S) -3- (2-methanesulfonylphenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- (2-methanesulfonylphenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) - [4-hydroxy-3- (6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-en-3-yl) phenyl] -ethanoate methyl; (3S, 5R, 6S) - [4-hydroxy-3- (6-phenyl-1-oxa-7-aza-spiro [4.5] decan-3-yl) phenyl] -ethanoate methyl; (3S, 5R, 6S) -3- [5- (Cyanomethyl) -2-methoxyphenyl] -6-phenyl-l-oxa-7-aza-spiro [4.5] decane; (5R, 6S) - [4-methoxy-3- (6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-en-3-yl) phenyl] carboxamide; (3S, 5R, 6S) - [4-methoxy-3- (6-phenyl-1-oxa-7-aza-spiro [4.5] decan-3-yl) phenyl] carboxamide; (3S, 5R, 6S) -3- (5-cyano-2-methoxyphenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (5R, 6S) - [4-methoxy-3- (6-phenyl-1-oxa-7-a-za-spiro [4,5] dec-3-en-3-yl) phenyl] -ethanoate methyl; (3S, 5R, 6S) - [4-methoxy-3- (6-phenyl-1-oxa-7-aza-spiro [4.5] decan-3-yl) phenyl] ethanoate methyl; (3S, 5R, 6S) -3- (5- (trifluoromethoxy) -2- (trifluoromethylsulfonyloxy) phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -7-. { [5- (dimethylaminomethyl) -lH- [1,2,3] triazol-4-y] methyl} -3- [2-isopropoxy-5- (trifluoromethyl) phenyl] -6-phenyl-l-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [5-fluoro-2- (2,2,2-trifluoroethoxy) phenyl) -6-phenyl-1-oxa-7- (1, 2,4-triazolyl-3) methyl) -7-aza-spiro [4.5] decane; (5R, 6S) -3- [2-dimethylamino-5- (trifluoromethoxy) f-enyl] -6-f-enyl-l-oxa-7-aza-spiro [4.5] dec-3-ene; (3S, 5R, 6S) -3- [2-dimethylamino-5- (trifluoron-β-ethoxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; or a pharmaceutically acceptable salt thereof.

14. A compound selected from: (3R, 5R, 6S) -3- (2-methoxy-5- (trifluoromethoxy) phenyl) -6-phenyl-1-oxa-7-aza-spiro [4,5] decane; (3R, 5R, 6S) -3,6-bis (fenu) -l-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- (2-methoxyphenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -7-benzyl-3- (2-methoxy-5-trifluoromethoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- (2-methoxy-5- (trifluoromethyl) phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2-hydroxy-5- (thiifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- (5-hydroxy-2-isopropoxyuene) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2,4-bis (methoxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2-difluoromethoxy-5- (thiifluoromethoxy) phenyl] -6-phenyl-1-oxa-7-aza-is-iro [4,5] decane; (3R, 5R, 6S) -3- [2-isopropoxy-5- (trifluoromethoxy) phenyl] -6-phenyl-1-oxa-7-aza-is-iro [4,5] decane; (3R, 5R, 6S) -3- [2- (eten-l-ü) -5- (trifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4,5] decane; (3R, 5R, 6S) -3- [2,5- bis (difluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [5-fluoro-2- (difluoromethoxy) phen] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [5-fluoro-2- (2,2,2-thiifluoroethoxy) phen] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- (5-fluoro-2-isopropoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2-iso? Ro? Oxy-5- (2,2,2-thiifluoroethoxy) fenu] -6-phene-l-oxa-7-aza-spiro [4,5 ]dean; (3R, 5R, 6S) -3- [2,5-bis (isopropoxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- (5-chloro-2-methoxy-phenyl) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2- (2,2,2-thiifluoroethoxy) -5- (trifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4,5] decane; (3R, 5R, 6S) -3- [2- (cyclopromethoxy) -5- (trifluoromethoxy) fenu] -6-phenyl-1-oxa-7-aza-is-iro [4,5] decane; (3R, 5R, 6S) -3- [2-benzuboxy-5- (trifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [5- (difluoromethoxy) -2- (2,2,2-thiifluoroethoxy) phenyl] -6-phenyl-1-oxa-7-aza-spurious [4,5] decane; (3R, 5R, 6S) -3- [2- (2,2-difluoroethoxy) -5- (difluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2- (cyclobutoxy) -5- (trifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2- (2-methoxyethoxy) -5- (thiifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [5- (trifluoromethoxy) -2- (trifluoromethylsulfonuoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2- (2,2-ducluoroethoxy) -5- (trifluoromethoxy) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2-cyclopropyl-5- (thiifluoromethoxy) fenu] -6-phenyl-1-oxa-7-aza-sp.O [4.5] decane; (3R, 5R, 6S) -3- (5-cyano-2-hydroxyl) -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [5-Cyano-2- (2,2,2-trifluoroethoxy) phen] -6-phen-1-oxa-7-aza-spurious [4,5] decane; (3R, 5R, 6S) -3- (5-cyano-2-isopropoxy-7) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2- (eten-l-ü) -5- (trifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2-acetyl-5- (trifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2-formyl-5- (tr-ifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- (3-fluoro-2-? Netoxy-5- (thiifluoro-methoxy) fenu) -6-phen-1-oxa-7aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2-cyano-5- (thiifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2-eti-5- (tr-fluoromethoxy) fenu] -6-phenyl-1-oxa-7-aza-is-iro [4,5] decane; (3R, 5R, 6S) -3- (6-fluoro-2-methoxy-phenyl) -6-phen-1-oxa-7-aza-espyro [4,5] decane; or a pharmaceutically acceptable salt thereof.

15. A compound selected from: (3S, 5R, 6S) -3- (2-cyclopropoxy-5- (trifluoromethoxy) phenyl) -6-phenyl-1-oxa-7-aza-spiro [4,5] decane; (3R, 5R, 6S) -3- [2-cyclopropoxy-5- (thiifluoromethoxy) fenu] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3S, 5R, 6S) -3- [2-cyclopropoxy-5- (thiifluoromethyl) phenyl] -6-phen-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2-cyclopropoxy-5- (difluoromethoxy) fenu] -6-phenyl-1-oxa-7-aza-is-iro [4,5] decane; (3R, 5R, 6S) -3- [2-cyclopropoxy-5- (thiifluoromethoxy) fenu] -6- (4-fluorophenyl) -l-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S) -3- [2-cyclopropoxy-5- (trifluoromethyl) phenyl] -6-phenyl-1-oxa-7-aza-spiro [4.5] decane; or a pharmaceutically acceptable salt thereof.

16. - A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, together with a pharmaceutically acceptable carrier or excipient.

17. The use of a compound according to any one of claims 1 to 15, for the manufacture of a medicament for the treatment or prevention of a physiological disorder associated with an excess of tachykinins.

18. The use of a compound according to any one of claims 1 to 15, for the manufacture of a medicament for the treatment or prevention of pain or inflammation.

19. The use of a compound according to any one of claims 1 to 15, for the manufacture of a medicament for the treatment or prevention of migraine.

20. The use of a compound according to any one of claims 1 to 15, for the manufacture of a medicament for the treatment or prevention of emesis.

21. The use of a compound according to any one of claims 1 to 15, for the manufacture of a medicament for the treatment or prevention of post-herpetic neuralgia.

22. A process for the preparation of a compound according to claim 1, comprising: (A.l), where the double bond represented by the dotted line is absent, reducing a compound of the formula (UA) (HA) wherein R1, R2, R3, R4, R5, R6, R9, R10 and X are as defined in claim 1; or (A.2), where the double bond represented by the dotted line is absent and X is two hydrogen atoms, reducing a compound of the formula (IIB) (IIB) or (B) where the line of thiazos represents a double bond, reacting a compound of the formula (III) (III) wherein each R45 is a C1-4 alkyl group, with a compound of formula (IV) (IV) wherein R50 is a leaving group; or (C) by reacting a compound of formula (V) with a compound of formula (VI): LG-R6"(VI) wherein R6 is a group of the formula R, as defined in claim 1 (other than H) or a precursor thereof and LG is a leaving group, and if R63 is a group precursor, converting it into a R6 group, or (D), when R1 is C6-C6 alkoxy, Ci-β fluoro-alkoxy, C2-β alkenoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl-C3-4 alkoxy or benzyl oxy , reacting a compound of formula (VII) (VII) with a suitable alkyl, fluoroalkyl, alkenyl, cycloalkyl, cycloalkalkyl or aralkyl halide in the presence of a base; or (E), cyclizing a compound of formula (VIII) (VIII) using dehydrating reagents; or (F), when the line of thiazos represents tm double bond, dehydrating a compound of formula (IX) (IX) using an acid such as trifluoroacetic acid; or (G), when the double bond represented by the thiazole line is absent, reacting a compound of formula (X) (X) with a compound of formula (IV), under the conditions of a Heck reducing reaction; or (H), by reacting a compound of formula (XX) (XX) with lithium naphthelenide; continuing each procedure, when necessary, by removing any protective group when present; and when the compound of formula (I) is obtained as a mixture of enantiomers or diastereoisomers, optionally resolving the mixture to obtain the desired enantiomer; and / or, if desired, by pouring the resulting compound of formula (I) or a salt thereof, into a pharmaceutically acceptable salt thereof.