MXPA06012014A - Benzoxazocines and their therapeutic use as monoamine reuptake inhibitors - Google Patents

Abstract

Compounds having therapeutic utility are of general formula (1) wherein R, is H, C 1-C6 alkyl optionally substituted with F or C3-C6 cycloalkyl or C2-C4 alkenyl;A is O, CH2 or S(O)n where n is 0-2;one of W, X, Y and Z is N, CH or CR3 and the others are CH;R2 is C5-C6 heteroaryl, C5-C10 cycloalkyl or cycloalkenyl optionally containing one or more heteroatoms selected from O, N and S(O)n where n is 0-2, and optionally substituted with R3;or a phenyl group optionally substituted in one or more positions with one or more substituents independently selected from halogen, CN, CF3, C1-C6 alkyl and OR1, or the phenyl group is fused to a five or six membered ring which may be carbocyclic, heterocyclic (containing 1-2 heteroatoms selected from O, N and S), aromatic or heteroaromatic (containing 1-2 heteroatoms selected from O and N);R3 is selected from halogen;CF3;CN;OR5;SO2N(R5)2;COR5;CO2R5;CON(R5)2;NR1,COR4;NR1SO2R4;NR1CO2R4;NR1,CON(R5)2;OC1-C6 alkyl substituted with R3;C1-C6 alkyl optionally substituted with unsubstituted R3;C3-C6 cycloalkyl optionally substituted with unsubstituted R3;C2-Cs alkenyl optionally substituted with unsubstituted R3;C2-Cs alkynyl optionally substituted with unsubstituted R3;aryl optionally substituted with unsubstituted R3;and five or six membered aromatic heterocycles containing 1-4 heteroatoms selected from N and O;R4 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl and heteroaryl;and R5 is H, C1-C6 alkyl;C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl or heteroaryl and is the same as or different to another R5;or a pharmaceutically acceptable salt thereof.

Description

BENZOXAZOCINES AND THEIR THERAPEUTIC USE AS MONOAMINE RECAPTATION INHIBITORS Field of the Invention This invention relates to novel benzoxazocine compounds that inhibit the reuptake of monoamine. In particular, the compounds of the present invention exhibit activity as analgesic agents and also as anti-emetics but may also find utility in a range of other therapeutic indications. BACKGROUND OF THE INVENTION Nefopam, ie 5-methyl-l-phenyl-3, 4, 5, 6-tetrahydro-lH-2,5-benzoxazocine hydrochloride, is a centrally acting non-narcotic analgesic. WO 03/092689 discloses that the individual enantiomers of nefopam are useful for the treatment of pain and vomiting. WO 2004/056788 discloses nefopam derivatives. Your publication date is after the priority dates now claimed. Brief Description of the Invention The novel compounds according to this invention are of the general formula (1): wherein Ra is H, Ci-Cß alkyl optionally substituted with F or C3-C6 cycloalkyl or C2-C4 alkenyl; A is 0, CH2 or S (0) n where n is 0-2; one of W, X, Y and Z is N, CH or CR3 and the others are CH; R2 is C5-C6 heteroaryl, C5-C10 cycloalkyl or cycloalkenyl optionally containing one or more heteroatoms selected from O, N and S (0) n where n is 0-2, and optionally substituted with R3; or a phenyl group optionally substituted at one or more positions with one or more substituents independently selected from halogen, CN, CF3, Ci-Cß alkyl and OR ?, or the phenyl group is fused to a five or six membered ring which it can be carbocyclic, heterocyclic (containing 1-2 heteroatoms selected from O, N and S), aromatic or heteroaromatic (containing 1-2 heteroatoms, selected from O and N); R3 is selected from halogen; CF3; CN; OR5; S02N (R5) 2; C0R5; C02R5; CON (R5) 2; NR! C0R4; NR? S02R4; NR; LC02R4; NRiCON (Rs) 2; O-Ci-Cß alkyl substituted with R 3; C ± -Cβ alkyl optionally substituted with unsubstituted R3; C3-C6 cycloalkyl optionally substituted with unsubstituted R3; C2-C6 alkenyl optionally substituted with unsubstituted R3; C2-C6 alkynyl optionally substituted with unsubstituted R3; aryl optionally substituted with unsubstituted R3; and five or six membered aromatic heterocycles containing 1-4 heteroatoms selected from N and O; R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, aryl and heteroaryl; and R 5 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl / C 3 -C 5 cycloalkyl, aryl or heteroaryl and is the same as or different from another R 5; or a pharmaceutically acceptable salt thereof. The compounds described in WO 2004/056788 can be excluded, for example, those of the general formula: wherein Ri is H, C? -C6 alkyl, optionally substituted with F or C3-C6 cycloalkyl or C2-C6 alkenyl; any of R 2 and R 3 are the same or different and are H, a halogen, CN, CF 3, -C β alkyl or OR ?, or R 2 and R 3 form a five or six membered ring which may be carbocyclic, heterocyclic (which contains 1-2 heteroatoms taken from 0, N or S), aromatic or heteroaromatic (containing 1-2 heteroatoms taken from 0 and N); one of W, X, Y and Z is N, or CR4 and the others are each CH; R4 is a halogen atom, CF3, CN, 0R7, S02N (R6) 2, C0R6, C02R6 CON (R6) 2, NR1COR5, NR1SO2R5, NR? C02R5, NR? CON (R6) 2, 0-alkyl of Ci- Cß optionally substituted with R 4, Ci-Cg alkyl optionally substituted with R 4, C 3 -C 6 cycloalkyl optionally substituted with R 4, C 2 -C 6 alkenyl optionally substituted with R 4, C 2 -C 6 alkynyl optionally substituted with R 4, aryl optionally substituted with R4, or a five or six membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, linked either through carbon or. nitrogen; R5 is Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl or heteroaryl; each of R6 (which may be the same or different) is H, Ci-Cß alkyl, C 2 -C β alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl or heteroaryl; and R7 is aryl or heteroaryl; or a pharmaceutically acceptable salt thereof. The compounds of the invention have utility as therapeutic agents. The compositions containing them and their therapeutic use are additional aspects of the invention. In addition, the compounds of the formula (1) wherein R3 is a halogen atom such as Br are useful as intermediates. Description of Preferred Modes It will be appreciated that the compounds according to the invention contain an asymmetrically substituted carbon atom. The presence of this asymmetric center in a compound of the formula (1) can give rise to stereoisomers, and in each case the invention will be understood to extend to all of these stereoisomers, including enantiomers and diastereomers, and mixtures that include racemic mixtures and not racemic of them. As used in this specification, the term "C?-C6 alkyl" refers to a straight or branched chain alkyl portion having from one to six carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. The term "C5-C6 heteroaryl" refers to a aryl system of five or six atoms, of which at least one atom is selected from 0, N and S. This term includes, for example, pyridine, tetrahydropyran, etc. The term "C al-Cß alkenyl" refers to a straight or branched chain alkyl portion having from two to six carbon atoms and further having a double bond, of either the E or Z stereochemistry where applicable .

This term includes, for example, vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl, etc. The term "C2-C6 alkynyl" refers to a straight or branched chain alkyl moiety having from two to six carbon atoms and further having a triple bond. This term includes, for example, ethinyl, 1-propargyl, 1- and 2-butinyl, etc. The term "C3-Cs cycloalkyl" refers to a saturated alicyclic moiety having from three to six carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "C5-C? 0 cycloalkenyl" refers to an unsaturated alicyclic portion having from five to ten carbon atoms and at least one double bond and includes, for example, phenyl and the like. The term "aryl" means an optionally substituted phenyl or naphthyl group. The term "carbocyclic" refers to a portion saturated alicyclic having five or six carbon atoms and includes, for example, benzofused cyclopentyl and cyclohexyl and the like. The term "heterocyclic" refers to a saturated heterocyclic moiety having five or six atoms but containing one or more heteroatoms selected from N, 0 and S, and includes, for example, benzofused pyrrolidinyl, tetrahydrofuranyl, piperidinyl, dioxalane and the like. Similar. The term "heteroaromatic" refers to aromatic ring systems of five or six atoms of which at least one atom is selected from O, N and S, and includes, for example, pyrrolyl, pyridinyl, diazolyl, diazinyl, triazolyl, triazinyl benzofused, furanyl, furanyl, oxazolyl, isoxazolyl or oxadiazolyl as well as furanyl, thiophenyl, pyridyl, indolyl, pyridazinyl, piperazinyl, pyrimidinyl and the like, for example benzofuranyl, quinolinyl, isoquinolinyl or quinazolinyl. These rings can be linked either through carbon or nitrogen. The term "halogen" means fluorine, chlorine, bromine or iodine. The compounds of the general formula (1) can be prepared by any suitable method known in the art and / or by the processes described below. It will be appreciated that where a particular stereoisomer of formula (1) is required, the synthetic process described in present can be used with the appropriate homochiral starting material and / or isomers maybe resolved from mixtures using conventional separation techniques (for example, HPLC). In the description and formulas below, variables such as R1 R2, R3, R4, s / -A, W, X, Y and Z are as defined in the foregoing, except where indicated otherwise. It will be appreciated that functional groups, such as amino, hydroxyl or carboxyl groups, present in the various compounds described below, and which are desired to be retained, may need to be in protected form before any reaction is initiated. In such examples, the removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details, see "Protectíve Groups in Organic Synthesis", Wiley Interscience, T W Greene, PGM Wuts. A process for preparing the compounds of the general formula (1), wherein W, X, Y or Z is N or C-Br and A is O or S (0) n, comprises cyclization with acid (e.g. toluenesulfonic) of a diol (2) which in turn can be obtained by reducing ketone (3) with a suitable reducing agent. (2) (3) The reduction of a keto amide of the general formula (3) can be carried out with reagents well known to those familiar in the art of synthetic organic chemistry. An example of a highly reactive reducing agent is lithium aluminum hydride, although reagents based on borane (for example borane complex, tetrahydrofuran) or reduction of sodium borohydride (for example with a nickel or cobalt salt link) can be equally effective. Likewise, the reduction of ketone in (3), for example with sodium borohydride, followed by cyclization with acid, for example with p-toluenesulfonic acid, then the final reduction of the amide group, for example with borane, also leads to compounds of the general formula (1). Ketones (3) can be prepared by the condensation of a carboxylic acid (4) or an active derivative of it, with an amine (5). The active acid derivatives of the formula (4) include, for example, acid anhydrides or acid halides, such as acid chlorides.

The coupling reaction can be performed using standard conditions for amidation reactions of this type. Thus, the reaction can be carried out in a solvent, for example an inert organic solvent such as an ether, for example a cyclic ether such as tetrahydrofuran, an amide, for example a substituted amide such as dimethylformamide, or a halogenated hydrocarbon. such as dichloromethane at low temperature, for example -30 ° C at room temperature, such as -20 ° C to 0 ° C, optionally in the presence of a base such as, for example, an organic base such as an amine, for example triethylamine or a cyclic amine such as N-methylmorpholine. Where an acid (4) is used directly, the reaction can be further carried out in the presence of a condensing agent, for example a diimide such as N, N-dicyclohexylcarbodiimide, advantageously in the presence of a triazole such as 1-hydroxybenzotriazole. Alternatively, the acid can be reacted with a chloroformate, for example ethyl chloroformate, before reaction with the amine (5). The acids (4) can be prepared by the Friedel-Crafts acylation of R2 with an anhydride (7). This reaction is carried out in an inert solvent (such as dichloromethane) in the presence of an acid catalyst.

Lewis (such as aluminum trichloride). (7) It is well recognized by those skilled in the art that such reactions can provide product mixtures and in turn that these mixtures can often be separated by flash column chromatography. For example, where Y = C-Br, W = X = Z = CH and R2 is phenyl, Friedel-Crafts acylation under the catalysis of aluminum trichloride provides two isomeric bromides (4a) and (4b). These can be easily separated by column chromatography and independently progress to the compounds of the general formula (1), wherein X or Y is C-Br, by the route described previously , The compounds of the general formula (1) wherein one of W, X, Y and Z is C-hal such as C-Br represent flexible intermediates which can be used for the preparation of other compounds of the general formula (1). For example, these compounds can be regularly converted to the corresponding nitrile (R3 = CN) either by reaction with cuprous cyanide in a dipolar aprotic solvent such as N-methylpyrrolidinone (? MP) or under conditions catalyzed by palladium. The nitrile can easily be converted, by hydrolysis, to the primary amides (R3 = CO? H2), esters and the corresponding carboxylic acids (CO2R5) or to the corresponding tetrazoles, by treatment with a suitable azide donor such as azide. of sodium or trimethylsilyl azide. In addition, the compounds of the general formula (1) wherein one of W, X, Y and Z is C-hal such as C-Br can be lithium with n-, sec- or tert-butyl lithium in an inert organic solvent such as an ether, for example a cyclic ether such as tetrahydrofuran, at a very low temperature, for example -78 ° C. The treatment with either a carbon (for example carbon dioxide, N, N-dimethylformamide or paraformaldehyde), sulfur (for example S02C12, followed by amidation, such as with ammonia) or nitrogen (diphenylphosphoryl azide, followed by reduction , as with REDAL) provides access, by subsequent derivation, to derivatives where R3 is C02R5, CO? (R5), CH2OR5, S02? (R4) 2,? R? COR4,? RxCOsRs or? R? CO? ( R5) 2. In addition, compounds of the general formula (1) wherein one or W, X, Y and Z is C-hal such as C-Br can be subjected to palladium catalyzed coupling reactions with carbon-based coupling partners. Thus, these compounds can be coupled to alkenes of the general type CH2 = CHR3 under Heck conditions, to alkynes of the general type CH = CHR3 under Sonogoshira conditions, or to metalloheterocycles, for example where the metal is tin, under Stille coupling conditions. This gives access to compounds where R3 is optionally substituted C2-C6 alkenyl or C2-Ce alkynyl, or a five-membered aromatic heterocycle containing 1-4 heteroatoms selected from? (such as in pyrrole, diazoles, triazoles or tetrazoles) and O (such as in furan, oxazoles or oxadiazoles). Such reactions of coupling ensure that the chains and rings are bonded through carbon. In addition to the examples described above, additional compounds of the formula (1) can be prepared by the interconversion of other compounds of the formula (1). Thus, for example, a compound wherein R3 is alkyl can be prepared by hydrogenation (using palladium on carbon in a suitable solvent, such as an alcohol, for example ethanol) of a corresponding compound wherein R3 is alkenyl. Any of the mixtures of final products or intermediates obtained can be separated at the bases from the physico-chemical differences of the constituents, in a known manner, in the final products or intermediates, for example by means of chromatography, distillation, fractional crystallization, or by forming a salt if appropriate or under possible circumstances. The compounds according to the invention exhibit inhibitory activities in vi tro with respect to the reuptake of monoamine (ie noradrenaline, serotonin and dopamine). The activity and selectivity of the compounds can be determined by the use of an appropriate monoamine reuptake assay. This invention also relates to a method of treatment for patients (including man and / or animals) mammals reproduced in the dairy, meat or skin industries or as pets) suffering from disorders or diseases that can be attributed to monoamine reuptake as previously described, and more specifically, a method of treatment involving the administration of the inhibitor of monoamine reuptake of the formula (1) as the active constituents. Therefore, the compounds of the formula (1) may be useful in the treatment of pain and vomiting. The pain and related conditions that can be treated include syndromes characterized by chronic pain and fatigue, fibromyalgia, chronic fatigue syndrome, complex regional pain syndrome, irritable bowel syndrome, facial pain and atypical chest pain. The compounds may also find utility in the range of other therapeutic indications such as depression, post-traumatic stress disorders, attention-deficit disorders, compulsive obesity disorders, pre-menstrual syndrome, substance abuse and sexual dysfunction.; A method of treatment (by which means the treatment or prophylaxis) of disease or conditions mediated by monoamine reuptake in mammals, in particular in humans, comprising the method of administering to the mammal an effective amount of a compound of the formula (1) above, or a pharmaceutically acceptable salt of the same; and a compound of the formula (1) for use in medicine, human or veterinary, particularly in the treatment (whereby the treatment or prophylaxis is proposed) of diseases or conditions mediated by monoamine reuptake; and the use of a compound of the formula (.1) in the preparation of an agent for the treatment (by which means the treatment or prophylaxis) of diseases or conditions mediated by monoamine reuptake. The disease or conditions referred to above include pain, vomiting, depression, post-traumatic stress disorders, attention-deficit disorders, compulsive obesity disorders, pre-menstrual syndrome, substance abuse and sexual dysfunction. The compounds of the formula (1) can be administered orally, topically, buccally, ocularly, rectally, vaginally, parenterally, intra-nasally, sub-surgically or by pulverized inhalation, for example in dosage unit formulations containing pharmaceutically carriers, adjuvants and vehicles. acceptable non-toxic. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular injections, intrasternal injection or infusion techniques. Also for the treatment of warm blooded animals such as rat mouse, rats, horses, cattle, sheep, dogs, cats etc., the compounds of the invention are effective in the treatment of humans. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, tablets, or aqueous suspensions. oily, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The composition may be in the immediate form or controlled release. Compositions proposed for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. in order to provide excellent and pharmaceutically acceptable preparations. Tablets containing the active ingredient in mixtures with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; agents binders, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and the therapy provides a sustained action over a long period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated by the techniques described in US 4256108, US 4166452 and US 4265874 to form osmotic therapeutic tablets for controlled release. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixing with water or an oily medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; dispersing agents or humectants can be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols , for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those discussed above, and flavoring agents may be added to provide an acceptable oral preparation. Those compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be naturally occurring gums, for example acacia gum or tragacanth gum, naturally occurring phosphatides, for example, soybean, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, 'for example sorbitan monooleate and condensation products' of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with adulterant agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile aqueous or oleaginous injectable suspension. This suspension can be formulated according to the known art using those dispersing agents or suitable humectants and suspending agents that have been mentioned above. The sterile injectable preparation can also be in a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.

Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any soft fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable solutions. The compounds of formula (1) can also be administered in the form of suppositories for rectal administration of the drug. Those compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. These materials are cocoa butter and propylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc. containing the compounds of Formula (1) are employed. For purposes of this specification, topical application includes mouthwashes and gargles. Dosage levels in the range of about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in treating the conditions indicated above (approximately 2.5 mg to approximately 7 g per patient per day). For example, vomiting can be effectively treated by administering from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce an individual dosage form will vary depending on the host treated and the particular mode of administration. For example, a proposed formulation for the oral administration of humans may vary from about 5 to about 95 percent of the total composition. The Unit dosage forms will generally contain between about 1 mg to about 500 mg of an active ingredient. However, it will be understood, that the dose level specified for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, administration diet period, route of administration. administration, rate of excretion, combion of drug and the severity of the particular disease subjected to the therapy. The following Examples illustrate the invention. They include compounds that are in the following Table.

All 1H NMR were recorded in a Bruker AC250. All chemical shifts (d) have been rounded to 2 decimal places, and the coupling constants (J) are measured in Hz and the nearest 0.1 decimal place. EXAMPLE 1 5-Benzyl-1-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin To a stirred solution of desmethylnefopam (96 mg, 0.41 mmol) in DMF (3 ml ) were added sodium hydride (15 mg, 0.49 mmol) and then benzyl bromide (0.7 ml, 0.61 mmol). The resulting blue solution was heated at 65 ° C for 2 hours. The reaction was stopped by the addition of water and the organic extracts were extracted into dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to give the crude material. Purification by column chromatography on silica gel (1- »2% MeOH / DCM) provided the objective product (45 mg, 34%) as a brown oil. dH (CDCl3; 250MHz) 2.74-2.80 (1 H,, one of CH2), 2.96-3.00 (1H, m, one of CH2), 3.88-4.07 (4H, m, four of CH2), 4.27-4.36 (1H ,, one of CH2), 4.92 (1H, d, J12.7, one of ArCH2NR2), 5.82 (1H, s, CHOR), 7.05-7.07 (1H, m, aromatic H), 7.26-7.42 (11H, aromatic H), 7.56-7.60 (2H, m, aromatic H) Example 2 5-Allyl-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin Sodium hydride (24 mg , 1.01 mmol) was added to a solution of desmethylnefopam (200 mg, 0.84 mmol) at RT. The resulting mixture was stirred for 2 hours then allyl bromide (0.12 ml, 1.33 mmol) was added dropwise. The blue solution was heated at 65 ° C for two additional hours, then stopped with water. The aqueous mixture was extracted with dichloromethane and the combined extracts were dried (MgSO), filtered and concentrated in vacuo to provide the objective product (66 mg, 28%). dH (CDCl3; 250MHz) 2.90-3.13 (2H, m, two of CH2), 3.64 (2H, d, J6.1, two of CH2), 4.01 (1H, bd, J13.6, one of CH2), 4.26 (1H, d, J12.1, one of ArCH2NR2), 4.38-4.49 (1H,, one of CH2) , 5.01 (1H, d, J12.1, one of ArCH2NR2), 5.42-5.49 (2H, m, two H-terminal alkane), 5.77 (1H, s, CHOR), 6.27-6.37 (1H, m, Alkylene H), 7.11-7.39 (8H, aromatic H), 7.51 (1H, bs, aromatic H). Example 3 5-Cyclopropyl-1-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine Sodium cyanoborohydride (106 mg, 1.69 mmol) was added to a stirred suspension of desmethylnefopam (100 mg, 0.42 mmol), acetic acid (0.24 ml, 4.22 mmol), (1-ethoxycyclopropyloxy) trimethylsilane (0.51 ml, 2.53 mmol) and 4Á molecular sieves in methanol (1.5 ml). The resulting coffee solution was heated at reflux temperature overnight. The reaction mixture was quenched by the addition of the sodium bicarbonate solution and extracted into dichloromethane. The combined organic phases were dried (MgSO 4), filtered and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (DCM-t »2% MeOH / DCM) to provide the objective product (84 mg, 68%). dH (CDCl3; 250MHz) 0.56 (4H, bs, cyclopropyl CH2CH2), 1.90-1.94 (1H, m, cyclopropyl CH), 2.88 (1H, ddd, J14.3, 6.1, 2.7, one of CH2CH2), 3.00 (1H, ddd, J14 .3, 7.3, 2.1, one of CH2CH2), 3.87 (1H, ddd, 12.5, 6.1, 2.1, one of CH2CH2), 3.96 (1H, d, J12.8, one of ArCH2NR2), 4.15 (1H, ddd, J12.5, 7.3, 2.7, one of CH2CH2), 4.86 (1H, d, one of ArCH2NR2), 5.84 (1H, s, CHOR), 6.99-7.00 (1H, m, aromatic H), 7.18-7.30 (8H, aromatic H). EXAMPLE 4 5-Propyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 5-Allyl-1-phenyl-1, 3,4,6-tetrahydro- 5H-benz [f] -2,5-oxazocine (66 mg, 0.24 mmol) was dissolved in THF (4 ml) and 10% Pd / C (2 micro-spatulas) was added. The reaction was stirred in a vessel under a hydrogen atmosphere for 3 hours. After this time, the mixture was filtered and the filtrate was concentrated in vacuo. Purification of the crude mixture by silica gel column chromatography (DCM-5% MeOH / DCM) provided the objective product as a pale yellow oil (42 mg, 62%). dH (CDCl3; 250MHz) 1.03 (3H, t, J7.3, CH3), 1.99-2.10 (2H, two propyl CH2CH2), 2.96-3.22 (4H, m, two propyl CH2CH2 and two CH2CH2 rings) , 4.02-4.10 (1H, m, ArCH2NR2), 4.37-4.51 (2H, m, two of CH2CH2) 5.03-5.31 (1H, bs, one of ArCH2NR2), 5.77 (1H, CHOR), 7.15-7.18 (3H, , aromatic H), 7.27-7.40 (5H, m, aromatic H), 7.63 (1H, bs, aromatic H). Example 5 5-Methylcyclopropyl-1-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -oxazocine Desmethylphenopam (110 mg, 0.43 mmol) was dissolved in anhydrous DMF (2 ml) under a nitrogen atmosphere and sodium hydride (as a suspension in 60% mineral oil, 21 mg, 0.52 mmol) was added. The resulting mixture was heated to 80 ° C. (Bromomethyl) cyclopropane (0.06 ml, 0.65 mmol) was added and the reaction mixture was kept between 80 and 90 ° C. Once the starting material showed that it had been consumed by TLC, the reaction was stopped by the addition of water and brine. The aqueous mixture was extracted three times with ethyl acetate, and the combined organic extracts were washed with brine, after being dried (MgSO 4), filtered and concentrated in vacuo to give a red / pink oil. Purification by silica gel column chromatography (DCM-1.5% MeOH / DCM) provided the objective product as a red oil (35 mg, 26%). dH (CDCl3; 250MHz) 0.08-0.20 (2H, m, two cyclopropyl CH2CH2), 0.57-0.63 (2H, m, two cyclopropyl CH2CH2), 0.99-1.04 (1 H, m, cyclopropyl CH), 2.41 (1H , dd, J12.5, 7.0, one of CH2), 2.70 (1H, dd, J12.5, 5.8, one of CH2), 2.83-3.00 (2H, two of CH2CH2), 3.90 (1H, ddd, J12 .5, 5.8, 2.4, one of CH2CH2), 3.95 (1H, d, 12.5, one of ArCH2NR2), 4.22 (1H, ddd, J12.5, 7.6, 3.2, one of CH2CH2), 4.77 (1H, d, 12.5, one of ArCH2NR2), 5.83 (1H, s, CHOR), 7.01 (1H, d, J7.0, aromatic H), 7.16-7.33 (8H, m, aromatic H). Example 6 -Isopropyl-l-phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin Desmethylnefopam (116 mg, 0.45 mmol) was dissolved in acetone (3 ml) during sieves 4Á molecular (tip spatula). A drop of acetic acid was added and the resulting mixture was stirred at RT for one hour. After this time, sodium cyanoborohydride (114 mg, 1.82 mmol) was added and the mixture was stirred overnight at RT, after which time, the TLC showed that the starting material had been consumed. The reaction mixture was filtered and the collected solids were washed with ethyl acetate. The filtrate was concentrated in vacuo to remove the acetone, giving a pale yellow residue. This was redissolved in dichloromethane and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, dried (MgSO 4), filtered and concentrated in vacuo to give the crude product. Purification by silica gel column chromatography (DCM- »l% MeOH / DCM) provided the desired compound (34 mg, 30%). dH (CDCl3; 250MHz) 1.13 (3H, d, < J6.7, one CH3 of N (CH3) 2), 1-25 (3H, d, J6.4, one CH3 of N (CH3) 2), 1.73 (1H, dd, J4.6, 1.5, CH), 2.77-3.11 (2H, m, two of CH2CH2), 3.71 (1H, d, J12.8, one of ArCH2NR2), 3.87 (1H, ddd, J12.2, 8.9, 1.8, one of CH2CH2), 4. 11 (1H, ddd, J12.2, 5.0, 2.3, one of CH2CH2), 4.34 (1H, d, J12.8, one of ArCH2NR2), 5.90 (1H, s, CHOR), 7.02 (1H, d, 7. 3, aromatic H), 7.16-7.30 (8H, aromatic H). Example 7 8- (4-Pyridyl) -5-methyl-1- (3-methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5 -methyl-1- (3-methoxy) phenyl-1,3,4-6-tetrahydro-5H-benz [f] -2,5-oxazocin, ie compound 21b in WO 2004/056788 (117 mg, 0.32 mmol), pyridin-4-boronic acid (52 mg, 0.42 mmol), Pd (PPh3) 4 (10 mol%) and KOH (2M solution in water, 0.48 ml) were suspended in DME (2 ml). The mixture was degassed and then purged with nitrogen after heating to reflux temperature under a nitrogen atmosphere for 17 hours. The mixture was allowed to cool to RT and diluted with ethyl acetate (20 ml) and washed with water (20 ml). The aqueous phase was extracted into ethyl acetate. (2 x 20 ml) and the combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo. Purification by column chromatography on silica gel (EtOAc-10% MeOH / EtOAc) provided the objective compound as a pale yellow oil (25 mg, 22%). dH (CDCl3; 250MHz) 2.50 (3H, s, NCH3), 2.60 (1H, ddd, J14.2, . 8, 2.6, one of CH2CH2), 2.86 (1H, ddd, 14.2, 8.3, 2.1, one • of CH2CH2), 3.75 (1H, d, J12.8, one of ArCH2NR2), 3.78 (3H, s, OCH3), 3.88 (1H, ddd, J12.5, 5.8, 2.1, one of CH2CH2), 4.22 (1H, ddd, 12.5, 8.3, 2.6, one of CH2CH2), 4.87 (1H, d, J12.8, one of ArCH2NR2), 5.81 (1H, s, CHOR), 6.79-6.91 (4H, m, aromatic H), 7.14 (1 H, d, J7.6, aromatic H), 7.22-7.28 (1H, m, aromatic H), 7.44-7.62 (4H, m, aromatic H), 8.65 (1H, d, J5 .8, aromatic H). 5-pyrimidinboronic acid nBuLi (3.02 ml, 2M hexane solution, 7.55 mmol) was added dropwise to a stirred solution of 5-bromopyrimidine (1 g, 6.29 mmol) and triisopropylborate (1.46 ml, 7.55 mmol) in anhydrous toluene ( 16 ml) and anhydrous THF (4 ml) at -70 ° C under a nitrogen atmosphere. The reaction mixture was stirred at -70 ° C for 30 mins and then removed from the cold bath. When the internal temperature reached -20 ° C, the reaction was stopped by the dropwise addition of 2M HCl (10 ml). The mixture was allowed to warm to RT and then separated. The aqueous phase was taken at pH 5.5 with 2M KOH and extracted into THF (3 x 25 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give a colorless solid. The solid was suspended in acetonitrile (2 ml), collected by filtration and dried on the sinter to give the objective boronic acid as a bright white solid (340 mg, 44%). dH (MeOD, 250MHz) 8.98 (2H, s), 9.14 (1H, s). Example 8 8- (5-Piri idin) -5-methyl-1- (3-methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -oxazocin 8-Bromo-5-methyl-1- (3-methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin, ie the compound 21b in WO 2004/056788 (118 mg, 0.3 mmol), CsF (148 mg, 0.98 mmol), 5-pyrimidine boronic acid (52 mg, 0.42 mmol) and Pd (PPh3) 4 (10 mol%) were suspended in DME (2 ml) and water (100 μL). The mixture was degassed and purged with nitrogen then heated at reflux temperature for 17 hours.

The reaction mixture was allowed to cool to RT then diluting with ethyl acetate (20 ml) and washing with water (20 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were dried (MgSO), filtered and evaporated to dryness to provide the crude material. Purification by column chromatography on silica gel (EtOAc-10% MeOH / EtOAc) provided the objective product as a pale yellow / brown solid (36 mg, 30%). dH (CDCl3; 250MHz) 2.53 (3H, s, NCH3), 2.68 (1H, ddd, 14.2, 5.8, 2.6, one of CH2CH2), 2.88 (1H, ddd, J14.2, 8.2, 2.2, one of CH2CH2) , 3.79 (1H, d, J12.8, one of ArCH2NR2), 3.79 (3H, s, OCH3), 3.89 (1H, ddd, J12.8, 5.8, 2.2, one of CH2CH2), 4.24 (1H, ddd, J12.8, 8.2, 2.6, one of CH2CH2), 4.89 (1H, d, J12.8, one of ArCH2NR2), 5.82 (1H, s, CHOR), 6.79-6.91 (3H, m, aromatic H), 7.17-7.29 (2H, m, aromatic H), 7.40-7.43 (2H, m, aromatic H), 8.95 (s, 2H, pyrimidine H), 9.20 (1H, s, pyrimidine H).

Example 9 5-Methyl-1- (3-methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5-methyl-1- (3- methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine, ie compound 21b in WO 2004/056788 (206 mg, 0.57 mmol), was suspended in toluene ( 3 ml) and was degassed under vacuum, then purged with nitrogen. Tetrakis palladium (33 mg) was added to the mixture, which was then subjected to the degassing / purging sequence with nitrogen again. A degassed solution of sodium carbonate (2M, 12 ml) and boronic ester (117 mg, 0.57 mmol) were added and the complete mixture was then degassed, purged with nitrogen and heated at 80 ° C overnight. The reaction mixture was allowed to cool, diluted with water (10 ml) and the resulting mixture was extracted into ethyl acetate (3 x 50 ml). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give the crude product. Purification by column chromatography on silica gel [EtOAc] was carried out twice to give a mixture of products. Mass spectrometry analysis suggested that the debrominated species, m / z (ES +) 284 (MH +), have been formed. dH dH (CDCl3; 250MHz) 2.51 (3H, s, N-CH3), 2.68 (1H, ddd, 14.2, 5.2, 2.9, one of CH2CH2), 2.88 (1H, ddd, 14.2, 9.0, 2. 6, one of CH2CH2), 3.78 (3H, s, OCH3), 3.81 (1H, d, 12.8, one of ArCH2NR2), 3.88 (1H, ddd, 12.8, 5.2, 2.6, one of CH2CH2), 4.23 (1H, ddd, J12.8, 9.0, 2.9, one of CH2CH2), 4.86 (1H, J12.8, one of ArCH2NR2), 5.76 (1H, s, CHOR), 6.78-6.86 (3H, m, aromatic H), 7.03 -7.05 (1H, m, aromatic H), 7.20- 7.27 (4H, m, aromatic H). Example 10 5-Methyl-1- (3-methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-8-sarboxamide 8-Cyano-5-methyl-1 - (3-methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine, ie compound 21b in WO 2004/056788 (73 mg, 0.24 mmol), is heated to reflux temperature in fcBuOH (3 mL) with KOH (20 mg, 0.36 mmol) for 90 mins. At the end of this time, the reaction mixture was allowed to cool to R. The mixture was then washed with brine (20 ml) and extracted into dichloromethane (3 x 20 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the crude amide as a yellow solid. The solid was suspended in ethyl acetate, collected by suction filtration, washed with heptane and dried on the sinter to provide the amide (24 mg, 31%). d (MeOD; 250MHz) 2.44 (3H, s, NCH3), 2.51-2.60 (1H, m (poorly resolved ddd), one of CH2CH2), 2.72-2.81 (1H, m (poorly resolved ddd), one of CH2CH2) , 3.75 (4H, s, OCH3 and one of ArCH2), 3.84-3.90 (1H, m (poorly resolved ddd), one of CH2CH2), 4.17-4.27 (1H, m (poorly resolved ddd), one of CH2CH2), 5.01 (1H, d, J12.5 , one of ArCH2), 5.83 (1H, s, CHOR), 6.80-6.83 (3H, m, aromatic H), 7.14-7.21 (2H, m, aromatic H), 7.70-7.76 (2H, m, aromatic H) . MS (ESP) 325 ([M-HD; (ESI +) 349 ([M + Na] +) 2-Benzoyl-4-fluorobenzoic acid and 2-benzoyl-5-fluorobenzoic acid 3-fluorophthalic anhydride (5 g, 33 mmol ) was suspended in benzene (17.7 ml) at RT under nitrogen, aluminum chloride (8.8 g, 66 mmol) was added in portions, the orange mixture returning in color, the reaction was heated to reflux temperature for 4 hours before cooling RT The yellow suspension was carefully added to 10% HCl (100 ml), yielding a white precipitate.The aqueous mixture was extracted into ethyl acetate (3 x 100 ml) and the combined organic extracts were dried (MgSO4), were filtered and concentrated in vacuo to give a mixture of keto, 2-benzoyl-4-fluorobenzoic acid and 2-benzoyl-5-fluorobenzoic acid as colorless crystals (8 g, quantitative yield) dH (MeOD, 250MHz) 7.17-7.25 (3H, m, ArH), 7.31-7.42 (2H, m, ArH), 7.48 (2H, d, J8.0, ArH), 7.69 (1H, d, J8.0, ArH). Benzoyl-6-fluoro-N- (2-hydroxyethyl) -W-methylbenzamide and 2-benzoyl-3-fluoro-.W- (2-hydroxyethyl) -N-methylbenzamide A crude mixture of 2-benzoyl-6-fluorobenzoic acid and 2-benzoyl-3-fluorobenzoic acid (7 g, 28 mmol) was suspended in dichloromethane (70 ml) at RT. A few drops of DMF, followed by oxalyl chloride (3 ml, 34 mmol) were added dropwise and the resulting mixture was stirred until the evolution of the gas had ceased, and the suspended solid had dissolved. The mixture was concentrated in vacuo and co-evaporated with dichloromethane (2 x 40 ml_) to provide the crude acid chloride. (2-Methylamino) -ethanol (2.24 ml, 28 mmol) and triethylamine (3.9 ml, 28 mmol) were dissolved in dichloromethane (50 ml) and cooled in an ice bath. The acid chloride was dissolved in dichloromethane (50 ml) and added dropwise to the cooled amine solution. The mixture was allowed to warm to RT and was stirred for 4.5 hours, after which the reaction point was stopped by the addition of the aqueous saturated ammonium chloride solution (200 ml). The organic extracts were extracted into dichloromethane (3 x 100 ml), and the combined extracts were dried (MgSO 4), filtered and concentrated in vacuo. Purification was carried out by column chromatography on silica gel by gravity (50% EtOAc / heptane to 100% EtOAc) with pre-absorption of the crude amide on silica. 2-Benzoyl-6-fluoro-N- (2-hydroxyethyl) -N-methylbenzamide (490 mg) was obtained as a 3: 4 mixture of two rotamers: dH (CDCl3; 250MHz) 3.04 (3H, s, CH3, major rotamer), 3.10 (3H, s, CH3, minor rotamer), 3.33-3.40 (2H, two of CH2CH2, major rotamer), 3.52-3.64 ( 2H, two of CH2CH2, rotamer 5. minor), 3.78-3.96 (4H, two of CH2CH2 for the major and minor rotamer), 7.22-7.27 (4H, m, ArH both rotamers), 7.28-7.42 (6H, m, ArH both rotamers), 7.55-7.61 (2H, ArH both rotamers), 7.75-7.83 (4H, m, ArH both rotamers). 2-Benzoyl-3-fluoro-N- (2-hydroxyethyl) -N-0 methylbenzamide (2.74 g) was obtained as two rotamers: dH (CDCl 3; 250MHz) 3.03 (3H, s, CH 3, one rotamer), 3.05 ( 3H, s, CH3, one rotamer), 3.55-3.59 (4H, m, two of CH2CH2 for each rotamer), 3.75-3.79 (4H, m, two of CH2CH2 for each rotamer), 7.16-7.27 (4H, m, ArH both rotamers), 7.44-7.63 (4H, m, ArH both rotamers), 7.84 (2H, d, J7.9, ArH both rotamers). 2-. { [3-Fluoro-2- (hydroxyphenylmethyl) -benzyl] -methylamino} - ethanol 2-Benzoyl-3-fluoro-? - (2-hydroxyethyl) -? - methylbenzamide (2.58 g, 8.57 mmol) was dissolved in anhydrous THF (25 ml) at RT under a nitrogen atmosphere. Borane-dimethylsulfide complex (2.0 M in THF, 18.8 ml, 37. 7 mmol) dropwise and the resulting mixture was stirred at RT overnight. The reaction was carefully cooled by the addition of HCl (10%, 36 ml). The mixture is then heated at reflux temperature for about 1 hour after cooling to room temperature. THF was removed -in vacuo and the remaining solution was partitioned between MTBE (40 ml) and water (60 ml). The aqueous phase was separated, basified with 2M NaOH (aq) and extracted into ethyl acetate (4 x 50 ml). The combined organic extracts were dried (MgSO), filtered and concentrated in vacuo to give 2-. { [3- fluoro-2- (hydroxyphenylmethyl) -benzyl] -methylamino} -ethanol as a viscous oil which was then recrystallized. dH (CDCl3; 250MHz) 2.17 (3H, s, CH3), 2.35-2.42 (1H, m, one of CH2CH2), 2.52-2.62 (1H, m, one of CH2CH2), 2.88 (1H, d, J12.5 , one of ArCH2NR2), 3.42 (1H, d, J12.5, one of ArCH2NR2), 3.62-3.65 (2H, two of CH2CH2), 6.38 (1H, s, CHOH), 6.96 (1H, d, J7. 3, ArH), 7.10-7.37 (7H, m, ArH). Example 11 10-Fluoro-5-methyl-1-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin 2-. { [3-Fluoro-2- (hydroxyphenylmethyl) benzyl] -methylamino} Crude ethanol (234 mg, 0.81 mmol) was heated to reflux temperature with pTSA (231 mg, 1.21 mmol) in toluene (4 mL). The reaction was kept open to allow the toluene / water to evaporate. After about 1.5 hours, a gummy residue was maintained in the reaction with flash evaporation. It was allowed to cool to RT at which point, the saturated aqueous sodium bicarbonate solution and ethyl acetate were added to solubilize the residue. The aqueous phase was extracted repeatedly with ethyl acetate, and the combined extracts were dried (MgSO), filtered and evaporated to dryness to provide the crude cyclized product. Purification by silica gel column chromatography by gravity [EtOAc] provided the objective compound, (90 g, 25%). dH (CDCl3; 250MHz) 2.47 (3H, S, CH3), 2.59 (1H, ddd, J13.9, . 6, 3.3, one of CH2CH2), 2.78 (1H, ddd, 13.9, 8.5, 2.6, one of CH2CH2), 3.58 (1H, d, J12.4, one of ArCH2NR2), 3.83 (1H, ddd, J12.3 , 5.6, 2.6, one of CH2CH2), 4.30 (1H, ddd, J12.3, 8. 5, 3.3, one of CH2CH2), 5.09 (1H, d, 12.4, one of ArCH2NR2), 5.94 (1H, d, J1.9, CHOR), 6.89-6.96 (1H, m, ArH), 7. 04 (1H, d, J7.6, ArH,), 7.19-7.32 (6H,, ArH) 2-. { [2-Fluoro-d- (hydroxylphenylmethyl) benzyl] methylamino} Ethanol 2-Benzoyl-6-fluoro-N- (2-hydroxyethyl) -N-methylbenzamide (440 mg, 1.46 mmol) was dissolved in dry THF (4 ml) under nitrogen. Borane-dimethyl sulfide was added (solution in THF 2.0M, 3.2 ml, 6.43 mmol) dropwise and the resulting mixture was stirred overnight at RT. The reaction was stopped by the addition of 2M HCl (6 mL) and heated to reflux temperature for 1 hour. The acidic mixture was then cooled and partitioned between MTBE (30 ml) and water (30 ml). The aqueous phase was separated and extracted with ethyl acetate (4 x 30 ml). The combined extracts were dried (MgSO 4) t filtered and concentrated in vacuo to give the crude amine. Purification by silica gel column chromatography by gravity [EtOAc] provided 2-. { [2-fluoro-6- (hydroxylphenylmethyl) benzyl] methylamino} Ethanol (19 mg, 5%). dH (250MHz; CDC13) 2.72 (3H, s, NCH3), 2.54-2.73 (2H, m, two of CH2CH2), 3.36 (1H, dd, J12.8, 2.1, one of ArCH2NR2), 3.63- 3.72 (3H , two of CH2CH2 and one of ArCH2NR2), 5.91 (1H, s, CHOH), 6.97-7.07 (2H, m, aromatic H), 7.22-7.40 (6H, m, aromatic H). Example 12 7-Fluoro-5-methyl-l-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -oxazocin 2-. { [2-Fluoro-6- (hydroxyphenylmethyl) benzyl] ethylamino} crude ethanol (20 mg, 0.069 mmol) was dissolved in toluene and pTSA (20 mg, 0.1 mmol) was added. The mixture was heated to 120 ° C in an open container to allow evaporation of the solvent. After 30 mins, a gummy residue was kept in the reaction vessel. The vessel was allowed to cool and the residue was dissolved in ethyl acetate (5 ml) and saturated aqueous sodium bicarbonate solution (10 ml). The aqueous phase was washed with ethyl acetate and the combined organic extract was dried (MgSO 4), filtered and concentrated in vacuo to give the product as a crude light brown oil (10 mg, 53%). dH (CDCl3; 250MHz) 2.50 (3H, s, NCH3), 2.68 (1H, ddd, J13.9, 6.3, 2.8, one of CH2CH2), 2.84 (1H, ddd, J13.9, 7.8, 2.1, one of CH2CH2), 3.90 (1H, ddd, J 12.5, 6.3, 2.1, -one of CH2CH2), 4.05 (1H, d, J13.4, one of ArCH2), 4.21 (1H, ddd, J12.5, 7.8 , 2.8, one of CH2CH2), 4.71 (1H, dd, J13.4, 3.4, one of ArCH2), 5.81 (1H, s, CHOR), 6.82 (1H, d, J7.6, aromatic H), 7.37 ( 1H, t, J8.5, aromatic H), 7.10-7.23 (2H, m, aromatic H), 7.25-7.35 (3H,, aromatic H), 7.37-7.45 (1H, m, aromatic H). The purity was measured at 50%. 3-Bromophenol protected with TBS To a solution of 3-bromophenol (100 g, 0.6 mol) in dichloromethane (600 ml) was added imidazole (100 g, 1.46 mol) at 0 ° C. After 10 min, TBDMS-CI (96 g, 0.64 mol) was added, and the mixture was stirred at RT overnight. The mixture was then diluted with MTBE (1 L) and filtered. The filtrate was washed with saturated ammonium chloride (4 x 200 ml), saturated bicarbonate. (200 ml) and brine (200 ml), before it was dried (MgSO 4), filtered and concentrated in vacuo to give the product as a yellow oil (156.6 g) which was used without further purification. dH (CDCl3; 250MHz) 7.10-6.77 (4H, m, aromatics), 0.99 (9H, s, C (CH3) 3), 0.21 (6H, s, 2 x CH3). 4-Bromo-2- (S-butyldimethylsilyloxy-benzoyl) -benzoic acid and 5-bromo-2- (S-butyldimethylsilyloxy-benzoyl) -benzoic acid A solution of 3-bromophenol protected with TBS (156.6 g, 0.54 mol) in anhydrous THF (160 ml) was added dropwise to a stirred suspension of magnesium turns (1.3 g, 0. 54 mol) in dry THF (240 ml). The Grignard formation started followed by the addition of 1 ml of solution. The resulting mixture was allowed to start until the reflux was stopped, and then this was added in a single portion to a stirred solution of 4-bromophthalic anhydride (122.4 g, 0.54 mol) in THF. anhydrous (240 ml). The reaction mixture was heated at reflux temperature overnight. After cooling to RT, the reaction was stopped by the addition of a saturated aqueous solution of ammonium chloride (250 ml) and the organic extracts were extracted into ethyl acetate (3 x 250 ml). The combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo to give the crude acid as a brown oil (226.6 g). The crude material was carried through the next step without further purification. dH (CDCl3; 250MHz) 8.07-6.75 (7H, m, aromatics), 0.99-0.94 (9H,, C (CH3) 3M 0.20-0.13 (6H, m, 2 x CH3). -hydroxyethyl) -yl-methyl-2- (S-butyldimethylsilyloxy-benzoyl) -benzamide To a solution of a mixture of 4-bromo-2- (3- M -ldyldimethylsilyloxy-benzoyl) -benzoic acid and 5-bromo-2 acid -butyldimethylsilyloxy-benzoyl) -benzoic acid (226.6 g, 0.52 mol) in anhydrous dichloromethane (900 ml), under an atmosphere of nitrogen, anhydrous N-N-dimethylformamide (1 ml) was added followed by the slow addition of oxalyl chloride (50.8 ml, 0. 57 mol), and the reaction was stirred at RT overnight. The dichloromethane was then removed in vacuo. Dichloromethane (2 x 500 ml) was added to the crude oil and evaporated in vacuo. The crude acid chloride was dissolved in dichloromethane (900 ml) ', cooled to 0 ° C (ice bath) and triethylamine (81 ml, 0.57 mol) was added dropwise. Then? -methanolamine (42.8 g, 0.57 mol) was added dropwise and the mixture was allowed to warm to RT overnight under a nitrogen atmosphere. The mixture was then quenched with brine (800 ml) and the layers were separated. The aqueous layer was then separated and washed with dichloromethane (800 ml), and the combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo to yield the mixture of regioisomers (255.5 g) as a dark brown oil. 100 g of the above brown oil was purified by column chromatography on silica gel (EtOAc: Heptane 3: 1). This gave 14 g of 5-bromo-N- (2-hydroxyethyl) -N-methyl-2- (S-Xoutyldimethylsilyloxy-benzoyl) -benzamide. dH (CDCl3; 250MHz) 7.59-7.25 (7H, m, aromatics), 3.91-3.57 (4H,, CH2-CH2), 3.11 and 2.99 (3H, 2 xs,? CH3), 0.98 (9H, s, C ( CH3) 3), 0.21 (6H, s, 2 x CH3). 5-Bromo-JV- (2-hydroxyethyl) -? - methyl-2- (3-tosyloxy-benzoyl) - benzamide TBAF (10.1 ml, 1M THF solution, 10.14 mmol) was added to a stirred solution of 5-bromo-N- (2-hydroxyethyl) -N-methyl-2- (S-Methyldimethylsilyloxy-benzoyl) -benzamide (5M). g, 10.14 mmol) in THF (60 ml) at RT. A solution of tosyl chloride (1.9 g, 10.14 mmol) in THF (60 ml) was then added dropwise and the mixture was heated at reflux temperature for 3 h. Further 10 mmol of triethylamine followed by 7 mmol of TsCl were added for an additional hour to drive the reaction to completion. After cooling RT the mixture was diluted with ethyl acetate (100 ml), washed with water (2 x 100 ml), dried (MgSO 4), filtered and concentrated in vacuo to give 7 g of an orange oil. . Purification by silica gel column chromatography [EtOAc-Heptane 2: 1] afforded the title compound (3.14 g, 58%) as a pale yellow oil. dH (CDCl3; 250MHz) 7.74-7.20 (11H, m, aromatics), 3.86-3.53 (4H, m, CH2CH2), 3.07 and 2.97 (3H, 2 xs,? CH3), 2.47 (3H, s, Ar- CH3). 2- ( {5-Bromo-2- [hydroxyl- (3-tosyloxy-phenyl) -methyl] -benzyl} - methylamino) -ethanol Borane dimethyl sulphide complex (2.0M in THF, 12.94 ml 25.88 mmol) was added dropwise to a solution of 5-bromo-N- (2-hydroxyethyl) -N-methyl-2- (3-tosyloxy-benzoyl) -benzamide (3.14 g, 5.88 mmol) in THF anhydrous (20 ml) at 0 ° C. The reaction mixture was allowed to stir at RT overnight. The crude mixture was then completely stopped by the addition of an aqueous 6M HCl solution (20 ml) and then heated at reflux temperature for 2 h. After cooling to RT, the THF was removed in vacuo. Water (10 ml) was added and the mixture was then basified to pH 10 by the addition of an aqueous solution of sodium hydroxide solution (50%), and then extracted with ethyl acetate (2 x 20 ml). The combined organic layers were then dried (MgSO 4), filtered and concentrated in vacuo to give a white / solid oil (3.17 g). Purification by silica gel column chromatography [EtOAc: Heptane 5: 1] provided the title compound (0.74g, 24%) as a colorless oil. dH (CDCl3; 250MHz) 7.67-6.83 (11H, m, aromatics), 5.72 (1H, s, CHOH), 3.73-3.67 (2H, m, CH2), 3.39-3.27 (2H, m, CH2), 2.63- 2.53 (2H, m, CH2), 2.44 (3H, s, Ar-CH3), 2.22 (3H, s, NCH3). Example 13 8-Bromo-5-methyl-1- (3-tosyloxy) phenyl-1, 3,4, 6-te rahydro-5H-benz [f] -2,5-oxazocin 2- (. {5- Bromo-2- [hydroxyl- (3-tosyloxyphenyl) methyl] benzyl} methylamino) ethanol (0.74 g, 1.43 mmol) was heated at reflux temperature under Dean-Stark conditions with pTSA (0.41 g, 2.14 mmol) in toluene (20 ml) for 2 h. The reaction mixture was allowed to cool and then diluted with ethyl acetate (10 ml). The mixture was washed with saturated aqueous sodium bicarbonate solution (2 x 10 ml). The combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo to give 0.65 g of product which was used without further purification. dH (CDCl3; 250MHz) 7.67-6.72 (11H, m, aromatics), 5.67 (1H, s, CH ~ 0), 4.55 (1H, d, J 13, ArCHAHBN), 4.11 (1H, ddd, J 13, 8 and 2.5, CHAHBC ^), 3.83 (1H, ddd, J 13, 8 and 2.5, CHAHBCH2), 3.60 (1H, d, J 13, ArCHñHBN), 2.79-2.59 (2H,, CH2CH2), 2.48 and 2.46 (6H , 2 xs, 2 x CH3). Example 14 8-Bromo-5-methyl-1- (3-hydroxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin Potassium hydroxide (0.30 g, 5.33 mmol ) was added to a stirred solution of 8-bromo-5-methyl-1- (3-tosyloxy) phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine • (0.65 g, 1.3 mmol) in MeOH (5 ml) and DMF (5 ml) and the mixture was heated at 60 ° C for 3 h. After cooling to RT, the crude mixture was poured into water (10 ml) and the mixture was extracted with dichloromethane (2 x 10 ml). The aqueous layer was then acidified to pH 9 and extracted with dichloromethane (2 x 10 ml). The combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo to give 0.42 g of a yellow oil. Purification by column chromatography on silica gel (MeOH / 5% DCM) provided the compound of the title (0.20 g, 44%) as a white solid. dH (CDCl3; 250MHz) 7.34-6.67 (7H, m, aromatics), 5.60 (1H, s, 'CH-O), 5.17 (1H, d, J 13, ArCHAHBN), 4.20 (1H, ddd, J 13, 8 and 2.5, CHAHBCH2), 3.80 (1H, ddd, J 13, 8 and 2.5, CHAHBCH2), 3.53 (1H, d, J 13, ArCHAHBN), 2.75-2.56 (2H, m, CH2CH2), 2.36 (3H , S, NCH3). Example 15 8-Cyano-5-methyl-1- (3-hydroxy) f-1, 3,4, 6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5-methyl- l- (3-Hydroxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin (100 mg, 0.29 mmol), Zn (1 mg, 0.02 mmol), Zn (OAc) 2 (7 mg, 0.034 mmol), Zn (CN) 2 (25 mg, 0.22 mmol), Pd2 (dba) 3 (37 mg, 0.04 mmol) and 1.1 '-bis (diphenylphosphino) ferrocene (18 mg, 0.034 mmol) were heated at 140 ° C in DMF (3 ml) and H20 (30 μl) for 4 h. The dark reaction mixture was allowed to cool to RT and diluted with water (20 ml). The resulting brown precipitate was collected by filtration and washed with water then with brine. The filtrate was extracted with ethyl acetate (2 x 60 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product as a brown oil. Purification by silica gel column chromatography by gravity • [dichloromethane] provided the desired product (25 mg, 29%) as a yellow oil. dH (CDCl 3; 250MHz) 7.45-6.70 (7H, aromatics), 5.65 (1H, s, CHO), 5.03 (1H, d, J 13, ArCHaHB-N), 4.26-4.18 (1H, m, CHAHBCH2), 3.81-3.75 (1H, m, CHAHBCH2), 3.61 (1H, d, J 13, ArCHAHB-N), 2.70-2.53 (2H, m, CH2CH2), 2.41 (3H, s, NCH3). Example 16 8-Cyclopropyl-5-methyl-1- (3-hydroxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5-methyl-1 - (3-hydroxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine (100 mg, 0.29 mmol), cyclopropylboronic acid (33 mg, 0.36 mol), K3P04 ( 217 mg, 1.01 mmol), Pd (OAc) 2 (4 mg, 0.015 mmol) and P (cyclohexane) 3 (9 mg, 0.029 mmol) were heated to 100 ° C in toluene (2.5 ml) and H20 (125 μl). During 4 hours. After cooling to RT, water (2.5 ml) was added and the mixture was extracted with ethyl acetate (2 x 5 ml), washed with brine, dried (MgSO 4), filtered and concentrated in vacuo. Purification by silica gel column chromatography by gravity [dichloromethane] provided the desired product (40 mg, 44%) as a colorless oil. dH (CDCl3; 250MHz) 7.27-6.69 (7H, m, aromatics), 5.61 (1H, s, CHO), 5.04 (1H, d, J 13, ArCHAHB-N) 4.23-4.15 (1H, m, CHAHBCH2), 3.83-3.78 (1H, m, CHAHBCH2), 3.66 (1H, d, J 13, ArCHaHB-N), 2.78-2.58 (2H, m, CH2CH2), 2.41 (3H, s, NCH3), 1.84-1.78 (1H ,, CHCH2), 0.95-0.90 (2H,, CH2CH2), 0.64-0.62 (2H, m, CH2CH2).

Example 17 8-Bromo-5-methyl-1- (3-allyloxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5-methyl-1 - (3-hydroxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin (50 mg, 0.14 mmol), allyl alcohol (33 mg, 0.57 mmol), Pd ^ (0Ac) 2 (1 mg, 0.0035 mmol), triphenylphosphine (2 mg, 0.0075 mmol), Ti (01Pr) 4 (10 mg, 0.035 mmol), molecular sieves (4 Á, 28 mg) were heated at 50 ° C in Benzene (1 ml) overnight. After cooling to RT, the black reaction mixture was poured into water (5 ml), extracted with MTBE (2 x 5 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product as a brown oil. Purification by silica gel column chromatography by gravity [dichloromethane] gave the desired product (16 mg, 30%) as a pale yellow oil. dH (CDCl3; 250MHz) 7.38-7.19 (3H, aromatics), 6.90-6.80 (4H, m, aromatics), 6.09- 5.96 (1H, m, CH = CH2), 5.71 (1H, s, CHO), 5.42 -5.25 (2H, m, CH = CH2), 4.76 (1H, d, J 13, ArCHAHB-N), 4.51 (2H, d, J 5, OCH2), 4.21-4.12 (1H, m, CHAHBCH2), 3.88 -3.80 (1H, m, CHAHBCH2), 3.63 (1H, d, J 13, ArCHñHB-N), 2.87-2.77 (1H, m, CH2CHAHB), 2.69-2.60 (1H, m, CH2CHAHB) 2.47 (3H1 s, NCH3). Example 18 8-Cyano-5-methyl-1- (3-allyloxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-cyano-5-methyl-1- ( 3-hydroxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin (50 mg, 0.17 mmol), aryl alcohol (49 mg, 0.68 mmol), Pd (OAc) 2 (1 mg, 0.0035 mmol), triphenylphosphine (2 mg, 0.0075 mmol), Ti (OiPr) 4 (20 mg, 0.07 mmol), molecular sieves (4 A, 40 mg) were heated at 50 ° C in benzene (2 mg). ml) overnight. After cooling to RT, the dark reaction mixture was poured into water (5 ml) and extracted with MTBE (2 x 5 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product as a brown oil. Purification by silica gel column chromatography by gravity [dichloromethane] provided the desired product (4 mg, 7%) as a pale yellow oil < dH (CDCl3; 250MHz) 7.65-6.81 (7H,, aromatics), 6.08-5.97 (1H, m, CH = CH2), 5.74 (1H, s, CHO), 5.42-5.25 (2H, m, CH = CH2) , 4.98 (1H, d, J 13, ArCHAHB-N), 4.51 (2H, d, J 5, OCH2), 4.31-4.23 (1H, m, CHAHBCH2), 3.90-3.82 (1H, m, CHAHBCH2), 3.74 (1H, d, J 13, ArCHAHB-N), 2.81-2.70 (2H,, CH2CH2), 2.51 (3H, s, NCH3). Example 19 8-Cyclopropyl-5-methyl-1- (3-allyloxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Cyclopropyl-5-methyl-1- (3-hydroxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2, 5-oxazocin (90 mg, 0.29 mmol), allylic alcohol (0.1 mL, 1.16 mmol), Pd (OAc) 2 (1 mg, 0.0035 mmol), triphenylphosphine (3 mg, 0.011 mmol), Ti (ΔMr) 4 (0.03 mL, 0.07 mmol), molecular sieves (4 A, 64 mg) were heated at 50 ° C in benzene (3 mL) overnight. After cooling to RT, the black reaction mixture was poured into water (5 ml), extracted with MTBE (2 x 5 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product as a brown oil. Purification by silica gel column chromatography by gravity [dichloromethane] provided the desired product (3 mg, 3%) as a pale yellow oil. dH (CDCl3; 250MHz) 7.24-6.76 (7H, m, aromatics), 6.04-5.97 (1H,, CH = CH2), 5.41 (1H, s, CHO), 5.41-5.24 (2H, m, CH = CH2), 4. 70 (1H, d, J 13, ArCHAHB-N), 4.49 (2H, d, J 5, OCH 2), 4.19- 4.11 (1H, m, CHAHBCH2), 3.88-3.82 (1H, m, CHAHBCH2), 3.71 ( 1H, d, J 13, ArCHAHB-N), 2.92-2.82 (1H, m, CH2CHAHB), 2.69-2.66 (1H, m, CH2CHAHB), 2.49 (3H, s, NCH3), 1.89-1.83 (1H, m , CHCH2), 0.98-0.90 (2H, m, CHCH2), 0.71-0.65 (2H, m, CHCH2). The following Examples were prepared in a similar manner. The starting materials of substituted xbromophenyl, used for the formation of Grignard, were either purchased commercially or synthetically generated by the way of the known organic chemistry, for example as in the following example where a nitro group was converted to a bromine via the intermediary amine. 2-Methoxy-6-amino-oluene 2-Methyl-3-nitroanisole (20 g, 0.12 mol) was suspended in methanol (200 ml) at RT under nitrogen. Pd / C (5%, 2 g) was added and the system was stirred under a hydrogen atmosphere overnight, until TLC indicated a product. The reaction mixture was filtered through celite, and the celite was washed with methanol (3 x 100 ml) and the filtrate was concentrated in vacuo. This provided 18 g of a red oil that was used without further purification. dH (CDCl 3; 250MHz) 7.01 (1H, 1, J 8, aromatics), 6.38 (2H, d, J 8, aromatics), 3.83 (3H, s, 0CH 3), 2.08 (3H, s, CH 3). 2-Me crude oxy-4-bromotoluene 2-methoxy-6-amino-toluene (max 120 mmol) was suspended in HBr (48%, 48 ml) and water (120 ml) and cooled to 0 ° C in a ice bath. Sodium nitrite (9.2 g) in water (24 ml) was added dropwise to cool the mixture, which turned yellow then brown. After 10 min, the excess nitrite was destroyed by the addition of urea (0.08 g) and the mixture was filtered rapidly cooled (0 ° C) acetone (480 ml) to give a clear yellow solution. CuBr (99.999%, 18.89, 131 mmol) was then added in portions and the mixture The resulting mixture was stirred at 0 ° C for 3 h. The evaluation of the gas was observed. The mixture was allowed to warm to room temperature, and then concentrated in vacuo. Then dichloromethane was added and the mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give the product (23.1 g, 96%) as a red oil. dH (CDCl3; 250MHz) 7.18-6.77 (3H, m, aromatics), 3.83 (3H, s, OCH3), 2.32 (3H, s, CH3). 5-Bromo-2- (3-methoxy-2-methylbenzoyl) -benzoic acid and 4-bromo-2- (3-methoxy-2-methylbenzoyl) -benzoic acid 2-methoxy-4-bromo-toluene (23.1 g, 115 mmol) in dry THF (35 ml) dropwise to a stirred suspension of magnesium turns (2.77 g, 115 mmol) and a crystal of iodine in dry THF (40 ml) under a nitrogen atmosphere. Until the addition, the reaction mixture was refluxed. After cooling to RT, this Grignard solution was added dropwise to a stirred solution of 4-bromophthalic anhydride (26.1 g, 115 mmol) in dry THF (45 ml) and the resulting mixture was heated at reflux temperature overnight . After cooling, the reaction was quenched with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic extracts were dried (MgSO 4), filtered and concentrated in vacuo to give the keto-acid crude mixture. (34 g) as a brown oil. This material was carried continuously over the subsequent stage. 5-Bromo-W- (2-hydroxyethyl) -27-methyl-2- (3-methoxy-2-methyl-benzoyl) -benzamide A crude mixture of 5-bromo-2- (3-methoxy-2-methylbenzoyl) acid ) -benzoic acid and 4-bromo-2- (3-methoxy-2-methylbenzoyl) -benzoic acid (34 g, 98.5 mmol) were dissolved in dichloromethane (200 ml) at RT. DMF (1 ml) followed by oxalyl chloride (9.67 ml, 13.98 g, 108.35 mmol) were added dropwise and the reaction stirred at RT overnight. The reaction mixture was then concentrated in vacuo and coevaporated with dichloromethane (2 x 200 ml) to provide the crude acid chloride. This was dissolved in dichloromethane (200 ml), it was cooled to 0 ° C, and triethylamine (15.35 ml, 11.22 g, 108.35 mmol) was added dropwise, followed by N-methylethanolamine and the mixture was allowed to warm to RT overnight. The reaction was then quenched with brine and extracted with dichloromethane. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude amide as a mixture of regioisomers. 5-Bromo-N- (2-hydroxyethyl) -N-methyl-2- (3-methoxy-2-methyl-benzoyl) -benzamide (10 g, 25%) was separated by silica gel column chromatography [EtOAc / heptane 4: 1]. dH (CDCl3; 250MHz) 7.55-6.91 (6H, m, aromatics), 3.98-3.69 (7H, m, OCH3 and CH2CH2), 3.15 and 2.99 (3H, 2 x s,? CH3), 2.20 and 2. 17 (3H, 2 x s, CH3). 2- ( {5-Bromo-2- [hydroxyl- (3-methoxy-2-methylphenyl) methyl] benzyl.} Methylamino) -ethanol Complex of borane-dimethyl sulfide (2.0 M, 55 ml, 0.11 mol ) was added dropwise to a stirred solution of 5-bromo-N- (2-hydroxyethyl) -N-methyl-2- (3-methoxy-2-methyl-benzoyl) -benzamide (10 g, '0.025 mol) in anhydrous THF (80 ml) at RT under nitrogen, and allowed to stir overnight. The reaction was cooled by the careful addition of 6M HCl (80 ml), and the resulting mixture was heated at reflux temperature for 2 hours. After cooling to RT, the THF was removed in vacuo and the mixture was partitioned between water (40 ml) and MTBE (80 ml). The aqueous phase was separated, basified with aqueous 2M aOH and extracted into ethyl acetate (3 x 90 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the desired amine as a viscous oil, which was recrystallized slowly (6.2 g, 63%). The material was used in the next step without further purification. dH (CDCl3; 250MHz) 7.41-7.25 (4H1 m, aromatics), 6.89 (1H, d, J 8, aromatics), 6.61 (1H, d, J 8, aromatics), 6.10 (1H, s, CHOH), 4.33 (1H, d, J 13, CHAHB?), 3.84 (3H, s, OCH3), 3.84-3.62 (2H, m, CH2), 3.26 (1H, d, J 13, CHAHB?), 2.77-2.73 (2H , m, CH2), 2.33 (3H, s,? CH3), 1.83 (3H, s, CH3). Example 20 8-Bromo-5-methyl-l- (2-methyl-3-methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 2- (. {5 -bromo-2- [hydroxyl- (3-methoxy-2-methylphenyl) -methyl] -benzyl] -methylamino) -ethanol (5 g, 12.6 mmol) was heated at reflux temperature in toluene (250 ml) with pTSA (3.65 g, 18.95 mmol) under Dean-Stark conditions for 4 hours. The reaction mixture was allowed to cool to RT, diluted with ethyl acetate (200 ml) and washed with a saturated aqueous solution of sodium bicarbonate (300 ml). The aqueous layer was extracted with ethyl acetate (3 x 200 ml) and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography [DCM] gave the objective product as a pale straw colorless oil (2.8 g, 59%). dH (CDCl3; 250MHz) 7.42-6.70 (6H, m, aromatics), 5.97 (1 H, s, CHO), 4.69 (1H, d, J 13, CHAHBN), 4.14-4.05 (1H, m, CHAHB), 3.89-3.73 (5H,, CHAHB, OCH3 and CHAHBN), 2.92-2.82 (1H, m, CHAHB), 2.69-2.59 (1H, m, CHAHB), 2.45 (3H, s, CH3N), 2.15 (3H, • 20 s, CH3). Example 21 8-Cyano-5-methyl-1- (2-methyl-3-methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5 -methyl-l- (2-methyl-3-methoxy) phenyl-1, 3,4,6-25 tetrahydro-5H-benz [f] -2,5-oxazocin (250 mg, 0.66 mmol), Zn (4 mg, 0.04 mmol), Zn (OAc) 2 (14 mg, 0.07 mmol), Zn (CN) 2 (50 mg, 0.44 mmol), 1,1 '-bis (diphenylphosphino) ferrocene (36 mg, 0.07 mmol ) and Pd2 (dba) 3 (74 mg, 0.08 mmol) were heated at 140 ° C in degassed DMF (3 ml) and H20 (30 μl) overnight. The mixture was allowed to cool to RT and water (10 ml) was added, yielding a brown precipitate. The precipitate was collected by filtration and washed with water and brine. The filtrate was then extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo to provide 100 mg of the crude product. Purification by silica gel column chromatography by gravity [DCM] gave the objective product as a yellow oil (70 mg, 33%). dH (CDCl3; 250MHz) 7.60 (1H, d, J 1.5, aromatics), 7.48 (1H, dd, < J 1.5 &8, aromatics), 7.12-7.01 (2H, m, aromatics), 6.82 (1H, d , J 8, aromatics), 6.46 (1H, d, J 8, aromatics), 5.97 (1H, s, CHO), 5.02 (1H, d, J 13, CHAHBN), 4.30-4.24 (1H, m, CHAHBCH2) , 3.96-3.80 (2H, m, CHAHBN and CHAHBCH2), 3.82 (3H, s, OCH3), 2.96-2.85 (1H, m, CH2CHAHB), 2.76-2.65 (1H, m, CH2CHAHB), 2.53 (3H, s , NCH3), 2.20 (3H, s, CH3). Example 22 8-Cyclopropyl-5-methyl-1- (2-methyl-3-methoxy) f-1, 3, 4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo- 5-methyl-1- (2-methyl-3-methoxy) phenyl-1, 3, 4, 6 tetrahydro-5H-benz [f] -2,5-oxazocin (295 mg, 0.71 mmol), cyclopropylboronic acid (89 mg, 0.96 mmol), P (cyclohexane) 3 (24 mg, 0.08 mmol), K3P04 (586 mg, 2.73 mmol) and Pd (OAc) 2 (10.4 mg, 0.04 mmol) were heated at 100 ° C in toluene (7 ml) and water (336 μl) overnight . The reaction mixture was allowed to cool and then diluted with ethyl acetate (30 ml). The organic mixture was washed with water (30 ml) and the aqueous phase was extracted into ethyl acetate (3 x 20 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give 0.29 g of crude product. Purification by column chromatography by gravity on silica gel [DCM] provided the objective product (100 mg, 38%) as a yellow oil / solid. dH (CDCl3; 250MHz) 7.11 (1H, t, J8, aromatics), 6.97 (1H, d, J 1.5, aromatics), 6.88-6.71 (4H, m, aromatics), 5.98 (1H, s, CHO) , 4.63 (1H, d, J 13, CHAHBN), 4.18-4.06 (1H, m, CHAHBCH2), 3.89-3.82 (5H, m, CHAHBN, CHAHBCH2 and OCH3), 2.98-2.88 (1H, m, CH2CHAHB), 2.72-2.64 (1H, m, CH2CHAHB), 2.50 (3H, s, NCH3), 2.16 (3H, s, CH3), 1.91-1.84 (1H, m, CHCH2), 0.99-0.91 (2H, m, CH2CH2), 0.73-0.66 (2H, m, CH2CH2). EXAMPLE 23 8-Bromo-5-methyl-1- (3-methoxy-4-methyl) f-1, 3,4, 6-tetrahydro-5H-benz [f] -2,5-oxazocine 2- ( {.5-bromo-2- [hydroxyl- (3-methoxy-4-methyl-f-enyl) -methyl] -benzyl} -methylamino) -ethanol (879 mg, 2.23 mmol) was heated to reflux temperature in toluene (9 ml) with pTSA (635 mg, 3.34 mmol) under Dean-Stark conditions for 3 hours. The reaction mixture was allowed to cool to RT, diluted with ethyl acetate (50 ml) and washed with a saturated solution of sodium bicarbonate (60 ml). The aqueous layer was extracted into ethyl acetate (3 x 50 ml) and the combined extracts were dried (MgSO), filtered and concentrated in vacuo. Purification by silica gel column chromatography by gravity [EtOAc] gave the objective product as a pale straw colorless oil (23 g, 28%). A second impure batch of the product was obtained from the column. dH (CDCl3; 250MHz) 2.18 (3H, s, CH3), 2.48 (3H, s, NCH3), 2.66 (1H, ddd, J14.2, 5.6, 2.7, one of CH2CH2), 2.84 (1H, ddd, J14 .2, 8.2, 2.1, one of CH2CH2), 3.67 (1H, d, J12.8, one of ArCH2NR2), 3.80 (3H, s, 0CH3), 3.86 (1H, ddd, J12.7, 5.6, 2.1, one of CH2CH2), 4.18 (1H, ddd, J12.8, 8.2, 2.7, one of CH2CH2), 4.80 (1H, d, J12.8, one of ArCH2NR2), 5.71 (1H, s, CHOR), 6.68 ( 1H, dd, J7.6, 1.2, one of ArH), 6.76 (1H, bs, one of ArH), 6.89 (1H, d, J 8.2, ArH), 7.06 (1H, d, J7.6, one of ArH), 7.32 (1H, dd, 8.2, 1.8, one of ArH), 7.39 (1H, d, 1.8, one of ArH). Example 24 8-Cyano-5-methyl-1- (3-methoxy-4-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5-methyl-1- (3-methoxy-4-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin (154 mg, 0.41 mmol) , Zn (2 mg, 0.03 mmol), Zn (OAc) 2 (10 mg, 0.05 mmol), Zn (CN) 2 (29 mg, 0.25 mmol), 1,1 '-bis (diphenylphosphino) ferrocene (30 mg, 0.05 mmol) and Pd (dba) 3 (55 mg, 0.06 mmol) were heated at 140 ° C in DMF (3 ml) and H20 (30 μl) overnight. The mixture was allowed to cool to RT and water (30 ml) was added, yielding a brown precipitate. The precipitate was collected by filtration and washed with water and ethyl acetate. The filtrate was then washed with brine (2 x 40 ml) and the combined aqueous phases were extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product. Purification by silica gel column chromatography [EtOAc] gave the objective product as a brown oil (75 mg, 57%). dH (CDCl3; 250MHz) 2.17 (3H, s, CH3), 2.46 (3H, s, NCH3), 2.65 (1H, ddd, J14.3, 5.1, 3.0, one of CH2CH2), 2.78 (1H, ddd, 14.3 , 8.6, 2.5, one of CH2CH2), 3.71 (1H, d, J13.0, one of ArCH2NR2), 3.79 (3H, s, 0CH3), 3.84 (1H, ddd, J12.8, 5.1, 2.5, one of CH2CH2), 4.26 (1H, ddd, 12.8, 8.6, 3.0, one of CH2CH2), 4.99 (1H, d, J13.0, one of ArCH2NR2), 5.73 (1H, CHOR), 6.63 (1H, d, 1.5, ArH), 6.72 (1H, s, ArH), 7.06 (1H, d, 7.6, ArH), 7.14 (1H, d, J8.2, ArH) 1 7.47 (1H, dd, 8.2, 1.8, ArH), 7.53 (1H, d, J1.5, ArH).

Example 25 5-Methyl-1- (3-methoxy-4-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-8-carboxamide 8-Cyano-5 methyl-l- (3-methoxy-4-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine (1.1 g, 3.56 mmol) was heated to reflux in MiuOH (24 ml) with potassium hydroxide (0.29 mg, 5.34 mmol) for 2 h. At the end of this time, the reaction mixture was allowed to cool to RT. The mixture was then washed with brine (50 ml) and extracted into dichloromethane (3 x 50 ml). The combined organic extracts were dried (MgSO), filtered and concentrated in vacuo to give the crude amide as a light brown solid. Purification by silica gel column chromatography [1% MeOH in DCM to 12% MeOH in DCM] afforded the title compound (385 mg, 32%). d (CDCl3; 250MHz) 2.16 (3H, s, CH3), 2.47 (3H, s, NCH3), 2.52-2.62 (1H, m (poorly resolved ddd), one of CH2CH), 2.75-2.88 (1H, m ( poorly resolved ddd), one of CH2CH2), 3.77 (4H, s, OCH3 and one of ArCH2), 3.81-3.92 (1H, m (poorly resolved ddd), one of CH2CH2), 4.15-4.28 (1H, m (resolved poorly ddd), one of CH2CH2), 4.89 (1H, d, J12.8, one of ArCH2), 5.77 (1H, s, CHOR), 6.76-6.75 (3H, m, aromatic H), 7.03-7.12 (2H , m, aromatic H), 7.59-7.68 (2H, aromatic H). Example 26 8-Cyclopropyl-5-methyl-1- (3-methoxy-4-yl) enyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5- methyl-l- (3-methoxy-4-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin (154 mg, 0.41 mmol), cyclopropylboronic acid (46 mg) , 0.53 mmol), P (cyclohexane) 3 (11 mg, 0.041 mmol), K3P04 (304 mg, 1.43 mmol) and Pd (OAc) 2 (5 mg, 0.02 mmol) were heated at 100 ° C in toluene (3 ml) and water (150 μl) for 3 hours 15 mins. The reaction mixture was allowed to cool and then diluted with ethyl acetate (30 ml). The organic mixture was washed with water (30 ml) and the aqueous phase was extracted into ethyl acetate (3 x 20 ml). The combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel column chromatography [EtOAc] provided the target product and recovered the starting material. dH (CDCl3; 250MHz) 0.64-0.71 (2H1, two cyclopropyl CH2CH2), 0.89-0.97 (2H, m, two cyclopropyl CH2CH2), 1.80-1.8.9 (1H,, cyclopropyl CH), 2.16 (3H, s , CH3), 2.48 (3H, s, NCH3), 2.63 (1H, ddd, 14.2, 5.6, 2.6, one of CH2CH2), 2.85 (1H, ddd, J14.2, 8.4, 2.3, one of CH2CH2), 3.70 (1H, d, 12.7, one of ArCH2NR2), 3.78 (3H, s, 0CH3), 3.84 (1 H, ddd, J12.5 , . 6, 2.3, one of CH2CH2), 4.17 (1H, ddd, J12.5, 8.4, 2.6, one of CH2CH2), 4.70 (1H, d, J12.7, one of ArCH2NR2), 5.73 (1H, s, CHOR ), 6.69 (1H, dd, J7.6, 1.2, one of ArH), 6.79 (1H, s, ArH), 6.86 (2H, d, 1.2, ArH), 6.94 (1H, s, ArH), 7.03 (1H, d, J7.6, ArH). Example 27 9-Bromo-5-methyl-1- (3,4-methylenedioxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-2. { [2- (Benzo- [1,3] -dioxol-yl-hydroxymethyl) -4-bromobenzyl] -methylamino} Ethanol (148 mg, 0.38 mmol) was heated at reflux temperature with pTSA (107 mg, 0.56 mmol) in toluene (3 ml) under Dean-stark conditions for 3 hours. The mixture was then cooled, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried (MgSO 4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel column chromatography [3% MeOH / 10% EtOAc MeOH / EtOAc] provided the product (89 mg, 62%). dH (CDCl3; 250MHz) 2.43 (3H, s, CH3), 2.60 (1H, ddd, J14.2, 5.3, 2.9, one of CH2CH2), 2.78 (1H, ddd, J14.2, 8.7, 2.4, one of CH2CH2), 3.61 (1H, d, J12.7, one of ArCH2N), 3.81 (1H, ddd, J12.5, 5.3, 2.4, one of CH2CH2), 4.20 (1H, ddd, 12.5, 8.7, 2.9, one of CH2CH2), 4.84 (1H, d, 12.7, one of ArCH2N), 5.61 (1H, s, CHOR), 5.93 (2H, s, ROCH2OR), 6.71-6.75 (3H, m, ArH), 7.07-7.14 ( 2H, m, ArH), 7.36 (1H, dd, 8.0, 4.0, ArH). Example 28 9-Cyano-5-methyl-1- (3,4-methylenedioxy) phenyl-1, 3,4,6-tetrahydro- 5H-benz [f] -2, 5-oxazocin A solution of 9-bromo-5-methyl-1- (3,4-methylenedioxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2, 5- oxazocin (89 mg, 0.23 mmol), Zn (1 mg, 0.012 mmol), Zn (CNM (16 mg, 0.138 mmol), Zn (OAc) 2 (2 mg, 0.011 mmol), 1.1 '-bis (diphenylphosphino) ferrocene (18 mg, 0.05 mmol) and Pd (dba) 3 (11 mg, 0.06 mmol) in DMF (2 ml) and H20 (20 μl) was degassed under vacuum for 15 minutes and then heated At 140 ° C overnight, the mixture was allowed to cool and water was added in. The organic materials were extracted into ethyl acetate and then washed with brine to remove the DMF The combined organic washes were dried (MgSO4). filtered and concentrated in vacuo to provide the crude product Purification by silica gel column chromatography [EtOAc] gave the product (21 mg, 27%) dH (CDCl3; 250MHz) 2.45 (3H, s, NCH3 ), 2.63 (1H, ddd, J14.3, 5.2, 2.8, one of CH2CH2), 2.76 (1H, ddd, 14.3, 8.4, 2.4, one of CH2) CH2), 3.70 (1H, d, J12.8, one of ArCH2NR2), 3.81 (1H, ddd, J12.6, 5.2, 2.4, one of CH2CH2), 4.20 (1H, ddd, J12.6, 8.4, 2.8 , one of CH2CH2), 4.90 (1H, d, J12.8, one of ArCH2NR2), 5.69 (1H, s, CHOR), 5.94 (2H, s, ROCH2OR), 6.69-6.78 (3H, m, ArH), 7.27-7.33 (2H, m, ArH), 7.51 (1H, dd, J7.9, 1.5, ArH). Example 29 9-Cyclopropyl-5-methyl-1- (3,4-mendylenedioxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine A mixture of 9-bromo-5 methyl-l- (3,4-methylenedioxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine (280 mg, 0.75 mmol), cyclopropylboronic acid (84 mg, 0.97 mmol), K3P0 (555 mg, 2.61 mmol), Pd (OAc) 2 (8.4 mg, 0.04 mmol) and P (cyclohexane) 3 (21 mg, 0.075 mmol) in toluene (5 mL) and H20 (250 μL) they were heated at 100 ° C for 3 hours, during which time it turned black. After cooling, water (12 ml) was added and the organic extracts were extracted into ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product. Purification (repeated) by silica gel column chromatography [EtOAc] provided the product (56 mg, 22%). dH (CDCl3; 250MHz) 0.58-0.63 (2H, m, two cyclopropyl CH2CH2), 0.86-0.94 (2H, m, two cyclopropyl CH2CH2), 1.75-1.84 (1H, m, cyclopropyl CH), 2.44 (3H, s, CH3), 2.55-2.63 (1H, m, one of CH2CH2), 2.75-2.84 (1H,, one of CH2CH2), 3.62 (1H, d, J12.5, one of ArCH2NR2), 3.81 (1H, ddd , J12.5, 5.6, 2.4, one of CH2CH2), 4.14-4.22 (1H, m, one of CH2CH2), 4.79 (1H, d, J12.5, one of ArCH2NR2), 6.63 (1H, s, CHOR) , 5.91 (2H, s, ROCH2OR), 6.74 and 6.75 (4H, 2 xs, ArH), 6.87 (1H, dd, J7.6, 1.9, ArH), 7.10 (1H, d, XI .9).

EXAMPLE 30 8-Bromo-5-methyl-1- (3,4-melenedioxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin 2 ~. { [2- (Benzo- [1,3] -dioxol-5-yl-hydroxymethyl) -5-bromobenzyl] -methylamino} -ethanol (715 mg, 1.82 mmol) and pTSA (519 mg, 2.73 mmol) were heated at reflux temperature in toluene (8 ml) under Dean-Stark conditions for 2 hours.

Once cooled to RT, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phases dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification by column chromatography on silica gel [100% EtOAc a % MeOH / EtOAc] yield 214 mg, (31%). dH (CDCl3; 250MHz) 2.45 (3H, s, CH3), 2.61 (1H, ddd, J14.1, 5.8, 2.8, one of CH2CH2), 2.79 (1H, ddd, J14.1, 8.2, 2.2, one of CH2CH2), 3.58 (1H, d, 12.8, one of ArCH2NR2), 3.81 (1H, ddd, J12.5, 5.8, 2.2, one of CH2CH2), 4.78 (1H, ddd, J12.5, 8.2, 2.8, one of CH2CH2), 4.80 (1H, d, J12.8, one of ArCH2NR2), 5.64 (1H, s, CHOR), 5.91 (2H, s, ROCH2OR), 6.70-6.77 (3H, m, ArH), 6.87 ( 1H, d, J8.3, ArH), 7.29-7.37 (2H, m, ArH). Example 31 8-Cyano-5-methyl-1- (3,4-melenedioxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5-methyl-l- (3, 4-methylenedioxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin (99 mg, 0.26 mmol), Zn (1 mg, 0.015 mmol), Zn (OAc) 2 (6 mg, 0.033 mmol), Zn (CN) 2. (18 mg, 0.156 mmol), 1, '-bis (diphenylphosphino) ferrocene (18 mg, 0.054 mmol) and Pd (dba) 3 (33 mg, 0.036 mmol) were degassed and then heated at 140 ° C overnight . The reaction mixture was cooled and water was added. The organic extracts were extracted three times with ethyl acetate and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the crude objective as a black oil. Purification by column chromatography on silica gel [EtOAc] gave the product 21 mg, (25%). dH (CDCl3; 250MHz) 2.46 (3H, s, CH3), 2.63 (1H, ddd, J14.3, 5.4, 3.1, one of CH2CH2), 2.75 (1H, ddd, J14.3, 8.3, 2.6, one of CH2CH2), 3.64 (1H, d, 12.8, one of ArCH2NR2), 3.81 (1H, ddd, J12.7, 5.4, 2.6, one of CH2CH2), 4.24 (1H, ddd, 12.7, 8.3, 3.1, one of .CH2CH2), 4.97 (1H, d, J12.8, one of ArCH2NR2), 5.68 (1H, CHOR), 5.93 (2H, s, ROCH2OR), 6.69-6.78 (3H,, ArH), 7.12 (1H, d, J7. 9, ArH), 7.45-7.52 (2H, m, ArH). EXAMPLE 32 8-Cyclopropyl-5-methyl-1- (3,4-mendylenedioxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5- methyl-l- (3,4-methylenedioxy) phenyl-1,3,3,6- tetrahydro-5H-benz [f] -2,5-oxazocin (90 mg, 0.24 mmol), cyclopropylboronic acid (26.8 mg, 0.312 mmol), K3P0 (178 mg, 0.84 mmol), Pd (OAc) 2 (3 mg, 0.012 mmol) and P (cyclohexane) 3 (7 mg, 0.024 mmol) were heated at 100 ° C in toluene (2 ml) and water (100 μl) for 3 hours. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product. Purification by column chromatography on silica gel [100% EtOAc at 5% MeOH / EtOAc] provided 8-cyclopropyl- (3,4-methylenedioxy) -nefopa 49 mg, (61%). dH (CDCl3; 250MHz) 0.67-0.72 (2H, m, two cyclopropyl CH2CH2), 0.91-0.99 (2H, two cyclopropyl CH2CH2), 2.48 (3H, s, CH3), 2.61 (1H, ddd, J14. 2, 5.7, 2.6, one of CH2CH2), 2.83 (1H, ddd, 14.2, 8.4, 2.5, one of CH2CH2), 3.64 (1H, d, 12.8, one of ArCH2NR2), 3.83 (1H, ddd, J12.5 , 5.7, 2.5, one of CH2CH2), 4.42 (1H, ddd, 12.5, 8.4, 2.6, one of CH2CH2), 4.74 (1H, d, J12.8, one of ArCH2NR2), 5.67 (1H, s, CHOH) , 5.91 '(2H, s, ROCH2OR), 6.75 (3H, s, ArH), 6.88-6.9 (3H, m, ArH) Example 33 8-Bromo-5-methyl-1- (3-ethoxy) phenyl-1 3,4-6-tetrahydro-5H-benz [f] -2,5-oxazocine 2- (. {5-Bromo-2- [hydroxyl- (3-ethoxy-phenyl) -methyl] -benzyl} -methylamino) -ethanol (1.06 g, 2.69 mmol) was heated to Reflux temperature under Dean-Stark conditions with pTSA (0.78 g, 4.03 mmol) in toluene (40 ml) for 2.5 h. The reaction mixture was allowed to cool and then diluted with ethyl acetate (20 ml). The mixture was washed with saturated aqueous sodium bicarbonate solution (2 x 20 ml) and the combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo to give 0.94 g of crude product. Purification by silica gel column chromatography [EtOAc] gave the product (0.60 g, 59%) as a colorless oil. dH (CDCl3; 250MHz) 7.37-6.87. { 7H, m, aromatics), 5.71 (1H, s, CH-O), 4.77 (1H, d, J 13, ArCHAHBN), 4.14 (1H, ddd, J 13, 8 and 2.5, CHAHBCH2), 4.00 (2H, q, J l, CH2CH3), 3.84 (1H, ddd, J 13, 8 and 2.5, CHAHBCH2), 3.62 (1H, d, J 13, ArCHAHBN), 2.85-2.79 (1H,, CHAHBCH2), 2.68-2.60 ( 1H, m, CHAHBCH2), 2.46 (3H, s, NCH3), 1.39 (3H, t, J1, CH2CH3). Example 34 8-Cyano-5-methyl-yl- (3-ethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5-methyl-1 - (3-ethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin (250 mg, 0.65 mmol), Zn (3 mg, 0.05 mmol), Zn (OAc) 2 (15 mg, 0.077 mmol), Zn (CN) 2 (46 mg, 0.4 mmol), Pd2 (dba) 3 (93 mg, 0.1 mmol) and 1.1 '-bis (diphenylphosphino) ferrocene (43 mg, 0.077 mmol) were heated at 140 ° C in DMF (5 ml) and H20 (100 μl) for 4 h.

The black reaction mixture was allowed to cool to RT and diluted with water. The resulting brown precipitate was collected by filtration and washed with water then brine. The filtrate was extracted with ethyl acetate (2 x 60 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product as a brown oil. Purification by silica gel column chromatography [DCM] gave the clean product (56 mg, 27%). dH (CDCl3; 250MHz) 7.50-6.78 (7H,, aromatics), 5.72 (1H, s, CH0) 1 4.96 (1H, d, J 13, ArCHAHB-N), 4.39-4.19 (1H, m, CHAHBCH2), . 3.98 (2H, q, J1, CH2CH3), 3.85-3.79 (1H, m, CHAHBCH2), 3.67 (1H, d, J 13, ArCHAHB-N), 2.82-2.58 (2H, m, CH2CH2), 2.43 ( 3H, s, NCH3), 1.38 (3H, t, J1, CH2CH3). EXAMPLE 35 8-Cyclopropyl-5-methyl-1- (3-ethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5-methyl-1 - (3-ethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin (100 mg, 0.26 mmol), cyclopropylboronic acid (29 mg, 0.33 mmol), K3PO4 ( 193 mg, 0. 91 mmol), Pd (0Ac) 2 (3 mg, 0.013 mmol) and P (cyclohexane) 3 (8 mg, 0.026 mmol) were heated at 100 ° C in toluene (2 ml) and H20 (100 μl) for 4 hours. After cooling to RT, water (2 ml) was added and the mixture was extracted with ethyl acetate, washed with brine, dried (MgSO 4), filtered and concentrated in vacuo. Purification by silica gel column chromatography [DCM] provided the clean product (20 mg, 23%) as a colorless oil. dH (CDCl3; 250MHz) 7.26-6.76 (7H, m, aromatics), 5.71 (1H, s, CHO), 4.75 (1H, d, J 12.5, ArCHAHB-N) 4.22-4.12 (1H, m, CHAHBCH2), 3.99 (2H, q, J7, CH2CH3), 3.88-3.79 (1H,, CHAHBCH2), 3.81 (1H, d, J 12.5, ArCHAHB-N), 2.90-2.61 (2H, m, CH2CH2), 2.50 (3H, s, NCH3), 1.89-1.82 (1H, m, CHCH2), 1.39 (3H, t, J1, CH2CH3), 0.96-0.92 (2H,, CH2CH2), 0.70-0.67 (2H, m, CH2CH2). Example 36 9-Bromo-5-methyl-1- (3-ethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 2- (. {4-Bromo -2- [hydroxyl- (3-ethoxy-phenyl) -methyl] -benzyl] -methylamino) -ethanol (1.20 g, 3.04 mmol) was heated to reflux temperature under Dean-Stark conditions with pTSA (0.88 g, 4.57 mmol) in toluene (50 ml) for 4 h. The reaction mixture was allowed to cool and then diluted with ethyl acetate (25 ml). The mixture was washed with saturated aqueous sodium bicarbonate solution (2 x 25 ml), and the combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo to provide 1.4 g of crude product. Purification by silica gel column chromatography [EtOAc] gave the product (0.59 g, 51%) as a colorless oil. dH (CDCl3; 250MHz) 7.37-6.76 (7H,, aromatics), 5.67 (1H, s, CH-0), 4.79 (1H, d, J 13, ArCHAHBN), 4.16 (1H, ddd, J 13, 8 y 2.5, CHAHBCH2), 4.01 (2H, q, J l, CH2CH3), 3.81 (1H, ddd, J 13, 8 and 2.5, CHAHBCH2), 3.63 (1H, d, J 13, ArCHAHBN), 2.84-2.78 (1H , m, CHAHBCH2), 2.66-2.63 (1H, m, CHAHBCH2), 2.44 (3H, s, NCH3), 1.40 (3H, t, J1, CH2CH3). Example 37 9-Cyano-5-methyl-1- (3-ethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin 9-Bromo-5-methyl-1 - (3-ethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin (150 mg, 0.39 mmol), Zn (2 mg, 0.03 mol), Zn (OAc) 2 (9 mg, 0.046 mmol), Zn (CN) 2 (28 mg, 0.24 mmol), Pd2 (dba) 3 (56 mg, 0.06 mmol) and 1.1 '-bis (diphenylphosphino) ferrocene (25 mg, 0.046 mmol) were heated at 140 ° C in DMF (3 ml) and H20 (30 μl) overnight. The black reaction mixture was allowed to cool to RT and diluted with water. The resulting brown precipitate was collected by filtration and washed with water then brine. The filtrate was extracted with ethyl acetate (2 x 80 ml), and the combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo to give the crude product. Purification by silica gel column chromatography [DCM] gave the clean product (12 mg, 10%). dH (CDCl3; 250MHz) 7.53-6.80 (7H, m, aromatics), 5.75 (1H, s, - CHO), 4.87 (1H, d, J 13, ArCHaHBN), 4.29-4.14 (1H, m, CHAHBCH2), 4.01 (2H, q, J 1, CH2CH3), 3.88-3.78 (1H, m, CHAHBCH2), 3.73 (1H, d, J 13, ArCHaHBN), 2.82-2.71 (1H, m, CHAHB-CH2), 2.68-2.59 (1H, m, CHAHBCH2), 2.46 (3H, s, N-CH3), 5 1.39 ( 3H, t, J 1, CH 2 CH 3). Example 38 9-Cyclopropyl-5-methyl-1- (3-ethoxy) f-1, 3,4, 6-tetrahydro-5H-benz [f] -2,5-oxazocine 9-Bromo-5-methyl- l- (3-ethoxy) phenyl-1, 3,4,6- 10 tephrahydro-5H-benz [f] -2,5-oxazocine (140 mg, 0.36 mmol), cyclopropylboronic acid (41 mg, 0.45 mmol), K3P04 (269 mg, 1.26 mmol), Pd (0Ac) 2 (5 mg, 0.02 mmol) and P (cyclohexane) 3 (11 mg, 0.04 mmol) were heated at 100 ° C in toluene (3 ml) and H20 (150 μl) for 4 hours. After cooling to RT, water (2 ml) was added and the mixture was extracted with ethyl acetate, washed with brine, dried (MgSO 4), filtered and concentrated in vacuo. Purification by silica gel column chromatography [DCM] gave the product (61 mg, 50%) as a colorless oil. 20 dH (CDCl3; 250MHz) 7.25-6.76 (7H, m, aromatics), 5.69 (1H, s, CHO), 4.79 (1H, d, J 13, ArCHAHBN), 4.23-4.16 (1H, m, CHAHBCH2), 4.01 (2H, q, J1, CH2CH3), 3.89-3.81 (1H, m, CHaHBCH2), 3.70 (1H, d, J 13, ArCHAHBN), 2.88-2.78 (1H, m, CHaHB-CH2), 2.68- 2.60 (1H, m, CHAHBCH2), 2.48 (3H, s, N-CH3), '25 1.83-1.72 (1H, m, CHCH2), 1.39 (3H, t, J7, CH2CH3), 0.92-0.88 (2H,, CH2CH2), 0. 62-0. 58 (2H, m, CH2CH2). Example 39 8-Bromo-5-methyl-1- (3-trifluoromethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 2- (. {5-bromine -2- [hydroxyl- (3-trifluoromethoxy-phenyl) -methyl] -benzyl] -methylamino) -ethanol (635 mg, 1.47 mmol) was heated to reflux under Dean-Stark conditions with pTSA (420 mg, 2.21 mmol ) in toluene (6 ml) for 2 hours. The reaction mixture was allowed to cool to RT and then diluted with ethyl acetate (30 ml). The mixture was washed with saturated aqueous sodium bicarbonate solution (50 ml) and extracted into ethyl acetate. The combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo to provide the crude cyclized product. Purification by silica gel column chromatography [EtOAc] provided the objective product (116 mg, 19%). dH (CDCl3; 250MHz) 2.47 (3H, s, CH3), 2.67 (1H, ddd ^ J14.3, 6.1, 2.5, one of CH2CH2), 2.84 (1H, ddd, J14.3, 7.8, 2.2, one of CH2CH2), 3.67 (1H, d, J12.8, one of ArCH2NR2), 3.86 (1H, ddd, J12.8, 6.1, 2.2, one of CH2CH2), 4.13 (1H, ddd, J12.8, 7.8, 2.5 , one of CH2CH2), 4.61 (1H, d, J12.8, one of ArCH2NR2), 5.79 (1H, s, CHOR), 6.85 (1H, d, J8.2, ArH), 7.11-7.19 (3H,, ArH), 7.31-7.36 (3H, m, ArH). Example 40 8-Cyano-5-methyl-1- (3-trifluoromethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin 8-Bromo-5-methyl-1- ( 3-trifluoromethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin (116 mg, 0.28 mmol), Zn (1 mg, 0.02 mmol), Zn (OAc) 2 (7 mg, 0.038 mmol), Zn (CN) 2 (20 mg, 0.17 mmol), Pd2 (dba) 3 (40 mg, 0.04 mmol) and 1,1 '-bis- (diphenylphosphine) ferrocene (20 mg, 0.036) mmol) were heated to 140 ° C in DMF (3 ml) and H20 (30 μl) overnight. The black reaction mixture was allowed to cool and diluted with water. The resulting brown precipitate was collected by filtration and washed with ethyl acetate. The filtrate was washed with brine (2 x 60 ml) and the combined aqueous phases were then washed with ethyl acetate (2 x 80 ml). The combined organic extracts were dried (MgSO) and concentrated in vacuo to provide the crude product. Purification by silica gel column chromatography [ethyl acetate / heptane 1: 1) gave the desired product (9 mg, 9%). dH (CDCl3; 250MHz) 2.50 (3H, s, CH3), 2.61-2.87 (2H, m, two of CH2CH2), 3.76 (1H, d, J13.1, one of ArCH2NR2), 3.87 (1H, ddd, J12.7, 5.4, 2.5, one of CH2CH2), 4.25 '(1H, ddd, J12.7, 8.4, 3.1, one of CH2CH2), 4.86 (1H, d, J13.1, one of ArCH2NR2), 5.82 (1H, s, CHOR), 7.11-7.16 (4H, m, ArH), 7.33-7.39 (1H, m, ArH, 7.52 (1H, dd, 7.9, 1.8, ArH), 7.57 (1H, bs, ArH ).

Example 41 8-Cyclopropyl-5-methyl-1- (3-trifluoromethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5-methyl-1 - (3-trifluoromethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine (160 mg, 0.39 mmol), cyclopropylboronic acid (43 mg, 0.5 mmol), K3P04 ( 288 mg, 1. 36 mmol), Pd (0Ac) 2 (4 mg, 0.019 mmol) and P (cyclohexane) 3 (11 mg, 0.039 mmol) were heated at 100 ° C in toluene (2 ml) and H20 (100 μl) for 4 hours. The reaction mixture, now black in color, was allowed to cool to RT. Water (50 ml) was added and the mixture was extracted into ethyl acetate (3 x 80 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude cyclopropyl analog. Purification by silica gel column chromatography [EtOAc / heptane 1: 1, then 100% EtOAc] provided 8-cyclopropyl- (m-trifluoromethoxy) -nefopam. dH (CDCl3; 250MHz) 0.67-0.74 (2H, m, two cyclopropyl CH2CH2), 0.89-1.00 (2H, m, two cyclopropyl CH2CH2), 1.82-1.93 (1H, m, cyclopropyl CH), 2.51 (3H, s, CH3), 2.68 (1H, ddd, J14.2, 5.7, 2.5, one of CH2CH2), 2.89 (1H, ddd, J14.2, 8.2, 2.0, one of CH2CH2), 3.74 (1H, d, J12 .8, one of ArCH2NR2), 3.87 (1H, ddd, J12.7, 5.7, 2.0, one of CH2CH2), 4.13 (1H, ddd, J12.7, 8.2, 2.5, one of CH2CH2), 4.58 (1H, d, J12.5, one of ArCH2NR2), 5.81 (1H, s, CHOR), 6.84-6.97 (3H, m, ArH), 7.09-7.20 (3H, m, ArH), 7.29-7.37 (1H, m, ArH). Example 42 9-Bromo-5-methyl-1- (3-trifluoromethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 2- (. {4-Bromo -2- [Crude hydroxyl- (3-trifluoromethoxy-phenyl) -methyl] -benzyl] -methylamino) -ethanol (1159 g, 2.69 mmol) was heated to reflux with pTSA (768 mg, 4.04 mmol) in xylene (12 ml) with Dean-Stark for 4 hours, 45 mins. The reaction mixture was allowed to cool and then washed with a saturated solution of sodium bicarbonate (100 ml). The organic extracts were extracted into ethyl acetate (2 x 100 ml) and the combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo to give the crude product as a 2: 1 mixture with the starting material. Purification by column chromatography on silica gel provided the objective product (189 mg, 17%). dH (CDCl3; 250MHz) 2.44 (3H, s, CH3), 2.64 (1H, ddd, 15.0, 5.0, 2.5, one of CH2CH2), 2.81 (1H, ddd, J15.0, 7.5, 2.5, one of CH2CH2) , 3.67 (1H, d, 12.5, one of ArCH2NR2), 3.84 (1H, ddd, J12.5, 5.0, 2.5, one of CH2CH2), 4.14 (1H, ddd, J12.5, . 0, 2.5, one of CH2CH2), 4.65 (1H, d, J12.5, one of ArCH2NR2), 5.75 (1H, s, CHOR), 7.09-7.19 (5H, m, ArH), 7.34 (1H, d, J8.0, one of ArH), 7.40 (1H, dd, J8.0, 1.9, one of ArH). Example 43 9-Cyclopropyl-5-methyl-1- (3-trifluoromethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin 9-Bromo-5-methyl-1- ( 3-trifluoromethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin (95 mg, 0.28 mmol), K3P04 (205 mg, 0.97 mmol), cyclopropylboronic acid (31 mg , 0.36 mmol), P (cyclohexane) 3 (8 mg, 0.028 mmol) and Pd (0Ac) 2 (3 mg, 0.014 mmol) were heated at 100 ° C in toluene (2 ml) and water (100 μl). The reaction mixture turned black in color after about 20 mins. At the end of 3 hours, the mixture was allowed to cool to RT, and water (30 ml) was added. The organic extracts were extracted into ethyl acetate (2 x 30 ml) and the combined extracts were dried (MgSO 4), filtered and concentrated in vacuo. Purification by silica gel column chromatography [EtOAc] provided the product. dH (CDCl3; 250MHz) 0.58-0.63 (2H, m, two of cyclopropyl CH2CH2), 0.90-0.94 (2H, two of CH2CH2), 1.73-1.79 (1H,, cyclopropyl CH), 2.45 (3H, s, CH3 ), 2.68 (1H, ddd, J15.0, 5.0, 2.5, one of CH2CH2), 2.87 (1H, ddd, 15.0, 7.5, 2.5, one of CH2CH2), 3.75 (1H, d, J12.5, one of ArCH2NR2), 3.88 (1H, ddd, J 12.5, 5.0, 2.5, one of CH2CH2), 4.19 (1H, ddd, J 12.5, 7.5, 2.5, one of CH2CH2), 4.67 (1H, J12.5, one of ArCH2NR2 ), 5.75 (1H, s, CHOR), 6.72 (1H, d, J2.5, one of ArH), 6.93 (1H, dd, J7.5, 2.5, ArH), 7.10-7.19 (4H, m, ArH ), 7.29-7.38 (1H, ArH) Example 44 9-Bromo-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 2- [(4-bromo-2 - (hydroxyl-o-tolylmethyl) -benzyl) -methylamino] -ethanol (790 mg, 2.18 mmol) was dissolved in toluene (8 ml) at RT. pTSA (623 mg, 3.27 mmol) was added and the resulting mixture was heated to reflux temperature under Dean-Stark conditions for 1.5 hours. Once cooled to RT, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude material as an oil. Purification by silica gel column chromatography [20% EtOAc / heptane at 30% EtOAc] provided the product (357 mg, 55% corrected yield) dH (CDCl3; 250MHz) 2.31 (3H, s, ArCH3 ), 2.44 (3H, s, NCH3), 2.63 (1H, ddd, J14.4, 5.3, 2.4, one of CH2CH2), 2.86 (1H, ddd, J14, 8.9, 2.1, one of CH2CH2), 3.76 (1H , d, J, 13.0, one of ArCH2NR2), 3.85 (1H, ddd, J12.7, 5.3, 2.1, one of CH2CH2), 4.12 (1H, ddd, J12.7, 8.9, 2.4, one of CH2CH2), 4.68 (1H, d, 13.0, one of ArCH2NR2), 5.95 (1H, s, CHOR), 7.02-7.22 (6H, m, ArH), 7.38 (1H, dd, 8.2, 2.1, ArH). Example 45 9-Cyano-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-5H- benz [f] -2,5-oxazocine 9-Bromo-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine ( 156 mg, 0.45 mmol), Zn powder (2 mg, 0.03 mmol), Zn (CN) 2 (32 mg, 0.27 mmol), Zn (OAc) 2 (10 mg, 0.054 mmol), '1.1'-bis (diphenylphosphino) ferrocene (30 mg, 0.054 mmol) and Pd2 (dba) 3 (55 mg, 0.06 mmol) were heated at 140 ° C in DMF (3 ml) and water (30 μl) under a nitrogen atmosphere overnight . After cooling, water was added and the resulting brown / black precipitate was collected by filtration by suction and washed well with ethyl acetate. The filtrate was washed with brine and extracted into ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude material as a very light brown oil. Purification by silica gel column chromatography [EtOAc] gave the product (79 mg, 60%). dH (CDCl3; 250MHz) 2.28 (3H, s, ArCH3), 2.45 (3H, s, ArCH3), 2.65 (1H, ddd, 14.4, 5.5, 2.4, one of CH2CH2), 2.85 (3H, ddd, J14.4 , 8.9, 2.1, one of CH2CH2), 3.82-3.90 (2H, m, one of CH2CH2 and one of ArCH2NR2), 4.07-4.17 (1H, m, one of CH2CH2), 4.74 (1H, d, 12.8, one of ArCH2NR2), 6.02 (1H, s, CHOR), 7.05 (1H, d, J6.7, ArH), 7.14-7.27 (4H, m, ArH), 7.34 (1H, d, 7.9, ArH), 7.54 (1H , dd, 7.9, 1.7, ArH). Example 46 9-Cyclopropyl-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin 9-Bromo-5-methyl-1- ( 2-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine (188 mg, 0.55 mmol) was dissolved in toluene (4 ml) and water (200 μl) at RT Cyclopropylboronic acid (61 mg, 0.71 mmol), K3P04 (409 mg, 1.93 mmol), Pd (OAc) 2 (6 mg, 0.03 mmol) and P (cyclohexane) 3 (15.4 mg, 0.055 mmol) were added. The mixture was heated at 100 ° C for a total of 3 hours, during the time in which the reaction mixture became black. After cooling to RT, the mixture was diluted with water and extracted into ethyl acetate. The organic phases were dried (MgSO4), filtered and concentrated in vacuo to give the crude product. Purification by silica gel column chromatography [EtOAc] gave the product (129 g, 81%). dH (CDCl3; 250MHz) 0.54-0.60 (2H, m, two cyclopropyl CH2CH2), 0.86-0.89 (2H, m, two cyclopropyl CH2CH2), 1.69-1.80 (1H, m, cyclopropyl CH) 1 2.34 (3H, s, ArCH3), 2.45 (3H, s, ArCH3), 2.62 (1H, ddd, 14.3, 5.5, 2.4, one of CH2CH2), 2.87 (1H, ddd, 14.3, 8.5, 2.1, one of CH2CH2), 3.75 ( 1H, d, J13.0, one of ArCH2NR2), 3.85 (1H, ddd, J12.7, 5.5, 2.1, one of CH2CH2), 4.11 (1H, ddd, J12.7, 8.5, 2.4, one of CH2CH2) , 4.64 (1H, d, J13.0, one of ArCH2NR2), 5.96 (1H, s, CHOR), 6.62 (1H, d, 1.8, ArH), 6.89 (1H, dd, J7.9, 1.8, ArH) , 7.05-7.20 (5H, ArH). Example 47 8-Bromo-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin 2 [(5-bromo-2- (hydroxyl-o-tolylmethyl) -benzyl) ethylamino] -ethanol (777 mg, 2.16 mmol) was dissolved in toluene (8 ml) at RT. pTSA (616 mg, 3.24 mmol) was added, and the resulting mixture was heated to reflux temperature under Dean-Stark conditions for 4 hours. The reaction was allowed to cool to RT and then diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. The organic washes were dried (MgSO4), filtered and concentrated in vacuo to provide the impure product. Purification by silica gel column chromatography [EtOAc / heptane 1: 1 to 100% EtOAc] gave the desired product (504 mg, 64%). dH (CDCl3; 250MHz) 2.29 (3H, S, ArCH3), 2.46 (3H, s, NCH3), 2.66 (1H, ddd, J14.4, 5.6, 2.4, one of CH2CH2), 2.89 (1H, ddd, J14 .4, 8.5, 2.1, one of CH2CH2), 3.77 (1H, d, 13.1, one of ArCH2NR2), 3.86 (1H, ddd, J12.7, 5.6, 2.1, one of CH2CH2), 4.09 (1H, ddd, 12.7, 8.5, 2.4, one of CH2CH2), 4.64 (1H, d, J13.1, one of ArCH2NR2), 5.97 (1H, s, CHOR), 6.74 (1H, d, J8.2, ArH), 7.07- 7.20 (4H, m, ArH), 7.29 (1H, dd, J8.6, 2.1, ArH), 7.41 (1H, d, 2.1, ArH). Example 48 8-Cyano-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin 8-Bromo-5-methyl-1- ( 2-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine (207 mg, 0.60 mmol), Zn (2 mg, 0.03 mmol), Zn (OAc) 2 (13 mg, 0.071 mmol), Zn (CN) 2 (42 mg, 0.36 mol), 1,1 '-bis (diphenylphosphino) ferrocene (40 mg, 0.072 mmol) and Pd2 (dba) 3 (75 mg, 0.082 mmol ) were heated at 140 ° C in DMF (5 ml) and H20 (50 μl) overnight. The black reaction mixture was cooled and water was added, producing a brown precipitate. The precipitate was washed with ethyl acetate and the filtrate was washed with brine to remove the DMF. The organic phase was dried (MgSO 4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel column chromatography [EtOAc] gave the desired product (39 g, 22%). dH (CDCl3; 250MHz) 2.33 (3H, s, ArCH3), 2.46 (3H, s, NCH3), 2.64 (1H, ddd, J14.9, 5.1, 2.6, one of CH2CH2), 2.77 (1H, ddd, J14 .9, 8.9, 2.4, one of CH2CH2), 3.78 (1H, d, J13.1, one of ArCH2NR2), 3.86 (1H, ddd, J12.7, 5.1, 2.4, one of CH2CH2), 4.18 (1H, ddd, 12.7, 8.9, 2.6, one of CH2CH2), 4.89 (1H, d, J13.1, one of ArCH2NR2), 5.99 (1H, s, CHOR), 6.91-6.98 (2H, m, ArH), 7.12- 7.22 (3H, ArH), 7.46 (1H, dd, J7.9, 1.8, ArH), 7.55 (1H, d, J1.5, ArH). Example 49 8-Cyclopropyl-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-5H- benz [f] -2,5-oxazocine 8-Bromo-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine ( 205 mg, 0.60 mmol) was dissolved in toluene (4 ml) and H20 (200 μl) at RT. Cyclopropylboronic acid (67 mg, 0.77 mmol) -, K3P04 (446 mg, 2.1 mmol), Pd (0Ac) 2 (7 mg, 0.03 mmol) and P (cyclohexane) 3 (17 mg, 0.06 mmol.) Were added. The resulting mixture was heated at 100 ° C for 3 hours. The mixture was then allowed to cool to RT then the mixture was partitioned between water and ethyl acetate. The organic phases were dried (MgSO 4), filtered and concentrated in vacuo to yield the crude product. Purification by silica gel column chromatography [EtOAc] provided the desired objective (117 g, 64%). dH (CDCl3; 250MHz) 0.67-0.74 (2H,, two of CH2CH2), 0.92-1.0 (2H, m, two of CH2CH2), 1.83-1.93 (1H, m, cyclopropyl CH), 2. 28 (3H, s, ArCH3), 2.48 (3H, s, NCH3), 2.66 (1H, ddd, 14.4, . 6, 2.3, one of CH2CH2), 2.95 (1H, ddd, J14.4, 8.5, 2.1, one of CH2CH2), 3.81 (1H, d, J12.8, one of ArCH2), 3.87 (1H, ddd, J12 .8, 5.6, 2.1, one of CH2CH2), 4.08 (1H, ddd, 12.8, 8.5, 2.3, one of CH2CH2), 4.56 (1H, d, J12.8, one of ArCH2NR2), 5.98 (1H, s, CHOR), 6.73 (1H, d, J7.9, ArH), 6.85 (1H, dd, J7.9, 1.8, ArH), 6.97 (1H, d, 1.8, ArH), 7.14-7.18 (4H, m, ArH). Example 50 9-Bromo-5-methyl-1- (3-pyridyl) -1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-2. { [4-Bromo-2- (hydroxypyridin-3-yl-methyl) -benzyl] -methylamino} Ethanol (100 mg, 0.29 mmol) was dissolved in xylene (2 mL) at RT. pTSA (434 mg, 2.28 mmol) was added and the resulting mixture was heated to 120 ° C in an open vessel until all the solvent and water had evaporated. The reaction vessel was removed from the heat and allowed to cool. Ethyl acetate (20 ml) and a saturated aqueous sodium bicarbonate solution (20 ml) were added to partition the gummy mixture. The organic phase was separated, and the aqueous phase was extracted into ethyl acetate (2 x 20 ml). The combined extracts were dried (MgSO 4), filtered and concentrated in vacuo to give the cyclized product as a pale brown oil. Purification by column chromatography on silica gel with a step gradient, [100% EtOAc at 3% / 5% / 10% MeOH / EtOAc)], provided the product (23 mg, 24%). dH (CDCl3; 250MHz) 2.46 (3H, s, NCH3), 2.66 (1H, ddd, 14.4, 5.5, 2.8, one of CH2CH2), 2.83 (1H, ddd, J14.4, 8.2, 2.1, one of CH2CH2) , 3.67 (1H, d, J13.1, one of ArCH2NR2), 3.86 (1H, ddd, J12.7, 5.5, 2.1, one of CH2CH2), 4.19 (1H, ddd, 12.7, 8.2, 2.8, one of CH2CH2 ), 4.73 (1H, d, J13.1, one of ArCH2NR2), 5.77 (1H, s, CHOR), 7.11-7.14 (2H, m, aromatic H), 7.24-7.29 (1H,, aromatic H), 7.39 (1H, dd, 7.9, 1.8, aromatic H), 7.56 (1H, d, 7.9, aromatic H), 8.53-8.57 (2H, m, aromatic H). Example 51 8-Bromo-5-methyl-1- (3-pyridyl) -1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-2. { [5-Bromo-2- (hydroxypyridin-3-yl-methyl) -benzyl] -methylamino} Ethanol (84 mg, 0.24 mmol) was dissolved in xylene (2 ml). pTSA (364 mg, 1.9 mmol) was added and the mixture was heated to reflux temperature in an open vessel to allow evaporation of the solvent and water. When the mixture was concentrated to a black gum, the container was removed from the heat and allowed to cool. The residue was partitioned between ethyl acetate (20 ml) and saturated aqueous sodium bicarbonate solution (20 ml). The aqueous phase was further extracted with ethyl acetate (2 x 20 ml), and the combined organic extracts were dried (magnesium sulfate), filtered and evaporated to dryness to give the crude product. It was purified by silica gel column chromatography [Ethyl acetate] to provide. the objective compound as an oil / solid. dH (CDCl3; 250MHz) 2.46 (3H, s, CH3), 2.58 (1H, ddd, 14.3, 6.1, 2.6, one of CH2CH2), 2.83 (1H, ddd, J14.3, 7.9, 2.1, one of CH2CH2) , 3.63 (1H, d, J13.1, one of ArCH2NR2). 3.86 (1H, ddd, J12.6, 6.1, 2.1, one of CH2CH2), 4.16 (1H, ddd, J12.6, 7.9, 2.6, one of CH2CH2), 4.68 (1H, d, J13.1, one of ArCH2NR2), 5.80 (1H, s, CHOR), 6.84 (1H, d, J8.3, aromatic H) l 7.21-7.27 (2H,, aromatic H), 7.32-7.40 (2H, m, aromatic H), 7.55 (1H, dd, J7.8, 1.6, aromatic H), 8.52 (1 H, dd, J4.6, 1.6, aromatic H), 8.54 (1H, d, J8.6, aromatic H). EXAMPLE 52 8-Cyano-5-methyl-1- (3-pyridyl) -1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine 8-Bromo-5-methyl-l- (3-pyridyl) -1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine (50 mg, 0.15 mmol), Zn (1 mg, 0.01 mmol), Zn (0Ac) 2 (4 mg, 0.02 mmol), Zn (CN) 2 (13 mg, 0.11 mmol), Pd2 (dba) 3 (18 mg 0.02 mmol) and 1,1'-bis (diphenylphosphine) ferrocene (9 mg 0.02 mmol) were added. they were heated at 140 ° C in DMF (2 ml) and H20 (20 μl) overnight. The black reaction mixture was allowed to cool and diluted with water (20 ml). The resulting brown precipitate was collected by filtration and washed with water then brine. The filtrate was extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo to give the crude product as a brown oil. Purified by silica gel column chromatography [dichloromethane] to provide the desired product (10 mg, 24%) as a yellow oil. dH (CDC13; 250MHz) 2.47 (3H, s, CH3), 2.58-2.84 (2H, m, CH2CH2), 3.68 (1H, d, J13.1, one of ArCH2NR2), 3.82-3.90 (1H, m, one of CH2CH2), 4.19-4.29 (1H, m, one of CH2CH2), 4.88 (1H, d, J13.1, one of ArCH2NR2), 5.84 (1H, s, CHOR), 7.11 (1H, d, J8.3, aromatic H) 1 7.22-7.30 (2H1 m, aromatic H), 7.49-7.55 - (3H, m, aromatic H), 8.52 (1H, dd, 4.6, 1.6 aromatic H), 8.55 (1H, d, J8.6, aromatic H). Biological Assay The assay was carried out according to the method described by Perovic et al., (1995), Arzneim-Forsch. Drug Res., 45: 1145. Assay for Inhibition of Noradrenaline Reuptake Activity Synaptosomes (100 μg) are incubated for 20 min at 37 ° C with Ci 0. l [3 H] norepinephrine in the absence (control) or presence of the test compound or the reference compound in a regulated solution containing 118 M NaCl, 5 mM KCl, 2.5 mM MgSO 4, 1.2 mM NaH 2 PO 4, 25 mM NaHCO 3, 11 mM glucose, 10 μM EGTA and 50 μM ascorbic acid (pH 7.4 ). The base control activity is determined by incubating the same mixture for 20 min at 0 ° C in the presence of 10 μM protriptyline to block reuptake. After incubation, samples are rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) and rinsed twice with ice-cold incubation buffer using a 96-cell cell harvester (Unifilter, Packard) to eliminate [3H] norepinephrine free. The filters are dried and the radioactivity retained is measured in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as a percentage inhibition of the reuptake control of [3 H] norepinephrine. The standard inhibitory reference compound is protriptyline, which is tested in each experiment in severe concentrations to obtain a curved inhibition of which its IC50 value is calculated. Assay for Inhibition of Serotonin Synaptosome Reuptake Activity (100 μg) is incubated for 15 min at 37 ° C with 0.1 μCi of [3 H] serotonin in the absence (control) or presence of the test compound or the reference compound in a buffer solution containing 118 M NaCl, 5 mM KCl, 2.5 mM MgSO4, 1.2 mM NaH2P04, 25 mM 25 mM NaHCO3, 11 mM glucose, 10 μM EGTA and 50 μM ascorbic acid (pH 7.4). The base control activity is determined by incubating the same mixture for 15 min at 4 ° C in the presence of 10 μM ipramin to block reuptake. After incubation, samples are quickly filtered under vacuum through glass fiber filters (GF / B, Packard) and rinsed twice with cold incubation buffer with ice using a 96-cell cell harvester 96 (Unifilter, Packard) to eliminate [3H] free serotonin. Filters are dried and retained radioactivity is measured in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as a percent inhibition of the control uptake of [3 H] serotonin. The standard inhibitory reference compound is imipramine, which is tested in each experiment in various concentrations to obtain an inhibition curve from which its IC50 value is calculated.

Claims (14)

1. CLAIMS 1. A compound of the general formula (1) characterized in that Ri is H, C? -C6 alkyl optionally substituted with F or C3-C6 cycloalkyl or C2-C alkenyl; A is O, CH2 or S (0) n where n is 0-2; one of W, X, Y and Z is N, CH or CR3 and the others are CH; R2 is C5-C6 heteroaryl, C5-C10 cycloalkyl or cycloalkenyl optionally containing one or more heteroatoms selected from O, N and S (0) n where n is 0-2, and optionally substituted with R3; or a phenyl group optionally substituted at one or more positions with one or more substituents independently selected from halogen, CN, CF3, C? -C6 alkyl and 0RX, or the phenyl group is fused to a five or six membered ring which it can be carbocyclic, heterocyclic (containing 1-2 heteroatoms selected from O, N and S), aromatic or heteroaromatic (containing 1-2 heteroatoms selected from O and N); R3 is selected from halogen; CF3; CN; 0R5; S02N (R5) 2; C0R5; C02R5; C0N (R5) 2; NR? C0R4; NR? S02R4; R! C02R4; NR! C0N (R5) 2; O-C6-C6alkyl substituted with R3; Ci-Cß alkyl optionally substituted with unsubstituted R3; C3-C6 cycloalkyl optionally substituted with unsubstituted R3; ^ C2-C6 alkenyl optionally substituted with unsubstituted R3; C2-C6 alkynyl optionally substituted with unsubstituted R3; aryl optionally substituted with unsubstituted R3; and five or six membered aromatic heterocycles containing 1-4 heteroatoms selected from N and O; R4 is Ci-Ce alkyl, C2-Cd alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, and heteroaryl; and R5 is H, C? -C6 alkyl, C2-C6 alkenyl, C2-Cd alkynyl, C3-C6 cycloalkyl, aryl or heteroaryl and is the same as or different from another R5; or a pharmaceutically acceptable salt thereof.
2. 2. A compound according to claim 1, characterized in that R2 is optionally substituted heteroaryl, cycloalkyl or cycloalkenyl.
3. 3. A compound according to claim 1, characterized in that R2 is optionally substituted phenyl.
4. 4. A compound according to claim 1, characterized in that it is selected from: 5-benzyl-1-phenyl-1, 3, 4, 6-tetrahydro-5H- [f] -2, 5-oxazocine; 5-allyl-1-phenyl-1,3,4,6,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 5-cyclopropyl-1-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 5-pro? Il-l-phenyl-1,3,4,6,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 5-methylcyclopropyl-1-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 5-isopropyl-1-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 8- (4-pyridyl) -5-methyl-1- (3-methoxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8- (5-pyrimidine) -5-methyl-1- (3-methoxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 5-methyl-1- (3-methoxy) phenyl-1,3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 5-methyl-1- (3-methoxy) phenyl-1,3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocin-8-carboxamide; 10-fluoro-5-methyl-l-phenyl-1,3,4,6-tetrahydro-H5-benz [f] -2,5-oxazocine; 7-fluoro-5-methyl-1-phenyl-1,3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-bromo-5-methyl-l- (3-tosyloxy) phenyl-1, 3,4,6- tetrahydro-H5-benz [f] -2,5-oxazocine; 8-bromo-5-methyl-1- (3-hydroxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-cyano-5-methyl-1- (3-hydroxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-cyclopropyl-5-methyl-1- (3-hydroxy) phenyl-1,3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-bromo-5-methyl-1- (3-allyloxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-cyano-5-methyl-1- (3-allyloxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-cyclopropyl-5-methyl-1- (3-allyloxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-bromo-5-methyl-1- (2-methyl-3-methoxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-cyano-5-methyl-1- (2-methyl-3-methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 8-cyclopropyl-5-methyl-1- (2-methyl-3-methoxy) phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 8-bromo-5-methyl-1- (3-methoxy-4-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 8-cyano-5-methyl-1- (3-methoxy-4-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 5-methyl-1- (3-methoxy-4-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-8-carboxamide; 8-cyclopropyl-5-methyl-1- (3-methoxy-4-methyl) phenyl-1,3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 9-bromo-5-methyl-1- (3,4-methylenedioxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 9-cyano-5-methyl-1- (3,4-methylenedioxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 9-cyclopropyl-5-methyl-1- (3,4-methylenedioxy) phenyl-1,3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-bromo-5-methyl-1- (3,4-methylenedioxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-cyano-5-methyl-1- (3,4-methylenedioxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-cyclopropyl-5-methyl-1- (3,4-methylenedioxy) phenyl-1,3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-bromo-5-methyl-1- (3-ethoxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-cyano-5-methyl-1- (3-ethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 8-cyclopropyl-5-methyl-1- (3-ethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 9-bromo-5-methyl-1- (3-ethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 9-cyano-5-methyl-1- (3-ethoxy) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 9-cyclopropyl-5-methyl-1- (3-ethoxy) phenyl-1, 3,4,6- tetrahydro-5H-benz [f] -2,5-oxazocine; 8-bromo-5-methyl-1- (3-trifluoromethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 8-cyano-5-methyl-1- (3-trifluoromethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 5-cyclopropyl-5-methyl-1- (3-trifluoromethoxy) phenyl-1,3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 9-bromo-5-methyl-1- (3-trifluoromethoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 9-cyclopropyl-5-methyl-1- (3-trifluoromethoxy) phenyl-1,3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 9-bromo-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 9-cyano-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 9-cyclopropyl-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-bromo-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 8-Cyano-6-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; 8-cyclopropyl-5-methyl-1- (2-methyl) phenyl-1, 3,4,6-tetrahydro-H 5 -benz [f] -2,5-oxazocine; 9-bromo-5-methyl-1- (3-pyridyl) -1, 3, 4, 6-tetrahydro-H5-benz [f] -2,5-oxazocine; 8-bromo-5-methyl-1- (3-pyridyl) -1,4,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; and 8-cyano-5-methyl-1- (3-pyridyl) -1,3,4,6- tetrahydro-5H-benz [f] -2,5-oxazocin. .
5. 5. A compound according to any preceding claim, characterized in that it is in the form of a single (+) or (-) enantiomer.
6. 6. A pharmaceutical composition for use in therapy, characterized in that it comprises a compound of any preceding claim, and a pharmaceutically acceptable diluent or carrier.
7. 7. Use of a compound according to any of claims 1 to 5, characterized in that it is for the manufacture of a medicament for the treatment or prevention of a condition associated with monoamine reuptake.
8. 8. Use according to claim 7, characterized in that the condition is selected from depression, post-traumatic stress disorders, attention deficit disorders, obsessive-compulsive disorders, premenstrual syndrome, substance abuse, micturition disorders and sexual dysfunction. .
9. 9. Use according to claim 7, characterized in that the condition is acute, chronic or neuropathic pain, dysmenorrhea or migraine headache.
10. 10. Use according to claim 9, characterized in that the treatment subject is also treated with an opiate.
11. 11. Use according to claim 9, characterized in that the treatment subject is also treated with an analgesia inducer selected from aceofen acetaminophen, non-spheroidal anti-inflammatory drugs, narcotic analgesics, local anesthetics, NMDA antagonists, neuroleptic agents, anti-inflammatory agents, -convulsive,. anti-spasmodics, anti-depressants and muscle relaxants.
12. 12. Use according to claim 7, characterized in that the condition is vomit.
13. 13. Use according to claim 12, characterized in that the vomiting is acute, delayed, post-operative, delayed phase or anticipatory vomiting.
14. 14. Use according to claim 12 or claim 13, characterized in that the vomiting is induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorder, movement, post-operative disease, surgery, gastrointestinal obstruction, reduced gastrointestinal mobility, pain visceral, migraine or an opioid analgesic. SUMMARY OF THE INVENTION Compounds having therapeutic utility are of the general formula (1) wherein R is H, Ci-Cß alkyl optionally substituted with F or C3-Ce cycloalkyl or C2-C alkenyl; A is 0, CH2 or S (0) n where n is 0-2; one of W, X, Y and Z is N, CH or CR3 and the others are CH; R2 is C5-C6 heteroaryl, C5-C10 cycloalkyl or cycloalkenyl optionally containing one or more heteroatoms selected from 0, N and S (0) n where n is 0-2, and optionally substituted with R3; or a phenyl group optionally substituted at one or more positions with one or more substituents independently selected from halogen, CN, CF3, Ci-Cs alkyl and 0R ?, or the phenyl group is fused to a five or six membered ring which it can be carbocyclic, heterocyclic (containing 1-2 heteroatoms selected from 0, N and S), aromatic or heteroaromatic (containing 1-2 heteroatoms selected from 0 and N); R3 is selected from halogen; CF3; CN; 0R5; S02N (R5) 2; C0R5; C02R5; C0N (R5) 2; NRi, C0R4; NR? S02R; NR? C02R4; NRX, CON (R5) 2; 0-C 1 -C 6 alkyl substituted with R 3; Ci-Cß alkyl optionally substituted with unsubstituted R3; C3-C6 cycloalkyl optionally substituted with unsubstituted R3; C2-C6 alkenyl optionally substituted with unsubstituted R3; C2-C6 alkynyl optionally substituted with unsubstituted R3; aryl optionally substituted with unsubstituted R3; and heterocycles five or six member aromatics containing 1-4 heteroatoms selected from N and O; R4 is d-Cß alkyl, C2-Cg alkenyl, C2-Cd alkynyl, C3-Cd cycloalkyl, aryl, and heteroaryl; and R5 is H, Ci-Cß alkyl; C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl or heteroaryl and is the same as or different from another R5; or a pharmaceutically acceptable salt thereof.