SUBSTITUTED OXIMES, HYDRAZONES AND OLEFINS AS NEUROKININ ANTAGONISTS

Abstract: Compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof, wherein: a is 0, 1, 2 or 3; b, d and e are independently 0, 1 or 2; R is H, C1-6 alkyl, -OH or C2-C6 hydroxyalkyl; A is an optionally substituted oxime, hydrazone or olefin; X is a bond, -C(O)-, -O-, -NR<6>-, -S(O)e-, -N(R<6>)C(O)-, -C(O)N(R<6>)-, -OC(O)NR<6>-, -OC(=S)NR<6>-, -N(R<6>)C(=S)O-, -C(=NOR<1>)-, -S(O)2N(R<6>)-, -N(R<6>)S(O)2-, -N(R<6>)C(O)O- or -OC(O)-; T is H, phthalimidyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyl or bridged cycloalkyl; Q is -SR<6>, -N(R<6>)(R<7>), -OR<6>, phenyl, naphthyl or heteroaryl; R<6a>, R<7a>, R<8a>, R<9a>, R<6> and R<7> are H, C1-6 alkyl, C2-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, phenyl or benzyl; or R<6> and R<7>, together with the nitrogen to which they are attached, form a ring; R<9a> is R<6> or -OR<6>; Z is morpholinyl, optionally N-substituted piperazinyl, optionally substituted (a), or substituted (b); g is 0-3 and h is 1-4, provided the sum of h and g is 1-7; wherein aryl, heterocycloalkyl, heteroaryl, cycloalkyl and bridged cycloalkyl groups are optionally substituted; methods of treating asthma, cough, bronchospasm, inflammatory diseases, and gastrointestinal disorders with said compounds, and pharmaceutical compositions comprising said compounds are disclosed.

Description: SUBSTITUTED OXIMES. HYDRAZONES AND OLEFINS AS NEUROKININ ANTAGONISTS BACKGROUND OF THE INVENTION The present invention relates to a genus of substituted oximes, hydrazones and olefins useful as antagonists of tachykinin receptors, in particular as antagonists of the neuropeptides neurokinin-1 receptor (NK-i) and/or neurokinin-2 receptor (NK2) and/or neurokinin-3 receptor (NK3). Neurokinin receptors are found in the nervous system and the circulatory system and peripheral tissues of mammals, and therefore are involved in a variety of biological processes. Neurokinin receptor antagonists are consequently expected to be useful in the treatment or prevention of various mammalian disease states, for example asthma, cough, bronchospasm, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, nociception, and various gastrointestinal disorders such as Crohn's disease. In particular, NK-i receptors have been reported to be involved in microvascular leakage and mucus secretion, and NK2 receptors have been associated with smooth muscle contraction, making NK1 and NK2 receptor antagonists especially useful in the treatment and prevention of asthma. Some NK-i and NK2 receptor antagonists have previously been disclosed: arylalkylamines were disclosed in U.S. Patent 5,350,852, issued September 27, 1994, and spiro-substituted azacycles were disclosed in WO 94/29309, published December 22, 1994. SUMMARY OF THE INVENTION Compounds of the present invention are represented by the formula I or a pharmaceutically acceptable salt thereof, wherein: a is 0, 1 , 2 or 3; b and d are independently 0, 1 or 2; R is H, C-1-6 alkyl, -OR 6 or C2-C 6 hydroxyalkyl; A is =N-OR 1 . =N-N(R 2 )(R3), =C(R 11 )(R 12 ) or =NR 5; X is a bond, -C(O)-, -0-, -NR 6 -, -S(0) e -, -N(R 6 )C(0)-, -C(0)N(R 6 )- -OC(0)NR 6 -, -OC(=S)NR 6 -, -N(R 6 )C(=S)0-, -C(=NOR 1 )-, -S(0) 2 N(R 6 )-, -N(R 6 )S(0) 2 -, -N(R 6 )C(0)0- or -OC(O)-, provided that when d is 0, X is a bond, -C(O)-, -NR 6 -, -C(0)N(R 6 )-, -N(R 6 )C(0)-, -OC(0)NR 6 -, -C(=NOR 1 )-, -N(R 6 )C(=S)0-, -OC(=S)NR 6 -, -N(R 6 )S(0) 2 - or -N(R 6 )C(0)0-; provided that when A is =C(R 11 )(R 12 ) and d is 0, X is not -NR 6 - or -N(R 6 )C(0)-; and provided that when A is =NR 25 , d is 0 and X is -NR 6 - or -N(R 6 )C(0)-; T is H, R 4 -aryl, R 4 -heterocycloalkyl, R 4 -heteroaryl, phthalimidyl, R 4 -cycloalkyl or R 10 -bridged cycloalkyl; Q is R 5 -phenyl, R 5 -naphthyl, -SR 6 , -N(R 6 )(R 7 ), -OR 6 or R 5 -hetero- aryl, provided that when Q is -SR 6 , -N(R 6 )(R 7 ) or -OR 6 , R is not -OR 6 ; R1 is H, C1-6 alkyl, -(C(R 6 )(R7)) n -G, -G 2 , -(C(R 6 )(R7)) p -M- (C(Ri3)(Ri 4 )) n -(C(R8)(R9)) u -G, -C(0)N(R 6 )-(C(Ri3)(Ri4 ))n . {C (R8)(R9)) lJ .G or -(C(R 6 )(R 7 ))p-M-(R -heteroaryl); R 2 and R 3 are independently selected from the group consisting of H, C-1-6 alkyl, -CN, -(C(R 6 )(R7)) n -G, -G 2 , -C(0)-(C(R 6 )(R9)) n -G and -S(0) e R 13 ; or R 2 and R 3 , together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of -0-, -S- and -N(R 19 )-; R 4 and R 5 are independently 1-3 substituents independently selected from the group consisting of H, halogeno, -OR 6 , -OC(0)R 6 , -OC(0)N(R 6 )(R7), -N(R 6 )(R7), C-1-6 alkyl, -CF 3 , -C 2 F 5 , -COR 6 , -C0 2 R 6 -CON(R 6 )(R 7 ), -S(0) e R 13 , -CN, -OCF 3l -NR 6 C0 2 R 16 , -NR 6 C0R , -NR8CON(R 6 )(R7), Ri5-phenyl, Ri5-benzyl, N0 2 , -N(R 6 )S(0) 2 R 13 or -S(0)2N(R 6 )(R 7 ); or adjacent R 4 substituents or adjacent R 5 substituents can form a -O-CH2-O- group; and R 4 can also be R 15 -heteroaryl; R 6 R7, R8, R6a R7 a> Rδa, Ri3 a n R 4 are independently selected from the group consisting of H, C1-6 alkyl, C2-C6 hydroxyalkyl, C Cβ alkoxy-Ci-Cβ alkyl, R 1 * 5-phenyl, and R 1 5-benzyl; or R 6 and R 7 , together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of -0-, -S- and -N(R19)-; R9 and R9a are independently selected from the group consisting of R 6 and -OR 6 R 10 and R 10a are independently selected from the group consisting of H and C1 -6 alkyl; R 11 and R 12 are independently selected from the group consisting of H, Cι-C 6 alkyl, -C0 2 R 6 , -OR 6 , -C(0)N(R 6 )(R7), C-|-C 6 hydroxyalkyl, -(CH 2 ) r OC(0)R 6 , -(CH 2 )r-OC(0)CH=CH 2 , -(CH 2 ) r O(CH 2 ) s -C0 2 R 6 -(CH 2 ) r -0-(CH2) s -C(0)N(R 6 )(R7) and -(CH 2 ) r N(R 6 )(R ); R 15 is 1 to 3 substituents independently selected from the group consisting of H, Ci-Cβ alkyl, Ci-Cε alkoxy, C-I -CQ alkylthio, halogeno, -CF 3 , -C2F5, -COR™, -C0 2 R 10 , -C(0)N(R10) 2 , -S(O) e R 10a , -CN, -N(R10)COR 1 0, -N(R10)CON(R10) 2 and -N0 2 ; R 16 is C1-6 alkyl, R 5-phenyl or Ri5- D enzyl; R19 is H, Cι-C 6 alkyl, -C(0)N(R10) 2> -CO2R 10 , -(C(R8)(R9)) f -C0 2 R 1 ° or -(C(R8)(R9)) U -C(0)N(R10) 2 ; f, n, p, r and s are independently 1 -6; u is 0-6; G is selected from the group consisting of H, R 4 -aryl, R 4 -hetero- cycloalkyl, R -heteroaryl, R 4 -cycloalkyl, -OR 6 , -N(R 6 )(R7), -COR 6 - -C0 2 R 6 , -CON(R7)(R9), -S(0) Θ R 13 ' -NR 6 C0 2 R 16 , -NR 6 COR7. -NR8CON(R 6 )(R 7 ), -N(R 6 )S(0) 2 R 13 , -S(0) 2 N(R 6 )(R7), -OC(0)R 6 , -OC(0)N(R 6 )(R7), -C(=NOR8)N(R 6 )(R ), -C(=NR 5)N(R 6 )(R7), -N(R8)C(=NR 2 5)N(R 6 )(R7), -CN, -C(0)N(R 6 )OR7 and -C(0)N(R9)-(R 4 -heteroaryl), provided that when n is 1 and u is 0, or when R9 is -OR 6 , G is not -OH or -N(R 6 )(R 7 ); M is selected from the group consisting of a double bond, -0-, -N(R 6 )-, -C(O)-, -C(R 6 )(OR7)-, -C(R8)(N(R 6 )(R7))-, -C(=NOR 6 )N(R7)-, -C(N(R 6 )(R7))=NO-, -C(=NR 5)N(R 6 )-, -C(0)N(R9)-, -N(R9)C(0)-, -C(=S)N(R9)-, -N(R9)C(=S)- and -N(R 6 )C(0)N(R7)-, provided that when n is 1 , G is not OH or -NH(R 6 ); and when p is 2-6, M can also be -N(R 6 )C(=NR 26 )N(R7)- or -OC(0)N(R 6 )-; G 2 is R 4 -aryl, R 4 -heterocycloalkyl, R 4 -heteroaryl, R -cycloalkyl, -COR 6 , -C0 2 R 16 -S(0) 2 N(R 6 )(R7) or -CON(R 6 )(R7); e is 0, 1 or 2, provided that when e is 1 or 2, R 13 and R 10a are not H; R 2 5 is H, C C 6 alkyl, -CN, Ri5-phenyl or Ri5-benzyl; Z is N- [ N- R JU -N H— or moφholinyl; g and j are independently 0-3; h and k are independently 1-4, provided the sum of h and g is 1-7; J is two hydrogen atoms, =0, =S, =NR 9 or =NOR 1 ; L and L 1 are independently selected from the group consisting of H, C Cβ alkyl, Cι-C 6 alkenyl, -CH 2 -cycloalkyl, Ri5-benzyl, Ri5-heteroaryl, -C(0)R 6 , -(CH 2 ) m -OR 6 -(CH 2 ) m -N(R 6 )(R7), -(CH 2 ) m -C(0)-OR 6 and -(CH 2 )m-C(0)N(R 6 )(R7); m is 0 to 4, provided that when j is 0, m is 1 -4; R 26 and R 2 are independently selected from the group consisting of H, Cι-C 6 alkyl, R 4 -aryl and R 4 -heteroaryl; or R 26 is H, C C 6 alkyl, R -aryl or R 4 -heteroaryl, and R 2 7 is -C(0)R 6 , -C(0)-N(R 6 )(R7), -C(0)(R 4 -aryl), -C(0)(R -heteroaryl), -S0 2 R 13 or -S0 2 -(R -aryl); R 26 is H, -(C(R 6 )(R 19 )) t -G, -(C(R 6 )(R7)) V -G 2 or -N0 2 ; t and v are 0, 1 , 2 or 3, provided that when j is 0, t is 1 , 2 or 3; R 2 9 is H, Cι-C 6 alkyl, -C(R 1 0) 2 S(O) e R 6 , R 4 -phenyl or R 4 -heteroaryl; RSO is H, Cι-C 6 alkyl, R 4 -cycloalkyl, -(C(Riθ) 2 ) w -(R4- ph enyl), -(C(Riθ) 2 )w-(R 4 -heteroaryl), -C(0)R 6 , -C(0)OR 6 , -C(0)N(R 6 )(R7), w is 0, 1 , 2, or 3; V is =0, =S or =NR 6 ; and q is 0-4. Preferred are compounds of formula I wherein X is -0-, -C(O)-, a bond, -NR 6 -, -S(0) e -, -N(R 6 )C(0)-, -OC(0)NR 6 or -C(=NORi)-. More preferred are compounds of formula I wherein X is -0-, -NR 6 -, -N(R 6 )C(0)- or -OC(0)NR 6 - Additional preferred definitions are: b is 1 or 2 when X is -0- or -N(R 6 )-; b is 0 when X is -N(R 6 )C(0)-; and d is 1 or 2. T is preferably R 4 -aryl, R 4 -heteroaryl, R 4 -cycloalkyI or R 10 -bridged cycloalkyl, with R 4 -aryl, especially R 4 -phenyl, being more preferred. Also preferred are compounds wherein R 6a , R 7 a, R8a and R 9a are independently hydrogen, hydroxyalkyl or alkoxyalkyl, with hydrogen being more preferred. Especially preferred are compounds wherein R 8a and R 9a are each hydrogen, d and b are each 1 , X is -0-, -NR 6 -, -N(R 6 )C(0)- or -OC(0)NR 6 T is R -aryl and R 4 is two substituents selected from C C6 alkyl, halogeno, -CF3 and Ci-Cβ alkoxy. Preferred definitions for T being R -heteroaryl include R 4 -quinoliπyl and oxadiazolyl. Also preferred are compounds of formula I wherein R is hydrogen. Q is preferably R 5 -phenyl, Rs-naphthyl or R 5 -heteroaryl; an especially preferred definition for Q is R 5 -phenyl, wherein R 5 is preferably two halogeno substituents. Preferred are compounds of formula I wherein A is =N-OR 1 or -=N-N(R 2 )(R 3 ). More preferred are compounds wherein A is =N-OR 1 . R1 is preferably H, alkyl, -(CH 2 ) n -G, -(CH 2 ) p -M-(CH 2 ) n -G or -C(0)N(R 6 )(R ), wherein M is -O- or -C(0)N(R 9 )- and G is -C0 2 R 6 , -OR 6 , -C(0)N(R 6 )(R9), -C(=NOR8)N(R 6 )(R7), -C(0)N(R9)(R 4 -heteroaryl) or R 4 - heteroaryl. R 2 and R 3 are independently preferably H, C Cβ alkyl, -(C(R 6 )(R7)) n -G or G 2 . Preferred definitions of Z are with the following groups being more preferred: O -- N --^C N - and C N- C N_ ■ This invention also relates to the use of a compound of formula I in the treatment of asthma, cough, bronchospasm, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, nociception, and various gastrointestinal disorders such as Crohn's disease. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I in a pharmaceutically acceptable carrier. The invention also relates to the use of said pharmaceutical composition in the treatment of asthma, cough, bronchospasm, inflammatory diseases such as arthritis, migraine, nociception, and various gastrointestinal disorders such as Crohn's disease. DETAILED DESCRIPTION As used herein, the term "alkyl" means straight or branched alkyl chains. "Lower alkyl" refers to alkyl chains of 1 -6 carbon atoms and, similarly, lower alkoxy refers to alkoxy chains of 1 -6 carbon atoms. "Cycloalkyl" means cyclic alkyl groups having 3 to 6 carbon atoms. "Bridged cycloalkyl" refers to C7-C10 saturated rings comprised of a cycloalkyl ring or a fused bicycloalkyl ring and an alkylene chain joined at each end to non-adjacent carbon atoms of the ring or rings. Examples of such bridged bicycloalkyl rings are adamantyl, myrtanyl, noradamantyl, norbornyl, bicyclo[2.2.1 jhepty I, 6,6-dimethylbicyclo[3.1.1 jheptyl, bicyclo[3.2.1]octyl, and bicyclo[2.2.2]octyl. "Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl or fluorenyl. "Halogeno" refers to fluoro, chloro, bromo or iodo atoms. "Heterocycloalkyl" refers to 4- to 6-membered saturated rings comprising 1 to 3 heteroatoms independently selected from the group consisting of -0-, -S- and -N(R 19 )-, with the remaining ring members being carbon. Examples of heterocycloalkyl rings are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. R 4 - heterocycloalkyl refers to such groups wherein substitutable ring carbon atoms have an R 4 substituent. "Heteroaryl" refers to 5- to 10-membered single or benzofused aromatic rings comprising 1 to 4 heteroatoms independently selected from the group consisting of -0-, -S- and -N=, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of single-ring heteroaryl groups are pyridyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl. Examples of benzofused heteroaryl groups are indolyl, quinolinyl, thianaphthenyl and benzofurazanyl. N-oxides of nitrogen-containing heteroaryl groups are also included. All positional isomers are contemplated, e.g., 1-pyridyl, 2- pyridyl, 3-pyridyl and 4-pyridyl. R 4 -heteroaryl refers to such groups wherein substitutable ring carbon atoms have an R 4 substituent. Where R 2 and R 3 or R 6 and R substituents on a nitrogen atom form a ring and additional heteroatoms are present, the rings do not include adjacent oxygen and/or sulfur atoms or three adjacent hetero¬ atoms. Typical rings so formed are morpholinyl, piperazinyl and piperidinyl. In the structures in the definition of Z, the substituents L and L 1 may be present on any substitutable carbon atom, including in the second structure the carbon to which the -N(R 6 )(R 27 ) group is attached. In the above definitions, wherein variables R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , R 14 , R 15 , R 30 and R 31 , for example, are said to be independently selected from a group of substituents, we mean that R 6 , R 7 , R 8 , R 9 , R10 ( R 13 , R 14 , R 15 , R 30 and R 31 are independently selected, but also that where an R 6 , R 7 , R 6 , R9, Riθ f R13_ R14 R15. R30 or R31 variable occurs more than once in a molecule, those occurrences are independently selected (e.g., if B is =NR 6 - wherein R 6 is hydrogen, X can be -N(R 6 )- wherein R 6 is ethyl). Similarly, R 4 and R 5 can be independently selected from a group of substituents, and where more than one R 4 and R 5 are present, the substitutents are independently selected; those skilled in the art will recognize that the size and nature of the substituent(s) will affect the number of substituents which can be present. Compounds of formula I can have at least one asymmetrical carbon atom and all isomers, including diastereomers, enantiomers and rotational isomers, as well as E and Z isomers of the oxime, hydrazone and olefin groups, are contemplated as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of formula I. Those skilled in the art will appreciate that for some compounds of formula I, one isomer will show greater pharmacological activity than other isomers. Compounds of the invention have at least one amino group which can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention. Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like. Compounds of formula I can be prepared using methods well known to those skilled in the art. Following are typical procedures for preparing various compounds; the skilled artisan will recognize that other procedures may be applicable, and that the procedures may be suitably modified to prepare other compounds within the scope of formula I. Procedure A: Compounds of formula I wherein R is H, a and d are each 1 , X is -O-, Q is R 5 -phenyl, T is R 4 -phenyl, A is =NOR 1 and the remaining variables are as defined above (see formula 8, below), can be prepared as shown in the following reaction scheme: In step 1 , the 3-(substituted phenyl)-2-propenoic acid of formula 1, wherein R 5 is as defined above, is reacted with an oxidizing agent such as dimethyl dioxirane or m-chloroperoxybenzoic acid (m-CPBA) in an inert organic solvent such as CH2CI2 or toluene. An acidic catalyst such as Amberlyst 15 or formic acid is added to give the desired lactone 2. Preferable reaction temperatures range from 0 to 60°C. In step 2, lactone _ is reacted with a suitable hydroxy-protecting group, for example an electrophile such as a compound of formula R 20 -R 17 wherein R 17 is a leaving group such as Cl or Br and R 20 is of the formula , wherein R 4 , R8a, R9a a nd b are as defined above, or wherein R 20 is trialkylsilyl. The reaction is carried out in the presence of a silver salt such as Ag2θ in an organic solvent such as dimethylformamide (DMF) ortetrahydrofuran (THF), most preferably DMF, at a temperature of 0 to about 50°C. In step 3, compound 3 is dissolved in an inert organic solvent such as CH2CI 2 , THF or toluene, preferably CH 2 Cl2, and reduced with a reagent such as DiBAL-H at temperatures from about -78°C to room temperature. In step 4, compound 4 is reacted with an amine of formula 5, wherein Z is as defined above, in an alcohol such as CH3OH, CH3CH2OH or more preferably CF3CH2OH, in the presence of a dehydrating agent such as molecular sieves and a reducing agent such as NaCNBH3 or under hydrogenating conditions (H2/Pd/C), at a temperature range of 0 to 60°C. In Step 5, a compound of formula _ is oxidized to the corresponding ketone of formula _ using an oxidizing agent such as pyridinium chlorochromate (PCC) or Jones reagent, preferably Jones reagent, in a suitable organic solvent such as CH CI 2 or toluene (for PCC) or acetone (for Jones reagent) at a temperature from about 0 to 50°C. Other suitable oxidizing agents include pyridinium dichromate (PDC), tetrapropylammonium perruthenate(VII)/4-methylmorpholine N-oxide (TPAP/NMO), and (COCI) 2 /DMSO. Step 6: In Step 6, the ketone of formula 7 is converted to the corresponding oxime of formula _ by treatment with a hydroxylamine derivative of the formula H 2 NOR 1 or a salt thereof, e.g., the HCl salt, wherein R 1 is as defined above, in a suitable organic solvent such as pyridine at a temperature of from about 25 to 100°C. Alternatively, a low molecular weight alcohol (e.g., CH3OH or CH 3 CH 2 OH) can be used as the solvent, in which case a base such as sodium acetate must be added. Alternatively, compounds of formula _ wherein R 1 is not H can be prepared from compounds of formula _ wherein R 1 is H by deprotonation with a suitable base, preferably NaH or CS2CO3, and subsequent treatment with a suitable electrophile such as an alkyl halide, acid chloride or isocyanate. When R 20 in oxime 8 is a trialkyl silyl hydroxy-protecting group such as (CH 3 ) 3 Si-, (f-Bu)Si(CH 3 ) 2 -, (Et)Si(/-Pr) - or (/-Pr) Si- (wherein Et is ethyl, / ' -Pr is isopropyl and f-Bu is tertiary butyl)), preferably (f-Bu)Si(CH3)2-, the oxime can be converted to the corresponding hydroxymethyl oxime of formula 8A, for example by treatment with fluoride ion, preferably TBAF: Oxime 8_A can be alkylated, acylated or the hydroxyl group can be activated displaced by sulfur or nitrogen nucleophiles. Alkylations are effected using a base, such as NaH, K 2 C03 or Cs 2 Cθ3, in a solvent such as DMF, THF or CH 2 CI 2 , with an alkylating agent such as an alkyl or benzyl halide or sulfonate. Acylations are effected using an appropriate carboxylic acid in the presence of a dehydrating agent, for example DEC in the presence of HOBT. Nitrogen and sulfur-containing groups can be introduced using Mitsunobu reaction conditions, for example DEAD and PPh3 in a solvent such as THF with a thiol or amide nucleophile. Corresponding compounds of formula I wherein A is a -=C(R 11 )(R 12 ) group are prepared by converting a compound of formula 7 to the corresponding alkene of formula 25 by treating the ketone of formula 7 with the Wittig reagent formed from Ph 3 PCHRii Ri 2 Ri7' (R17- = ci, Br, I) and a suitable base such as NaH, LDA, or R18N(TMS) 2 (R 18 = Li, Na, or K) preferably NaN(TMS) 2 , in a suitable organic solvent such as THF or ether, preferably THF, at a temperature from -15 to 65°C. Other suitable reagents for this transformation include the phosphonates (EtO) 2 P(0)CHR 11 R 12 . Corresponding compounds of formula I wherein A is a =N-N(R 2 )(R 3 ) group are prepared by converting a compound of formula 7 to the corresponding hydrazone of formula 26 by treating the ketone of formula 7 with a substituted hydrazine of formula H 2 NNR 2 R 3 in a suitable organic solvent such as CH3OH or CH3CH2OH, preferably CH3CH2OH, in the presence of an acidic catalyst such as acetic acid at a temperature in the range of 0 to 80°C. Procedure B: Compounds of formula I wherein R is H, a and d are each 1 , X is -O- or -S-, Q is Rδ-phenyl, T is H, R-^-aryl, R-4-cycloalkyl, R-4-alkyl, R4- bicyclo or tricycloalkyl, and the remaining variables are as defined above (see compound 35, below), can be prepared according to the following reaction scheme: In step 1 , the ester (preferably methyl) of the substituted aryl acetic acid of formula IS, wherein R 19 is a lower alkyl group, preferably methyl, is reacted with a compound of formula 14, wherein R 17 ' is as defined above and Pg is a suitable protecting group such as tetrahydropyranyl, and a base to prepare a compound of formula 15. The base can be chosen from any strong base including LDA or lithium bis(trimethylsilyl)amide. The reaction is carried out in an inert organic solvent such as THF at temperatures of -15 to about 65°C. In step 2, a compound of formula __ is reacted with an acid in a solvent such as CH3OH, at temperatures ranging from -10 to 65°C. The acid need not to be used in stochiometric amount. Alternatively, a compound of formula 16 can be prepared directly from step 1 without isolating the compound of formula 15: the reaction mixture obtained after the work up of the reaction described in step 1 can be dissolved in the solvent and reacted with the acid. In step 3, a compound of formula 16 is reacted with an acid such hydrobromic acid (HBr) dissolved in a suitable solvent such as acetic acid. The reaction is performed at temperatures ranging from 5 to 45°C. In step 4, the carboxylic acid of formula 17 is reacted with a halogenating agent such as SOCI2 or (COCI)2 in an appropriate solvent such CH2CI2 to form the acid haiide of formula 29. In step 5, the compound of formula 29 is reacted with an alkylating agent such as diazomethane to obtain the compound of formula __. This reaction may be performed at temperatures lower than ambient using an appropriate solvent such as Et,2θ. In step 6, a compound of formula 30 is reacted with a compound of formula 5 (defined above) to obtain a compound of formula __. The reaction is carried out in a suitable solvent, e.g. EtOAc, at temperatures below 85°C. Bases such as Et3N may be beneficial to the reaction. In step 7, a compound of formula __ is reacted with a compound of formula 32 , wherein X is -O- or -S-, T is H, R 4 -aryl, R 4 -cycloalkyl, R 4 -alkyl, R 4 -bicyclo or tricycloalkyi, and R 83 , R9a_ D and R 4 is as defined above in an appropriate solvent, e.g. CH2CI2, with a Lewis acid, e.g. BF3, at temperatures lower than 50°C. In step 8 a compound of formula 33 is reacted with a compound of formula 34 > wherein A is as defined above, in a solvent such as pyridine, to obtain the desired product of formula 35. Procedure C: Compounds of formula I wherein R is H, a and d are each 1 , A is =NOR 1 , X is -0-, Q is R 5 -phenyl, T is R 15 -phenyl (R 15 is a subset of R 4 ), and the remaining variables are as defined above (see compound __, below), can be prepared according to the following reaction scheme: Steps 1 to 4 are preferably carried out in an inert solvent such as an ether (e.g. Et 2 0, THF, or dioxane) under an inert atmosphere (N 2 or Ar). In step 1 , the anion (Li, Na or K) of ethyl 1 ,3-dithiolane-2- carboxylate is added to the cinnamate __3 at any suitable temperature, preferably -78°C to -55°C. Step 2, deprotection of the carboxy group in _7_ is carried out with any suitable reducing agent (e.g. UAIH4 or diisobutylaluminum hydride) at any suitable temperature, preferably between 0°C and 25°C. In step 3, the hydroxy group of __ is reacted with t-butyldimethylsilyl chloride and a suitable base (e.g. pyridine, Et^N, dimethylaminopyridine, or diisopropylethylamine) at any suitable temperature, preferably between 0°C and 25°C. Step 4 is preferably carried out by first adding a suitable base (e.g. KH or [(CH3)3Si] 2 NK) to the solvent containing 39 and subsequently adding the alkylating agent (e.g. a benzyl chloride or bromide) to obtain 40. Any suitable temperature can be used, preferably between -78°C and 0°C for the deprotonation and between 25°C and 80°C for the alkylation . In step 5, removal of the silyl protecting group on 40 is preferably carried out with a fluoride source such as HF in CH3CN or tetrabutyl- ammonium fluoride in an inert solvent such as an ether as described above. This step can also be carried out with acid (e.g. HOAc, CF3CO2H, tosic acid, H2SO4, or HCl) and water in an inert solvent such as an ether as described above, or in a chlorinated hydrocarbon (e.g. CH2CI2, 1 ,2- dichloroethane, or CHCI3). Any suitable temperature can be used, preferably temperatures between 0°C and 80°C. In step 6, oxidation of the dithiolanyl ring of 41 is preferably carried out with an oxidizing agent such as HgCI04, gN03, Ag 2 o, copper chloride with copper oxide, thallium nitrate, N-chlorosuccinimide, or N- bromosuccinimide in an inert solvent such as an ether (e.g. Et 2 0, THF, or dioxane), CH3COCH3, or CH3CN. Any suitable temperature can be used with preferable temperatures between 0°C and 80°C. Compounds 42 and 43 are present in equilibrium. Preparation of the oxime of formula 44 in step 7 is preferably carried out on the mixture of 42 and 43 with a suitably substituted hydroxylamine (as its acid salt e.g. HCl or maleate, or as its free base) and a suitable base such as sodium acetate or pyridine in a protic solvent (e.g. water, CH30H, CH3CH OH, or isopropanol). Any suitable temperature can be used, with preferable temperatures between 25°C and 100°C. In step 8, preferably 44 is treated with a suitable oxidizing agent (e.g. pyridinium chlorochromate, chromium trioxide-pyridine, pyridinium dichromate, oxalyl chloride-dimethylsulfoxide, acetic anhydride- dimethylsulfoxide, or periodinane) in an inert solvent such as chlorinated hydrocarbons (e.g. CH 2 CI 2 , 1 ,2-dichloroethane, or CHCI3) to obtain the ketone __. Any suitable temperature can be used with preferable temperatures between -78°C and 25°C. Step 9 is preferably carried out with a suitably substituted amine (as its acid salt e.g. HCl or maleate or as its free base) and a hydride source such as NaBHsCN or sodium triacetoxyborohydride in a protic solvent (e.g. CH3OH, CH 3 CH 2 OH, or CF3CH2OH) with 3A sieves to obtain __. Any suitable temperature can be used with preferable temperatures between 0°C and 25°C. Procedure D: Compounds of formula I as defined above can be prepared as shown in the following reaction scheme: Step 1 : C: R 21 = -N(CH 3 )OCH 3 ) In step 1 , a compound of formula 47A. wherein Q is as defined above, is reacted with a base such as lithium disopropylamide (LDA) or KH in an inert organic solvent such at THF or DME to generate a dianion. An acid chloride, ester or amide of formula 46A. 46B. or 46C is added to give a ketone of formula 4_. Preferable reaction temperatures ranges from -78°C to 30°C. Alternatively, compounds of formula __ can be generated by the reaction of a compound of formula __, preferably 46C. with a metallated species of formula QCH2Mt where Mt is a metal, such as MgHal, wherein "Hal" is halogen, or lithium. The metallated species QCH2Mt can be generated by conventional procedures, such as treatment compounds of formula QCH2Hal with Mg or by treating QCH3 with an organolithium base. -* ln step 2, for compounds of formula I wherein R is not hydrogen, the ketone 4_ is reacted with a suitable base, such as LDA or KH in an inert organic solvent such as THF. For compounds wherein R is alkyl or hydroxyalkyl, a compound R-R 17" , wherein R 17 " is leaving group such as Br, I or triflate is added. For compounds wherein R is OH, an appropriate oxidizing agent such as dimethyldioxirane or Davis reagent is added. Preferable reaction temperatures range from -78° to 50°C. Step 3: In step 3, ketone 49 is reacted with a base such as LDA in a solvent such as THF, then an olefin of formula _≥__ is added, wherein R 17" is as defined above, to give the adduct 51. Preferable reaction temperatures range from -78°C to 60°C. Step 4: In step 4, ketone 51 is reacted with HA', wherein A' is NH-OR 1 , NH- N(R )(R 3 ) or NHR 26 , in an organic solvent such as pyridine at a temperature from 25°C to 150°C to give a compound of formula 52. Step 5: In step 5, a compound of formula 52 is oxidized by ozonolysis to give an aldehyde of formula 5_l Suitable organic solvents include EtOAc, ethanol or the like. Preferable reaction temperatures are from -78 to 0°C. Step 6: In step 6, an aldehyde of formula __ is reacted with a compound of formula Z-H, wherein Z is as defined above, as described in Step 9 of Procedure C. Altematively, a compound of formula I can be prepared from 51 by the following reaction scheme: Compound 51 is oxized to a compound of formula 54 under conditions similar to those described for step 5 above. The aldehyde of formula 54 is reacted with a compound of formula Z-H in a manner similar to that described in Step 6, and the resultant ketone is then reacted with a compound of the formula HA' as described above in Step 4 to obtain the compound of formula I. Procedure E: Compounds of formula I wherein X is -O- or a bond and d is 1 or 2 can be prepared by the following reaction scheme, starting with ketone 4_ from Procedure D. Alternatively, compounds of formula __ can be prepared from compounds of formula 46D. wherein X is -0-, R 6a and R 7a are each H, and d is 1 , which, in turn, are prepared according to the following reaction scheme: wherein compounds of formula 55, wherein R 21 is alkoxy or -N(CH3)OCH3 and R 17' is as defined above are reacted with alcohols of the formula HO-(C(R8a)(R9a)) b .y j n he presence of a suitable base such as CS2CO3 or KHMDS to give the desired ether 46D. Step 1 : In step 1 , compounds of formula 49 treated with an appropriate base, such as NaH, are reacted with alkylating agents of the formula R 33 C(0)CH 2 R 17 or R 33 C(0)CH=CH wherein R 33 is alkoxy or -N(CH3)OCH 3 and R 17 is as defined above. Step 2: In step 2, compounds of formula 55 can be converted to the corresponding oxime of formula 5Z in a manner similar to that described in Procedure D, Step 4. Step 3: In step 3, compounds of formula 5Z (or 55, i.e., wherein A' is O) are converted to the corresponding aldehyde 55 (or lactol from the keto-ester 55) by treatment with a suitable reducing agent such a DIBAL, in an suitable inert organic solvent such as THF, at a temperature from about -100 to -20°C. Step 4: In step 4, compound 58 is reacted with an amine ZH in a manner similar to that described in Procedure B, Step 9, to obtain the compound of formula I. Alternatively, as shown in the following reaction scheme, compounds of the formula 5£, wherein R is H, A' is =0, X is -O- and R 33 is alkoxy can be converted to the corresponding lactol of formula 60 by treatment with a suitable reducing agent such a DIBAL, in an suitable inert organic solvent such as THF, at a temperature from about -100 to -20°C: The lactol is then reacted with an amine ZH as described in Procedure A, Step 4, to give the amino alcohol 5. Procedure F: Compounds of formula I wherein R is H, d is 1 , R 6a and R 7a are each H, X is a bond, -(C(R9a)(R8a)) b . is -CH(OH)(C(R8a)(R9a)) b1 . j wherein b1 is 0 or 1 and R8a and R Q a are generally as defined above, but are preferably not R 15 -phenyl or R 15 -benzyl, and the remaining variables are as defined above, are prepared by the following procedure (In the scheme below, Z is exemplified by 4-hydroxy-4-phenylpiperidine, but other Z-H amines can also be used.): In Step 1 , the amine of formula 65 is condensed with the acid of formula 54 using standard methods, for example a coupling agent such as DCC or EDCI in the presence of a base such as pyridine or Et3N (when necessary) is used in a solvent such as THF at temperatures from 0 to 50°C, preferably room temperature. In Step 2, the alkene of formula 55 is converted to the nitro- substituted compound of formula 55 by refluxing the alkene in nitromethane in the presence of a base such as an alkoxide, a tert.- ammonium hydroxide or alkoxide, a trialkyl amine or a metal fluoride salt. The nitromethane can act as the solvent, or another solvent such as an alcohol, an ether, DMSO or DMF also can be used. In Step 3, the nitro-oxobutyl compound of formula 55 is reacted with the olefin of formula 52 and C6H5NCO in the presence of a trace amount of a base such as E.3N, in an inert, non-hydroxylic solvent such as THF or CH2CI2 to obtain the isoxazolinyl compound of formula 55. Reaction temperatures range from 0 to 40°C, with room temperature preferred. In Step 4, the keto group is reduced, for example by refluxing with a reagent such as borane-dimethylsulfide complex. In Step 5, the isoxazolinyl ring is opened by treatment with Raney Nickel under conditions well known in the art. In Step 6, the ketone is converted to the oxime as described in Procedure A, Step 6. The hydroxy-substituted compounds prepared above can be oxidized to the corresponding ketones, for example by treatment with Jones reagent. The resultant ketones can be converted to the corresponding bis-oximes using the methods described in Procedure A, Step 6. Procedure G: Compounds of formula I wherein R is H, d is 0, X is -C(O)- and the remaining variables are as defined above, are prepared by the following procedure (As above, other Z-H amines can also be used.): T In Step 1 , a compound of formula 55 is reduced in a manner similar to Procedure F, Step 4. In Step 2, the resultant nitrobutyl compound of formula 71 is reacted with a carboxyl derivative of formula 72, wherein R 34 is a leaving group such a phenoxy, or an activating group such as p-nitro- phenyl, imidazolyl or halogeno, in the presence of a base such as potassium tert.-butoxide, in a solvent such as DMSO. Reaction temperatures range from 0 to 30°C. In Step 3, the nitro group is converted to the oxime by treatment with CS2 in the presence of a base such as E.3N in a solvent such as CH3CN. The oxime can be converted into other oximes of formula I, i.e., wherein A is =N-OR 1 and R 1 is other than H, by the methods described in Procedure A, Step 6. Similarly, compounds of formula I wherein d is 0, X is a bond, -(C(R9a)(R8a)) b _ j s -CH(OH)CH 2 - and the remaining variables are as defined above, are prepared by reducing the keto group of compound 23 using well known techniques, for example by treatment with NaBH4, followed by converting the nitro group to the oxime as described above. Procedure H: Compounds of formula I wherein R is H, d is 0, X is -NH-, A is =NH, -(C(R9a)(R8a)) b _τ j s -(CH 2 )b2-T, wherein b2 is 1 or 2 and the remaining variables are as defined above, are prepared by the following procedure (As above, other Z-H amines can also be used.): _ In Step 1 , the nitrobutyl compound of formula 21 is reduced to the corresponding nitrile by treatment with CS2 in the presence of a base such as E.3N in a solvent such as CH3CN at temperatures of 20 to 70°C. In Step 2, the nitrile of formula 74 is reacted at elevated temperatures with an amine of formula NH2-(CH2)_2-T in the presence of a catalyst such as a trialkylaluminum, in a solvent such as CH2CI2 or toluene. The following procedure can be used to prepare similar compounds wherein -(C(R9a)(R8a)) b _ j s -CH 2 (C(R9a)(R8a))_ anc | A is =NOR 1 : In Step 1 , a oximeamide of formula 25_ prepared by treating a compound of formula 74 with hydroxylamine, is reacted with a carbonyl derivative of formula _2 in a solvent such as pyridine at a temperature of about 70°C to obtain an oxadiazolyl compound of formula 25- In Step 2, the oxadiazolyl ring is opened by treatment with a reducing agent such as LAH, in a solvent such as ether, at temperatures of 20 to 60°C to obtain the desired compounds of formula I. Preparation of starting materials: Starting materials of formula 22 wherein X is -NR 6 - or -S- and Z, R 4 , R 5 , R 6a and R 7a are as defined above can be prepared as shown in the following reaction scheme: In step 1 , compound 1, wherein R 5 is as defined above, is treated with a halogenating agent such as I2 or N-bromosuccinimide in an organic solvent such as CH3CN, THF or DMF at a temperature in the range of 0 to 25°C to give the halolactone _. In step 2, compound 9 is dissolved in an alcohol R 22 OH wherein R 22 is a lower alkyl group such as methyl or ethyl, preferably methyl. A base such as CS 2 CO 3 or Na 2 Cθ 3 is added and the mixture stirred at a temperature range of 0 to 50°C to give the epoxide 1_). Alternatively, a lower alkyl ester of 1 can be epoxidized by a suitable epoxidizing agent such as dimethyl dioxirane or m-CPBA to obtain a compound of formula 1_. In step 3, a solution of epoxide V_ in an alcohol such as CH 3 OH, CH3CH 2 OH, or more preferably CF 3 CH2OH, is treated with a nucleophile R <=> ■ XH of the formula ^ _-v>- ■ , wherein X is -NR 6 - or -S-, and R 4 is as defined above, at 0 to 90°C to give the lactone H. Step 4: Using the reactions of Procedure A, steps 3 and 4, convert the lactone of formula H to the desired product of formula ZL- In a similar manner, starting materials of formula __ wherein X is -NR 6 - and T, Z, R 5 , R 6a and R 7a are as defined above can be prepared as described above by treating an epoxide of formula 10 with an amine of formula HN(R 6 )-T and converting the resultant lactone to the compound of formula 28. Also in a similar manner, an epoxide of formula 10 can be treated with a thiol of formula HS(C(R 8a )(R 9 a)) b -τ to obtain the corresonding lactone, which can be converted to the desired compound using Procedure A, steps 3 and 4. Sulfides can be converted to the sulfoxides and sulfones by oxidation with suitable reagents such as m- CPBA or potassium peroxymonosulfate. Diol starting materials of formula 21 21 wherein Z and R 5 are as defined above, can be prepared as shown in the following reaction scheme: In step 1 , compound 1 is dissolved in an inert organic solvent such as CH2CI2 or toluene, preferably CH2CI2, and treated with a reagent such as (COC 2, SOCI2 or PCI3, most preferably (COC 2, in the presence of a catalytic amount of DMF and at temperatures from 0 to 75°C to give compound 18. Step 2: In step 2, compound 15 is dissolved in pyridine at room temperature and treated with an amine of formula 5_ as defined above, to give the compound 15- Alternatively, compound 15 is dissolved in an inert organic solvent such as CH2CI2 or toluene, preferably CH2CI2, the mixture is cooled to 0°C and a tertiary amine base such as E.3N or (CH3)3N is added, followed by an amine 5-; the reaction is allowed to warm to room temperature to give the product 15. Other coupling methods known to those skilled in the art, such as EDC coupling, may also be employed. In step 3, the amide IS is converted to the corresponding amine by standard reduction procedures, for example, it is taken up in an inert organic solvent and treated with a reducing agent at 0 to 80°C to give the amine 2_. Suitable solvents include ether, THF, CH2CI2 and toluene, preferably THF. Reducing agents include LAH, BH3 » Mβ2S and DiBAL-H, preferably LAH. ln step 4, the amine 20 is converted to the diol 21 by standard dihydroxylation procedures, for example, it is dissolved in a mixture of acetone and water at room temperature and treated with NMO and OSO4. Intermediate furanones for use in Procedure A, for example those of formula 52, can be prepared as follows: A furanone of formula 51 undergoes conjugate addition with a variety of nucleophiles, e.g., thiolates, azides and aryl anions to obtain compounds of formula Q2. For example, compounds of formula 6 wherein Q is phenyl is prepared by treating 51 with phenyllithium in the presence of CuCN and (CH 3 ) 3 SiCI. In the above procedures, T and Q generally are exemplified as R 5 -phenyl and R 4 -phenyl, respectively, but those skilled in the art will recognize that in many cases, similar procedures can be used to prepare compounds wherein T and Q are other than substituted-phenyl. Reactive groups not involved in the above processes can be protected during the reactions with conventional protecting groups which can be removed by standard procedures after the reaction. The following Table 1 shows some typical protecting groups: Table 1 Group to be . Group to be Protected and Compounds of formula I have been found to be antagonists of NK-i and/or NK2 and/or NK3 receptors, and are therefore useful in treating conditions caused or aggravated by the activity of said receptors. The present invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. Compounds of this invention can be administered in conventional oral dosage forms such as capsules, tablets, powders, cachets, suspensions or solutions, or in injectable dosage forms such as solutions, suspensions, or powders for reconstitution The pharmaceutical compositions can be prepared with conventional excipients and additives, using well known pharmaceutical formulation techniques. Pharmaceutically acceptable excipients and additives include non-toxic and chemically compatibile fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like. The daily dose of a compound of formula I for treating asthma, cough, bronchspasm, inflammatory diseases, migraine, nociception and gastrointestinal disorders is about 0.1 mg to about 20 mg/kg of body weight per day, preferably about 0.5 to about 15 mg/kg. For an average body weight of 70 kg, the dosage range is therefore from about 1 to about 1500 mg of drug per day, preferably about 50 to about 200 mg, more preferably about 50 to about 500 mg/kg per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient. Following are examples of preparing starting materials and compounds of formula I. As used herein, Me is methyl, Bu is butyl, Br is bromo, Ac is acetyl, Et is ethyl and Ph is phenyl. Preparation 1 α-[[[(3.5-bis(trifluoromethy0phenyl]methoxy]methyl]-β-(3.4- dichlorophenyl)-4-hvdroxy-4-phenyl 1 -piperidinebutanol Step 1 : Cool a solution of 3-(3,4-dichlorophenyl)-2-propeneoic acid (100 g, 461 mmol) in dry DMF (500 mL) to 0°C and treat with Cs 2 C0 3 (100 g, 307 mmol, 0.66 eq). Stir the resulting off-white slurry for 15 min, tl .i add CH3I (33 mL, 530 mmol, 1.15 eq) via syringe. After 1 h, add additional DMF (250 mL), stir the slurry for 14 h and partition between EtOAc (1.5 L) and half saturated aqueous NaHCθ3 (500 mL). Separate the organic layer and extract the aqueous layer twice with EtOAc (1 L, 500 mL). Wash the combined organic layers with half saturated aqueous NaHC03 (500 mL) and water (5 x 500 mL), then dry (Na 2 S04) and concentrate to obtain 105.4 g (456 mmol, 99%) of methyl 3-(3,4- dichlorophenyl)-2-propenoate as light brown needles. Step 2: Treat a solution of the product of Step 1 (15 g, 65 mmol) in dry THF (250 mL), kept cool in a large ambient temperature water bath, with Dibal-H (140 mL, 140 mmol, 2.15 eq) over 30 min. Stir the resulting solution for 30 min at 23 °C, pour into E.2O (500 mL), treat with water (5 mL), 15 % NaOH (5 mL) and water (15 mL). Stir for 5 min, dilute the mixture with E.2O (200 mL) and treat with 15 % NaOH (15 mL). Add MgSθ4 to cause a colorless precipitate. Remove the aluminum salts by filtration through a course glass frit. Wash the solids with E.2O (1 L) and concentrate the filtrate in vacuo Xo give 13.2 g (65 mmol, 99%) of 3-(3,4- dichlorophenyl)-2-propene-1-ol as an off-white solid. Step 3: Treat a solution of the product of step 2 (13.2 g, 65 mmol) in CH 2 CI 2 (250 mL) at 0 °C with pyridine (7.89 mL, 97.5 mmol, 1.5 eq) and dimethylaminopyridine (397 mg, 3.25 0.05 eq), followed by CH3COCI (6.48 mL, 74.75 mmol, 1.15 eq). Allow the mixture to warm to 23 °C, pour into 1 M HCl (100 mL) and wash the resulting organic layer again with 1 M HCl (100 mL), followed by water (5 x 100 mL; pH=6.5-7). Dry the organic layer (Na2S04) and concentrate to obtain 15.4 g (62.9 mmol, 97%) of 3- (3,4-dichlorophenyl)-2-propene-1 -ol acetate as a colorless oil. Step 4: Treat a solution of the product of step 3 (15 g, 61 mmol, dried by azeotropic distillation with toluene, 1 x 50 mL) in dry THF (250 mL) at -78°C with chlorotriethylsilane (20.2 mL, 120 mmol, 2.0 eq) rapidly followed by the addition of potassium bis(trimethylsilyl)amide (183 mL, 91.5 mmol, 1.5 eq of 0.5 M in toluene) via addition funnel over 50 min. Allow the mixture to warm to 23°C and heat to reflux for 3 h. Gradually cool the solution overnight, then quench with saturated NH4CI (150 mL). Stir the resultant mixture vigorously for 3h, treat with 1 M HCl (150 mL) and then extract with Et2θ (500 mL). Extract the aqueous layer with E.2O (400 mL), wash the combined organic layers with 5% NaOH (300 mL) and extract with 5 % NaOH (8 x 150 mL). Cool the combined aqueous layers to 5°C and, maintaining the temperature at 5-10 °C, acidify with cone. HCl (ca 175 mL) to pH 1. Extract the aqueous layer with CH2CI2 (2 x 800 mL), dry (Na2Sθ4) and concentrate to give 13.4 g (54.5 mmol, 89%) of 3-(3,4- dichlorophenyl)-4-pentenoic acid as a faint yellow oil. Step 5: Treat a solution of the product of step 4 (5.0 g, 20.4 mmol) in dry CH2CI2 (60 mL) with purified -CPBA (7 g, 40 mmol, 2 eq) [wash 13 g of commercial 55% mCPBA in 250 mL of benzene with pH 7.4 buffer (5 x 30 mL), dry (Na2Sθ4) and concentrate to obtain about 9 g of pure - CPBA]. Stir for 48 h, add Amberlyst 15 (1.2 g) and stir the mixture for 8 h. Remove the Amberlyst by filtration through a medium porosity glass frit, rinsing with EtOAc. Wash the filtrate with saturated Na2Sθ3:NaHCθ3 (1 :1) (100 mL). Dry the resulting organic layer and concentrate in vacuo. Take up the crude resulting product in hexane:CH2Cl2 (1 :1 ) and filter to give 3.3 g (12.6 mmol, 62%) of a mixture of isomers (3:2, trans / cis) of 4- (3,4-dichlorophenyl)-dihydro-5-(hydroxymethyl) 2(3H)-furanone as a colorless soft solid. Concentrate the filtrate to give 2.0 g of a viscous oil. Purify the oil by silica gel chromatography (column: 7 x 15 cm; solvent: hexane:EtOAc, 5:4 gradient to 1 :1 ) to give 1.07 g (4.1 mmol, 20%) of the pure cis isomer as an oil to give a total yield of 4.3 g (16.47 mmol, 81 %). Step 6: Treat a solution of the product of step 5 (3.3 g, 12.6 mmol, 3:2 ratio of stereoisomers by NMR) in dry DMF(10 mL) with 3,5-bistrifluoro- methylbenzyl bromide (5.9 mL, 32.2 mmol, 2.5 eq) followed by Ag2θ (5.8 g, 25.3 mmol, 2 eq), wrap the vessel in foil and stir for 2.5 days. Apply the resultant crude material to a pad of silica gel (10 cm x 4 cm) packed with hexane:EtOAc (1 :1 ). Wash the pad with the same solvent until no further product is eluted as shown by TLC and concentrate the resulting filtrate in vacuo to give the crude product as a solid (10 g). Dissolve the resultant residue in hexane:EtOAc (4:1 ) and purify by silica gel chromatography (column: 7.5 x 19; solvent: hexane:EtOAc (4:1 )) to give 3.33 g (6.8 mmol, 54%) of (trans)-[[[(3,5-bis(trifluoromethyl)phenyl]methoxy]methyl]-4-(3,4- dichlorophenyl)-dihydro-2(3H)-furanone and 1.08 g (2.2 mmol, 17%) of the corresponding cis isomer for a total yield of 71%. Trans isomer: HRMS (FAB, M+H+): m/e calc'd for [C2θHi5θ 3 Cl2F 6 ] + : 487.0302, found 487.0312.C/S isomer: HRMS (FAB, M+H+): m/e calc'd for [C2θHi5θ3CI 2 F 6 ]+: 487.0302, found 487.0297. Step 7: Cool a solution of the cis isomer of the product of step 6 (2.1 g, 4.31 mmol) in dry CH2CI2 (50 mL) to -78°C and treat with Dibal-H (5.1 mL, 5.1 mmol, 1.2 eq; 1 M in CH2CI2). Stir for 2 h at -78°C, then treat the solution with NaF (905 mg, 22 mmol, 5 eq) and water (400 μL, 22 mmol, 5 eq). Allow the suspension to warm to 23°C and stir for 45 min. Dilute the mixture with Et2θ (50 mL) and filter through a pad of silica gel (6.5 cm x 2 cm; 150 mL vacuum glass frit) packed with hexane:EtOAc (1 :1 ). Wash the pad with hexane:EtOAc (1 :1 ) until no further product is evident by TLC (ca. 600 mL). Concentrate the filtrate to give 1.92 g (3.86 mmol, 91%) of (c/s)-[[[(3,5-bis(trifluoromethyl)phenyl]methoxy]methyl]-4- (3,4-dichlorophenyI)-tetrahydro-2-furanol as a foam which is used without further purification. Step 8: Treat a solution of the product of step 7 (1.92 g, 3.86 mmol) in 2,2,2 trifluoroethanol (10 mL) with powdered 3A MS (3.5 g) followed by 4-hydroxy-4-phenylpiperidine. Stir the resulting suspension under N2 for 1 h at 23°C, then add NaCNBH 3 (533 mg, 8.6 mmol, 2 eq) and stir for 20 h. Filter the resultant mixture through a pad of silica gel (9.5 cm x 2.5 cm, 600 mL, vacuum glass frit) packed and eluted with EtOAc:triethylamine (9:1 ) (ca. 500 mL) until no further product is apparent by TLC. Remove the solvent to obtain 2.77g (>90% ) of the title compound as a colorless foam. HRMS (FAB, M+Na+): m/e calc'd for [C31H32NO3CI2F6]---: 650.1663, found 650.1647. Preparation 2 Using the trans isomer of Preparation 1 , step 6, carry out the procedure of Preparation 1 , steps 7-8 to obtain the title compound. HRMS (FAB, M+H + ): m/e calc'd for [C3iH 3 2N0 3 Cl2F6] + : 650.1663, found 650.1654. Preparation 3 Steps 1 -2: Treat a solution of the product of Preparation 1 , step 4 (1.6 g, 6.5 mmol) in dry benzene (15 mL) at 5°C with CICOCOCI (680 μL, 7.8 mmol, 1.2 eq) followed by DMF (10 μL). Stir the resulting solution for 3 h at 23°C, concentrate in vacuo, azeotrope with benzene (1 x 15 mL), dissolve in dry CH2CI2 (15 mL) and cool to 0°C. Treat a solution of 4- hydroxy-4-phenyl piperidine (2.3 g, 13 mmol, 2 eq) in dry CH2CI2 (20 mL) with pyridine (1.57 mL, 19.5 mmol, 3 eq) and cool to 0°C. Add the acid chloride via cannula over a period of 20 min. Stir the resulting solution for 15 min, warm to 23°C, dilute with CH2CI2 (150 mL) and wash consecutively with 10% aqueous citric acid (2 x 50 mL), water (1 x 50 mL) and aqueous saturated NaHC03 (1 x 50 mL), dry (Na2Sθ4) and concentrate. Purify the crude product by silica gel chromatography (column: 7 x 14 cm; eluant: hexane/EtOAc (1 :1 ) (1 L) gradient to hexane/ EtOAc (3:5) (2 L)) to provide 1.995 g (4.94 mmol, 76%) of the desired amide as a colorless solid. Step 3: Treat a solution of the amide from step 2 (4.11g, 10.2 mmol) in dry THF (50 mL) with L1AIH4 (20.4 mL of 1 M solution in ether, 20.4 mmol, 2 eq). Stir for 30 min at 23°C, then pour the mixture into E.2O (300 mL) and treat with water (750 μL), then 15 % NaOH (750 μL) followed by water (3 mL). Remove the resulting aluminum salts by filtration through a glass frit, concentrate the filtrate, dissolve in hexane/EtOAc/triethyl amine (49:49:2) and filter through a plug of silica gel (10 x 4 cm), eluting with 800 mL of solvent. Concentrate the filtrate to give 3.38 g (8.67 mmol, 85%) of the desired amine as a yellow oil. Step 4: Treat a solution of the product of step 3 (3.0 g, 7.69 mmol) in acetone/water (15 mL / 30 mL) with NMO (1.35 g, 11.5 mmol, 1.5 eq) followed by OSO4 (3.9 mL of 2.5 % w/w solution in f-butanol, 0.38 mmol, 0.05 eq). After stirring for 17 h, treat the mixture with saturated aqueous Na2Sθ3 (100 mL) and stir for 1 h. Concentrate the mixture in vacuo, extract the resulting aqueous solution with CH2CI2 (3 x 100 mL), dry the resulting organic layer (Na2S04) and concentrate. Purify the crude product by silica gel chromatography (7 x 20 cm; eluant: gradient: CH2CI2/ CH 3 OH/triethylamine (180:5:150) to (140:5:50) to (100:5:150) to (10:1 :1 ) to obtain 932 mg (2.19 mmol, 29%) of the trans diol as light amber oil and 1.455g (3.4 mmol, 45%) if the cis diol as a colored oil. Pool mixed fractions to obtain an additional 221 mg of product as a mixture of isomers, giving a total yield of 6.11 mmol, 80%. HRMS (FAB, M+H + ): m/e calc'd for [C 2 2H28Cl2N0 3 ] + : 424.1446, found 424.1435. Preparation 4 1-ff(3.5-bis(trifluoromethvπphenyl]methoxy]-3-^3.4-dichlorophenvπ-5-f4- hvdroxv-4-phenvl-1 -piperidinvn-2-pentanone Treat a solution of the product of Preparation 1 (2.0 g, 3.08 mmol) in acetone (90 mL, 0 °C) with Jones reagent (9 mL of H2Crθ4 in H2SO4 (ca. 8 M)). Stir the light orange suspension at 0°C for 1 h, then partition between CH2CI2 (150 mL) and saturated aqueous NaHC03 (150 mL). Extract the aqueous layer with CH2CI2 (3 x 150 mL), back extract the combined organic layers with saturated aqueous NaHCθ3 (150 mL), dry (Na2S04) and concentrate to give 1.94 g crude product. Purify by silica gel chromatography (column: 4 cm x 15 cm; eluant: EtOAc:hexane: triethylamine (66:33:2)) to obtain 1.64 g (2.53 mmol, 82%) of the title compound as a colorless foam. HRMS (FAB, M+H+): m/e calc'd for [C31 H 30 NO 3 Cl2F 6 ]+: 648.1507, found 648.1496. Preparation 5 β-(3.4-dichlorophenvπ-4-hydroxy-α-[(methylphenylamino)methyl]-4- phenyl-1 -piperidinebutanol Step 1 : Cool a solution of the product of Preparation 1 , step 4 (6.4 g, 26 mmol) in dry CH3CN to 0°C and treat with l 2 (19.8 g, 78 mmol, 3 eq). Store the solution at 0°C for 100 h, then pour into saturated aqueous NaHC0 3 (250 mL)/saturated aqueous Na 2 S03 (100 mL)/E.2θ (400 mL). Extract the aqueous layer with Et2θ (200 mL) and wash the combined Et2θ layers with a mixture of saturated aqueous Na2S03 (25 mL) and brine (100 mL). Dry the organic layer over MgSθ4 and concentrate to give a light yellow solid. Purify the crude material by recrystallization (hot isopropanol, 2 x) to obtain 7.42g (19.9 mmol, 77%) of 4-(3,4-dichloro- phenyl)-dihydro-5-(iodomethyl)-2(3H)-furanone as an off-white solid. Step 2: Treat a solution of the product of step 1 (1.5 g, 4.02 mmol) in dry CH 3 OH (15 mL) under N with Cs C0 3 (1.57 g, 4.8 mmol, 1.2 eq). Stir for 30 min, then pour the suspension into E.2O (200 mL)/water (100 mL). Extract the aqueous layer with E.2O (100 mL), wash the combined ether layers with 40 mL of saturated NaCl, dry (MgSθ4), and concentrate to give 1.11 g (4.02 mmol, >99%) of methyl β-(3,4-dichlorophenyl)- oxiranepropanoate as a colorless oil. Step 3: Treat a solution of the product of step 2 (368 mg, 1.34 mmol) in 2,2,2 trifluoroethanol (1 mL) with Λ/-methyl aniline (217 μL, 2.01 mmol, 1.5 eq) and stir for 6 h at 23°C followed by 6 h at 80°C. Cool to 23°C, concentrate in vacuo and purify by silica gel chromatography (column: 3.5 x 12 cm; eluant: hexane:EtOAc (4:1)) to provide 446 mg (1.3 mmol, 97 %) of 4-(3,4-dichlorophenyl)-dihydro-5-[(methylphenylamino)methyI]-2(3H)- furanone as a white solid. Step 4: Cool a solution of the product of step 3 (435 mg, 1.24 mmol) in dry CH 2 CI 2 (10 mL) to -78°C and treat with Dibal-H (1.56 mL, 1 M in CH2CI2). Stir the solution for 2 h, then add NaF (273 mg, 6.5 mmol, 5 eq) and water (117 μL, 6.5 mmol, 5 eq). Dilute the mixture with Et2θ (100 mL) and warm to 23°C. Treat the mixture with MgSθ4, stir for 10 min, filter through a sintered glass frit and concentrate. Take up the residue in hexane:EtOAc (1 :1 ) and filter through a pad of silica gel (7 x 2 cm) with about 150 mL of hexane:EtOAc (1 :1 ). Concentrate the filtrate to obtain 415 mg (1.17 mmol, 95%) of the desired lactol as a colorless film. Step 5: Treat a solution of the product of step 4 (415 mg, 1.17 mmol) in 2,2,2 trifluoroethanol with 4-hydroxy-4-phenyl piperidine (450 mg, 2.54 mmol, 2 eq) and 3A MS (1 g). Stir for 2h, treat the mixture with NaCNBH 3 (157 mg, 2.54 mmol, 2 eq) and stir the resulting suspension vigorously for 16 h. Evaporate the solvent in vacuo, take up the crude in EtOAc, apply to a silica gel column (3.5 x 12 cm) packed with hexane :EtOAc:triethylamine (66:33:2) and elute with gradient elution: EtOAc:triethyl amine (98:2) to EtOAc:CH 3 OH:triethylamine (80:20:2), to obtain 569 mg (1.11 mmol, 95%) of the title compound as a colorless foam. HRMS (FAB, M+H+): m/e calc'd for [C29H 3 5N2θ2CI 2 ] + : 513.2076, found 513.2063. Compounds of Preparations 5A to 5C are prepared in a similar manner, using the appropriate amines in step 3: Prep. T Amine HRMS HRMS calc'd Found (FAB, M+H+) 5A N-methyl- 633.1980 633.1995 (3,5-bistri- fluoromethyl- Cf 3 phenyl) benzyl amine 5B -o N-methyl 527.2232 527.2246 benzyl amine 5C H 3 N-methyl-(3- 585.2651 585.2644 isopropoxy) benzyl amine Preparation 6 Substituted piperidines - Method A Dissolve 4-aminomethyl-piperidine (30.00 g, 0.263 mol) in CH3OH (500 mL), cool to -30°C under N2, add di-t-butyl dicarbonate (38.23 g, 0.175 mol) in CH3OH (100 mL) dropwise, warm slowly to 23°C and stir for 16 h. Concentrate, add CH2CI2 (700 mL), wash with saturated aqueous NaCl (2x200 mL), dry organic solution (MgS04), filter and concentrate to give 36.80 g of a 86:14 mixture of the title compound and 1 ,1 -dimethyl- ethyl 4-[(1 ,1-dimethylethyloxycarbonyl)methyl]-1-piperidinecarboxylate. Step 2A: Dissolve the product (19.64 g, 0.0916 mol, 22.84 g of the mixture) of Step 1 in dry CH 2 CI (350 mL) and cool to 0°C under N . Add pyridine (10.87 g, 11.1 mL, 0.137 mol) then chlorovaleryl chloride (15.63 g, 13.0 mL, 0.101 mol), warm slowly to 23°C and stir for 16 h. Add saturated aqueous NH4CI (300 mL), separate layers and extract with CH2CI2 (2x250 mL). Dry combined organic extracts (MgS04), filter and concentrate. Purify by chromatography (1000 mL of flash silica gel; eluant: 1 :1 EtOAc:hexane, then EtOAc). Combine appropriate fractions and concentrate to give 25.36 g (0.0762 mol, 84%) as a colorless oil. MS (CI/CH 4 ): m/e 333 (M+1 ) Step 2B: t"Bu0 H Treat the product of Step 1 in a procedure similar to that described for Step. 2A, using chlorobutryl chloride. MS (FAB): m/e 319 (M+1 ) Step 3: Prep. 6A: t ^ u ° ro O Wash NaH (3.84 g, 0.160 mol, 6.40 g of 60 wt%) with hexane (25 mL), suspend in dry THF (150 mL) and cool to 0°C under N2. Add the product (25.35 g, 0.0762 mol) of Step. 2A in dry THF (150 mL) dropwise. Stir at 23°C for 30 mins, reflux for 6 h, and stir at 23°C for 16 h. Cool to 0°C and add water (150 mL) and 1 N HCl (150 mL). Concentrate and extract with EtOAc (3x200 mL). Wash combined organic extracts with saturated aqueous NaCl, dry (MgSθ4), ilter and concentrate. Purify by chromatography (600 mL of flash silica gel; eluant: 5% CH3OH-CH2CI2). Combine appropriate fractions and concentrate to give 21.62 g (0.0729 Treat the product of Step 2B in a procedure similar to that described for Prep. 6A. MS (FAB): m/e 283 (M+1 ). Prep. 6C: l - Bu Y 0 Cr S Combine the product (1.50 g, 5.06 mmol) of Prep. 6A and Lawesson reagent (1.13 g, 2.78 mmol) in dry THF (20 mL) under N2. Stir at 23°C for 20 h. Concentrate and purify by chromatography (200 mL of flash silica gel; eluant: 1 :3 EtOAc:hexane, 1 :2 EtOAc:hexane, then 1 :1 EtOAc:hexane). Combine appropriate fractions and concentrate to give 1.30 g (4.16 mmol, 82%) as a green oil. MS (FAB): m/e 313 (M+1 ). Prep. 6D: Dissolve the product (2.50 g, 8.43 mmol) of Prep. 6A in dry THF (30 mL), add borane-DMS (16.9 mL of 2.0 M in THF, 33.74 mmol) and reflux for 20 h. Cool to 0°C and add CH 3 OH (20 mL). Concentrate, add EtOH (50 mL) and K2CO3 (4.66 g, 33.74 mmol). Reflux for 4 h and cool to 23°C. Add water (100 mL), concentrate and extract with CH2CI2 (4x50 mL). Dry combined organic extracts (MgS04), filter and concentrate. Purify by chromatography (200 mL of flash silica gel; eluant: 7% CH3OH-CH2CI2). Combine appropriate fractions and concentrate to give 1.72 g (6.09 mmol, 72%) of the title compound as a colorless oil. MS (FAB): m/e 283 (M+1 ). Prep. 6E: Dis the product (1.50 g, 5.06 mmol) of Prep. 6A in dry THF (20 mL) and cool to -78°C under N 2 . Add [(CH 3 ) 3 Si]2NLi (5.5 mL of 1.0 M in THF, 5.5 mmol) and stir at -78°C for 1 h. Add bromomethylcyclopropane (0.820 g, 0.59 mL, 6.07 mmol), warm slowly to 23°C and stir for 16 h. Add saturated aqueous NH4CI (40 mL), extract with EtOAc (3x30 mL), wash combined organic extracts with saturated aqueous NaCl, dry (MgSθ4), filter and concentrate. Purify by chromatography (175 mL of flash silica gel; eluant: 2% CH3OH-CH2CI2 then 4% CH3OH-CH2CI2). Combine appropriate fractions and concentrate to give 0.93 g (2.65 mmol, 53%) of the title compound as a colorless oil. MS (FAB): m/e 351 (M+1 ) Prep. 6F: Treat the product of Prep. 6 A in a procedure similar to that described for Prep. 6G, using allyl bromide. MS (CI/CH4): m/e 337 (M+1 ). Step 3: Separately dissolve the products of Prep. 6A to 6H in CH2CI2, add trifluoroacetic acid and stir at 23°C for 4 h. Concentrate, add 1 N NaOH, extract with CH2CI2, dry the combined organic extracts (MgS04), filter and concentrate to obtain the corresponding substituted piperidines: Preparation 7 Substituted piperidines - Method B Step 1 ; Prep. 7A: H °t_ N "C N* -^S > Combine 1 -benzyl-4-piperidone (2.00 g, 10.6 mmol) and 3- pyrrolinol (0.92 g, 10.6 mmol) in titanium isopropoxide (3.75 g, 3.9 mL, 13.2 mmol) and dry CH 2 CI 2 (4 mL). Stir at 23°C under N 2 for 5 h. Add EtOH (30 mL) and NaCNBH 3 (0.66 g, 10.6 mmol) and stir for 16 h. Add water (50 mL) and CH2CI2 (50 mL), filter through celite, separate filtrate layers and extract with CH2CI2 (2x50 mL). Wash combined organic extracts with saturated aqueous NaHC03, dry (MgSθ4), filter and concentrate. Purify by chromatography (150 mL of flash silica gel; eluant: 10% CH3OH with NH3-CH2CI2, 15% CH3OH with NH 3 -CH 2 CI 2 , then 20% CH3OH with NH3-CH2CI2.) Combine appropriate fractions and concentrate to give 1.88 g (7.22 mmol, 68%) as a colorless oil. MS (CI/CH4): m/e 261 (M+1 ). Using the procedure of Prep. 7A and the appropriate amine, prepare Preps. 7B and 7C: Prep- 7B: MS (FAB): m/e 302 (M+1 ) Prep. 7C: C N -(£ N ^® MS (CI/CH4): m/e 271 (M+1). Step 2: Separately treat each of Preps. 7A, 7B and 7C with Pd/C catalyst in CH3OH and formic acid at 23°C under N2 for 16 h. Filter each mixture through celite, washing with CH3OH, concentrate the filtrates, add 1.0 N NaOH and extract with 1 :4 EtOH:CH 2 Cl2, dry, filter and concentrate to Preparation 8 Substituted Piperidines - Method C Step 1 : Using 1 ,1-dimethyethyl 4-formyl-piperidinecarboxylate and the appropriate amine in a reductive amination procedure similar to that described in Example 42, Step 9, Preparations 8A, 8B and 8C are prepared: Prep. 8A: OH MS(CI/isobutane): m/e313 (M+1 ) Prep. 8B ,.: MS(CI/CH 4 ):m/e313 (M+1 ) Prep. 8C: MS(FAB):m/e299 (M+1 ) Step 2: Using the procedure described in Preparation 6, Step 3, prepare the following compounds: Preparation 9 Substituted Heptan- and Hexanaldehydes Step 1 Treat a suspension of 4[3,5-bis(trifluoromethyl)phenyl]butyric acid (5.15 g, 17.55 mmol) in dry E.2O (50 ml) with SOCI2 (2.6 ml, 2 equiv.) and add 3 drops of pyridine. Stir for 15 h at ambient temperature, then decant the solution from pyridine hydrochloride and evaporate in vacuo to obtain the acid chloride (5.4 g, 99%) as an oil. Cool a 1 M solution of [(CH3) 3 Si] 2 NLi (50 ml, 8.3 g, 49.63 mmol) in THF to -30°C and add a solution of 3,4-dichlorophenylacetic acid (4.09 g, 19.8 mmol) in dry THF (20 ml) dropwise, maintaining the temperature at or below -14°C. Stir at 0°-5°C for 1 h. Cool the reaction mixture to -78°C and add a solution of 4-[3,5-bis(trifluoromethyl)phenyl]butyryl chloride (5.41 g, 16.97 mmol) in dry THF (10 ml) dropwise over 15 min. Stir at 0°C for 1 h, then allow to warm up to room temperature and stir for 1 h. Pour on 50 ml of 1 N HCl and ice, stir 30 min and extract the aqueous layer with EtOAc. Wash with saturated aqueous NaHC03 (200 ml), dry (MgSθ4), filter and concentrate in vacuo to obtain 7.5 g of crude product. Purify by flash chromatography over 180 g silica gel (particle size 32-63) and elute with hexane: CH2CI2 (70:30) to obtain 3.86 g (8.71 mmol, 51%) of the title crystalline compound. 1 H NMR (CDCI3, 300 MHz) δ: 7.72(s, 1 H Ar),7.60(s, 2H Ar), 7.41 (d, J=8.3, 1 H Ar), 7.29(s, 1 H Ar), 7.02(m, 1 H Ar), 3.66(s, 2H, CH ), 2.72(t, 2H, CH 2 , J=7), 2.54(t, 2H, CH 2 , J=7), 1.94(m, 2H, CH 2 ). IR (CH 2 CI 2 ): 1720 cm-1 (C=0). Using a similar procedure with the appropriate acid, prepare the following compounds: Yield 66%. 1 H NMR (CDCI3, 200 MHz) δ: 7.72(s, 1 H Ar), 7.60(s, 2H Ar), 7.38(d, 1 H Ar, J=8), 7.26(1 H Ar), 6.98(m, 1 H Ar), 3.65(s,2H, CH 2 ), 3.02(t, 2H, CH 2 , J=6.4), 2.86(t, 2H, CH 2 (t, 2H, CH 2 , J=6.4)). IR (CH2CI2): 1720 cm-1 ( C =θ). Yield 60%. FAB-Ms: m/z 383 ([Cι gH20 35 Cl2θ4 + H]+, 47%). Add a solution of the product of Step 1 (3.80 g. 8.57 mmol) in dry THF (20ml) to a stirred solution of [(CH 3 ) 3 Si]2NLi (9.35 ml, 9.3 mmol) in THF at -78°C. Add a solution of 2-chloro-N-methoxy-N-methyl-acetamide (1.18 g, 8.58 mmol) in THF (10 ml) dropwise over 10 min, add 1.2 g of Kl, allow the reaction mixture to warm to room temperature over a period of 1 h and stir overnight. Add 10 ml of saturated aqueous NH4CI and evaporate the solvent in vacuo. Partition the residue between CH2CI2 (150 ml) and H2O (150 ml). Wash the organic layer with aqueous NaHC03 (150 ml), dry (MgS04), filter and evaporate in vacuo to obtain 3.6 g (77%) of the oily product. FAB-Ms: m/z 544 ([C23H21 35 Cl2F6N03 + H]+, 61 %). Using the procedure of Step 2, treat compounds 9-1 A and 9- 1 B of Step 1 to obtain: Yield 77%. FAB-Ms: M/Z 530 ([C22H * i 9 35 Cl2F6Nθ3 + H]+, 52%). Yield: 77%. FA β + H]+ 30%). Step 3: Treat a solution of the product of Step 2 (3.5 g,6.43 mmol) in dry pyridine (10 ml) with O-methoxylamine HCl (0.65 g, 7.78 mmol) and heat to 60°C for 1 h. Remove the pyridine in vacuo, partition the residue between CH2CI2 and water. Dry over MgSθ4, filter and evaporate in vacuo to obtain the mixture of E- and Z-oximes. Separate E-oxime and Z- oxime by flash chromatography using 120 g of Siθ2 (particle size 32-63) and eluant: EtOAc:hexane (20:80) to obtain 2.91 g (79%) of E-isomer and 0.47 g (12.8%) of Z-isomer. 9-3fE^: FAB-Ms (E-isomer): m/z 573 ([C24H24 35 Cl2F6N2θ3 + H]+, 27%). H NMR- E-isomer (CDCI3, 300 MHz) δ 4.08 (H-γ). 2_2{Z): FAB-Ms (Z-isomer): m/z 573 ([C24H24 35 Cl2F6N2θ3 + H]+, 70%). H NMR- Z-isomer (CDCI3, 300 MHz) δ 4.69 (H-γ). Using the procedure of Step 3, treat compounds 9-3A and 9- 3B to obtain the following: Yield: 73% of E-isomer (m.p. 62-64°C) and 18% of Z-isomer. 9-3A ( E^: MS-CI+/CH4 (E-isomer): m/z 559 ([C23H22 35 Cl2F6N2θ3 + H]+, 100%). 1 H NMR- E-isomer (CDCI3, 300 MHz) δ 4.11 (H-γ). 9-3AfZ^: MS-CI+/CH4 (Z-isomer): m/z 559 ([C23H22 35 Cl2F6N2θ3 + H]+ 100%). 1 H NMR-Z-isomer (CDCI3, 300 MHz) δ 4.71 (H-γ). (9-3B(E); 9-3B(Z)) Yield: 61 % of E-isomer (m.p. 114-118°C) and 23% of oily Z-isomer. 9-3B(Ei: FAB-Ms (E-isomer): m/z 513 ([C24H30 35 Cl2N2θ6 + H]+, 42%). H NMR- E-isomer (CDCI3, 300 MHz) δ 4.10 (H-γ). 9-3B-TZΪ: FAB- Ms (Z-isomer): m/z 513 ([C24H30 35 Cl2N2θ6 + H]+, 60%). To a solution of the E-isomer of Step 3 (9-3(E)) (1.43 g, 2.54 mmol) in THF (20 ml) at -78°C , add 6 ml of 1 M Dibal-H in hexane (6 mmol) over a period of 5 min. Stir at -78°C for 30 min, then add 15 ml of H2O and 1 g of NaF. Allow the reaction mixture to warm to room temperature, dilute with EtOAc (100 ml), separate organic layer from aqueous, dry (MgSθ4), filter and evaporate in vacuo. Treat the residue with Et2θ, filter and evaporate in vacuo. Use the product immediately, without purification. Using the procedure described in step 4, treat preparative compounds 9-3A(Z), 9-3B(E) and 9-3B(Z) to obtain the corresponding aldehydes 9-A(Z), 9-B(E) and 9-B(Z). Preparation 10 Treat a solution of 2-thiopheneaceticacid (1.6 g, 11.2 mmole) in anhydrous THF (100 mL, -78°C) with lithiumhexadimethylsilazide (24.5 mmole, 1 M THF soln.). Warm the solution to 0°C over a period of 2 h, then cool to -78°C and add ethyl [[3,5-bis(trifluoromethyl)phenyl]-methoxy]- acetate (3.55g, 11.2 mmole) dropwise as a THF solution (10 mL). Stir the resulting mixture for 4 h and allow the temperature to warm to 0°C. Quench the reaction with 1 ml HOAc and stir for 4h. Dilute the reaction with EtOAc (lOOmL), wash the organics with water (2X 50mL) and brine (1X 50 mL), dry (Na2S04) and concentrate to obtain 3.4 g of crude product. Purify by silica gel chromatography (3:7 Et2θ:hexane ) to give the title compound, 2.8 g (7.3 mmole, 65.4 %) as a colorless foam. MS: (CI+/CH4) (M+H+) 383. Preparation 11 Treat a solution of 4-picoline (1.42g, 15 mmole) in anhydrous THF (50 mL, -10°C) with phenyllithium (15 mmole, 8.3 mL cyclohexane:E.2θ) and stir for 1 h at 0°C. Cool the solution to -78°C and add the product of Example 47, Step 1 (5.27g, 15 mmole) dropwise as a THF solution (10 mL). Stir the resulting mixture for 4 h (-78°C to 0°C) and quench with saturated aqueous NH4CI (10 mL). Extract with EtOAc (100mL), wash with water (2X50mL), brine (50 mL), dry (Na2S04), and concentrate. Purify the crude by silica gel column chromatography (8:2 EtOAc:hexane) to obtain the title compound. (2.5 g, 44%). MS: (CI+/CH4) (M+H+) 378. Preparation 12 Step 1 : Treat a solution of 3,5-bis(triflouromethyl)benzaldehyde (10 g, 0.04 moles) in toluene (130 mL) with carboethoxymethylenetriphenyl- phosphorane (14.38 g, 0.041 moles) and reflux in toluene for six hours. Remove the solvent under vacuum and dissolve the residue in CH2CI2 and filter through a pad of silica gel (50 g) on a suction filter. Concentrate the filtrate and dry under vacuum to give the title compound (13.01 g) as a white solid. MS(CI, M+H+), m/e 313. Step 2: Treat a degassed solution of the product of Step 1 (31.0 g, 0.04 mmoles) in EtOH (60 mL) with 10% Pd/C (1.3 g), introduce H 2 gas to a pressure of 20 psi. and shake at room temperature for 2 hours. Filter through celite and remove solvent by vacuum distillation to obtain the title compound (13.0 gm). MS(CI, M+H+), m/e 315. Step 3: Treat an EtOH solution (200 mL) of the product of Step 2 (13 g, 0.041 moles) with an aqueous solution of NaOH (50%, 12 ml, 0.26 moles). Heat the solution at reflux for 3 h. Cool the mixture to room temperature and remove the solvent by vacuum distillation. Dissolve the residue in water (150mL) and acidify to pH 2 with concentrated HCl. Extract the product into EtOAc (2 x 10OmL), wash the EtOAc layer with water (2x 50 mL), dry (MgS04) and remove the solvent by vacuum distillation to afford a white solid (11.26 g). M. p. 65-67 °C. MS (Cl, M+H+) m/e 287. Step 4: Treat a solution of the product of Step 3 (11.26 g, 0.039 moles) in CH2CI2 (300 mL) with oxalyl chloride (5.99 g, 0.047 moles, added dropwise with stirring) and a trace of DMF. Stir the mixture at room temperature for 2 h and heat to reflux for 15 min. Cool the reaction to room temperature and concentrate to dryness under vacuum. Repeatedly dissolve the residue in toluene (2 x 100 mL) and concentrate to dryness to afford an off-white solid. Dissolve the solid in CH2CI2 (100mL) and add dropwise into a cold (0°C) solution of phenol (3.7 g, 0.04 moles) in a mixture of CH2CI2 (100 mL) and pyridine (15 mL). Stir at room temperature overnight and concentrate to a yellow oil. Redissolve in CH2CI2 (100 mL), wash with aq. 1 M HCl (2 x 50 mL), water (1 x 50 mL) and dry (MgS04). Remove the solvent by vacuum distilation to afford a light yellow solid (9.2 g). M.p. 39-40°C. MS (Cl, M+H+) m/e 363. Preparation 13 Treat a suspension of 3.5-bis(trifIuoromethyl)phenyl acetic acid (5 g, 18 mmoles) in CH2CI2 (100 mL) with oxallyl chloride (4.7 g, 3.3 mL, 37 mmoles) and a trace (3 drops) of DMF. Stir the mixture at room temp. under N2 for 1 h and then heat to reflux for 1 h. Cool the mixture and remove the solvent in vacuo. Dilute the residue (5.2 g) with toluene (20 mL) and concentrate under reduced pressure (3 times). Dilute a portion (2.9 g, 10 mmoles) of the crude residue with CH2CI2 (10 mL) and add to a rapidly stirred biphasic mixture of water (30 mL), concentrated NH4OH and CH2CI2 (30 mL). Stir the mixture an additional 15 min to obtain a precipitate. Separate the organic phase, dilute with 10 mL of EtOAc to dissolve the precipitate and dry (MgS04). Remove the solvent by vacuum distilation and triturate the residue with Et 2 0/hexane (30 mL, 4:1 ). Collect the solid (2.48 g) by vacuum filtration and dry under vacuum. Dissolve a portion of the solid (1.47 g, 5.4 mmoles) in THF (20 mL) and add solid UAIH4 (0.51 g, 50 mmole) in small portions. Heat the mixture to reflux for 3 h, cool and then treat with 20 mL of a mixture of CH3OH and 2N NaOH (9:1 ). After rapidly stirring for 20 minutes, remove the precipatate by filtration through celite. Dilute the organic phase with EtOAc (25 mL) and extract with 1 N HCl (30mL). Basify the aqueous phase with 3 N NaOH and extract with CH2CI2 (2 x 30 mL). Dry the organic phase (MgSθ4) and concentrate under vacuum to give 0.22 g of the title compound. Concentrate the EtOAc layer from above under vacuum to a reddish oil and triturate with E.2O to obtain an additional 0.11 gms of the title compound as the HCl salt. MS(CI, M+H+), m/e 258. Example 1 1- r ff3.5-bisftrifluoromethvπphenyl]methoxy1-3-f3.4-dichlorophenvπ-5-(4- hvdroxy-4-phenyl-1 -piperidinvπ-2-pentanone O-methyloxime Treat a solution of the product of Preparation 4 (270 mg, 0.417 mmol) in dry pyridine (5 mL) with O-methoxylamine HCl (52 mg, 0.626 mmol, 1 .5 eq) and heat to 60°C for 30 min. Allow the vessel to cool to 23°C and remove the pyridine in vacuo. Take up the crude product in a minimal amount of CH2CI2 (2 mL) and apply to a silica gel column (2.5 cm x 15 cm) packed with hexane :EtOAc:triethylamine (66:33:1 ). Elute with the same solvent system to obtain 190 mg (0.281 mmol, 67%) of the title compound as a colorless foam. HRMS (FAB, M+H+): m/e calc'd for [032^3^030^6]+: 677.1772, found 677.1785. Examples 1 A to 1 F are prepared from the product of Preparation 4 in a procedure similar to that described for Example 1 : Ex. A Starting HRMS HRMS Material (FAB, M+H+) Found calc'd 1A =N-OH hydroxyl 663.1616 663.1625 (Z isomer) amine-HCI 1 B HO-N= hydroxyl 663.1616 663.1631 (E isomer) amine-ΗCI 1 C =N-OCH2Ph O-benzyl- 753.2085 753.2069 hydroxyl amine-ΗCI 1 D =N-OCH2CH3 O-ethyl- 691.1929 691.1922 hydroxyl amine-ΗCI 1 E =N-OCH2CH=CH2 O-allyl- 703.1929 703.1946 hydroxyl amine-ΗCI 1 F =N-OC(CH3)3 O-r-butyl- 719.2242 719.2252 hydroxyl amine-HCI 1G H2NOCH2CO2H =N-OCH2COOH 721 (M+1 ) • HCl 1 H =N-0(CH2) 2 COOH H2NO(CH2) 2 - 735.1827 735.1807 Cθ2H » HCI Example 2 Treat a solution of triethyl phosphonoacetate (18 μL, 0.11 mmol, 1.1 eq) in dry THF (1.5 mL) at 0°C with [(CH 3 ) 3 Si] NNa (110 μL of 1 M THF, 0.11 mmol, 1.1 eq). Stir for 30 min at 0°C and add a solution of the ketone from Preparation 4 in dry THF (1.5 mL), using THF (0.5 mL) for quantitative transfer. Allow the reaction to warm to 23°C and stir for 24 h. Quench the mixture with water and extract with CH2CI2 (3 x 25 mL). Wash the combined organic layers with 5 % aqueous NaOH, dry (Na2Sθ4) and concentrate to give the crude product as on oil. Purify by preparative TLC (0.5 mm silica gel; eluant: CH2CI2/CH3OH (saturated with ammonia) (95:5) to obtain 41 mg (.057 mmol, 57%) of the title compound as a film. HRMS (FAB, M+H + ): m/e calc'd for [C 3 5H36Nθ4F 6 Cl2] + : 718.1926, found 718.1915. Examples 3-4 Resolve the racemic compound of Example 1A by HPLC using a Daicel Chiralcel AD chiral chromatography column (2.0 cm. x 50.0 cm., 13% isopropanol in hexane). Four injections of 100 mg each provide: Example 3, the (+) isomer: 150 mg; t R = 10 min.; T = +6 - 5 ° > ( c=0 - 01 - CHCI 3) Example 3A, the (-) isomer: 140 mg; t R = 17 min.; 0 = -9.5°, <c=0.01 , CHCI 3 ) In a similar manner, resolve the compound of Example 1 B to obtain Examples 4 and 4A: Enantiomer A: tπ = 21 min.; HRMS (FAB, M+H+): m/e calc'd for [C3i H 31 N2θ3F 6 Cl2] + : 663.1616, found 663.1601 ; Enantiomer B: tR = 31 min.; HRMS (FAB, M+H+): m/e calc'd for [C 31 H 31 N2θ3F6Cl2] + : 663.1616, found 663.1621. Prepare examples 5-6 from the products of Example 3 and 3A, respectively, in a manner similar to that described in Example 8, using CH3I as the alkyl halide and DMF as the solvent. Example 5 HRMS (FAB, M+H+): m/e calc'd for [C 3 2H33N2θ3F 6 Cl23 + : 677.1772, found 677.1769. Example 6 HRMS (FAB, M+H + ): m/e calc'd for [C 3 2H33N2θ3F 6 Cl2] + : 677.1772, found 677.1762. Example 7 Treat a solution of the ketone of Preparation 4 (100 mg, 0.154 mmol) in ethanol (3 mL) with acetic acid (3 drops) followed by 1-amino-4- methyl-piperizine. Stir the mixture at 60°C for 1 h, concentrate and triturate with water using sonication. Filter the resulting colorless solid and wash with water (3 mL) to give 86 mg (0.115 mmol, 75 %) of the product as a colorless solid, mp 48-49°C. HRMS (FAB, M+H + ): m/e calc'd for [C36H4θN4θ2CI 2 F 6 ] + : 745.2511 , found 745.2502. Using a similar procedure but substituting 4- aminomorpholine, dimethylhydrazine and 4-amino-1-piperazineethanol for 1-amino-4-methyl-piperizine, obtain compounds 7A, 7B and 7C, respectively, as E/Z mixtures: Example 8 Treat a solution of Example 1A (400 mg, 0.603 mmol) in dry DMF (12 mL) at 0 °C with 60% NaH in mineral oil (48 mg), stir for 40 min and treat with methyl bromoacetate (60 μL, 0.633 mmol, 1.05 eq). Stir for 30 min, pour into EtOAc (250 mL) / half saturated NaHCθ 3 (200 mL) and extract. Wash the organic layer with water (2x100 mL), then brine (10 mL) and dry over Na 2 S0 4 . Purify the crude mixture by silica gel chromatography (4 x 15 cm; hex/EtOAc 1 :1 w/ 2% NEt 3 ) to give 361.8 mg (0.492 mmol, 82%) of the pure product as an oil. HRMS (FAB, M+H+): m/e calc'd for [0 34 ^ 4 ^6^05]+: 735.1827, found 735.1839. Using a similar procedure, treat the product of Example 1 A with the appropriate alkyl halide to obtain the following compounds 8A-8L: * Followed by desilylation with 1 M TBAF in THF (3 h, 23°C). Followed by deprotection of the trityl group by stirring in PPTS/MeOH for 3 h at 60°C. Example 9 Treat a solution of the product of Example 8 (57 mg, 0.078 mmol) in MeOH (3mL) at 0 °C with gaseous ammonia for 5 min. After venting 2-3 times, seal the vessel with a polypropylene cap and stir until TLC shows the reaction is complete (20h) to give (56 mg, 0.078 mmol, >99%) of the pure product as a colorless powder. HRMS (FAB, M+H+): m/e calc'd for [033^3^6^04]+: 720.1831 , found 720.1841. Using a similar procedure, treat the product of Example 8 with the appropriate amine to obtain the following compounds 9A, 9B and 9E; treat the product of Example 8A to obtain 9C and 9D; and treat the products of Examples 8C and 8D to obtain 9F and 9G, respectively: Examples 10 to 18 Using the procedures described below, compounds of the following structural formula were prepared, wherein the definitions of R 1 are shown in the table below: Example 10: Treat a solution of the product of Example 1 (100 mg, 0.151 mmol) in CH 2 CI 2 (1 mL) with CH 3 NCO (9 μL, 0.151 mmol, 1 eq) and pyridine (18 μL, 0.227 mmol, 1.5 eq) and stir for 60 hr. Concentrate in vacuo and purify by silica gel chromatography (2.5 x 18 cm; EtOAc/Hex 2:1 w/ 2% NEt 3 ) to give 88 mg (0.122, mmol 81%) of the pure product as a film. Example 11 : Treat a suspension of H 2 NOH « HCI (47 mg, 0.68 mmol, 5 eq) in ethanol with KOH in MeOH (680 μL, 0.68 mmol, 5 eq), sonicate for 5 min and then add to a solution of Example 8B (95 mg, 0.135 mmol) in ethanol (5 mL). Heat for 2.5 h at 60 °C, filter, concentrate in vacuo and purify by silica gel chromatography (2.5 x 14 cm; CH CI 2 /MeOH (NH 3 ) 95:5) to give 98.3 mg (0.134 mmol, 99%) of the product as a film. Example 12: Use a procedure similar to that described in Example 11 using the product of Example 8B as the starting material, H2NOCH 3 »HCI as the alkoxyl amine and 2,2,2-trifluoroethanol as the solvent. Example 13: Treat a solution of Example 8H (50 mg, 0.068 mmol) in 1 ,2 dichloroethane (1 mL) with carbonyldiimidazole (60 mg, 0.38 mmol, 5 eq), stir for 10 hr at reflux, and concentrate in vacuo. Purify by silica gel chromatography (1.5 x 121 cm; CH 2 CI 2 /MeOH (NH 3 ) 98:2) to give 40 mg (0.052mmol, 77%) as a film. Example 14: Treat a solution of Example 1 G (100 mg, 0.139 mmol) in THF (2 mL) and Λ/-isopropyl-1 -piperazine-acetamide (77 mg, 0.417 mmol, 3 eq) with Et3N (29 μL, 0.209 mmol, 1.5 eq) and DEC (40 mg, 0.209 mmol, 1.5 eq), stir until complete by TLC (72 hr), and partition between EtOAc (50 mL) / 10 % citric acid (20 mL). Wash with water (25 mL), sat'd NaHC03 (25 mL), brine (10 mL), and dry over Na 2 S0 4 . Purify by silica gel chromatography (2.5 x 10 cm; CH 2 CI 2 /MeOH (NH 3 ) 9:1 ) to give 36.2 mg (0.041 mmol, 29%) of the desired product as a foam. Example 15: In a similar fashion to Example 14, use 2-ami no- 1 ,3,4- thiadiazole as the amine to obtain the desired product. Example 16: In a similar fashion to Example 14, use 3-aminopyrazine- 2-carboxylic acid as the amine to obtain the desired product. Example 17: In a similar fashion to Example 14, use (+/-)-3-amino-1 ,2- propanediol as the amine to obtain the desired product. Example 18: In a similar fashion to Example 14, use 2-methoxyethyl amine as the amine to obtain the desired product. Examples 19, 19A and 19B Using the procedures described below, compounds of the structural formula above were prepared, wherein the definitions of R 1 are shown in the following table: Example 19: Step 1 : Prepare the allyl oxime ether of the product of Example 22, Step 2, using a procedure similar to that used in Example 1 , employing O- allylhydroxylamine HCl as the alkoxyl amine. Step 2: Deprotect the silyl protective group in a procedure similar to that describe in Example 22, Step 4. Step 3: Alkylate the hydroxyl group with 3,5-dichlorobenzylbromide in a procedure similar to that in Example 22. Step 4: Treat a solution of the product of step 3 (285 mg, 0.426 mmol) in 80% aqueous EtOH with Pd(PPh3)4 (25 mg, 0.021 mmol, 0.05 eq) and triethylammoniumformate (2.13 mL of 1 M solution in THF, 5 eq) and stir at reflux for 4 h. Cool, concentrate and purify by silica gel chromatography (2.5 x 16.5 cm; hex EtOAc 1 :1 w/ 2% NEt.3) to give 185 mg (0.3095 mmol, 73%) as a film. Step 5: Treat the product of step 4 in a similar fashion to Example 8, using BrCH 2 CN as the alkyl halide. Example 19A: Treat the product of Example 19, step 4, in a similar fashion to Example 8, using 2-bromo-1 -(f butyldimethylsiloxy)ethane as the alkyl halide, followed by desilylation (3 h, 23°C) with 1 M TBAF in THF. Example 19B: Treat the product of Example 19 in a similar fashion to Example 11 to obtain the desired product. Examples 20, 20A, 20B, 20C and 20D Using the procedures described below, compounds of the structural formula above were prepared, wherein the definitions of R 1 are shown in the following table: Example 20: Using a procedure similar to Example 47, substitute 3,5 dichlorobenzyl alcohol for 3,5 bistrifluorobenzyl alcohol in step 1 ; proceed in a similar manner through steps 2, 3, and 4, using allylhydroxylamine HCl as the alkoxyl amine in step 4. Proceed in a similar fashion through steps 5 and 6, using piperidinopiperidine in place of 4-phenyl-4- piperidinyl acetamide. Treat the resultant product using a procedure similar to Example 19, step 4, to obtain the desired compound. Example 20A: Treat the product of Example 20 in a similar fashion to Example 8, using BrCH2CN as the alkyl halide to obtain the desired product. Example 20B: Treat the product of Example 20A in a similar fashion to Example 11 to obtain the desired product. Example 20C: Treat the product of Example 20 in a similar fashion to Example 8 using 2-bromo-1-(r butyldimethylsiloxy)ethane as the alkyl halide, followed by desilylation (3 h, 23°C) with 1 M TBAF in THF to obtain the desired product. Example 20D: Treat the product of Example 20 in a similar fashion to Example 8 using CH3I as the alkyl halide to obtain the desired product. Examples 21, 21 A, 21 B and 21 C Using the procedures described below, compounds of the structural formula above were prepared, wherein the definitions of R 1 are shown in the following table: Example 21 Step 1 : Prepare the oxime precusor using a procedure similar Example 20, using 1-(pyrrolidinocarbonylmethyl)piperizine in place of piperidinopiperidine. Step 2: Treat the product of step 1 , in a similar fashion to Example 8, using CH3I as the alkyl halide to obtain the desired product. Example 21 A: Treat the product of Example 21 , step 1 , in a similar fashion to Example 8, using 2-bromo-1-(/butyIdimethylsiloxy)ethane as the alkyl halide, followed by desilylation (3 h, 23°C) with 1 M TBAF in THF to obtain the desired product. Example 21 B: Treat the product of Example 21 , step 1 , in a similar fashion to Example 8, using BrCH 2 CN as the alkyl halide to obtain the desired product. Example 21C: Treat Example 21 B in a similar fashion to Example 11 to obtain the desired product. Example 22 Step 1 : β-(3,4-dichlorophenyl)-α-[[[dimethyl(1 ,1 -dimethylethyl)silyl]oxy]- methyl]-4-hydroxy-4-phenyl-1 -piperidinebutanol Treat a solution of the diol from Preparation 3 (19.8g, 46.6 mmol), Et3N (13 mL, 93.2 mmol) and dimethylaminopyridine (564 mg, 4.66 mmol) in CH2CI2 (300 mL)with TBSCI (8.44 g, 55.9 mmol) at 0°C. Allow the resulting solution to warm to room temperature and stir for 12-18 hours. Quench the reaction with water and extract with CH2CI2 (3 x 200 mL), combine the organic layers, dry over MgSθ4, filter and concentrate under reduced pressure to give the crude product. Purify by silica gel chromatography (column: 10 cm x 24 cm; pack column in CH2CI2 and elute using a gradient of 100% CH 2 Cl2 to 10% CH3OH/CH2CI2) to obtain 21.5 g (39.8 mmol, 85%) of the title compound as a tan foam. Step 2: 3-(3,4-dichlorophenyl)-1 -[[dimethyl(1 ,1 -dimethylethyl)silyl]oxy]-5- (4-hydroxy-4-phenyl-1 -piperidinyl)-2-pentanone Treat a solution of the alcohol from Step 1 (21.5 g, 39.8 mmol) in CH2CI2 (600 mL) with PDC (22.5 g, 59.9 mmol). Stir the resulting black mixture for 12 h. Filter the reaction mixture through a plug of celite and wash plug with CH2CI2 (200 mL) and EtOAc (200 mL). Concentrate the filtrate under reduced pressure to give the crude product as a black oil. Purify by silica gel chromatography (column: 10 cm x 24 cm; pack column in CH2CI2 and elute using a gradient of 100% CH2CI2 to 5% CH 3 OH(NH3)/CH 2 Cl2) to obtain 16 g (29.9 mmol, 75%) of the title compound as a tan foam. Step 3: 3-(3,4-dichlorophenyl)-1-[[dimethyl(1 ,1-dimethylethyl)silyl]oxy]-5- (4-hydroxy-4-phenyl-1 -piperidinyl)-2-pentanone O-methyloxime Treat a solution of the ketone from Step 2 (6.6 g, 12.3 mmol) and NaOAc (6.05 g, 73.8 mmol) in EtOH (110 mL) and H2O (27 mL) with NH2OCH3ΗCI. Stir the resulting solution for 12-18 hours at room temperature. Concentrate under reduced pressure and partition the resulting residue between CH2CI2 (100 mL) and H2O (100 mL). Extract the aqueous layer with CH2CI2 (3 x 100 mL), dry the combined organic layers over MgSθ4, filter and concentrate under reduced pressure to yield the crude product as a pale oil. This product is carried on without purification to the next step. HRMS (FAB, M+H+): m/e cal'd for [C29H43N2θ 3 SiCI 2 ] + : 565.2420, found 565.2410. Step 4: 3-(3,4-dichlorophenyl)-1 -hydroxy-5-(4-hydroxy-4-phenyl-1 - piperidinyl)-2-pentanone O-methyloxime Treat a solution of the crude oxime from Step 3 (< 12.3 mmol) in THF (400 mL) with TBAF (15.4 mL, 15.4 mmol, 1 M in THF) at 0°C. Stir the solution for 2 hours. Quench the reaction with water and extract the aqueous phase with EtOAc (3 x 100 mL). Dry the combined organic layers over MgSθ4 , filter and concentrate under reduced pressure to give the crude product as a yellow oil. Purify by silica gel chromatography (column: 7.5 cm x 20 cm; pack column in CH2CI2 and elute using a gradient of 100% CH 2 CI 2 to 5% CH 3 OH(NH 3 )/CH2CI 2 ) to obtain 16 g (29.9 mmol, 75% from Example CAA2) of the title compound as a white solid. HRMS (FAB, M+H + ): m/e cal'd for [C23H29N 2 0 3 Cl2] + : 451.1555, found 451.1553. Step 5: 3-(3,4-dichlorophenyl)-1 -[(2,4-difluorophenyl)methoxy]-5-(4- hydroxy-4-phenyl-1-piperidinyl)-2-pentanone O-methyloxime Treat a solution of the hydroxy-oxime (200 mg, 0.44 mmol) of Step 4 in DMF at 0°C with NaH (12 mg, 0.48mmol). Stir the resulting mixture for 30 mins at 0°C. Add 2,4-difluorobenzylbromide (60 μL, 0.465 mmol) in one portion and remove cooling bath. Stir the reaction for 12-18 hours at room temperature. Quench the reaction with H2O and extract with EtOAC (3 x 30 mL). Dry the combined organic layers over MgSθ4, filter and concentrate under reduced pressure to give the crude compound as a yellow oil. Purify by silica gel chromatography (column: 2.5 cm x 15 cm; pack column in 50% EtOAc/Hexane and elute using a gradient of 50- 100% EtOAc/Hexane) to obtain 128mg (0.22 mmol, 50% ) of the title compound as a pale oil. HRMS (FAB, M+H+): m/e cal'd for [C 3 oH 3 3N2θ 3 Cl2F2] + : 577.1836, found 577.1832. Examples 22A to 22AL, shown in the following table, are prepared from the product of Example 22, Step 4 in a procedure similar to that described for Example 22, Step 5, using the appropriate halide: Example 22AH: Using 2-acetoxy-1 -bromo-1 -phenylethane as the halide, prepare 1 -(acetyloxy)-3-(3,4-dichlorophenyl)-5-(4-hydroxy-4-phenyl-1 - piperidinyl)-2-pentanone O-methyloxime. HRMS (FAB, M+H+): m/e cal'd for [C25H3i N 2 0 4 Cl2] + : 493.1661 , found 493.1652. Example 22AI: Using α-methylbenzylbromide as the halide, prepare 3- (3,4-dichlorophenyl)-5-(4-hydroxy-4-phenyl-1 -piperidinyl)-1 -(1 - phenylethoxy)-2-pentanone O-methyloxime. HRMS (FAB, M+H+): m/e cal'd for [C2iH27N2θ 3 CI 2 ] + : 555.2181 , found 555.2181. Example 22AJ: Using cinnamoylbromide as the halide, prepare 3-(3,4- dichlorophenyl)-1 -[3-phenyl-2-propenyloxy]-5-(4-hydroxy-4-phenyl-1 - piperidinyl)-2-pentanone O-methyloxime. Mass spectrum (FAB): 567. Example 23 Treat the product of Example 22, Step 4 (0.203 g) in THF (5 mL) at 0°C with 1 -phenyl-5-mercaptotetrazole (0.16 g), stir for 30-40 min. and add this mixture to a solution of DEAD (142 μL) and Ph 3 P (0.236 g) in THF (2.5 mL) also at 0°C. Stir the combined mixture for 30 min. and evaporate the solvent under reduced pressure. Purify the residue by silica gel chromatography eluting with mixtures of NH3/MeOH/CH2Cl2 to give the title compound (0.038 g). Analysis: Calc'd for C30H32N6O6CI2S. H2O; C, 57.23, H, 5.44, N,13.25. Found: C, 57.70, H, 5.17, N, 12.91. Using the product of Example 22, Step 4, as starting material in the procedure of Example 23, prepare Examples 23A and 23 B, using 4,6-dimethylpyrimidine-2-thiol and phthalimide, respectively: Example 23A: HRMS (FAB, M+H + ): m/e calc'd for [C29H35N4θ 2 SCI 2 ] + : 573.1858, found 573.1845. Example 23B: HRMS (FAB, M+H + ): m/e calc'd for [C31 H 3 2 3θ4CI 2 ] + : 580.1770, found 580.1771. Example 24 Treat the product of Example 22, Step 4 (0.18 g) with HOBT (54 mg) and 3,5-bis-trifluorobenzoic acid (0.13 g) in CH2CI2 (40 mL) at 0°C. To this cooled mixture add DEC (76 mg) and stir for a further 18 h. Wash the solution with H2O (20 mL), dry the organic layer over MgSθ4, filter and evaporate give a foam. Purify the crude product by silica gel chromatography eluting with mixtures NH3/MeOH/CH2Cl2 to give the title compound (0.18 g). Analysis: Calc'd for C32H30N2O4CI2F6. I .5H2O; C, 53.49, H, 4.63, N, 3.90. Found: C, 53.39, H, 4.31 , N, 3.78. Example 25 Step 1 : Add the product of Example 22, Step 4 (1.8 g) and TFA (0.31 μL) to o iodoxybenzoic acid (2.24 g) in DMSO (20 mL). Stir the mixture for 2 h and add ice/H 2 0 (50 mL), cone. NH 4 OH soln. (5 mL) and EtOAc (50 mL). Stir the mixture and filter to remove solids. Wash the solid residue with H 2 0 (2X20 mL) and EtOAc (2X20 mL). Combine the filtrates, separate the organic layer and wash with H2O (2X25 mL), dry over MgS04, filter and evaporate to give 3-(3,4-dichlorophenyl)-5-(4-hydroxy-4-phenyl-1- piperidinyl)-2-(2-methoxyimino)pentanal (1.8 g) as a foamy solid. Mass spectrum (FAB): 449. Step 2: Treat the product of Step 1 (0.2 g) in CF 3 CH 2 OH (5 mL) with 3A molecular sieves (1.0 g) and 3,5-bistrifluoromethylbenzylamine (0.14 g). Stir the mixture for 90 min. and add NaBHsCN (0.12 g). After 18 h. filter the reaction mixture through a pad of celite, rinse the celite with MeOH (10 mL) and evaporate the combined filtrates. Partition the residue between CH2CI2 (15 mL) and 20% KOH (15 mL). Separate the organic layer and extract the aqueous layer with CH2CI2 (2X20 mL). Combine the organic extracts, dry over MgSθ4, filter and evaporate to give a solid. Purify the crude by silica gel chromatography eluting with NH3/MeOH/CH2Cl2 mixtures to give the title compound (0.1 g) HRMS (FAB, M+H + ): m/e calc'd for [C 3 2H34N 3 θ6Cl2F 6 ] + : 676.1932, found 676,1940. Example 25A: 3-(3,4-Dichlorophenyl)-5-(4-hydroxy-4-phenyl-1 - piperidinyl)-1 -[[(2-methoxyphenyl)methyl]amino]-2-pentanone O- methyloxime. Using the product of Example 25, Step 1 as starting material, prepare the compound of Example 25A using 2-methoxybenzylamine in a procedure similar to that described in Example 25, Step 2. HRMS (FAB, M+H+): m/e calc'd for [C31 H 3 7N 3 0 3 Cl2] + : 570.2290, found 570.2291 Example 26 Treat the product of Example 25A (50 mg) in CH2CI2 (5 mL) with HOBT (12.4 mg) and AcOH (1 mL) and cool to 0°C. To the cold solution, add DEC (17.6 mg) and stir for a further 18 h. Wash the reaction mixture with 10% NH4OH soln. (3 mL). Reextract the aqueous layer with CH2CI2 (3X3 mL), combine the organic portions, dry over MgS04, filter and evaporate to give a solid. Purify the crude by by silica gel chromatography eluting with NH3/MeOH CH2Cl2 mixtures to give the title compound (0.042 g). Analysis: Calc'd for C33H39N3O4CI2. 0.5H 2 O; C, 63.76, H, 6.49, N, 6.76. Found: C, 63.83, H, 6.85, N, 6.95. Example 27 Treat the product obtained in Preparation 5A in a similar manner to the procedures described in Preparation 4 and Example 1 to obtain the desired product. HRMS (FAB, M+H+): m/e cal'd for [033^6^02^6]+: 690.2089, found 690.2085. Example 28 Dissolve the product of Preparation 9 in anhydrous CH3OH, filter, add 0.82 g (4.6 mmol) of 4-phenyl-4-hydroxypiperidine and 1.1 g of MgSθ4, and stir 30 min at room temperature. Add NaCNBH3 (0.40 g, 6.38 mmol) and stir at room temperature under N2 for 15 h. Filter and evaporate in vacuo. Partition the residue between CH2CI2 (150 ml) and H2O. Wash the organic layer with brine, dry (MgSθ4), filter and evaporate in vacuo (1.90 g). Purify by flash chromatography (50 g Siθ2; eluant: hexane:EtOAc (70:30)) to obtain 1.06 g (61.63%) of the crystalline hemihydrate of the title compound. M.p. 115-118°C. FAB-Ms: m/z 675 ([C33H34 3 5d2F6N2θ2 + H]+, 100%). Maleate hemihydrate m.p.56-60°. Use the appropriate aldehyde from Preparation 9 and the appropriate amine in the procedure of Example 28 to obtain the compounds shown in the following table: Example 29 Step 1 : Treat the product of Preparation 3 (0.469 g) in a solution of THF (1 mL) and DMF (l mL) at 0°C with NaH (50 mg), stir for 15 min., then add benzyl bromide (0.145 mL). Stir the resulting mixture for 18 h , evaporate the solvent under reduced pressure and partition the residue between CH2CI2 (50 mL) and H2O (50 mL). Separate the organic layer, wash with brine (50 mL) dry over MgS04, filter and evaporate. Purify the product by silica gel chromatography eluting with NH3/MeOH/CH2d2 mixtures to give α-[[phenylmethoxy]methyl]-β-(3,4-dichlorophenyl)-4-hydroxy-4- phenyl-1 -piperidinol (0.2 g). Step 2: Oxidize the product of Step 1 (0.1 g) according to the procedure of Preparation 4 to give 1 -[[phenylmethoxy]methyl]-3-(3,4-dichlorophenyl)-5- (4-hydroxy-4-phenyl-1 -piperidinyl)-2-pentanone (0.178 g). Step 3: Treat the product of Step 2 (0.16 g) with O-methoxylamine HCl as in the procedure of Example 1 to obtain the title compound (0.14 g). HRMS (FAB, M+H + ): m/e calc'd for [C 3 oH35N2θ 3 Cl2] + : 541.2025, found 541.2018 Using the product of Preparation 3 and the appropriate halide, prepare the compounds of Examples 29A to 29K, shown in the following tables, using a procedure similar to that described in Example 29: Example 30 Step 1 : Using the procedure of Example 29, replace O-methoxylamine HCl with hydroxylamine in Step 3 obtain 2-[[[2-(3,4-dichlorophenyl)-1- [[(3,5-dimethoxyphenyl)methoxy]methyl]-4-(4-hydroxy-4-phenyl-1- piperidinyl)-2-pentanone oxime. Step 2: Treat the product of Step 1 (0.40 g) in DMF (10 mL) at 0°C with NaH (55 mg) then methylbromoacetate (0.115 g). Stir the mixture and allow to warm to room temperature over 2 h. Partition the reaction mixture between EtOAc (50 mL) and H2O (15 ml). Separate the organic layer, wash with H2O (2 X 15 mL), dry over MgSθ4, filter and evaporate. Purify the residue by silical gel chromatography eluting with mixtures of NH 3 /MeOH/CH 2 Cl2 to give methyl-2-[[[2-(3,4-dichlorophenyl)-1 -[[(3,5- dimethoxyphenyl)methoxy]methyl]-4-(4-hydroxy-4-phenyl-1- piperidinyl)butylidene]amino]oxy]acetate (0.32 g). Step 3: Treat the product of Step 2 with 4% NH3/CH3OH (10 mL) in a sealed bottle and stir for 3 days at room temperature. Evaporate the solution to dryness and purify by silical gel chromatography eluting with mixtures NH3/MeOH/CH 2 Cl2 to give the title compound (0.25 g). HRMS (FAB, M+H + ): m/e calc'd for [C33H39N 3 θ6CI 2 ] + : 644.2294, found 644.2282. Example 31 Using a procedure similar to that described in Example 8, treat the ketone of Preparation 4 with diethyl methyiphosphonoacetate to obtain the title compound as an E/Z mixture. HRMS (FAB, M+H+): m/e calc'd for [C34H34CI F 6 Nθ4] + : 704.1769, found 704.1757. Example 32 Treat a suspension of (CH3θCH2)Ph3PBr (0.21 g, 0.6 mmol) in dry THF (10 mL) with NaN(TMS) (0.6 mL of a 1.0 M solution in THF) at 0°C. After 30 minutes, add the product of Preparation 4 (0.05 g, 0.08 mmol) in dry THF (5 mL) and slowly warm the reaction to room temperature over 1 hour. Stir for 3 hours at room temperature and quench by the addition of water. Extract with CH2CI2 (3 x 25 mL). Wash the combined organics with brine, dry (Na2Sθ4) and concentrate. Purify the crude material on two preparative TLC plates (20 x 20 cm, 0.5 mm thickness) eluting with CH2CI2 and CH3OH saturated with ammonia (98:2) followed by reelution with hexane and 2-propanol (90:10) to provide the product (24 mg, 47%) as a white sticky foam (E/Z mixture). HRMS (FAB, M+H+): m/e calc'd for [C 3 3H34Cl2F 6 N0 3 ]+: 676.1821 , found 676.1834. Use the appropriate alkyl-substituted Wittig reagents (alkyl- PPhsBr) in the procedure of Example 32, to prepare the following compounds: Example 33 Treat the product of Example 31 (0.69 g, 0.98 mmol) in dry CH 2 CI 2 (30.0 mL) at 0°C with a solution of DiBAI-H (3.9 mL of a 1 M solution in CH2CI2). Warm to room temperature and stir for 15 minutes. Quench by slowly adding saturated aqueous Na2S04. Dilute with water and extract with CH2CI2 (3 x 50 mL), wash with brine, dry (Na2Sθ4) and concentrate. Purify the crude material on a flash column (100 g Siθ2; eluant CH2Cl2:CH3θH saturated with ammonia 95:5) to give the desired product as a white powder (0.52 g, 79%). HRMS (FAB, M+H+): m/e calc'd for [C33H34CI2F6NO3]- : 676.1820, found 676.1815. Example 34 Treat the product of Example 33 (0.5 g, 0.7 mmol) in dry THF (20 mL) with NaH (0.28 g of a 60 % dispersion in mineral oil, 7 mmol) and acetic anhydride (0.36 g, 3.5 mmol) at room temperature and stir for 18 hours. Cool to 0°C and treat with CH2CI2 (50 mL) and water (10 mL). Wash the organic layer with water, dry (Na2S04) and concentrate. Purify the crude material on a flash column (Siθ2; elute with CH2Cl2:CH3θH saturated with ammonia 95:5) to give the desired product as a white foam (0.42 g, 79%). HRMS (FAB, M+H+): m/e calc'd for [C 3 5H3 6 Cl2F6N0 4 ] + : 718.1926, found 718.1922. Using the product of Example 33 as the starting material and the appropriate electrophile in the procedure of Example 34, the following compounds are prepared: + : + : Examples 35, 35A, 35B, 35C Using the procedures described below, compounds of the following structural formula were prepared, wherein the definitions of A are shown in the table below: Example 35: Treat the product of Example 34 (0.8 g, 0.11 mmol) in THF/H 2 0 (5:2, 4 mL) with NaN 3 (0.036 g, 5 mmol) and Pd(PPh 3 ) 4 (0.013g, 0.01 mmol) and heat to reflux for 1 hour. Cool to room temperature and dilute with Et 2 0 (10 mL). Separate the organic layer and extract the aqueous layer with additional E. 2 O (2 x 5 mL).Wash the combined organic layers with brine, dry (Na 2 Sθ4) and concentrate. Purify the crude material on a flash column (Siθ2; elute with CH 2 Cl2:CH3θH saturated with ammonia 95:5) to give the desired product as a white sticky foam (0.039 g, 51%). Example 35A: Treat the product of Example 35 (0.21 g, 0.3 mmol) in THF (20 mL) with Ph 3 P (0.095 g, 0.36 mmol) and water (0.25 mL) at room temperature and stir for 2 hours. Add additional P i 3 P (0.1 g) and stir for 30 minutes. Concentrate and purify the crude product on a flash column (Siθ2; elute with CH 2 Cl 2 :CH3θH saturated with ammonia 90:10) to give the desired product as a dark foam (0.11 g, 50%). HRMS (FAB, M+H + ): m/e calc'd for [C33H35CI 2 F 6 N2θ2] + : 675.1980, found 675.1979. Example 35B: Use the product of Example 34 as the starting material and dimethylamine in the procedure of Example 35 with THF as the solvent to obtain the desired product. Example 35C: Use the product of Example 34 as the starting material and diethanolamine in the procedure of Example 35 with THF as the solvent to obtain the desired product. Example 36 Treat the product of Example 1 A (0.036 g, 0.05 mmol) with CH3I (1 mL) at room temperature and place in the refrigerator for 18 h. Remove the excess CH 3 I under a stream of N 2 . Dissolve the residue in CH3OH and add water until turbid. When crystals have formed, remove the solvent with a pipette. Wash the crystals with water and pump dry to give the product as a white solid (0.031 g, 78%) HRMS (FAB, M+H+): m/e calc'd for [C 3 2H 33 Cl2F 6 N2θ 3 ]+: 677.1772, found 677.1765. Examples 37 to 37E Using the product of Example 1A in the procedure described in Example 8, reacting with 4-bromobutyronitrile, 5-bromovaleronitrile and 6-bromocapronitrile, respectively , the products of Examples 37 to 37B were obtained; subsequent treatment with hydroxylamine as described in Example 11 resulted in compounds 37C to 37E. Example 38 Step 1 : Cool a solution of CH 3 P(0)(OCH 3 ) 2 (0.55 g, 4.4 mmol) in dry THF (10 mL) to -78°C and add n-BuLi (2.75 mL of a 1.6 M solution in hexanes) dropwise. Stir for 45 min at -78°C and add a solution of 4-(3,4-dichloro- phenyl)glutaric anhydride (0.52 g, 2 mmol) in dry THF (5 mL). Stir for 2 hours at -78°C and quench by adding 1 N HCl (15 mL). Extract with EtOAc (3 x 25 mL), wash the combined organic layers with brine, dry (Na2S04) and concentrate. Purify the crude material on a flash column (100 g Siθ2; elute with EtOAc:CH 3 OH:HOAc 90:10:2) to give an oil (0.55 g, 75%). Step 2 : Add K2CO3 (1.0 g, 7.2 mmol) to a solution of the product of step 1 (2.0 g, 5.2 mmol) and 3,5-bis(trifluoromethyl)benzaldehyde (1.9 g, 7.9 mmol) in dry CH3CN (60 mL) at room temperature. Stir for 5 hours and filter the crude reaction mixture through filter paper. Concentrate and purify the crude reaction through a flash column (Siθ2; elute with EtOAc: CH3OH: HOAc 90:10:2) to give a white solid (2.0 g, 77%). Step 3: React the product of step.2 (5.8 g, 11.6 mmol) with H2 gas (balloon) in the presence of 10% Pd/C (0.58 g, 10 % w/w) for 3 hours at room temperature. Pass the crude reaction through a short pad of silica gel eluting with EtOAc to give 3.7 g of product (64%) to be used directly in the next step. Step 4: Treat a cooled (0'C) solution of 4-phenyl-4-hydroxypiperidine (1.6 g, 8.9 mmol) in DMF (50 mL) with 4-methylmorpholine (0.89 g, 8.9 mmol), HOBT (1.0 g, 7.4 mmol) and the product of step 3 (3.7 g, 7.4 mmol). Stir at 0°C for 30 min and room temperature for 6 h. Concentrate and dilute the residue with 1 :1 water:EtOAc (200 mL). Wash the organic layer with brine, dry (Na2S04) and concentrate. Purify the crude reaction product on a flash column (Siθ2; elute with EtOAc: hexane 4:5) to give a white foam (1.45 g, 35%). Step 5: Treat a solution of the product of step 4 (0.5 g, 0.75 mmol) in pyridine (30 mL) with CH3ONH2ΗCI (0.1 g, 1.2 mmol) and heat to 60°C for 1.5 hours. Concentrate and purify the residue on a flash column (Siθ2; elute with CH2Cl2:CH3θH saturated with ammonia 95:5) to give the title compound (0.52g, 99%) as a white solid and a mixture of E and Z oxime isomers. Step 6: Treat a solution of the product of step 5 (0.2 g, 0.29 mmol) in CH2CI2 (15 mL) at 0°C with DiBAI-H (64 μL of a 1 M solution in CH2CI2). After 10 minutes, quench by the addition of saturated aqueous Na2S04, dry by the addition of solid Na2S04 and concentrate. Purify the crude material on two preparative TLC plates eluting with CH2Cl2:CH3θH saturated with ammonia 95:5 to give the title compound ( 0.027 g, 14% of oxime isomer A and 0.046 g, 24% of oxime isomer B). Isomer A: HRMS (FAB, M+H + ): m/e calc'd for [C 33 H35Cl2F 6 N2θ2] + : 675.1980, found 675.1986. Isomer B: HRMS (FAB, M+H + ): m/e calc'd for [C 33 H35Cl2F 6 N2θ2] + : 675.1980, found 675.1986. Example 39 The compounds described in Examples 39 to 39N are prepared in a similar manner to that described in Example 20, using the appropriate oxime and the appropriate amine: Examples 40 and 40A Example 40: R 2 is -C(0)NH 2 Reflux the product of Preparation 4 (52 mg) in EtOH (1.5 mL) with semicarbazide HCl (75 mg) and KOAc (75 mg) for 1 h. Extract the resultant mixture with water, NaHC0 3 and CH 2 CI2, dry the organic layer and evaporate to obtain a white foam. MASS (FAB, M+H+) m/e 705. Example 40A: R 2 is -C(0)CH 3 Reflux the product of Preparation 4 (42 mg) in EtOH (1.5 mL) with acetylhydrazide (80 mg) and HOAc (25 mg) for 1 h. Extract as in Example 40 and isolate the product by preparative TLC on silica gel, eluting with CH2Cl 2 :CH 3 θH (12:1 ) to obtain the desired compound as a foam. MASS (FAB, M+H+) m/e 704 Example 41 Step 1 : 3-(3,4-dichlorophenyl)-dihydro-2(3H)-furanone Heat [(CH 3 ) 3 Si]2NLi (230 ml, 1.0 M in THF) under N2 to 45°C and add 3,4 dichlorophenyl acetic acid methyl ester (40 g, 0.183 moles) dissolved in 60 ml of dry THF dropwise over 2 h. Stir the solution at 45°C for another 2.5 h. Cool the solution to room temperature, add a dry THF solution (30 ml.) of THP-protected Br(CH2)2θH dropwise over 1 h., and stir the solution for 24 h. Cool the solution in an ice bath and quench the reaction by adding, dropwise, 250 ml. of 1.0 M aqueous HCl. Extract the solution with E.2O, wash the organic layer twice with 1.0 M aqueous HCl, then with water, and dry over anhydrous Na2Sθ4. Remove the solvent, dissolve the residue in CH3OH and add 0.5 g of pTSA. Stir the solution at room temperature overnight, remove the solvent, add CH3OH (500 ml) and stir for 6 h. Remove the solvent again, add more CH3OH (500 ml.), stir overnight and remove the solvent. Dissolve the resulting oil in CH2CI2 (1200 ml.), wash twice with saturated aqueous NaHCθ3, then water, and dry over anhydrous Na2S04. Remove the solvent in vacuo. Purify the reaction mixture by flash chromatography (Siθ2) using EtOAc: hexanes (3:7) as eluent. Yield: 22 g. CI-MS: 231 (100%), 233 (65%). Step 2: alpha-(2-bromoethyl)-3,4-dichlorophenylacetic acid Treat the product of Step 1 (21.25 g, 91.96 mmoles) at room temperature with 130 ml. of HOAc saturated with HBr gas. Stir at room temperature for 2 days, then pour into 800 ml. of ice-water with stirring. Store the resultant gum in a freezer for two days, then decant the liquid from the solidified gum. Triturate the solid, filter, wash with water and air dry. Yield: 26.2 g (m.p. = 80-81 °C). Step 3: alpha-(2-bromoethyl)-3,4-dichlorophenylacetic acid chloride Dissolve the product of Step 2 (8.1 g, 25.96 mmoles) in 20 ml. of dry CH2CI2. Add oxalyl chloride (8.1 g, 62.3 mmoles), followed by 50 μl of dry DMF and heat the solution to reflux for 3 h. Cool the solution to room temperature and remove the solvent and excess reagent using reduced pressure. Yield: 8.2 g (IR: 1785 cm "1 ). Step 4: 5-bromo-1 -diazo-3-(3,4-dichlorophenyl)--2-pentanone Prepare a solution of diazomethane from 15 g of MNNG by reaction with 45 ml of 40% aqueous KOH topped with 150 ml. of Et2θ and cool in an ice bath. Add an E.2O solution (40 ml.) of the product of Step 3 (8.2 g, 24.8 mmoles) in small volumes, stir the solution in the ice bath for 15 min, then heat to reflux for 30 min. Remove the solvent in vacuo. Purify the resulting mixture by flash chromatography on silica gel using CH2CI2 as eluent. Yield: 7.0 g (IR: 2100 cm" 1 , 1630 cm" 1 ). Step 5: 1 -diazo-3-(3,4-dichlorophenyl)-5-(4-hydroxy-4-phenyl-1 - piperidinyl)-2-pentanone Dissolve the product of Step 4 (3.93 g, 11.7 mmoles) in 50 ml of dry EtOAc. Add 4-hydroxy-4-phenyl-1 -piperidine (2.55 g, 14.4 mmoles), followed by dry Et 3 N (13.3 ml.). Heat under N 2 at 60-65°C for 28 h. Cool to room temperature, filter the solid and wash with EtOAc. Apply the filtrate to a silica gel column and elute the column with 1.5% CH3θH(NH3)/ EtOAc. Yield: 2.34 g; CI-MS : m/e = 432 (M+H+, 35ci+37ci isotope). Step 6: 3-(3,4-dichlorophenyl)-1-[(3,5-dimethylphenyl)methoxy]-5-(4- hydroxy-4-phenyl-1 -piperidinyl)-2-pentanone Dissolve 3,5-dimethyl benzyl alcohol (1.32 g, 9.71 mmoles) in 4.0 ml of dry CH2CI2 and add BF3 etherate (0.44 ml, 3.56 mmoles). Add a dry CH2CI2 solution (2.0 ml.) of the product of Step 5 (0.7 g, 1.62 mmoles) dropwise at room temperature, under N2, over a period of 4.5 h. Stir the mixture at room temperature for another 30 min, then quench the reaction with water (6.0 ml) followed, after 10 min of stirring, by E.3N (2.0 ml). Stir for 15 min, then dilute with 90 ml of CH2CI2. Wash the organic layer with water and dry it over anhydrous Na2S04. Purify the reaction mixture by flash chromatography (Siθ2), eluting the column first with 30% EtOAc/ hexanes, then, after elution of the excess of 3,5-dimethyl benzyl alcohol, change the eluent to 40% EtOAc/Hexanes. Yield: 0.435 g. HRMS (FAB, M+H+): m/e calc'd for [C31 H36Nθ3Cl2] + : 540.2072; found 540.2075. Step 7: Add methoxylamine HCl (75 mg, 0.9 mmoles) to the product of Step 6 (0.32 g, 0.59 mmoles) dissolved in 3.0 ml of dry pyridine. Heat the solution under N2, at 60-65°C for 90 min, then remove the pyridine in vacuo. Purify the reaction mixture by preparative TLC, eluting the silica gel plates with EtOAc:Hexanes:CH 3 OH(NH 3 ) (25:75:2.5). Extract the title compound with MeOH(NH 3 ):EtOAc (5:95). Yield: 0.209 g. HRMS (FAB, M+H+): m/e calc'd for [C32H39N2θ3Cl2]+: 569.2338; found 569.2335. Examples 41 A to 41 P are prepared from the product of Example 41 , Step 5, by reaction with suitable alcohols or mercaptans using a procedure similar to the one described for Example 41 , Step 6. The resulting ketones are reacted with methyloxime hydrochloride using a procedure similar to the one described in Example 41 , Step 7. Example 42 Step 1 : Methyl 3-(3,4-dichlorophenyl)-3-[2-(ethoxycarbonyl)-2-(1 ,3- dithiolanyl)]-propanoate Dissolve [(CH 3 ) 3 Si]2NLi (171.0 mL of 1.0 M solution, 0.171 mol) in dry THF (170 mL), cool to -78°C under N2, add ethyl 1 ,3-dithiolane-2- carboxylate (33.2 g, 0.186 mol) in dry THF (120 mL) dropwise and stir at -78°C for 20 mins. Add methyl 3,4-dichlorocinnamate (34.8 g, 0.150 mol) in DMPU (180 mL) dropwise. Stir at -78°C for 5 h. Add CH3OH (30 mL), warm to -30°C and add saturated aqueous NH4CI (500 mL) and water (500 mL). Extract with EtOAc (3x400 mL), dry combined organic extracts (MgSθ4), fil er and concentrate. Purify by chromatography (2.5 L of flash silica gel; eluant: 5% EtOAc-hexane then 15% EtOAc-hexane). Combine appropriate fractions and concentrate to give 53.6 g (0.131 mol, 87%) of the title compound as a colorless oil. MS (FAB): m/e 409 (M+1 ) Step 2: 2-(Hydroxymethyl)-2-[3-[3-(3,4-dichlorophenyl)-1 -hydroxy]- propyl]-1 ,3-dithiolane Dissolve the product (75.10 g, 0.183 mol) of Step 1 in dry THF (700 mL), cool to 0 O C under N 2 , add LiAIH 4 (275 mL of 1.0 M in Et 2 0, 0.275 mol) dropwise and stir at 0°C for 30 mins, then at 23°C for 16 h. Add water (10 mL) dropwise followed by 25 wt % NaOH (10 mL). Dilute with CH2CI2 (500 mL) and filter through celite. Extract celite with CH2CI2 via a soxhiet extractor. Concentrate combined organic solutions and triturate with hexane to give 56.8 g (0.167 mol, 92%) of the title compound as a white solid (mp=122-124°C). MS (FAB): m/e 339 (M+1 ) Step 3: 2-(Hydroxymethyl)-2-[3-[3-(3,4-dichlorophenyl)-1 -[dimethyl(1 ,1 - dimethylethyl)silyloxy]]-propyl]-1 ,3-dithiolane Dissolve the product (67.80 g, 0.200 mol) of Step 2 in dry THF (1300 mL), add Et^N (30.30 g, 41.8 mL, 0.300 mol) and dimethylamino- pyridine (4.90 g, 0.040 mol) and cool to 0°C under N2. Add t-butyl- dimethylsilyl chloride (36.14 g, 0.240 mol) in dry THF (200 mL) dropwise. Warm slowly to 23°C and stir for 72 h. Add water (1000 mL), extract with EtOAc, dry combined organic extracts (MgSθ4), filter, and concentrate. Purify by chromatography (2.0 L of flash silica, eluant 1 :2 EtOAc:hexane). Combine appropriate fractions and concentrate to give 89.4 g (0.197 mol, 99%) of the title compound as a colorless oil. MS (FAB): m/e 453 (M+1) Step 4: 2-[[3,5-Bis(trifluoromethyl)phenyl]methoxymethyI]-2-[3-[3-(3,4- dichlorophenyl)-1 -[dimethyl(1 ,1 -dimethylethyl)silyloxy]]-propyl]-1 ,3- dithiolane Dissolve the product (89.40 g, 0.197 mol) of Step 3 in dry THF (1 L), cool to 0°C under N , add [(CH 3 )3Si]2NK (434 mL of 0.5 M solution, 0.217 mol) dropwise. Add 3,5-bis(trifluoromethyl)benzyl bromide (75.65 g, 45.2 mL, 0.246 mol), stir at 0°C for 30 mins, then warm slowly to 23°C. Reflux for 16 h, then cool to 23°C. Add saturated aqueous NH4CI (500 mL) and water (500 mL), extract with EtOAc, dry combined organic extracts (MgS04), filter, and concentrate. Purify by chromatography (3.0 L flash silica, eluant: 10% CH2Cl2-hexane, 20% CH2Cl2-hexane, then 25% CH2Cl2-hexane). Combine appropriate fractions and concentrate to give 105.5 g (0.155 mol, 79%) of a yellow oil. MS (FAB): m/e 547 (M+1 ) Step 5: 2-(Hydroxymethyl)-2-[3-[3-(3,4-dichlorophenyl)-1 -[dimethyl(1 ,1 - dimethylethyl)silyloxy]]-propyl]-1 ,3-dithiolane Dissolve the product (80.30 g, 0.118 mol) of Step 4 in CH3CN (750 mL) and add 48% aqueous HF (55.2 mL, 1.53 mol), stir at 23°C for 16 h, concentrate and add water (300 mL). Add 2.0 N NaOH until pH is 3-4 and then add saturated aqueous NaHCθ3. Extract with CH2CI2, wash combined organic extracts with saturated aqueous NaCl, dry (MgS04), filter, and concentrate to give 66.7 g (0.118 mol, 100%) of a yellow oil. Step 6: 1 -[[3,5-Bis(trifluoromethyl)phenyl]methoxy]-3-(3,4-dichloro- phenyl)-5-hydroxy-2-pentanone Dissolve the product (99.8 g, 0.176 mol) of Step 5 in THF (1000 mL) and water (105 mL), add CaCθ3 (44.10 g, 0.440 mol), stir for 5 mins, then add Hg(CI04)2 (159.7 g, 0.352 mol) in water (185 mL) dropwise. Stir the resultant white precipitate at 23°C for 5 h, filter, wash the solid with water and EtOAc. Separate layers of filtrate and extract with EtOAc. Wash combined organic extracts with saturated aqueous NaCl, dry (MgS04), filter, and concentrate to give 86.1 g (0.176, 100%) of the title compound as a yellow oil. MS (FAB): m/e 471 (M+1 - H 2 0) Step 7: 1-[[3,5-Bis(trifluoromethyl)phenyl]methoxy]-3-(3,4-dichloro- phenyl)-5-hydroxy-2-pentanone O-methyloxime Dissolve the product (86.1 g, 0.176 mol) of Step 6 in EtOH (840 mL) and water (165 mL), add CH 3 C0 2 Na (72.2 g, 0.881 mol) and CH3ONH2 HCl (44.12 g, 0.528 mol). Reflux for 16 h, cool to 23°C and concentrate. Add water (800 mL), extract with CH2CI2, treat organic extracts with charcoal and MgSθ4, filter, and concentrate. Purify by chromatography (2.0 L of flash silica, eluant: 1 :1 CH2Cl2:hexane then 1 :1 EtOAc:hexane). Combine appropriate fractions and concentrate to give 67.6 g (0.130 mol, 74%) of the title compounds as a yellow oil. The E and Z oxime isomers can be separated by chromatography (10.0 g of mixture on 1.5 L of flash silica; eluant: 10% EtOAc-hexane, 20% EtOAc-hexane, then 30% EtOAc- hexane; gives 6.57 g of desired Z isomer). MS (FAB): m/e 518 (M+1 ) Step 8: 1 -[[3,5-Bis(trifluoromethyl)phenyl]methoxy]-3-(3,4-dichloro- phenyl)-4-formyl-2-butanone O-methyloxime Dissolve oxalyl chloride (2.01 g, 15.82 mmol) in dry CH2CI2 (30 mL) and cool to -78°C under N 2 , add DMSO (2.47 g, 31.64 mmol) in dry CH2CI2 (12 mL) dropwise and stir at -78°C for 15 mins. Add the product of Step 7 (6.56 g, 12.66 mmol) in dry CH2CI2 (20 mL) dropwise and stir at -78°C for 3 h. Add diisopropylethylamine (4.91 g, 37.97 mmol) and stir at -78°C for 1 h. Warm slowly to 0°C and stir at 0°C for 30 mins. Add water (150 mL) and extract with CH2CI2. Wash combined organic extracts with saturated aqueous NaCl, dry (MgSθ4), filter, and concentrate to give 6.53 g (12.66 mmol, 100%) of a yellow oil. MS (FAB): m/e 516 (M+1 ). Step 9: Dissolve the product (1.05 g, 2.03 mmol) of Step 8 and 4- phenylamino-piperidine (1.08 g, 6.13 mmol) in CF3CH2OH (10 mL), add crushed 3A sieves (1 g) and NaBHsCN (0.26 g, 4.07 mmol), and stir at 23°C for 4 h. Concentrate and add water (60 mL) and EtOAc (60 mL). Filter through celite, separate layers of filtrate and extract aqueous solution with EtOAc. Dry combined organic extracts (MgS04), filter and concentrate. Purify by chromatography (200 mL of flash silica gel; eluant:3% CH3OH-CH2CI2). Combine appropriate fractions and concentrate to give 0.98 g (1.45 mmol, 66%) of the title compound as a yellow oil. MS (FAB): m/e 676 (M+1 ) The following compounds of formula 42A to 42Z are prepared by reacting the product of Example 42, Step 8, with an appropriate amine according to the procedure of Example 42, Step 9: Example 43 Dissolve the product (0.380 g, 0.578 mmol) of Example 42J in THF (3 mL) and CH 3 OH (1 mL). Add 1 N KOH (2.7 mL, 2.70 mmol) and reflux for 16 h. Cool to 23°C and add 1 N HCl (5 mL) and water (20 mL). Extract with CH2CI2 (3x20 mL), wash combined organic extracts with saturated aqueous NaCl, dry (MgS04), filter and concentrate to give 0.312 g (0.496 mmol, 86%) of the title compound as a yellow foam. MS (FAB): m/e 629 (M+1 ) Example 44 Dissolve 3-pyrrolidinol (0.033 g, 0.375 mmol) in dry THF (2 mL) and cool to 0°C under N2. Add diisopropylethylamine (0.097 g, 0.13 mL, 0.750 mmol) then add bromoacetyl bromide (0.076 g, 0.033 mL, 0.375 mmol) in dry THF (1 mL). Stir at 0°C for 30 mins. Add the product (0.20 g, 0.341 mmol) of Example 42B in dry THF (3 mL), warm to 23°C slowly and stir for 16 h. Concentrate, add water (20 mL), extract with EtOAc, wash combined organic extracts with saturated aqueous NaCl, dry (MgS04), filter, and concentrate. Purify by chromatography (70 mL of flash silica gel; eluant: 10% CH 3 OH-CH 2 CI 2 then 20% CH 3 OH-CH 2 CI 2 ). Combine appropriate fractions and concentrate to give 0.118 g (0.165 mmol, 49%) of the title compound as a yellow oil. MS (FAB): m/e 713 (M+1 ). Using the appropriate amine in the procedure of Example 44, the following compounds of formula 44A and 44B are prepared: Example 44A Example 44B MS (FAB) : m/e 686 (M+1 ) Example 45 Treat a suspension of sarcosine methyl ester hydrochloride (6.02 g, 43 mmole) in CH2CI2 (250 ml) at 0°C with 3,5 - bistrifluoromethyl benzoyi chloride (7.7 ml, 42.5 mmole) and Et3N (12.5 ml, 89.7 mmole). Stir the mixture at 20°C for 1 h. Add water (150 ml) to the mixture and separate the organic layer. Dry (MgS04) and concentrate the organic layer to give crude product. Purify by silica gel chromatography (eluant: EtOAc:hexane (6:4)) to obtain 12 g (81 %). Treat a solution of 3,4-dichlorolphenyl acetic acid (4.15 g, 20 mmole) in anhydrous THF (50 ml) at -60°C with [(CH3)3Si]2Nϋ (46.2 ml, 46.2 mmole) and slowly warm the mixture to 0°C for 4h. Transfer this solution to a solution of the product of Step 1 (5.46 g, 16 mmole) in anhydrous THF (8 ml) at -30°C. Warm the reaction to -10°C over 1 h, stir at 0°C for 1 h and at 20°C for 4h. Add 50% of aqueous HOAc (15 ml) and extract with EtOAc twice. Separate the organic layer, dry (MgSθ4) and concentrate to give the crude product. Purifiy by silical gel chromatography (eluant: hexane/EtOAc, 6:4) to give 5.21 g (69%) of the product. HRMS (FAB, M+H+) = m/e calc'd for [C 19 H 14 Nθ2Cl2F 6 ]+ = 472.0306, found 472.0306 Treat a solution of the product of Step 2 (0.96 g, 2 mmole) in THF (6 ml) at -78°C with [(CH 3 ) 3 Si] 2 NLi (2.5 ml, 2.5 mmole) and stir at -78°C for 25 h. Add a solution of 1-bromo-3-methyl-2-butene (0.42 g) in THF (1 ml) to the above anion solution at -78°C, slowly warm the solution to 0°C and stir at 20°C for 2 h. Add saturated NH4CI solution (5 ml), extract with EtOAc twice wash the combined EtOAc extracts with brine, dry (MgSθ4) and concentrate to give a crude product. Purify by column chromatography (silica gel; eluant: EtOAc:hexane, 2:8) to obtain 1 g of product (87%). MS (FAB, M+H+) m/e 540. Treat a solution of the product of Step 3 (0.22 g, 0.4 mmole) in pyridine (3 ml) at 70°C with methoxyamine HCl (95 mg, 1.14 mmole), stir at 70°C for 6.5 h and then cool to 20°C. Add water to the reaction mixture, extract the solution with EtOAc, dry (MgSθ4) and concentrate the EtOAc extracts to give the crude product. Purify by silica gel chromatography (eluant: hexane:Et2θ, 1 :1) to give 74 mg (32%) of Z-isomer and 130 mg (56%) of E-isomer oximes. MS (FAB, M+H+) = m/e 569. Treat the product of Step 4 (0.387 of E-isomer, 0.68 mmole) in a solution of EtOAc saturated with O3 (7.5 ml) at -78°C for 5 min. Purge the solution with N2, add (CH3)2S (1.5 ml) and warm the solution from -78°C to 20°C over 1 h. Concentrate the solution to give the desired aldehyde which is used directly in the next reaction without further purification. MS (FAB.M + H+) = m/e 543. Step 6: Treat the product of Step 5 with 4-hydroxy-4-phenyIpiperidine in a procedure similar to that described in Example 42, Step 9, to obtain the title compound in overall 77% yield. HRMS(FAB,M+H+) = m/e calc'd for [c33H34N3O3CI2F6]+:704.1881 , found 704.1875. Example 46 By following a procedure similar to that of Example 45, using the appropriate reagents, the title compound is prepared. HRMS(FAB, M+H+)=m/e calc'd for [C33H34N2θ3Cl2F6] + =691.192, found 691.1938. Step 1 : Stir a solution of 2-chioro-N-methyl-N-methoxy acetamide (28.2 g, 205 mmol), 3,5-bistrifluoromethyl benzyl alcohol (50.0g, 205 mmol, 1 eq) and CSCO3 (134 g, 416 mmol) in dry DMF (410 mL) for 20 h. Pour into 1 L E.2O+ 500 mL hexane+500 mL water. Extract the water layer with 2 x 1 L Et2θ, combine the organic layers, wash with water (2 x 500 mL) followed by brine (500 mL). Dry over MgSθ 4 , concentrate in vacuo to give 70.2 g (>99%) of the product as a viscous oil. Step 2: Treat a suspension of Mg turnings (1.8 g) in dry Et2θ (12 mL) at 30°C with a-3,4-trichlorotoluene (10.2 mL) in Et2θ (65 mL) dropwise over 1 h, then stir at 23°C for 20 min. Add the Grignard reagent dropwise to a solution of the product of step 1 (15.0 g, 43.4 mmol) in 350 mL Et2θ at -78°C. Stir for 15 min at -78°C, warm to 23°C, pour into 500 mL 0.5N HCl. Extract with Et2θ, combine organic layers, wash with brine, dry (MgS04) and concentrate. Triturate the crude product in cold pentane to give 23.3 g of the pure product as a colorless powder. Step 3: To [(CH3) 3 SI] NNa (67.4 mL, 1.0 M in THF) in THF (540 mL) at -78°C, add the product of step 2 (30.0 g, 67.4 mmol) as a solution in 120 mL THF dropwise over 30 min. Stir for 2 h, then, over 30 min, add 2-iodo- Λ/-methoxy-Λ/- methylacetamide (Prepare by stirring a solution of 2-chloro- Λ/-methoxy-Λ/- methylacetamide (10.58 g, 77.6 mmol) and Nal (11.9 g) in 190 mL acetone for 18 h in the dark. Remove the solvent in vacuo, add 300 mL THF and filter the suspension through a pad of Celite. Concentrate the filtrate and dissolve the crude in 80 mL THF.). Allow to warm to 23°C, adding 15 mL saturated NH 4 CI when the internal temperature reaches 0°C, then concentrate in vacuo. Add 750 mL CH 2 CI , 1.5 L Et2θ, and 750 mL water. Wash the organic layer with brine, dry over Na 2 S0 4 , and concentrate. Purify the crude product by filtration through a plug of silica gel using CH 2 CI 2 /Et2θ/hexane (1 :1 :2) as eluent to give 32.4 g, 88% of the product as a viscous oil. Step 4: Using a procedure similar to that of Example 1 , treat the ketone of step 3 to obtain the corresponding oxime methyl ether in 80 % yield. Step 5: Treat a solution of the product of step 4 (2.02 g, 3.5 mmol) in THF (40 mL, -78°C) with DIBAL (1 M in hexane, 10 mL, 10 mmol) for 10 min. Quench the reaction mixture with sat'd. aq. Na2Sθ4 (2 mL) and allow to warm to room temperature. Dilute the solution with E.2O (750 mL), dry (Na2Sθ4) and concentrate to give the crude aldehyde as a colorless oil. The aldehyde is used immediately without any further purification. Step 6: To a solution of the aldehyde from step 5 (184 mg, 0.36 mmol) in CF3CH OH(2 mL) add 4-phenyl-4-piperidinyl acetamide (157 mg, 0.72 mmol), 3 A crushed molecular sieves, and NaBHsCN (98 mg, 1.6 mmol). Stir the reaction mixture for 1 h, concentrate and purify by silica gel chromatography (eluent: CH Cl2:CH 3 OH:NH3 aq. (20:1 :0.1 )) to give the Z isomer of the title compound as a colorless foam. HRMS (FAB, M+H+): m/e calc'd for [C34H36Cl2F6N 3 0 3 ] + : 718.2038, found 718.2050. Using the product of Step 5 and the appropriate amine in the procedure of Step 6, the following compounds are prepared: Example 48 Use the products of Preparations 10 and 11 , and others prepared in a similar manner, in the procedure of Example 47 to obtain the following compounds: Example 49 To a solution of 3,4-dichlorocinnamic acid (5.4 g, 20 mmoles), 4- hydroxy-4-phenylpiperidine (3.6 g, 20.3 mmoles) and E.3N (3 mL) in dry THF (100 mL), add a THF suspension of EDCI (3.85 g, 20 mmoles in 30 mL dry THF). After 2 h, add water (100 mL) and extract the product into EtOAc (100mL). Wash the organic phase with aqueous K2CO3 (50 mL) followed by 0.5 M HCl ( 50 mL). Dry the organic phase (MgS04) and remove the solvent under reduced pressure. The crude product crystallizes (7.5 g) on standing. HRMS (FAB, M+H + ): m/e calc'd for [C 2 oH2θN0 2 Cl2] + : 376.0871 , found 376.0856. Treat a solution of the product of Step 1 (0.5 g, 1.37 mmoles) in CH3NO2 (10 mL) with 1 mL of Triton B (40% benzyltrimethylammonium hydroxide in CH3OH). Heat the stirred solution to reflux for 3.5 h. Cool the mixture, neutralize with 1 M HCl and dilute with water (30 mL). Extract the product into EtOAc (2x 30 mL), dry (MgS04) and concentrate to an oil. Purify by silica gel chromatography (eluant: EtOAC/Hexane (1 :1 to 2:1 )) to obtain 0.309 g of the title compound and 0.160 g starting material. HRMS (FAB, M+H + ): m/e calc'd for [C21 H 2 3N2θ4Cl2] + : 437.1035, found 437.1023. Step 3a: Treat a solution of 3,5-bis(trifluoromethyl)bromobenzene (45.87 g, 0.156 moles) in degassed toluene (300 mL) with allyltributyltin (54.47 g, 0.164 moles) and [(C 6 H5) 3 P] 4 Pt (1.8 g, 1.44 mmoles) and reflux for 24 h. Distill the toluene at atmospheric pressure and distill the residue under reduced pressure (10 mm Hg) at 90-100°C to afford 23.89 g of the title compound. B.p.: 92-97°C at 10 mm Hg. MS (Cl, M+H+), m/e 255. Step 3: Treat a THF solution (15 mL) of a mixture of the products of Step 2 (1.8 g, 4.1 mmoles) and Step 3a (2.2 g, 8.6 mmoles) with CβHsNCO (1.67 g, 14 mmoles), followed by four drops (~ 0.05 g) of dry Et^N and stir the mixture for 20 h at room temperature under N 2 . Dilute with hexane (5 mL) and filter to remove solids. Concentrate the filtrate to an oil and purify by flash silica gel chromatography (eluant: EtOAc/hexane 1 :1 ) to give the two diastereoisomers of the title compound (total yield: 1.3 g): diastereoisomer A: 0.8 g; diastereoisomer B: 0.5 g. Diastereoisomer A: HRMS (FAB, M+H+): m/e calc'd for [C32H29N 2 0 3 Cl2F6] + : 673.1459, found 673.1462; M.P. 80-85°C Diastereoisomer B: HRMS FAB, M+H+): m/e calc'd for [C 3 2H2_N2θ3Cl2F6] + : 673.1459, found 673.1455; M.P. 85-88°C. Treat a cold (5°C), stirred solution of the product of Step 3 (2.02 g, 3 mmoles in 50 mL of dry THF) under N2 with neat 10 M (CH3)2S-BH3 (O.δmL). Heat at reflux for 3 h, cool to room temperature and quench the reaction with 1 N HCl (5 mL). Evaporate the solvent with warming under reduced pressure, treat the mixture with 50 mL of CH3OH and 2 g of K2CO3, stir with heating at reflux for 6 h. Cool the mixture, dilute with water (75 mL) and extract the product into CH2CI2 (2 x 50). Wash the organic layer with water (2 x 30 mL), dry (MgSθ4) and remove the solvent under vacuum. Purify the residue by silica gel flash chromatography (eluant: EtOAc/hexane/CH 3 OH, 4:5:1 to 6:3:1 ) to afford 0.330 g of diastereoisomer A and 0.180 g diastereoisomer B. Diastereoisomer A: HRMS (FAB, M+H+): m/e calc'd for [C32H3iN2θ2CI F 6 ] + : 659.1667, found 659.1665 Diastereoisomer B: HRMS (FAB, M+H+): m/e calc'd for [C32H3iN2θ2CI 2 F 6 ] + : 659.1667, found 659.1665. Wash Raney Nickel (0.3 g, 50% aqueous suspension) with EtOH (4 x 5 mL), add EtOH (15 mL), glacial HOAc (0.250 g) and the the product of Step 4 (diastereoisomer A, 0.3 g, 0.45 mmoles), degas and evacuate the mixture under vacuum. Introduce an atmosphere of H2 gas and stir the mixture vigorously overnight at room temperature. Purge the mixture with N2, filter through celite and concentrate under vacuum. Pass the residue through a pad of silica gel, eluting with EtOAc, and concentrate to an oil to afford 0.206 g of the title compound as a mixture of diastereoisomers. HRMS (FAB, M+H + ): m/e calc'd for [C 3 2H32N0 3 Cl2F 6 ] + : 648.1496, found 648.1507. Step 6: Treat a solution of the product of Step 5 (0.25 g, 0.37 mmoles) in CH3OH (2 mL) and pyridine (3 mL) with CH3ONH2 HCl (0.50 gms, 0.71 mmoles) and heat at reflux for 3 h. Evaporate the solvent and dissolve the residue in EtOAc (5 mL), wash with water, dry (MgS04) and concentrate to afford 0.106 g of a mixture of diastereoisomers. HRMS (FAB, M+H + ): m/e calc'd for [C33H33N2O3CI2F6] -: 691.1929, found 691.1938. Examples 50 to 56 Using the procedures described below, compounds of the following formula were prepared, wherein the variables are as defined in the table: Ex. A R 6 R 9 HRMS HRMS (FAB, M+H+): (FAB, M+H+): m/e m/e calc'd found R 7 R 8 50 =NOCH 3 -CH 2 C(0)CH 2 - 689.1772 689.1765 51 =NOCH 3 -CH2C(=NOH)CH2- 704.1881 704.1889 52 =NOCH 3 -CH 2 C(=NOCH )CH2- 718.2038 718.2051 Example 50: Treat a cold (-5°C) acetone (10 mL) solution of the product of Example 49 (0.3 g, 0.433 mmoles) with 0.8 mL of freshly prepared Jones reagent (Crθ 3 , H 2 SO4). Stir for 15 min and neutralize to pH 8 with 2 mL of saturated aqueous NaHCθ3 diluted with 15 mL of water. Extract the product with CH 2 CI2 (2 x 10 mL), dry (MgS0 4 ) and remove the solvent by vacuum distillation to give a light brown solid (0.3 g). Purify the product by preparative silica gel TLC (CH 2 CI 2 /CH 3 OH/NH 4 OH, 9:1:0.6) to give a yellow gummy solid (0.14 g). Example 51 : Treat a mixture of the product of Example 50 (0.06 g, 0.087 mmoles), HONH2ΗCI (0.03 g, 0.43 mmoles) with pyridine ( 0.3 mL) in CH3OH (0.5 mL) and reflux with stirring under an inert atmosphere for 4 h. Cool the reaction mixture to room temperature, dilute with water (5 mL) and extract the product into EtOAc (2 x5 mL). Wash the organic phase with water (2x 5 mL), dry (MgSθ 4 ) and concentrate under reduced pressure to an oil. Purify the product by preparative silica gel TLC (eluant: EtOAc/hexane, 2:1) to afford the title compound as a white solid (0.032 g). M.p.: 55-60°C. Example 52: Treat a mixture of the product of Example 50 (0.04 g, 0.0578 mmoles) with CH3ONH 2 ΗCI (0.024 g, 0.29 mmoles) in a manner similar to that describd in Example 51 to afford the title compound as a yellow gum (0.02 g). Example 53: Treat a 25 mL THF solution the product of Example 1 , Step 2 (1.3 g, 2.97 mmoles) with 10 M (CH3) S-BH3 (0.9 mL, 9 mmoles) with stirring under N 2 . Heat the mixture to reflux for 2 h, cool to 5°C and quench the reaction with 1.5 M H 2 SO 4 . Dilute the mixture with 30 mL of water and extract the product into EtOAc (2 x 30 mL). Dry the organic layer (MgS04) and concentrate to dryness to afford a white solid. Take up the residue in CH3OH (40 mL) and add solid K2CO3 (1 gm). Heat the mixture to reflux for 2 h, cool, filter through celite and concentrate to 1/3 the original volume. Dilute the mixture with water (25 mL), extract into EtOAc (2 x 30 mL), wash the organic layer with water (2 x 25 ml), dry and remove the solvent under vacuum to afford 1.06 g of the title compound. MS(CI, M+H+), m/e 423. Step 2: Treat a suspension of potassium tert-butoxide in 5 mL of DMSO with a solution of the product of Step 1 (0.4 gm, 0.944 mmoles in 10 mL of DMSO). Stir at room temperature for 30 min, then treat with a solution of the product of Preparation 12 (1.369 g, 3.78 mmoles) in DMSO (10 mL). Stir the mixture at room temperature overnight under an inert atmosphere. Dilute the mixture with water (25 mL) and extract with EtOAc. Wash the organic phase with water (2 x 25 mL), dry and concentrate under reduced pressure to give a semisolid. Triturate the solid with Et2θ and filter to give a light yellow solid (0.56 g). Recrystallize from CH2CI2 to give 0.36 g of a white solid. M.p. 145-150° Step 3: Treat the product of Step 2 (0.25 g, 0.36 mmoles) in 5 mL of CH3CN with Et3N (0.5 g, 0.5 mmoles) and CS2 (0.4 g, 5 mmoles). Heat the reaction to 50°C for 5 h. Remove solvent and excess volitiles by vacuum distillation and purify the product by preparative TLC (eluant, EtOAc/hexane / CH3OH, 5:4:1 ) to give the title compound (0.147 g). Example 54: Treat a solution of the product of Example 53 (0.05 g, 0.074 mmoles) in THF (1 mL) with a suspension of NaH (3.2 mg of a 60% dispersion in mineral oil, from which oil is removed by washing with 0.5 mL of hexane, 0.08 mmoles NaH) in THF (0.5 mL) at room temperature for 30 min with stirring under an inert atmosphere. Cool the mixture to -70°C and treat with an 0.2 M solution of CH3I in THF (0.4 mL, 0.08 mmoles). Gradually warm the mixture to 10°C. Add water (2 ml) and extract the product into EtOAc (5 mL), dry (MgSθ4) and concentrate under reduced pressure to give a yellow solid. Purify the product by preparative silica gel TLC (EtOAc/hexane, 2:1 ) to afford the title compound (0.012 g). Example 55: Step 1 : Treat a solution (5 mL) of the product of Example 53, Step 1 (0.24 g, 0.56 mmoles) in CH3CN (5 mL) with Et 3 N (0.6 mL). Stir for 10 min at room temperature, add neat CS2, stir the mixture under N2 overnight and then heat to 70°C for 1 h. Remove solvent and excess volitles by vacuum distillation and the purify the product by preparative silica gel TLC (EtOAc/hexane, EtOAc/hexane 6:4, then CH 3 OH/EtOAc/ hexane 1 :5:5) to afford 0.132 gm of the title compound. MS(CI, M+H+), m/e 389. Step 2: Treat a solution of the product of Step 1 (0.201 g, 0.516 mmoles in 2 mL of CH2CI2) with a solution of AI(CH3)3 in hexane (0.26 mL of 2M AI(CH3)3 in hexane). In a separate flask, treat a solution of of the product of Preparation 13 (0.167 g, 0.568 mmoles in 2 mL of CH2CI2) with I(CH3)3 (0.284 mL of 2 M AI(CH3)3) and mix thoroughly. After 20 min, mix the two solutions and warm the resulting mixture to 70°C overnight with stirring under N2. Dilute the reaction mixture with EtOAc (5mL) and treat with 0.2 M HCl (5mL) with thorough mixing. Wash the EtOAc layer with water, dry (MgS04) and concentrate to an oil. Purify the product by preparative silica gel TLC (eluant: EtOAc/Hexane/CH3θH, 5:4:1 ) to afford 0.0135 g of the title compound. Example 56: Step 1 : Treat the product of Example 55, Step 1 (0.33 g, 0.85 mmoles) in 6 mL of a mixture of CH3OH and pyridine (5:1 ) with HONH HCl (0.08g, 1.1 mmoles) and heat for 1 h at reflux with stirring under N 2 . Cool the mixture to room temperature and remove the solvent by vacuum distillation. Purify the residue by preparative silica gel TLC (eluant: EtOAc/hexane, 2:1 ) to obtain a white solid (0.350 gm). HRMS (FAB, M+H+): m/e calc'd for [C2iH26N 3 0 2 Cl2] + : 422.1402, found 422.1404. Step 2: Treat the product of Step 1 (0.1 g, 0.24 mmoles) in dry pyridine (1.5 mL) at 0°C with 3,5-bis(trifluoromethyl)benzoyl chloride (0.07 gm, 0.25 mmoles) with stirring under N2. Warm the reaction to room temperature over 1/2 h, then heat at 80°C for 1 h. Remove the solvent by vacuum distillation and purify the product by preparative silica gel TLC (EtOAc/hexane 1 :1 ) to afford a clear glassy solid (0.127 g). MS(CI, M+H+), m/e 611. Step 3: Treat a solution of the product of Step 3 (0.1 g, 0.155 mmoles in 3mL of E.2O) with three portions (50 mgs each) solid UAIH4. Stir the mixture under N2 for 1 h at room temperature and then carefully quench with a mixture of CH3OH and 3M NaOH (1 :1 , 2mL). Remove solids by filtration through celite and remove solvent by vacuum distillation to afford a gummy residue. Purify the product by preparative silica gel TLC (eluant, EtOAc/hexane/CH3θH, 8:1 :1 ) to afford the title compound as a glassy solid (0.27 g). The following formulations exemplify some of the dosage forms of this invention. In each, the term "active compound" refers to a compound of formula I. EXAMPLE A Tablets No. Inαredient mα/tablet mα/tablet 1 Active Compound 100 500 2 Lactose USP 122 1 13 3 Corn Starch, Food Grade, as a 10% 30 40 paste in Purified Water 4 Corn Starch, Food Grade 45 40 5 Magnesium Stearate 3 7 Total 300 700 Method of Manufacture Mix Item Nos. 1 and 2 in suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1 -3 minutes. Compress the mixture to appropriate size and weight on a suitable tablet machine. EXAMPLE B Capsules No. Inαredient mα/tablet mα/tablet 1 Active Compound 100 500 2 Lactose USP 106 123 3 Corn Starch, Food Grade 40 70 4 Magnesium Stearate NF 4 7 Total 250 700 Method of Manufacture Mix Item Nos. 1 , 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1 -3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine. EXAMPLE C Sterile Powder for Injection Inαredient mα/vial mg/vial Active sterile powder 100 500 For reconstitution add sterile water for injection or bacteriostatic water for injection. The in vitro and in vivo activity of the compounds of formula I can be determined by the following procedures. activity Test compounds are evaluated for their ability to inhibit the activity of the NK * ι agonist Substance P on the isolated guinea pig vas deferens. Freshly cut vas deferens are removed from male Hartley guinea pigs (230-350g) and suspended in 25 ml tissue baths containing Kreb's Henseleit solution warmed to 37°C and constantly aerated with 95% O2 and 5% CO2. Tissues are adjusted to 0.5 g and allowed to equilibrate for a period of 30 minutes. The vas deferens are exposed to an electrical field stimulation (Grass S48 Stimulator) every 60 seconds at an intensity that will cause the tissue to contract 80% of its maximum capacity. All responses are recorded isometrically by means of a Grass force displacement transducer (FT03) and Harvard electronic recorder. Substance P inhibits the electrical field stimulated-induced contractions of the guinea pig vas deferens. In unpaired studies, all tissues (control or drug treated) are exposed to cumulative concentations of Substance P (1X10" 10 M - 7X10" 7 M). Single log-concentations of the test compounds are given to separate tissues and allowed to equilibrate for 30 minutes before a Substance P concentation-response curve is generated. At least 5 separate tissues are used for each control and individual drug- concentation for every drug assay. Inhibition of the Substance P is demonstrated by a rightward shift of its concentration-response curve. These shifts are used to determine the pA2 value, which is defined as the negative log of the molar concentration of the inhibitor which would require that twice as much agonist be used to elicit a chosen response. This value is used to determine relative antagonist potency. Isolated Hamster Trachea NK? Assay General methodology and characterization of hamster trachea responses to neurokinin agonists as providing an NK2 monoreceptor assay is found in CA. Maggi, et al., Eur. J. Pharmacol. 166 (1989) 435 and J.L Ellis, et al., J. Pharm. Exp. Ther. 267 (1993) 95. Continuous isometric tension monitoring is achieved with Grass FT-03 force displacement transducers connected to Buxco Electronics preamplifiers built into a Graphtec Linearcorder Model WR 3310. Male Charles River LAK±VG (SYR) hamsters, 100-200 g fed weight, are stunned by a sharp blow to the head, loss of corneal reflex is assured, the hamsters are sacrificed by thoractomy and cutting the heart. Cervical trachea segments are removed to room temperature Krebs buffer, pH 7.4, aerated with 95% O2 - 5% CO2 gas and cleaned of adhering tissue. The segments are cut into two 3-4 mm long ring segments. Tracheal rings are suspended from transducers and anchored in 15.0 ml water jacketed organ baths by means of stainless steel hooks and 6-0 silk. Baths are filled with Krebs buffer, pH 7.4, maintained at 37°C and continuously aerated with 95% O2 - 5% CO2 gas. Tracheal rings are placed under 1.0 g initial tension and allowed a 90 min equilibration period with four 1 μM NKA challenge, wash and recovery cycles at 20 min intervals. 30 min vehicle pretreatment is followed by cumulative additions of rising doses of NKA (3 nM - 1 μM final concentration, 5 min intervals between additions). The final NKA response is followed by a 15 min wash and recovery period. 30 min pretreatment with a test compound or its vehicle is followed by cumulative additions of rising doses of NKA (3 nM - 10 μM final concentration if necessary, 5 min intervals between additions). The final NKA response is followed by a 1 mM carbachol challenge to obtain a maximal tension response in each tissue. Tissue responses to NKA are recorded as positive pen displacements over baseline and converted to grams tension by comparison to standard weights. Responses are normalized as a % of the maximal tissue tension. EDso's are calculated for NKA from the control and treated NKA dose responses and compared. Test compounds resulting in an agonist dose ratio > 2 at a screening concentration of 1 μM (i.e. pA2 > = 6.0) are considered actives. Further dose response data is obtained for actives so that an apparent pA2 estimate can be calculated. PA2 is calculated either by estimation of K * as described by Furchgott (where pA 2 = - Log Kj, R.F. Furchgott, Pharm. Rev. 7 [1995] 183) or by Shild Plot Analysis (O. Arunlakshana & H.O. Shild, Br. J. Pharmacol. 14[1959] 48) if the data is sufficient. Effect of NKι_Antaαonists on Substance P-lnduced Airway Microvascular Leakage in Guinea Piαs Studies are performed on male Hartley guinea pigs ranging in weight from 400-650 g. The animals are given food and water ad libitum. The animals are anesthetized by intraperitoneal injection of dialurethane (containing 0.1 g/ml diallylbarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane). The trachea is cannulated just below the larynx and the animals are ventilated (Vy = 4 ml, f = 45 breaths/min) with a Harvard rodent respirator. The jugular vein is cannulated for the injection of drugs. The Evans blue dye technique (Danko, G. et al., Pharmacol. Commun ' .. 1 , 203-209, 1992) is used to measure airway microvascular leakage (AML). Evans blue (30 mg/kg) is injected intravenously, followed 1 min later by i.v. injection of substance P (10 μg/kg). Five min later, the thorax is opended and a blunt-ended 13-guage needle passed into the aorta. An incision is made in the right atrium and blood is expelled by flushing 100 ml of saline through the aortic catheter. The lungs and trachea are removed en-bloc and the trachea and bronchi are then blotted dry with filter paper and weighed. Evans blue is extracted by incubation of the tissue at 37°C for 18 hr in 2 ml of formamide in stoppered tubes. The absorbance of the formamide extracts of dye is measured at 620 nm. The amount of dye is calculated by interpolation from a standard curve of Evans blue in the range 0.5-10 μg/ml in formamide. The dye concentration is expressed as ng dye per mg tissue wet weight. Test compounds were suspended in cyclodextran vehicle and given i.v. 5 min before substance P. Measurement of NK? Activity In Vivo Male Hartley guinea pigs (400-500 gm) with ad lib. access to food and water are anesthetized with an intraperitoneal injection of 0.9 ml/kg dialurethane (containing 0.1 g/m diallylbarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane). After induction of a surgical plane of anesthesia, tracheal, esophageal and jugular venous cannulae are implanted to facilitate mechanical respiration, measurement of esophageal pressure and administration of drugs, respectively. The guinea pigs are placed inside a whole body plethysmograph and the catheters connected to outlet ports in the plethysmograph wall. Airflow is measured using a differential pressure transducer (Validyne, Northridge CA, model MP45-1 , range ± 2 cmH2θ) which measures the pressure across a wire mesh screen that covers a 1 inch hole in the wall of the plethysmograph. The airflow signal is electrically integrated to a signal proportional to volume. Transpulmonary pressure is measured as the pressure difference between the trachea and the esophagus using a differential pressure transducer (Validyne, Northridge, CA, model MP45-1 , range ± 20 cm H2O). The volume, airflow and transpulmonary pressure signals are monitored by means of a pulmonary analysis computer (Buxco Electronics, Sharon, CT, model 6) and used for the derivation of pulmonary resistance (R|_) and dynamic lung compliance (Coyr-)- Bronchoconstriction Due to NKA Increasing iv doses of NKA are administered at half log (0.01-3 μg/kg) intervals allowing recovery to baseline pulmonary mechanics between each dose. Peak bronchoconstriction occurs within 30 seconds after each dose of agonist. The dose response is stopped when Coyn is reduced 80-90% from baseline. One dose-response to NKA is performed in each animal. Test compounds are suspended in cyclodextran vehicle and given i.v. 5 min before the initiation of the NKA dose response. For each animal, dose response curves to NKA are constructed by plotting the percent increase in R|_ or decrease in Co n against log dose of agonist. The doses of NKA that increased R|_ by 100% (Rι_100) or decreased Coyn by 40% (Coyn40) from baseline values are obtained by log-linear interpolation of the dose response curves. Neurokinin Receptor Binding Assavfs) Chinese Hamster ovary (CHO) cells transfected with the coding regions for the human neurokinin 1 (NK1 ) of the human neurokinin 2 (NK2) receptors are grown in Dulbecco's minimal essential medium supplemented with 10% fetal calf serum, 0.1 mM non-essential amino acids, 2 mM glutamine, 100units/ml of penicillin and streptomycin, and 0.8 mg of G418/ml at 37°C in a humidified atmosphere containing 5% CO2. Cells are detached from T-175 flasks with a sterile solution containing 5mM EDTA in phosphate buffered saline. Cells are harvested by centrifugation and washed in RPMI media at 40°C for 5 minutes. The pellet is resuspended inTris-HCI (pH7.4) containing 1 uM phsphoramidon and 4 ug/ml of chymostatin at a cell density of 30 x 10 6 cells/ml. The suspension is then homogenized in a Brinkman Polytron (setting 5) for 30- 45 seconds. The homogenate is centrifuged at 800 x g for 5 min at 4°C to collect unbroken cells and nuclei. The supernatant is centrifuged in a Sorvall RC5C at 19,000 rpm (44,00 x g) for 30 min at 4°C. The pellet is resuspended, an aliquot is removed for a protein determination (BCA) and washed again. The resulting pellet is stored at -80°C To assay receptor binding, 50 μl of [3H]-Substance P (9-Sar, 11 -Met [02]) (specific activity 41 Ci/mmol) (Dupont-NEN) (0.8 nM for the NK-1 assay) or [ 3 H]-Neurokinin A (specific activity 114 Ci/ mmole) (Zenca) (1.0 nM for the NK-2 assay) is added to tubes containing buffer (50 mM Tris-HCI (pH 7.4) with 1 mM MnCI and 0.2% Bovine Serum Albumin) and either DMSO or test compound. Binding is initiated by the addition of 100μl of membrane (10-20 μg) containing the human NK-1 or NK-2 receptor in a final volume of 200 μl. After 40 minutes at room temperature, the reaction is stopped by rapid filtration onto Whatman GF/C filters which have been presoaked in 0.3% polyethylenimine. Filters are washed 2 times with 3 ml of 50 mM Tris-HCI (pH7.4). Filters are added to 6 mis of Ready-Safe liquid scintillation cocktail and quantified by liquid scintillation spectrometry in a LKB 1219 RackBeta counter. Non-specific binding is determined by the addition of either 1 μM of CP-99994 (NK-1 ) or 1μM SR- 48968 (NK-2) (both synthesized by the chemistry department of Schering- Plough Research Institute). IC50 values are determined from competition binding curves and Ki values are determined according to Cheng and Prusoff using the experimentally determined value of 0.8 nM for the NK-1 receptor and 2.4 nM for the NK-2 receptor. NK3 activity is determined by following a procedure similar to that described in the literature, e.g., Molecular Pharmacol., 48 (1995), p. 711 -716. % Inhibition is the difference between the percent of maximum specific binding (MSB) and 100%. The percent of MSB is defined by the following equation, wherein "dpm" is disintegrations per minute: °/ M^R - ( d P m °f unknown) - (dpm of nonspecific binding) (dpm of total binding) - (dpm of nonspecific binding) It will be recognized that compounds of formula I exhibit NK-j, NK2 and/or NK3 antagonist activity to varying degrees, e.g., certain compounds have strong NK-- antagonist activity, but weaker NK2 and NK3 antagonist activity, while others are strong NK2 antagonists, but weaker NK-i and NK3 antagonists. While compounds with approximate equipotency are preferred, it is also within the scope of this invention to use compounds of with unequal NK1/NK2/NK3 antagonist activity when clinically appropriate. Using the test procedures described above, the following data (% inhibition or Ki) were obtained for preferred and/or representative ounds ol formula I: % Inhibition % Inhibition Ex. NKi Ki (NK NK 2 Ki (NK 2 ) Ki (NK 3 ) (1μM dose) (nM) (1 μM dose) (nM) (nM) 1 88.0 25 95.0 20 109 1 C 44.0 ~ 16.0 — — 2 69.0 40 17.0 — — 7 69.0 121 13.0 — — 22AK 67 132 95 2.0 — 22AL 12.0 — 100 2.0 — 35C 93 2.0 0.0 -- — 39F 93 4.3 96 12.0 — 42L 91 4.6 86 123.0 — Compounds of the present invention exhibit a range of activity: percent inhibition at a dosage of 1μM ranges from about 0 to about 100% inhibition of NK-| and/or about 0 to about 100% inhibition of NK 2 . Preferred are compounds having a Ki <100nM for the NK-i receptor. Also preferred are compounds having a Ki <100nM for the NK2 receptor. Another group of preferred compounds are those having a Ki ≤IOOnM for each of the NK--and NK 2 receptors.

Claims: We claim: 1. A compound represented by the structural formula or a pharmaceutically acceptable salt thereof, wherein: a is 0, 1 , 2 or 3; b and d are independently 0, 1 or 2; R is H, C-ι-6 alkyl, -OR 6 or C2-C6 hydroxyalkyl; A is =N-OR 1 - =N-N(R2)(R3), =C(R 11 )(R 12 ) or =NR25 ; X is a bond, -C(O)-, -0-, -NR 6 -, -S(0) e -, -N(R 6 )C(0)-, -C(0)N(R 6 )- -OC(0)NR 6 -, -OC(=S)NR 6 -, -N(R 6 )C(=S)0-, -C(=N0R1)-, -S(0) 2 N(R 6 )-, -N(R 6 )S(0) 2 -, -N(R 6 )C(0)0- or -OC(O)-, provided that when d is 0, X is a bond, -C(O)-, -NR 6 -, -0(O)N(R 6 )-, -N(R 6 )C(0)-, -OC(0)NR 6 -, -C(=N0R1)-, -N(R 6 )C(=S)0-, -OC(=S)NR 6 -, -N(R 6 )S(0) 2 - or -N(R 6 )0(O)O-; provided that when A is =C(R 1 )(R 12 ) and d is 0, X is not -NR 6 - or -N(R 6 )C(0)-; and provided that when A is =NR 25 , d is 0 and X is -NR 6 - or -N(R 6 )C(0)-; T is H, R 4 -aryl, R 4 -heterocycloalkyl, R 4 -heteroaryl, phthalimidyl, R 4 -cycloalkyl or R 10 -bridged cycloalkyl; Q is R5-phenyl, R5-naphthyl, -SR 6 , -N(R 6 )(R 7 ), -OR 6 or R5-hetero- aryl, provided that when Q is -SR 6 , -N(R 6 )(R 7 ) or -OR 6 , R is not -OR 6 ; R1 is H,.Cι-6 alkyl, -(C(R 6 )(R )) n -G, -G 2 , -(C(R 6 )(R )) p -M- (C(Rl3)(Rl4) )n -(C(R8)(R9)) u -G, -C(0)N(R 6 )-(C(Rl3)(Rl4)) n . { C(R8)(R9 ))u . G or -(C(R 6 )(R 7 )) p -M-(R 4 -heteroaryl); R 2 and R 3 are independently selected from the group consisting of H, C1-6 alkyl, -CN, -(C(R 6 )(R )) n -G, -G 2 , -C(0)-(C(R8)(R9)) n -G and -S(0) e R 13 ; or R 2 and R 3 , together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of -0-, -S- and -N(R 19 )-; R 4 and R 5 are independently 1 -3 substituents independently selected from the group consisting of H, halogeno, -OR 6 , -OC(0)R 6 , -OC(0)N(R 6 )(R 7 ), -N(R 6 )(R 7 ), d-e alkyl, -CF 3 , -C 2 F 5 , -COR 6 , -C0 2 R 6 , -CON(R 6 )(R 7 ), -S(0) Θ R 13 , -CN, -OCF3, -NR 6 C0 2 R 16 , -NR 6 COR 7 -NR8CON(R 6 )(R 7 ), R^-phenyl, Ri5-benzyl, N0 2 , -N(R 6 )S(0) 2 R 13 or -S(0)2N(R 6 )(R 7 ); or adjacent R 4 substituents or adjacent R 5 substituents can form a -O-CH2-O- group; and R 4 can also be R 15 -heteroaryl; R 6 , R 7 , R8, Rδa R 7 a R8a ; Ri3 anc j R14 are independently selected from the group consisting of H, C-ι-6 alkyl, C2-C6 hydroxyalkyl, C1-C6 alkoxy-C Cβ alkyl, R 15 -phenyl, and R 5 -benzyl; or R 6 and R 7 , together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of -0-, -S- and -N(R19). ; R 9 and R 9a are independently selected from the group consisting of R 6 and -OR 6 R 10 and R 10a are independently selected from the group consisting of H and C1 -6 alkyl; R 11 and R 12 are independently selected from the group consisting of H, C r C 6 alkyl, -C0 2 R 6 , -OR 6 , -C(0)N(R 6 )(R 7 ), C-|-C 6 hydroxyalkyl, -(CH 2 )rOC(0)R 6 , -(CH 2 ) r OC(0)CH=CH 2 , -(CH2)rO(CH2)s-C0 2 R 6 , -(CH 2 )rO-(CH 2 )s-C(0)N(R 6 )(R 7 ) and -(CH 2 ) r -N(R 6 )(R 7 ); R 15 is 1 to 3 substituents independently selected from the group consisting of H, C Cβ alkyl, C-i-Cβ alkoxy, C1-C6 alkylthio, halogeno, -CF 3 , -C2F5, -COR™, -C0 2 R 10 , -C(0)N(R10) 2 , -S(O) e R 10a , -CN, -N(R 1 0)COR 0, -N(R10)CON(R10) 2 and -N0 2 ; R 16 is C1-6 alkyl, R 15 -phenyl or R 15 -benzyl; R 19 is H, CrC 6 alkyl, -C(0)N(R10) 2 , -C0 2 R 1 °, -(C(R8)(R9)) f -C0 2 R 10 or -(C(R8)(R9)) U -C(0)N(R10) 2 ; f, n, p, r and s are independently 1-6; u is 0-6; G is selected from the group consisting of H, R 4 -aryl, R 4 -hetero- cycloalkyl, R 4 -heteroaryl, R -cycloalkyl, -OR 6 , -N(R 6 )(R 7 ), -COR 6 - -C0 2 R 6 -CON(R )(R9), -S(0) e R 13 ' -NR 6 C0 2 R 16 , -NR 6 COR 7 - -NR8CON(R 6 )(R 7 ), -N(R 6 )S(0) 2 R 13 , -S(0) 2 N(R 6 )(R 7 ), -OC(0)R 6 , -OC(0)N(R 6 )(R 7 ), -C(=NOR8)N(R 6 )(R 7 ), -C(=NR 2 5)N(R 6 )(R 7 ), -N(R8)C(=NR 5)N(R 6 )(R 7 ), -CN, -C(0)N(R 6 )OR 7 , and -C(0)N(R9)-(R 4 -heteroaryl), provided that when n is 1 and u is 0, or when R 9 is -OR 6 , G is not -OH or -N(R 6 )(R 7 ); M is selected from the group consisting of a double bond, -0-, -N(R 6 )-, -C(O)-, -C(R 6 )(OR 7 )-, -C(R8)(N(R 6 )(R 7 ))-, -C(=NOR 6 )N(R 7 )-, -C(N(R 6 )(R 7 ))=NO-, -C(=NR 2 5)N(R 6 )-, -C(0)N(R9)-, -N(R9)C(0)-, -C(=S)N(R9)-, -N(R9)C(=S)- and -N(R 6 )C(0)N(R 7 )-, provided that when n is 1 , G is not OH or -NH(R 6 ); and when p is 2-6, M can also be -N(R 6 )C(=NR 5)N(R 7 )- or -OC(0)N(R 6 )-; G 2 is R 4 -aryl, R 4 -heterocycloalkyl, R 4 -heteroaryl, R 4 -cycloalkyl, -COR 6 , -C0 2 R 16 , -S(0) 2 N(R 6 )(R 7 ) or -CON(R 6 )(R 7 ); e is 0, 1 or 2, provided that when e is 1 or 2, R 13 and R 10a are not H; R25 is H, d-Cβ alkyl, -CN, Ri5-phenyl or Ri5-benzyl; Z is , R 30 -N - or morpholinyl; g and j are independently 0-3; h and k are independently 1 -4, provided the sum of h and g is 1-7; J is two hydrogen atoms, =0, =S, =NR 9 or =NOR 1 ; L and L 1 are independently selected from the group consisting of H, C-i-Cβ alkyl, C-i-Cβ alkenyl, -CH2-cycloalkyl, R 5 -benzyl, R 1 5-heteroaryl, -C(0)R 6 , -(CH 2 )m-OR 6 , -(CH 2 )m-N(R 6 )(R 7 ), -(CH 2 ) m -C(0)-OR 6 and -(CH 2 )m-C(0)N(R 6 )(R 7 ); m is 0 to 4, provided that when j is 0, m is 1-4; R26 and R27 are independently selected from the group consisting of H, Ci-Ce alkyl, R 4 -aryl and R -heteroaryl; or R 26 is H, Ci-Ce alkyl, R -aryl or R 4 -heteroaryl, and R 7 is -C(0)R 6 , -C(0)-N(R 6 )(R 7 ), -C(0)(R 4 -aryl), -C(0)(R -heteroaryl), -S0 2 R 13 or -S0 2 -(R 4 -aryl); R28 is H, -(C(R 6 )(Ri9)) t -G, -(C(R 6 )(R 7 )) V -G2 or -N0 2 ; t and v are 0, 1 , 2 or 3, provided that when j is 0, t is 1 , 2 or 3; R 9 is H, Cι-C 6 alkyl, -C(Riθ) 2 S(0) e R 6 , R -phenyl or R 4 -heteroaryl; R30 is H, Cι-C 6 alkyl, R 4 -cycloalkyl, -(C(R 10 ) 2 ) w -(R 4 -phenyl), -(C(R 1 °) 2 )w-(R 4 -heteroaryl), -C(0)R 6 , -C(0)OR 6 , -C(0)N(R 6 )(R 7 ), w is O, 1 , 2, or 3; V is =0, =S or =NR 6 ; and q is 0-4. 2. A compound of claim 1 wherein X is -0-, -C(O)-, a bond, -NR 6 -, -S(0) e -, -N(R 6 )C(0)-, -C(0)NR 6 , -OC(0)NR 6** or -C(=NORl)-. 3. A compound of claim 1 or 2 wherein Q is R 5 -phenyl, R 5 -naphthyl or R 5 -heteroaryl. 4. A compound of any of claims 1 , 2 or 3 wherein Z is 5. A compound of any of claims 1 , 2, 3 or 4 wherein A is =N-OR 1 . 6. A compound of any of claims 1 , 2, 3, 4 or 5 wherein Q is R 5 -phenyl, R 6a R 9a -(C) d -x-(C) b - i I T is R 4 -aryl, R is H, a is 1 , A is =NOR 1 , R 7a Rδa is -CH 2 -0-CH 2 , -CH 2 -N(R 6 )C(0)-, -CH 2 NR 6 CH 2 - or CH 2 C(0)NR 6 -, and Z is 7. A compound of any of claims 1 , 2, 3, 4, 5 or 6 wherein R 1 is H, alkyl, -(CH 2 )n-G, -(CH2) P -M-(CH 2 )n-G or -C(0)N(R 6 )(R 7 ), wherein M is -O- or -C(0)N(R 9 )- and G is -C0 2 R 6 , -OR 6 , -C(0)N(R 6 )(R 9 ), -C(=NOR8)N(R 6 )(R 7 ), -C(0)N(R 9 )(R 4 -heteroaryl) or R 4 -heteroaryl. 8. A compound of claim 1 selected from: and 9. A pharmaceutical composition comprising an effective amount of a compound of any of claims 1 , 2, 3, 4, 5, 6, 7 or 8 and a pharmaceutically acceptable carrier. 10. The use of a compound of any of claims 1 , 2, 3, 4, 5, 6, 7, or 8 for the preparation of a medicament for treating asthma, cough, bronchospasm, central nervous system diseases, inflammatory diseases and gastrointestinal disorders.

Inventors: ALAIMO CHERYL L, ASLANIAN ROBERT G, CARRUTHERS NICHOLAS I, GANGULY ASHIT, KIRKUP MICHAEL P, LUPO ANDREW, MANGIARACINA PIETRO, MCCORMICK KEVIN D, PIWINSKI JOHN J, REICHARD GREGORY A, SHANKAR BANDARPALLE, SHIH NENG-YANG, SPITLER JAMES M, TING PAULINE C, ALAIMO, CHERYL, L., ASLANIAN, ROBERT, G., CARRUTHERS, NICHOLAS, I., GANGULY, ASHIT, KIRKUP, MICHAEL, P., LUPO, ANDREW, MANGIARACINA, PIETRO, MCCORMICK, KEVIN, D., PIWINSKI, JOHN, J., REICHARD, GREGORY, A., SHANKAR, BANDARPALLE, SHIH, NENG-YANG, SPITLER, JAMES, M., TING, PAULINE, C.
Applicants: SCHERING CORP, SCHERING CORPORATION
Application year: 1996
Main classification: C07D211
IPC codes: A61K31, A61P1, A61P11, A61P25, A61P29, A61P43, C07D205, C07D207, C07D211, C07D295, C07D333, C07D401, C07D403, C07D405, C07D409, C07D413, C07D417, C07D451