MXPA98000046A

MXPA98000046A - Antiphungic agents of triazol, use of them, compositions that contain them and procediminto to prepare mys

Info

Publication number: MXPA98000046A
Application number: MXPA/A/1998/000046A
Authority: MX
Inventors: Jonathan Fray Michael; Simon Bell Andrew; John Whittle Peter; Patrick Marchington Alan; Richardson Kenneth; Thomas Stephenson Peter
Original assignee: Pfizer Limited
Priority date: 1995-06-26
Filing date: 1998-01-07
Publication date: 1998-11-12

Abstract

An antifungal agent of the formula: (or formula) or a pharmaceutically acceptable salt thereof, wherein Ar is a phenyl group substituted with 1 to 3 substituents each independently selected from halo and CF3, and X is a group of formulas : (see formula

Description

ONTIFUNGIC AGENTS OF TRIflZOL, USE OF THEM, COMPOSITIONS THAT CONTAIN THEM AND PROCEDURE TO PREPARE THEMSELVES This invention relates to denatured tpazol which have anti-fury activity and are useful in the treatment of rungic infections in animals, including humans. ttsi, and i? invention provides formula compounds; and pharmaceutically acceptable salts thereof, in which Ar is a group > or phenyl substituted with 1 to 3 substituents each independently selected from halo and CF3 and X is a group of formul s: where Z is H or F and He + is a 5-membered aromatic heterocyclic group, which contain nitrogen and optional + e contains an oxygen or sulfur atom and is linked to the femlo, pin di lo or pi n mi mi nor what for a -i orno < Carbon or nitrogen and optionally substi tuted with 1 to 3 substi + uyen + is each selected independently from halo, alkyi, or, (alooxi, Oi - 4) rnet 1I0, 2- (alcox? Ci -4 letoxi eti 1, 2-h? drox? eiox? net ?, lo?)?,? n?,? NRi R2 or -CH2CONRIR2, where Rl and R are one of them ndependien H or C1-4alkyl, phenylthio or phenylalkyl or Ci-2 and both of which the aforementioned lenyl group is optionally substituted with halo, k -ifluoromethyl or alkyl 1-4; -NHCO-C1-4alkyl, -NHSO2-alkyl C1-4, -NH0NR1R2, where R1 and R2 are defined above, mercapto and -S (0) -alkyl Ci -t, where n is 0, 1 or 2. "Halo" means F, Cl , Br or I. Preferred alkyl groups are methyl, ethyl and isopropyl and preferred alkoxy groups are rnetox and ethoxy Z is preferably H. Preferably, "Het" is a pyrazolyl group, irrii dazole 1, 0, tpazolyl, thiadiazolyl, oxadiazolyl, pyrrolyl. , thiazolyl or tetrazolyl, optionally substituted as e has previously indicated, in particular a group-razol-1-? l,? razol-3-1I0,? razol-4-? lo,? rn? dazol-1-? lo, Lrn? dazol ~ 2 -? lo,? rn? dazol-4-yl, 1, 2,3-tr? azol-l-? lo, 1, 2, 3-tr? azol-2? l, 1, 2, 3-tnazol ~ 4-yl, 1,2,4-tr? Azol-1-yl, 1, 2, 4-tr? Aolol-3-yl, 1, 2, 4-tpazol-4-1I0, l, 3 , 4-tnd? Azole-2 ~? Lo, 1,, 4-oxad? Azol ~ 2-? Lo, 1,2,4-oxadiazol-5? Lo,? Rrol-1-? Lo, t? azole-5-or tetrazole-5α, these groups being optionally substituted with 1 to 3 substituents as defined above and in particular with 1 to 3 (preferably 1 or 2) substituents each independently selected from chlorine , bromine, fluorine, iodine, C1-3alkyl, arnyl, ethoxymethyl, 2-rnetoxyethoxynethane, 2-hydroxethoxyphenethyl, methylthio, nitro-sulphonyl, rnercapto, phenylthio, methanesulfonarnide, 3-rnet-lure Cyanomethyl, cabarnoi l etiio, acetarnido and benzyl. The most preferred compounds are not substituted or contain a substituent as defined above. Specific examples of "Het" are pyrazol-1-yl, 3-am? Nop? Razol ~ l-? or, 1-ethoxyrnetipropyl-4-yl, 1-ethoxyrnetiipyrazol-5-yl, 4-bromopyrazol-3-yl, 3-r-methane-sulphonamidopyrolol-1-yl, 3- (3-methylureido) pyrazole- It is 3-acetamidodozolol-1-yl, 1-methylpyrazol-5-yl, l-r-ethylpypyrazol-3-yl, l-et? lp? razol-5-yl, l-isopropyl? ? razol-5-yl, 1-ethopropylp? razol-5-yl, l-carbarnoylmethyl? razol-3-yl, 1-cyanomethyl-pyrazol-3-yl, pyrazol-3-yl, pyrazol-4-yl, 3- r? nyl-4-yl, l-rnetiiirnidazol-2-yl, imidazol-l-yl, 2-rnetiiimidazol-1-yl, l-ethoxyrnethyl-2-phenylthioirn-dazole-5-yl, 1- ethoxyrnetylidene-dazole-2-yl, 4-rnethylnidazol-1-yl, 1-ethoxyrnethyl-dazol-5-yl, irn-dazol-2-yl, l-rnethylnidazol-5-yl, l-ethyl imidazole-5- 1 lo, l-rnetyl-2-phenylthioirnidazol-5-yl, imidazol-4-yl, 1,2,3-riazol-2-yl, 1,2-triazole-l-? lo, 1-ethoxyrnethyl-1,2,4-triazol-5-yl, l-ethoxyrnethyl-3-methylthio-l, 2,4-t-riazole - ?? - Lio, 1, 2, 3 - < pazo -4 - 1 lo, l- (2 inetoxyeto imet Ll) -1,2,3- t pazol -5- i io, 1- benzyl -1, 2,3- »r zol-5-io, i ~ (2-hydroxyiot- or ime 1) -1, 2, 3 -tp zol -5-1 1, 5-rnet? 1-1,2,3-tnazol-4- io, 3 -rnet i lt IO-I, 2, k -t pazo -1 -i lo, 1 -ethoxnne] -1, 2-3-tpazol-5-? Io, 4-? Net i-, 2, 4 - tpazol-3 ~? Lo, 3 -mercapto-4 -inet i] -1, 2, 4 ~ -t pazol - 5 -? Lo, 1 - et lJ, 2, 4-tp zol-5- lyo, 1-ethe irnetyl-1,2,3- * r azol-4-? Lo, 2-ethoxy? Rne 1-1, 2, 3 - »pazol-4-? L ?, 1,2,4-tpazol-4-yl, 4-chloro-1,2, -triazol-5-l, 4-bromo-1,2, 3-tp zol -5- lio, 4 -iodo-1, 2,3- * p zol-5- Lio, 4 - ("1 uoro -1,2,3-tpazol -5-? Lo, L, 2 , 4- tpazol-3-lyo, ^ -methansul f-oml-1, 2, 4-t pazol ~ 3-? Lo, 3-methanesul foni 1 -,?, 4-tpazol-l-yl, 1-ethoxy net? l-3-? netansulfon? ll, 2, 4-t aiolol-5-? lo, 5-ariuno-1,3,4-t? ad? azole-2-? lo, 5 ~ rnet ? i -i, 3,4-oxadLazol -2-? lo, 5 -metí i tío -l, 3,4-oxad? azol-2-? lo, 5-? netanosul fon? l-1, 3, 4 -oxad? azole -2-? lo, 3-am? no ~ l, 2, 4-oxad? azole -5-? lo, 5-arn? no-l, 3, 4-oxad? azol -2 -lio , 1-rnet? 1 tetrazole-5? Lo, 1-benzyl tet azole-5-l, tetrazol-5-yl, tlazol-5? Lo and 2, 5- dimet? L? Rrol- 1 - X is preferably a group of formula: .Het wherein Z is H or F and, more preferably, a group of formula where "Het" is defined above. X is most preferably a group of formula: wherein "Het" is selected from (a) an unsubstituted 1,2,3-trolol-1-yl group, (b) a 1, 2, 4-tpazol-1-yl group 0 1,2, 4-tetrazol-4-unsubstituted, (c) a 1,2,3-triazolyl or 1, 2,4-t-riazolyl group linked to the adjacent phenyl group by a carbon atom and optionally substituted on a nitrogen atom with C 1-4 alkyl, (preferably methyl) or (C 1-4 alkoxy) -methyl (preferably ethoxyrnethyl), (d)? m? dazol-1? unsubstituted, (e) a group? razol-3-? the unsubstituted, a non-substituted root group-4? or a group? l-met? lp? razol-5- Lio and (f) a group? rn? dazol-4-? or 1-met? l? rn? dazol-5-? lo. flr is preferably a phenyl group substituted with 1 or 2 substituents each selected i ndepend in-* einen * e between halo and CF3. More preferably, Rr is a femlo group substituted with 1 or 2 substituents each selected from cilia independently between F, Cl and Br. A most preferred case, f? R is 2, 4- Lfluorofemlo, 2- chlorophenyl or? fl uro-femlo. When the compounds (I) can be extruded into tertiary forms, it should be understood that the invention includes all tau torne. The acceptable salts of the compounds of formula (I) include acid addition salts formed from acids that form non-toxic salts, such as the hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate salts. , phosphate or hydrogen phosphate, acetate, naleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methane sulfonate, benzenesulfonate and p-toluenesulphonate. Some of the compounds may also form basic salts such as sodium, potassium and tetraqluilarnonium salts. A list of pharmaceutically suitable salts is found in the work of Berge et al. 3. Pharm. Sci. 65, 1-iq (1977). The compounds of formula (T) contain at least two centers of chirals (* *) and, therefore, there exist at least two diastereomeric pairs of enantiomers, that is: This invention includes the individual stereoisomers of the compounds of formula (I) and mixtures thereof. The separation of the diastereomers can be achieved by conventional techniques, for example by fractional crystallization, chromatography or HPLC of a mixture of diastereomers of a compound of formula (I) or of one of its salts or suitable derivatives. An individual enantiomer of a compound of formula (I) can also be prepared from the corresponding optically pure intermediate or by resolution, either by HPLC of the racemate using a suitable chiral support or by fractional crystallization of diastereomeric salts formed by reaction of the racemate with a suitable optically active acid, for example lR - (-) or 1S- (+) -10-camphorsulfonyl acid, 3-bormocarnfor-1-sulfonamide or (-) - 3-bromocar- 8-sulfonic. In general, the (2R, 3) forms of the compounds (I) are preferred. Preferred individual compounds are the following: (2R, 3 <El) -2- (2,4-difluorophen? L) -3- (4 ~ C? Rnidazol-l-ll Ifeni 1) 1 - (1,2, 4- r? Azol-1-? L) butan-2-ol, (2R, 3S) 2- (2,4-difluorofeml) -3- (4- [l, 2,3-tr? Azol-l- l] phen? l) -l- (l, 2,4-tr? azoi-l-l) butan-2-ol, (2R, 3S) -2- (2,4 ~ d? fluorophen? l) - 3- (4-Cl, 2,3-tnazol-4-yl Ifenyl) -l- (1, 2,4-tnazol-1-yl) bu- * an-2-ol, (2R, 3) - 2- (2,4-d? Fluorophen? L) -3- (4-Cl, 2,4-tr? Azol-l-? L] phen? L) -l- (, 2,4-t-riazole - 1-11) butan-2-ol, (2R, 3C) -2- (2,4-d? Fluorophen I) -3- (4 ~ [1, 2,4-tpazol-3-i Ifenil) -1 - (, 2,? - * riazol ~ l-? L) butan-2-ol, (2R, 3S) -2- (2, ~ d? Fluoroten? L) -3- (4-Cl,, 4 - * nazol-4-? l] phen? l) -l- (1, 2,4-tr? azol-l-l) butan-2-ol and (2R, 3S) -2- (2,4- d? fluorophen? l) -3- (4-L "l-Inet? lp? razol-5-? l3fen? l) -l- (l, 2,4-tr? azol-l-? l) butan The compounds of formula (I) can be prepared as follows: Via fl Compounds of formula (I) can be prepared by reduction of a 3-buten-2-ol derivative of formula (II): wherein flr and X are those defined for formula (I) In a typical procedure, the reduction of compound (II) is carried out by neither catalytic drogenation, using for example a heterogeneous catalyst such as palladium, palladium or rhodium on carbon or Raney nickel, or a homogeneous catalyst, for example - * ps- (p-phenyl-phosphine) chloro-rodium, in both cases in a suitable organic solvent, for example ethanol or ethyl acetate. The reaction is preferably carried out between ambient temperature and the reflux temperature of the solvent and at a pressure of 1 to 5 atmospheres (100-500 lPa) usually proceeds satisfactorily around room temperature and a pressure of hydrogen of 2 atmospheres. This reduction technique usually results in final products (T) mainly in the form (2R, 3S) or (2R, 3S / 2S, 3R). The reduction can also be effected by using dumide which can be generated in situ by decomposition of the potassium salt of azodiacarboxylic acid (3. Org. Chern., 1965, 30, 1965) or an acyl- or sulphomyl hydrazide (e.g. toluenesulfonyl hydrazide) either by the action of a base, for example sodium ethoxide, or by thermal decomposition in an appropriate solvent, for example ethanol, butanol or a hydrocarbon such as toluene or xylene (3. flrn. Chem. Soc., 1961, 93, 3729; Tetrahedron, 1976, 32, 2157). Using this procedure, quantities of both pairs of diastereomers are often produced, ie, (2R, 35) and (2R, 3R) or (2R, 3S / 2S, 3R) and (2R, 3R / 2S, 3S) , enough for them to be separated by chromatography. Catalytic hydrogenation at higher temperatures (eg, 50 ° to 100 ° C) and for a prolonged period of time (eg 15 to 20 hours), while reducing the methanol group, eliminates sirnul * aneamento any protective groups such as substituents (alkoxy Ci -) me-t full, 2- (alkox? C -4) t oxi -me-t 1 lo,? - hi droxiet oxirnet 1I0 or benoilo, which are linked to a nitrogen atom of the "Het" group (see, v. gr, examples 59, 64 and 66). Many intermediate formulas of formula (TT) are known compounds at least in general terms, see, e.g., documents UO 09/05581 or U.S.P. 4,952,232 and others may be prepared by analogy with the procedures described in these references or with the techniques illustrated herein in the section entitled "Preparations". A chemical procedure for certain key iodophenyl intermediates can be illustrated, for example, as follows: 1. 1 Toluene (±): can be result in the forms (+) and (-) After, these yodofeml-interrnediarios can be transformed into the intermediate compounds (TI) by various procedures. For the compounds (II) in which "Het" is linked to the adjacent phenyl group by a nitrogen atom, the following route can be used: Copper catalyst / K2C03 Heat For the compounds (II) in which "Het" is linked to the adjacent phenyl group by a carbon atom, the following route can be used. When "Het" is not substituted, it is preferred to protect "Het" with a protecting group 0, preferably a protecting group (C 1-4 alkyloxy, C 2- (C 1-4 alkoxy) ethoxyH.-methyl, benzyl, or trityl, preferably an ethoxyrnethyl group , 2-methoxyethoxyrnethion, benzyl or trityl, which group can be subsequently removed by conventional techniques, for example, by acid hydrolysis (alkoxirnetyl, aminethoxyphenyl or trityl alone) or by catalytic hydrogenation, if necessary. [In fact, the final products (I) in which "Het" is substituted with (C 1-4 alkoxy) rnet ?, C 2 - (C 1-4 alkoxy) ethoxy? 3 rnet? Or benzyl are also active as anti fungal agents on their own merits.] A protective group is not necessary, for example, when an N-alkylheterocycle is required as indicated in Preparation 53 in which a final product containing an N-rnethyl substituent is prepared.This way is conveniently illustrated by the use of 1, 2,3-tpazol, as follows: ) of the protective group Q As indicated above, 0 is preferably ethoxirhexyl, 2-rnet-oxethoxyrnethyl, benzyl or titanium, the first two of these groups being removed by acid hydrolysis, for example by using a dilute aqueous solution of hydrochloride acid (see, v. ., Examples 38 and 42 illustrating this technique), the benzyl group being elusible by catalytic hydrogenation (see, v. gr-, Example 63) and the trityl group by hydrolysis with tp fluoroacetic acid. When the final products (T) are desired in which "Het" is not substi tuted, it is possible to separate the protective group 0 in the last stage of the entire reaction scheme, as described in Examples 38, 42 and 63, although 0 can be eliminated simultaneously with the reduction of the methylene group, if desired, as described, for example, in Examples 59, 64 and 66. In addition, Preparation 11 illustrates a route to intermediate (II) in the that "Het" is a 1,2,3-tpazol-4-? lo group. The routes to intermediate compounds (II) in which X contains a pyridyl radical are illustrated in Preparations 22 and 24. Preparation 25 illustrates a pathway to intermediate compounds (II) in which "Het" is a group 5- ammo-l, 3, 4-t? ad? azol-2 -lio. Preparation 21 illustrates an alternative to the preparation of intermediate compounds (Ilfl) in which "Het" is N-linked to the adjacent phenyl group. This Preparation can be illustrated in general terms as follows: MßjNCIlj Mej T-butyl hydroperoxide (HA) via B A femthio, benzyl, (C 1-4 alkoxy) methyl substituent, 2- (alkoxy C 1-4) ethoxymethyl or 2-hydroxyethoxymethyl in "Het" can be removed, if desired, by catalytic hydrogenation similar to the procedure of the Via fl, for example on palladium or Raney nickel, at approximately 200-666 kPa, between room temperature and 100 ° C in a solvent such as methanol or ethanol. Via C The compounds of formula (I) in which "Het" is a 1, 2, 4-tpazolyl group can be prepared from the corresponding forrnamide compounds (ie, the corresponding compounds with a group). forrnami or bonded to the phenyl, pipdyl or pyridinyl group of X) by reaction with f-orrn Lhi drazma, for example, by reaction at elevated temperature (typically between 150 ° and 250 ° C for about an hour and a half) , in the absence of a solvent or in the presence of an organic solvent such as DMF (dirnerine rorrnarnide) or N, N-dirnetiiaceta ida, at the reflux temperature of the solvent. The starting compounds are typically obtained by the route illustrated in Preparation 19. Via I) The compounds of formula (I) in which "Het" is a group 5- (alkyl Ci) - 1, 3, 4-Oxad? Azole-2? Can be prepared by reaction of the corresponding hydrazmcarboxylic compounds (-CONHNH2) with an alkyl of formula (C1-4 alkyl) -C-0C2Hs, II NH or with one of its salts, preferably the hydrochloride (see, e.g., Example 37). The reaction is typically carried out in an organic solvent such as ethanol or dioxane, at a temperature between room temperature and that of solvent reflux. The reaction is preferably carried out at reflux. Preparation 23 illustrates an Ip preparation of a compound razinocarbonyl compound (benzol Lhidraz ida) of pa r-t ida. Via F Certain groups N-μrotors, for example (alkoxL Ci ~ 4)? Net, (preferably etox irn ti lo),? - (alkox? Ci -) et o-xirnetyl (eg 2-methox) íotoxirnetiio) and? -hydroxyethyl ether, when they are bound to a nitrogen atom of "Het", can also be eliminated by acid hydrolysis, for example by hydrolysis using dilute hydrochloric acid, at reflux, in a solvent such as ethanol ( see, e.g., Examples 38 and 42). N-Roteg compounds can be prepared as described in La Via fl. Finally, a protective group can be removed by acid hydrolysis, preferably by using p-fluoroacetic acid (see, eg, Example 78). Via F Compounds (I) in which "Het" is substituted with a group (C? -4 alkyl) t? O can be prepared by alkylation of the corresponding mercapto substituted compounds, typically by first reaction with a base strong and then with a compound of formula (C 1 -C 4 alkyl) -01 wherein O 1 is a suitable leaving group.

L8 Preferred bases are sodium hydride and n-butylium. The preferred outgoing group is iodine. The reaction is typically carried out in an organic solvent such as DHF and around room temperature. Although split GJ thiols can generally be prepared according to Via fl, Preparation 31 illustrates a specific pathway for the compounds in which "Het" is 5-rnercapto -1, 3, 4 -oxad? zol-2- ílo. Via G lf) Compounds (I) in which "Het" is substituted with (C 1-4 alkyl) sulphide or (C 1-4 alkyl) sulfonyl can be prepared by oxidation of the corresponding compounds (alkyl 0? ) of the Via F using, respectively, around- a molar equivalent or an excess of an agent Suitable oxidant, for example, rn-chloroperoxybenzoic acid. Typically, the coupler compound in an organic solvent such as di-chloromethane is cooled to -70 ° and treated with the appropriate amount of rn-chloroperoxybenzoic acid, for example in dichloromethane. After the solution is left Heat to room temperature and stir until the reaction is complete (for example, for 24 hours). Via H The compounds (I) in which "Het" is an oxydiazolyl group of the formula: wherein R 1 and R 2 are each independently H or C 1-4 alkyl, they can be prepared by reaction of the corresponding substituted compounds with (C 1-4 alkoxy) carbonyl (preferably rnetoxy carboni Lo) with a hydroxyanhydrangement of formula: 2 It is preferred to generate the hydroxyguanidine in situ from the corresponding acid salt (e.g. the hemisulfate) and a base (e.g., ethoxide or sodium hydride). The reaction is typically carried out in an anhydrous organic solvent such as anhydrous ethanol and preferably in the presence of a dehydrating agent such as 3fi or 4fl molecular sieves. Reaction temperatures between room temperature and reflux temperature can be used. The reflux temperature is preferred. Preparation 23 illustrates the typical preparation of a starting alkoxycarbonyl compound. Via I The compounds of formula (I) in which "Het" is an oxadiazolyl group of formula: wherein R1 and R2 are each independently H or C1-4 alkyl, can be prepared by reaction of an ether "active" of the corresponding compounds substituted with carboxy with a thiosernicarbazide of formula: = C - NR1R2 I NHNH2 in a suitable organic solvent, for example di chloroform or dirnethylformamide. The "active" (or "reactive") ester is typically formed in situ by reacting the corresponding acid with an activating agent such as 1-hydroxybenzotriazole in the presence of such a coupling agent (3-d). ? rnet? lam? noprop? l) -3-et? icarbod ?? rn? da. Preparation 32 illustrates the typical preparation of a carboxy-substituted starting compound. Lane 3 The compounds of formula (I) can also be prepared by reaction of a ketone of the formula: with a nucleophile of formula: X-CH-CH3 (IV) or a compound of the formula: I X-CH-CH3 (IVA) in which X and Ar are as defined for formula (I) and is Li, Zn-Hal or Mg-Hal. Hal-Cl, Br or I. The nucleophile is typically prepared by reacting the corresponding ethyl compound, X-CH2-CH3, with a strong base such as N-butylillithium, lithium diisopropylamide, or lithium hexamethiisldiazide, in which case the The contraction of (IV) is Li +. Alternatively the compound (IVA) can be prepared by halogen-netal exchange, by treatment of a haloethylene compound X-CH-CH 3 I Hal with an alkyl lithium, for example butyllithium or with a metal, for example zinc, in the presence of iodine and , optionally, lead or 7 magnesium, in which case 11 is Li, 7n-Hal or l? g-Hal. Tl-laL-Cl, Br or T, preferably rl .. Via K The compounds of formula (I) in which "Het" is substituted with a group of formula -NHCO-alkyl Ci -4 can be prepared by acilaoion of the corresponding corresponding starting compound substituted with the NH2 group, using an acid chloride or anhydride of formula (alkyl C? ~ 4) -C0Cl or (Talquil Ci -lO) 2 ?. Analogously, by-reaction e? these starting compounds with a (C 4 -4) alkane sulfonyl chloride? compounds are obtained in which "Het" is substituted with a group of formula -NHSO? alkyl C? ~. In addition, by reacting these starting compounds with an isocyanate of C 1-4 alkyl, compounds (T) are obtained in which "Het" is substituted with -NHCONH-Ci-alkyl. It is also possible to carry out these reactions at an early stage of the synthesis process on appropriate intermediates, as illustrated in Preparations 8 to 10. Via L When "Het" is 1,2,3-tpazol-4? lo or 5- (C 1-4 alkyl) -l, 2,3-tpazol-4-yl, then the final products (I) can be prepared co or follow: e -4) PN3'X "/ strong base C 1-4 alkyl, C 5 -t, or both cycloalkyl tet Co Ra together with that of nitrogen to which they are linked represent pyrrole dino or pipepdmo and X is a counterion such as chlorine or bromine) The reaction is typically carried out in ether co or solvent. It is preferred to use azidotris (diethylarnino) phosphonium bromide, typically with potassium t-butoxide co or base. The starting ketones can be prepared by conventional procedures such as those illustrated in Preparations 47 and 48. Route Ri Compounds (I) in which "Het" is attached to the adjacent alkyl or heterocyclic ring by a carbon atom and it is substituted in a nitrogen atom with C1-4alkyl, (C1-C4alkyl, C1-4alkyl, cyanomethyl or carbamoyl-phenyl alkoxy, can be prepared by N-alkylation of the corresponding non-substi tuted compounds, for example using the halide or C.sub.4-4 alkyl tosylate, C.sub.4-4 alkoxy halide, cyanoinethyl halide or the appropriate carbaryl halide halide (eg, chloride, bromide or iodide), typically in the presence of a Acid acceptor (for example carbonate or potassium) and in a suitable organic solvent When the tautomeria of the ring is possible, the reaction can be produced in one or more nitrogen atoines but the resulting mixture of end products can be separated. a by chromatography. Via M The compounds of formula (I) in which X is formula wherein "Het" is a group I, 2,3-triazole-4-? lo and Z is H or F, can also be prepared by reaction of a compound of formula: first with a sugar (Al? C? ~ 4) s? lano (preferably azidot runet? l if tin) and then with water. The compounds of artid (VI) can be prepared according to the following scheme (analogous to that of Preparation CH- C- SiMe, Cu I KOH Compound (VI) Via O Compounds of formula (T) in which "Het" is linked to the adjacent phenyl or pyridyl group by a nitrogen atom may also be prepared according to the following reaction scheme: Hec -H Copper powder Base (eg K CO) where "Het" is linked by a nitrogen atom to the adjacent pyridyl or pyridyl ring, Z is the one defined for formula (I) and Y is CH or N. The reaction is typically carried out with application of heat until 150 ° C (and in a manner analogous to the procedure of preparation 1). The starting compounds can be prepared as described in pathway A by reduction with diimide. The preferred copper catalyst is copper bronze. This route can also be used to prepare the compounds (I) in which "Het" is attached to a 3-pi-phenyloyl or 4-pi-rrnrn-d-nyl group.

Via P Compounds of formula (I) in which "Het" is linked to the adjacent phenol, pipdoyl or piprinyl group by a carbon atom may also be prepared by the coupling reactions of Stille, Terashuna, Suzuki or Negishi, by reacting the corresponding compound in which the femlo, pindmyl or pipinidinyl group is substituted with a movable group such as Cl, Br, I or OSO2CF3 (-OTf) with a compound of formula Het-h wherein is Sn (Me) 3, - n (n-Bu) 3, -BE 2, -B (0H) -2 or ZnCl, where Het is defined for the formula (I), in the presence of a palladium or nickel, preferably tetraLis (triphenylphosphine) palladium (0).

When the leaving group is -OTf, lithium chloride is added to the reaction mixture. The best way to carry out the reaction is by heating a co-dioxane in a suitable organic solvent. The "Het" binding point is generally found in the position adjacent to the substituted nitrogen atom. It may be necessary to protect a nitrogen atom of "Het" as described in Via A. The N-protecting group can then be removed in a conventional manner. Via 0 Compounds in which "Het" is substituted with halogen can be prepared by conventional halogenation techniques, for example, using N-chlorosuccinadine, N-? brornosucci narnida, N-yodosuccmarnida or "electflúor" r hi (tetr-afl uoroborat o) of l-chloro-met LÍ 4- fl uoro-1,4-diazabicyclo C2.2.2. ] octane- see] - Che, - soc. Cornrnun. 1992, 5951. Via R Compounds in which "Het" e 3-rnercapto-4- (alkyl C? -i4) -1 / 2, -t r-yiazole-bi can be prepared by cyclization of the corresponding compound wherein the phenyl, pipdinyl or pippudini ring is substituted with CONHMHCSNH-C? -14 alkyl, omitting, for example, sodium rnetoxide in ethanol, typically at reflux. Via When "Het" is substituted with a nitric group, then it can be eliminated, if desired, by treatment with hydrogen peroxide, typically in acetic acid to reflux. Via T A tprnethylsilyl group in "Het" can be removed by treatment with an aqueous solution of potassium hydroxide, for example in ethanol, typically at reflux. The pharmaceutically acceptable acid addition salts of the compounds (I) are isolated directly from the reaction mixture or are prepared by mixing solutions containing the free base and the desired acid. The salt generally precipitates from the solution and is collected by filtration or recovered by evaporation of the solvent.

Similarly, conventional salts of compounds forming these salts can be prepared conventionally by reaction of a suitable compound (I) with sodium hydroxide, for example. The compounds of formula (I) and their salts are antifungal agents, useful in the curative or prophylactic treatment of fungal infections and animals, including humans. For example, they are useful in the treatment of superficial fungal infections in man, caused, among other organisms, by species of C ia, Trichoph ton, llicr osporum or Epider ophy on, or in mucosal infections caused by Candida al icans (for example, pruritus and vaginal candidiasis). They can also be used in the treatment of systernic fungal infections caused, for example, by species of Candida (e.g., Candida albicans), Cryptococcus neoforrnans, Aspergillus flavus, Aspergillus 11 furni gatus, Coccidioides, Paracoccidioides, Hi stpp asrna or Blastomyces. It has been found that the compounds of this invention unexpectedly exhibit a good broad spectrum activity, including good activity against clinically important Aspergillus fungi. The evaluation of the antifungal activity of the compounds can be carried out by determining the minimum anhibitone concentration (MIC), which is the concentration of the tested compounds, in a suitable medium, at which the growth of the particular microorganism. In practice, a series of agar plates, or micro-assay plates with liquid medium, each containing the compound to be tested at a certain concentration, is inoculated with a standard culture of, for example, Cryptococcus neoforrnans, and then each plate It is incubated 48 hours at 37 ° C. The plates are then examined to determine the presence or absence of growth of the fungus and the appropriate value of the MIC is recorded. Other microorganisms used in these assays can be Candida albicans, Aspergillus furigatus, Trichophyton spp. , Microsporu spp. , Epiderrnophyton floccosurn, Coccidioides írnmitis and Tor? Lopsis glabrat. The in vivo evaluation of the compounds can be performed at a series of dosage levels by intraperitoneal or intraperitoneal injection or by oral administration to mice or rats that have been inoculated, for example, with a strain of Candida albicans, Aspergillus furnigatus or Cryptococcus neofor. ans The activity can be calculated on the number of survivors of a group of treated mice after the death of a group of untreated mice. For models of infection with Candida spp. the level of dosage at which the compound provides 50% protection against the lethal effect of the infection (DPso) is also determined. For models of infection with Aßperfillus spp. the number of mice cured of the infection after an established dose allows an additional evaluation of the activity. For the models of infection with Cryptococcus SPP., the number of colony forming units existing after a given dose is determined and compared with a control to determine the effectiveness of the compound. A preliminary assessment of liver toxicity potential can also be made, based on the increase in liver weight with r-es? Ecto to a control. For human use, the anti-fungal compounds of formula (I) and their salts can be administered alone, but generally be administered in admixture with a pharmaceutical carrier selected taking into account the chosen route of administration and practice. usual pharmaceutical. For example, they can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules and ovules, alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring agents or dyes They can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, it is best to use them in the form of a sterile aqueous solution which may contain other substances, for example salts or glucose sufficient for the resulting solution to be isotonic with the blood. The solubility of a compound of formula (I) in an aqueous medium can be increased by formation of a complex with a hydroxyalkyl derivative (see EP-A-0,149,197) or sulfoalkyl (see WO 91/11172) of a ciciodextrin for the preparation of an appropriate pharmaceutical composition. Preferably, the preferred sky is alpha-beta- or garnrna-cyclodextrin and preferably is beta-cyclodextrin. Preferably, the derivative is a hydroxypropyl or tetrasuiphobutyl derivative of a CLclodextpna, in particular beta-cyclodextrin. For parenteral and parenteral administration to pac Human lenses, the target dose of the antifungal compounds of formula (I) and their salts will be between 0.01 and 20 mg / kg, preferably between 0.5 and 5 mg / kg (in a single dose or in divided doses) when administered orally or parenterally. Thus, the tablets or capsules of the compounds may contain from 5 mg to 0.5 g of active compound for the administration of a single unit or of two or more units at a time, as appropriate. In any case, the doctor will determine the actual dose that will be most appropriate for an individual patient and that will vary with the patient's age, weight and response in particular. The above doses are illustrative of a medium case; naturally, there may be individual cases in which higher or lower doses are recommended and these doses are within the scope of the invention. Alternatively, the anti-fungal compounds of formula (I) can be administered in the form of suppositories or pesapo or can be applied topically in the form of lotion, solution, cream, ointment or odorous powder. For example, they can be incorporated into a cream constituted by an aqueous emulsion of pollen and particles or they can be incorporated, at a concentration between 1 and 10%, in an ointment constituted by a base of white wax or paraffin white along with stabilizers and preservatives that may be necessary. Therefore, this invention also provides a pharmaceutical composition containing a compound of formula (T), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. This invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof or its compositions, for use as a medicament, in particular co-or antifungal agent. This invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or its compositions, for the manufacture of an anti-ointment agent. This invention further provides a method of treating an animal (including a human eer) to cure or prevent a fungal infection, which consists of treating said animal with an effective amount of a compound of formula (I), or with one of its ingredients. suitable salts or compositions, pharmaceutically acceptable.

This invention also provides any new intermediates described herein, for example the compounds of formula (V) and the compounds of formula (II) in which "Het" is attached to the feml group, pyridyl or adjacent pyrirnidinyl by a carbon atom. -bond. The following examples illustrate the preparation of the compounds of formula (I).

EXAMPLE 1 (2R, 3 / 2S, 3R) -2 ~ (2, 4-TJI fluoro-pheny1) -3- (4-L "p? Razol-l -ill feni 1) -1 (1.2, 4 -tr? azol-l-? l) hutnn ~ 2-ol A solution of 2- (2,4-difluorophemethyl) -3- (4-Cpyrazole-1-yl] phen? II- (1, 2,4-tr? Azol-1-yl) -3-buten-2 -ol (0.8 g, 2 mmol preparation 3) in 100 ml of ethanoi was hydrogenated at a pressure of 200 kPa on 10% palladium on charcoal (0.1 g) for 4 hours at room temperature. catalyst (0.3 g) and the hydrogenation was continued for 2 hours.The mixture was filtered through "Arbocel" (trademark) and the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography on silica eluting with dichloromethane / methanol (98: 2) Fractions containing the desired product were pooled and evaporated under reduced pressure The residue was crystallized from methanol to give the title compound as a solid mcolor (280 rng, 34%), mp 176 ~ 177 °. C. Analysis for C 21 H 19 F 2 N 5 O: Found: C 63.87, H 4.73, N 17.55 Calculated: C 63.79, H 4, 84 N 17.71%.

EXAMPLE 2 (2R, 3S / 2S, 3R) and (2R, 3R / 2S, 3S) -2- (2, 4-D? F luorofeml) -3- (4-L ~ l-met? L? Rn? dazol-2-? l] phen? l) -l- (l, 2,4-nazol-l-? l) butan-2-ol A mixture of 2- (2,4-d? Fluorofeml) -3- (4-Cl-neti l? Rnrn? Dazol-2-? L] phen? Ll- (l, 2,4-t pazol-1 - íl) -3-buten-2-ol (0.45 g, i.l marble-Preparation 13) and p-toluene-sulfonyl hydrazine (l.O g, 5.5 mrnol) was suspended in 20 ml of toluene and heated to reflux for 4 hours. The cooled mixture was diluted with ethyl acetate (50 nl) and then washed twice with an aqueous solution of sodium hydroxide (2N, 50 nmol). The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a yellow oil. The crude product was purified by chromatography on silica eluting with ethyl acetate / methanol (97: 3). The pure fractions were combined and evaporated to give a colorless foam. The foam was triturated with hexane / ether to give the title compound, by enantiomeric (2R, 3R / 2S, 3), as colorless solid (0.07 g, 15%), m.p. 159 ~ 161 ° C. Analysis for C22H21F2NSO: Found: C 64.39, H 5.01, N 16.97 Calculated: C 64.53, H 5.17 N 17.11%. 1 H-NMR (300 MHz, CDCl 3): 6 = 1-60 (d, 3H), 3.42 (q, 1H), 3.65 (s, 3H), 4.63 (d, 1H), 4.78 (s, 1H), 5.01 (d, 1H), 6. 43 (m, 1H), 6.61 (m, 1H), 6.91 (s, 1H), 6.94 (rn, 1H), 7.04 (s, 1H), 7.04 (s, 1H), 7.06 (d, 2H), 7.38 (d, 2H), 7.78 (s, 1), 7. 94 (s, 1H) ppm. Following elution with ethyl acetate / methanol 95: 5, after collecting and evaporating the appropriate fractions, a colorless foam was obtained. Trituration with hexane / ethyl acetate gave the title compound, enantiornepco couple (2R, 3S / 2, 3R), as a colorless solid (0.1 g, 22%), m.p. 153-155 ° C. Analysis for C22H21F2N5O: Found: C 64.50, H 5.19, N 16.92 Calculated: C 64.53, H 5.17 N 17.11%. 1 H-NMR (300 MHz, CDCl 3): 6 = 1.14 (d, 3 H), 3.38 (q, 1 H), 3.79 (s, 3 H), 3.86 (d, 1 H), 4.80 (d, 1 H), 4.81 (s) , 1H), 6.75 (rn, 2H), 6.98 (s, 1H), 7.10 (s, 1H), 7.46 (in, 1H), 7.58 (d, 2H), 7.61 (d, 2H), 7.70 (s, 1H), 7.74 (s, 1H), ppm.

EXAMPLE 3 fl 30 The following compounds were prepared using the procedure of Example 1 or Example 2, as specified in the table.

It will be noted that in some examples using the procedure of Example 2, only the predominant diastereomeric pair was isolated.

F The RS / SR isomer of Example 15 was obtained by the procedure 1. Then, the example was repeated by the procedure of Example 2, obtaining a good separation of the diastereomers μox I1P C in a cojumna "0DS2" eluted with methanol / water (60:40) from which the RR / SS isomer first eluted.

H-NMR (300 MHz, CDCl 3): EXAMPLE 12 drl.li (d, 3H), 1.24 (+, 3H), 2.62 (s, 2H), 3.38 (q, IH), 3.80 (q, 2H), 3.82 (d, 1H), 4.80 (d, 1H) , 4.82 (s, 1H), 5.42 (s, 2H), 6.7 -6.8 (rn, 2H), 7.46 (?, 1H), 7.63 (d, 2H), 7.70 (s, 1H), 7.72 («3, IH), 7.70 (d, 1H), 7.89 (d, 2H), pprn.

EXAMPLE 14 6 = 1.24 (t, 3H), 1.57 (d, 3H), 3.38 (q, 2H), 3.41 (q, 1H), 4.63 (d, 1H), 4.82 < s, 1H), 5.26 (ABq, 2H), 6.43 (rn, 1H), 6.61 (rn 1H), 6.g6 dn, 1H), 7.08 (d, 2H), 7.24 (s, 5H), 7.26 (d , 2H), 7.3-7.7 (rn, 2H), 7.76 (3, 1H), 7.87 (s, 1H) pprn.

EXAMPLE 19 (2R, 3S / 2S, 3R) 6 = 1.17 (d, 3H), 1.22 (t, 3H), 3.3g (q, 1H), 3.5g (q, 2H), 3, 86 (d, 1H), 4.77 (s, 1H), 4.80 ( d, 1H), 5.33 (s, 2H), 6.78 (rn, 2H), 7.16 (d, 2H), 7.50 dn, 1H), 7.74 (s, 1H), 7.76 (, 1H), 7.80 (d, 2H) pprn.

EXAMPLE 19 (2R, ER / 2S, 3S) 6 = 1.19 (, 3H), 1.60 (d, 3H), 3.46 (q, 3H), 4.65 (d, 1H), 4.77 (s, 1H), 5.12 (d, 1H), 5.20 (s, 1H), 6.44 (td, 1H), .62 (td, 1H), 6. 4 (q, 1H), 7.06 ( d, 2H), 7"08 (d, 2H), 7.50 (d, 2H), 7.76 (s, 1H), 7.05 (s, 1H) ppm.

EXAMPLE 22 6 ^ 1.14 (< j, 3H (, 2.64 (<? ,, 3H), 3.30 (q, 1H), 3.84 (d, 1H), 4.80 (d, 1H), 4"07 (ß, 1H), 6.79 (rn, 2H), 7.48 (rn, 1H), 7. 63 (, 4H), 7. ^ (s, H- \), 7.76 (, 1H), 0.44 (, 1H) pprn.

EXAMPLE 25 6 = 1.15 (d, 3H), 1.22 (t, 3H), 3.40 (q, 1H), 3.75 (q, 2H), 3.90 (d, 1H), 4.85 (d, 2H), 5.70 (s, 2H), 6.75 (rn, 2H), 7. 50 (rn, 1H), 7.67 (s, 4H), 7.75 (s, 1H), 7.82 (s, 1H), 7.90 (s, 1H) pprn.

EXAMPLE 28 6 = 1.13 (d, 3H), 3.34 (q, 1H), 3.80 (d, 1H), 4.76 (d, 1H), 4.80 (, 1H), 5.5g (s, 2H), 6.7-6.8 (rn, 2H), 7.05 (rn, 2H), 7. 20 (rn, 5H), 7.46 (rn, 1H), 7.54 (d, 2H), 7.70 (s, 1H), 7.72 (s, 1H), 7.74 (s, 1H) pprn.

EXAMPLE 31 fl 34 The following compounds were prepared using a procedure similar to that described in Example 2 EXAMPLE 34 1 H-NMR (300 MHe, CDCl 3): 6 = 1.64 (d, 3H), 3.50 (q, 1H), 3.71 (d, 1H), 5.03 (d, 1H), 5.05 (s, 1H), 6.48 (rn, 1H), 6.67 (m, 1H), 6.92 (q, 1H), 7.68 (rn, 2H) ), 7.80 (s, 1H), 7.85 (s, 1H), 8.00 (s, 1H), 8.Q5 (, 1H), 9.05 (, 1H) ppm.

EXAMPLE 35 2R, 3 / ?, 3R) -2- (2,4-D-fluoro-phen-1) -3- (4-C-1-e-ox-rnet-l-rni-dazol-5-l] fon 1) - l- (, 2,4- pazol-1-? 1) hutan-2-ol) A solution of 2R, 33/25, 3R) -2- (2,4-dif-luo-phenyl) -3- (4- [1-ethoxy-rnet-l-2-phenylthioimidazol-5-yl] phenyl) -l- (1, 2,4-triazol-1-yl) butan-2-ol (0.44 g, 0.8 mmol - see Example 14) in 30 ml of ethanol was hydrogenated under a pressure of 200 kPa on Raney nickel (0.07 g) for 4 hours at room temperature. The catalyst was removed by filtration through "ñrbocel" (trademark) and the filtrate was evaporated under reduced pressure. The residue was partitioned between dichloromethane (50 rnl) and water (20 rnl). The separated organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on a silica column eluting with dichloromethane / methanol (g5: 5). The fractions containing the product were combined and evaporated under reduced pressure to give the title compound (0.17 rng, 50%) in foam form, which was characterized by * H-NMR spectroscopy (300 MHz, CDC13) 6 = 1.14 (d, 3H), 1.22 (5, 3H), 3.36 (q, 1H), 3.55 (q,? H), 3.89 (d, 1H), 4.80 ( s, 1H), 4.82 (d, 1H), 5.29 (s, 2H), 6.78 (rn, 2H), 7.19 (s, 1H), 7.50 (rn, 1H), 7.5g (s, 4H), 7.70 (s, 1H), 7.76 (s, 1H), 7.77 (s, 1H) ppm.

EXAMPLE 36 (2R, 3S / 2S, 3R) -2- (2,4-Difluorophenyl) -3-C4-C 1.2, 4-triazol-4-yl) phenyl 3 -1- (1,, 4-riazole- l-il) butan-2-ol An intimate mixture of 2- (2, -di-fluorophenyl) -3- (4-forrnamidofen? L) -l- (1, 2,4-triazol-1-yl) butan-2-ol (4.4 g, 12 mmoles - see Preparation 19) and formyl idrazma (7.0 g, rrn 0. 13 min.) Was stored at 240 ° C for an hour and a half. The cooled mixture is redissolved in dichloromethane (100 rnl) and water (100 rnl). The aqueous phase was extracted with dichloroethane (100 rnl) and the organic extracts were combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by post-treatment chromatography, with a gradient of diurnomer-thio-methanol (98: 296: 495: 590: 10). Fractions containing the desired product were pooled and evaporated under reduced pressure. The crude product was triturated with ether to give the title compound (2.1 g, 44%), as white solid, m.p. 238-240 ° C. final i sis for C20H18F2N6O: Found: C 60.60, H 4.52, N 20.91 Calculated: C 60, 59, H 4.58, N 21.21%. The title compound was resolved by chiral HPLC using an Ohiralpak AD column (trademark) and eluting with 30: 70 sopropanol / hexane. Fractions containing each individual enantiomer were pooled and evaporated under reduced pressure. The enantiomer that eluted in the first place was the 2S, 3R form.

EXAMPLE 37 (2R, 3S / 2S, 3R) -2- (2,4-Diflurophenyl) -3-i; 4- (5-methyl-l, 3,4-oxadiazol-2-yl) phen.l3-l - (1, 2,4-riazol-l-yl) -putan-2-ol A suspension of (2R, 3S / 2S, 3R) -4-C2- (2, 4-d? Fluoro-phenyl) -2-hLdrox? -l- (1, 2, 4-tpazol-l-? L) ut-3-? l] -benzoylhydrazide (0.3 g, 0.8 mmol - see Preparation 23) and ethyl acetirnidate hydrochloride (0.24 g, 2 rnoles) in 5 mL of ethanol was heated to reflux for 3 hours. The cooled mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in 10 ml of dioxane and then heated to reflux for 18 hours. The mixture was evaporated under reduced pressure and then partitioned between dichloromethane (20 ml) and water (20 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give the title compound (0.18 g, 62%), as a colorless solid, m.p. 182-184 ° C. final i s s for C21 H19F2N5O2: Found: C 61.44, H 4.56, N 16.92 Calculated: C 61.30, H 4.66, N 17.03%.

EXAMPLE 3B (2R, 3S / 2S, 3R) -2- (2,4-Difluorophenyl) -3- (4- [1, 2,4-triazol-3-yl) phenyl3-l- (lJ2,4) hydrochloride -triazol-l-yl) -butan-2-olJ hydrate A solution of (2R, 3S / 2S, 3R) d-2- (2,4-difluoropheniD-3- (4-Cl-ethoxy? Methyl-1, 2,4-triazol-5-yl] phenyl) butan- 2-ol (0.12 g, 0. 3 rnnols - see Example 9) in 1 ml of ethanol was treated with dilute hydrochloric acid (5M, 0.7 ml) and the mixture was then heated to reflux for 3 hours. The mixture was evaporated under reduced pressure and the residue was azeotropically distilled with toluene (5 mL). The residual foam was triturated with ethanol / ethyl acetate to give the title compound (O.og g, 76%) as colorless solid, m.p. 197 -? 03 ° C. Analysis for C20H18 2N6O.HCIH2O: Found: C 53.42, H 4.30, N 18.42 Calculated: C 53.40, H 4.48, N 18.68%.

EXAMPLE 39 ft 41 The following compounds were prepared from the corresponding N-ethoxyrnet il-substituted using the procedure of Example 38.

EXAMPLE 42 (2R, 3S) -2- (2,4-Difluorophenyl) -3- (4- [1, 2,3-triazol-4-yl-3-phenyl) -1- (1, 2,4-riazole-1-yl) butan-2-ol A solution of (2R, 3S) -2- (2,4-difluorophenyl) -3-L "4- (1-ethoxymethyl-1,2,3-t-peace-5-yl) eni13-1- (1, 2, -triazol-1-yl) butan-2-ol (5.2 g, 0.11 mol - see Example 25) in 50 ml of ethanol was treated with dilute hydrochloric acid (2N, 12 rnl) and the mixture was heated to reflux for 1 hour The mixture was cooled to room temperature and the solvent was removed under reduced pressure The residue was dissolved in water (50 ml) and the mixture was neutralized by the addition of solid sodium carbonate and extracted with ethyl acetate ( 2 x 100 ml) The combined extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a colorless foam.The crude product was extracted by column chromatography of SLlice, eluting with ethyl acetate / d? Et? Lamina 95: 5, followed by ethyl acetate / methanol 90:10 and then 80:20.The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound as described above. colorless cougar (3.7 g, 82%), Corlo25 = -63.8 °. Analysis for C20H18F2N6O: Found; C 60.39, H 4.64, N 21.00 Calculated: C 60.59, H 4.58, N 21.21%.

EXAMPLES 43 fi 45 The following compounds were prepared from the corresponding N-ethoxyrnethylchloride using the procedure of Example 42.

EXAMPLES 46 ft 50 The following compounds were prepared using the procedure of Example 1 or Example 42, as specified in the Table.

EXAMPLE 47 iH-Rf N (300 MHz, CDC13): o = 1.12 (d, 3H), 1.24 (t, 3H), 3.78 (rn, 3H), 3.96 (q, 1H), 4.91 (broad s, H), 5.47 (d, 1H), 5.69 (s, 2H), 7.19 (, 2H), 7.31 (rn, 1H), 7.6-7.75 (m, 7H), 7.79 (s, 1H) ppm.

EXAMPLE 51 (2R, 3S / 2S, 3R) -2- (2,4-Di luoroenyl) -3- (4-C5-p? Ethylthio-l, 3,4-oxadiazol-2-yl.lfen? ) -! - (!, 2, 4-triazol-1-yl) -butan-2-ol.

NaH GD CH3I A solution of hydrochloride (2R, 3S / 2S, 3R) -2- (2,4-difluoro-phenol) -3- (4-C5-rnerca? To-1, 3,4-oxadiazole-2-hydrochloride) ? l) phenyl] -l- (l), 2,4-triazole-1-yl) butan-2-ol (0.5 g, 1.1 mmol - see Preparation 31) in DMF (5 ml) was treated with sodium hydride (80% dispersion in oil, 0.07 g). 2.4 rnrnoies) and the solution was stirred at room temperature for 45 minutes. Iodomethane (0.07 ml, 1.1 mmol) was added to the mixture which was stirred for a further hour and then evaporated under reduced pressure. The residue was repaired in otyl acetate (20 ml) and water (20 ml). The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on a column of silica, eluting with a gradient of dichloromethane / methanol or! (100: 0, 98: 2, 96: 4). They collected the fractions containing the desired product and evaporated under reduced pressure to give a gum. By trituration of the gum with oter / hexane, the title compound (0.23 g, 45%) was obtained as solid pale yellow, which was characterized by iH-NMR spectroscopy (300 MHz, CDCI3): 6 = 1.14 ( d, 3H), 2.78 (s, 3H), 3.36 (q, 1H), 3.85 (d, 1H), 4.79 (d, 1H), 4.89 (s, 1H), 6, 7-6.8 (? N, 2H), 7.48 (rn, 1H), 7.62 (d, 2H), 7.73 (d, 2H), 7.95 (s, 1H), 0.01 (s, 1H).

EXAMPLE 52 (2R, 3S / 2S, 3R) -2- (2,4-Difluorophenyl) -3- (4- [5-methyl-sulfonyl-3,4-oxadiazol-2-yl) phenyl3-l- (1, 2,4-riazol-1-yl) butan-2-ol, roxybenzoic A solution of (2R, 3S / 2S, 3R) -? - (2, 4 -di f luoro f in 11) -3- (4- Lb -inet lithium -1, J, 4 -oxadia ol -2 - 11) phen? L] - l- (1,2, 4- tp zol l-11) butan-2-ol (0.19 g, 0.4 mmol - see Example bl) in 5 nl of dichloro-methane was cooled to ~~ OOC and treated with a solution of rn-chloroperoxybenzoic acid ( 50%, 0.6 g, 1, .6 rnmoles) in dichloromethane (10 ml). The solution was allowed to warm to room temperature and stirred for 24 hours. The mixture was washed with an aqueous solution of sodium hydroxide (2M, ml), dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a dichloromethane / methanol gradient (99: 190: 10). The fractions containing the desired product were combined and evaporated under reduced pressure to give a foam which was triturated with ether / hexane to give the title compound (0.12 g, 66%) as cream solid, m.p. 180-183 ° C. final i sis for C21 Hi 9 F2 Ns 0 «S: Found: C 52.93, H 3.83, N 14.34 Calculated: C 53.04, H 4.03, N 14.73%.

EXAMPLE 53 (2R, 3S / 2S, 3R) -2- (2,4-Di luoro-enyl) -3- (4-C3-methyl-sulfonyl-l, 2,4-riazol-1-yl) phenyl] - 1- (1, 2,4-triazol-1-yl) butan-2-ol. eroxybenzoic The title compound was prepared from the corresponding derivatized derivative (see Example 2) by a procedure similar to that of Example 52 and had a melting point of 139-141 ° C. final i sis for C21H20F2 6O3 S: Found: C 53.26, H 4.19, N 17.49 Calculated: C 53.16, H 4.25, N 17.71%.

EXAMPLE 54 (2R, 3S / 2S, 3R) -2- (2,4-Di-luo-phenyl) -3- (4- [1-ethoxymethyl-3-ethylsulfonyl-l, 2,4-yiazol-5-yl) phenyl ] -l- (1, 2,4-triazol-1-yl) butan-2-ol. zoic The title compound was prepared from the product of Example 11 by a procedure similar to that of Example 52. Finishing for C2"H2 ß F2 N ß O4 S: Found: C 53.74, H 5.13, N 15.72 Calculated : C 54.12, H 4.02, N 15.78%.

EXAMPLE 55 (2RJ3S / 2S, 3R) -2- (2,4-D? Uoro-enyl) -3- (4- [3-amino-l, 2,4-oxadiazol-5? L) phen? L] -l- (1, 2,4-r? azol-1-yl) -butan-2-ol. 4Á Metallic sodium (0.3 g, 13 rnrnoles) was added to a mixture of hydroxanhydride hydrochloride hemisilfate (0.86 g, 6.5 mmol) and 4A molecular sieves (1.3 g) in 8 rnl of ethanol. Once all sodium had disappeared, methyl ester of (2R, 3S / 2S, 3R) -4-C2 ~ (2,4-d? Fluoro-phenyl) -2-hydroxyl-1-methyl acid was added to the mixture. - (1, 2, 4-tr? Azol-1-yl) but-3? L] benzoic acid (0.5 g, 1.3 mmol - see Preparation 23 (n)) and the mixture was heated to reflux for 1 hour. The mixture was neutralized with glacial acetic acid, diluted with 50 nmol of water and then extracted with 50 nmol of ethyl acetate. The organic extract was washed with a saturated sodium carbonate solution (20 nmol), dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica, eluting with ethyl acetate / methanol 95: 5. The fractions containing the desired product were combined, evaporated under reduced pressure and then triturated with ether / hexane to give the title compound (0.025 g, 5%) as colorless solid, m.p. 234-237 ° C. Analysis for C20H18F N6O2 S: Found: C 58.40, H 4.48, N 20.01 Calculated: C 58.24, H 4.40, N 20.38%.

EXAMPLE 56 (2R, 3S / 2S, 3R) -2- (2,4-Dif uoro enyl) -3- (4- [5-atnino-l, 3,4-oxadiazol-2-yl) phenyl3-1- (1, 2, 4-triazol-1-yl) -butanol A mixture of acid (2R, 3S / 2S, 3R) ~ 4 - [.? - (2, 4-di-f-1-chlorophenyl) -2-hydroxyl- was stirred at room temperature for 2 days. (1,2,4- 1 r? Azol-l-? L) ut-3-? L-lbenzo? Co (0.5 g, 1.3 inrnolos - veaso Preparation 32), 1 -hydroxiben otriazol onohi drato ("HOBT" ) (0.18 g, 1.3 immoles), carbazide (0.12 g, 1.3 immoles), triet il mine f? .37 ml,? H immobile), hydrochloride l-r3 ~ d? Rnet i lain nopropí 11 - 3 -et bound carbonate ("DfiPCD") (0.51 g, 2.6 min), i rne 11 fo pnaini da (0 rnl) and dichlorornetane (25 ml). The solvents were removed under reduced pressure and the residue was grained on silica, eluting with a gradient of dichloromethane / methanol (98: 2, 95: 5, 92: 8). Fractions containing the desired product were combined and evaporated under reduced pressure. Trituration with chloroform gave the title compound in the form of colorless solid, m.p. 237-242 ° C. final isis for C20H18F2N6O2.3 / * H2O: Found: C 55.98, H 4.24, N 19.80 Calculated: C 56.39, H 4.61, N 19, 73 X.

EXAMPLE 57 (2RJ3S / 2S, 3R) -2- (2,4-Difluorophenyl) -3- (3-E2,5-dimethyl-pyrrol-1-yl)] pyridin-2-yl) -! - (! 2, -triazol-1-yl) butan-2-ol. ilamine After a solution of diisopropylamine (1.7 ml, 12 mrnol) in 50 ml of dry THF at -20 ° C under a nitrogen atmosphere, a solution of n-butyllithium in hexane (2.5 M, 4.9 ml. 12 rnmoles). After stirring for 15 minutes, the mixture was cooled to -70 ° C and treated with a solution of 5- (2,5-d? Rnet? Lpyrrol-1-yl) -2-ethylpyridine (2.38 g, 12 mmoles - see Preparation 33) in 15 rnl of THF. The resulting mixture was stirred at this temperature for 45 minutes and then treated with a solution of 1- (2,4-d? Fluoro-phenyl) -2- (1, 2,4-triazole-1-yl) ethanone. (2.6 g, 12 mrnols - see, for example, EP-fi-0069442) in 30 rnl of THF. The solution was stirred at this temperature for half an hour and the reaction was quenched by the addition of an aqueous solution of citric acid (10%, 70 nmol) and allowed to warm to room temperature. The mixture was diluted with 100 mL of water and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a gradient of acetic acid / hexane (30:70, 50:50), to give the title compound (0.5 g, 10%) as a colorless solid, m.p. 1'38-139 ° C. Finish for C23H23F2N5O: Found: C 65.31, H 5.36, N 16.58 Calculated: C 65.23, H 5.48, N 16.54%.

EXAMPLE 58 (2R, 3S / 2S, 3R) -2- (2,4-Di-luoyl-enyl) -3-y6-Cl, 2,4-triazol-1-yl] -pyrimin-4-yl) -l -yl, 2,4-riazol-1-yl) butan-2-ol.

The title compound was prepared from 4-ethyl-6- (1, 2,4-tr? A, -Ol-l-yl) pyridine (see Preparation 34) using a similar procedure to the previous example, pf 205-207 ° C (in ethyl acetate / methanol). finalisis par-a C18H16F2N8O. Found: C 54.37, H 3.99, N 28.08 Calculated: C 54.27, H 4.05, N 28.13%.

EXAMPLE 59 2- (2,4-Difluorophenyl) -3- (2-fluoro-4-Cl, 2,3-triazole-4-yl] phenyl) -l- (1, 2,4-triazole-1- il) butan-2-ol.

A solution of 2- (2,4-d? Fluorophenyl) -3- (2-fluoro-4- l-Cetox? Met? Ll, 2,3-tpazol-5? L] phen? L) -l- (1, 2,4-triazol-1-yl) -3-buten-2-ol (0.26 g, 0.5 nmol - see Preparation 52) in 20 ml of ethanol was hydrogenated at a pressure of 333 kPa about 10% palladium on charcoal (0.2 g) for 18 hours at 50 ° C. The mixture was filtered through "firbocel" (trademark) and the filtrate was concentrated under reduced pressure. The residue was purified by * flash chromatography on silica, eluting with a gradient of ethyl acetate / hexane (1: 1, 3: 1, then 1: 0). The diastereoissiners produced were not separated, therefore the fractions containing both isomers were combined and evaporated under reduced pressure to give the title compound as a colorless foam (0.042 g, 18%). The product was characterized as a 5: 1 mixture of the diastereoisomers (? R, 3S / 2S, R) and (2R, 3R / 2S, 3S) by NMR. 1 H NMR (300 MHz, CDCl 3): ft - 1.12 (d, 2.5H), 1.56 (d, 0.5H), 3.90 (q, IH), 3.98 (d, 0, 8H), 4.69 (d, 0.2H), 4.82 (s, 0.8H), 4.93 (s, 0.2H), 5.01 (d, 0.8H), 5.11 (d, 0.2H), 6.8 (rn, 2H), 7.4-7.65 (rn, 4H), 7.76 (s, 1H), 7.83 (s, 1H), 7, 98 (s, 1H), 12.7 (broad s, 1H) ppm.

EXAMPLE 60 (2R, 3S / 2S, 3R) -2- (2, 4-Di luoro-enyl) -3- (4-C5-methyl-1, 2,3-triazol-4-yl-3-phenyl) -! - (1, 2,4-riazol-1-yl) -butan-2-ol. f fi A suspension of azido-t-pyridinium-phosphonium bromide (0.52 g, 1.4 mmol - see Tetrahedron Letters 1990, 3L, 4987 for its preparation) in 10 rnl of dry ether was treated with a solution of (2R 3S / 2S, 3R) -2- (2, 4-d? Fluoropheni 1) -3- (4-? Ropano? Lfeml) -l- (1, 2, 4-tpazol-l-yl) butan-2-ol (0.5 g , 1. 3 immoral - see Preparation 47) in 10 rni of diethyl ether. Catalytic amounts of potassium t-butoxide were added until a permanent color change occurred and then the mixture was stirred at room temperature overnight. The reaction was quenched by the addition of a saturated solution of ammonium sulfate and the layers were separated. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica, eluting with ethyl acetate / diethylanine (19: 1) followed by ethyl acetate / rne-tanol (19: 1). The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (0.05 g, 9%) as a colorless solid, m.p. 169-171 ° C. final i sis for C2iH2? F2N6? .i 4Et-20: Found: C 61.71, H 5.13, N 19.42 Calculated: C 61.68, H 5.14, N 19.62%.

EXAMPLE 61 (2R, 3S / 2S, 3R) -2- (2,4-Difluorophenyl) -3- (4- [1, 2,3-triazol-4-yl) phenyl-1- (1, 2.4 -triazol-l-il) butan-2-ol The title compound was prepared from (2R, 3S / 2S, 3R) -? - (2,4 ~ d? Fluorophen? L) -3- (4-ethane? Lfen? L) ~ l- (1, 2,4-tr? Azole-1-yl) butan-2-ol (see Preparation 48) by the procedure of Example 60. The product was characterized by its 1 H-NMR and was denative to the product of Example 15 (for 2N, 3S / 2S, 3R). 1 H-NMR (300 MHz, CDC13): 6 = 1.18 (d, 3H), 3.39 (q, 1H), 3.93 (d, 1H), 4.76 (s, 1H), 4, 82 (S, 1H), 6.77 (rn, 2H), 7.50 (q, 1H), 7.60 (s, 1H), 7.73 (s, 1H), 7.80 (s, IH) ), 7.81 (d, 1H), 7.98 (s, IH) pprn.

EXAMPLE 62 (2R, 3S / 2S, 3R) -2- (2,4-Difluorophenyl) -3-γ4-C2-methoxymethyl-l, 2,3-triazol-4-ylphenyl) -l- (l, 2 , 4-riazol-1-yl) butan-2-ol and (2R, 3S / 2S, 3R) -2- (2,4-difluorophenyl) -3- (4-Cosyl-ethoxymethyl-, 2J3-triazole- 4-ylphenyl) -l- (l, 2,4-triazol-l-yl) butan-2-ol A solution of (2R, 3S / 2S, 3R) -2- (2,4-di fluorophenyl) -3- (4, 1,2, 3-triazol-4-yl] phenyl) -l- (1,2 , 4-triazol-1-yl) butan-2-ol (5.0 g, 1.2 mmol - a product of Example 15) in 40 ml of butan-2-one was treated with potassium carbonate (0.35 g, 2.4 mrnol) followed by chlorohexyl ether (0.12 nl, 1.2 mmol). The mixture was stirred at room temperature for 18 hours. The solvent was prepared under reduced pressure and the residue was partitioned between water (10 mL) and ethyl acetate (20 mL). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic layers were extracted with brine (2 x 10 ml), dried over sodium sulfate and evaporated under reduced pressure. The colorless solid residue was subjected to flash chromatography on silica, eluting with a gradient of hexane / isopropanol (49: 1, 9: 1). The pure fractions containing each regioisornero were combined and evaporated under reduced pressure. Both title compounds were obtained by trituration with ether, as colorless solids. The structure of each regioisornero was assigned by measuring by n.O.e. (2R, 3S / 2S, 3R) -2- (2,4-d? Fluor-ofen? L) -3- (4-C2-ethoxy? Met? L-1, 2, 3-tr? Azol-4) -? l3 phenyl) -1- (1,2,4-tpazol-1-yl) butan-2-ol (0.17 g, 30%), has a fusion product of 118-120 ° C. finalysis for C23H2 «F2Nß? 2: Found: C 60.80, H 5.48, N 18.03 Calculated: C 60.78, H 5.32, N 18.49%. (2R, 3S / 2S, 3R) -2- (2,4-d? Fluorophen? L) -3- (4-Cl-ethoxy? Rnet? L-1,2,3-tpazol-4-yl. ) -l- (1,2,4-t-riazol-1-yl) butan-2-ol (0.097 g, 17%), has a melting point of 153-156 ° C. Finish for C23 H2 «F2 Nß O2: Found: C 60.77, H 5.42, N 18.13 Calculated: C 60.78, H 5.32, N 18.49%.

EXAMPLE 63 (2R, 3S / 2S, 3R) -2- (2,4-Difluorophenyl) -3- (4- [1, 2,3-triazol-4-yl) phenyl-1- (1, 2.4 -triazol-l-il) butan-2-ol A solution of (2R, 3S / 2S, 3R) -2- (2,4-d? FluorOfen? L) -3 ~ (4-Cl-benz? Ll, 2,3-tr? Azol-5? : fen? l) -l- (l, 2,4-tr? azol ~ l ~? l) bu-an-2-ol (0.03 g, 0.6 rnmoles - a product of Example 28) in 100 rnl of methanol hydrogenated at a pressure of 333 kPa over 10% palladium on charcoal (0.1 g) for 18 hours at 100 ° C. The mixture was filtered through "firbocel" and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica, eluting with a dichloromethane / methanol gradient (39: 1, 19: 1). The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound as a colorless solid (0.18 g, 71%). It was confirmed that the product was identical to the product of Example 44 by NMR. finalysis for C20H18F2N6O: Found: C 61.10, H 4.96, N 20.50 Calculated: C 60.59, H 4.58, N 21.21%, EXAMPLE 64 2-B2,4-Difluoro-enyl) -3- (4- [1,2,3-triazol-4-yl) phenyl-3-l- (1,2,4-triazol-1-yl) butan-2-ol A solution of 2- (2,4-difluorophenyl) -3- (4-Cl-benzyl-l, 2,3-triazole-5-yl] phenyl) -l- (1, 2,4-triazole) -il) -3 ~ buten-2-ol (0.15 g, 0.3 mmol - see Preparation 43) in 100 mL of methanol was hydrogenated at a pressure of 333 I-Pa over 10% palladium on charcoal (0.1 g) for 18 hours at 100 ° C. The cooled mixture was filtered through "firbocel" and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica, eluting with dichloromethane / methanol (19: 1). Fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound as a gum (0.1 g, 81%). The product was a mixture of diastereoisomers by NMR.

EXAMPLE 65 2- (2,4-Difluorophenyl) -3- (3-Cl, 2,3, triazol-4-yl) phen? L-1 - (1, 2,4-triazol-1-yl) butan- 2-ol The title compound, as a mixture of diastereomers, was prepared by a procedure similar to that of Example 42, in the form of colorless solid, m.p. 168-170 ° C. The starting compound was prepared in a manner analogous to the procedure of Example 1 and Preparation 12. finaii is for Q20H18F2N6O: Found: C 60.93, H 4.59, N 20.94 Calculated: C 60.59, H 4, 58, N 21.21%.

EXAMPLE 66 C2R, 3S) -2- (2,4-Difluorophenyl) -l- (lH-1, 2,4-triazol-1-yl) -3-C4- 1H-1,2,3-triazole- 4-yl) phenyl3-2-butanol (+) - 3-bromocamphor-10-sulfate of (R) -2- (2,4-di fluoro-phenyl) -3- (4-iodo phenyl) -l- (lH-1,2,4-t-riazole -1-yl) -3-buten-2-ol. A solution of (+) - 3-bromocarnfor-10-silonic acid (36.3 g, 0.110 mol) in 40 nrn of TNS was added to a solution of 2- (2,4-d? Fluorophen? L) -3- (4-iodo in? L) -1- (1H-1,2,4-tpazol-1-yl) -3-buten-2-ol (50 g, 0.110 mol) in 300 ml of TMS. After addition in the seed crystal, the resulting suspension was granulated for 20 hours at the temperature of temperature. After continuing the granulation for 1 hour at low temperature, a white solid (22 g, 0.03 mole) was collected by filtration. The chiral purity was determined as 95% ee by chiral HPLC using a Chiralcel OD (trademark) device and eluting with the nol / hex not 40:60. 11) (R) -2- (2,4-di-1-oropheni1) -3- (4-iodopheni 1) -1- (1H-1, 2,4-tpazol-1-yl) -3-buten- 2-A mixture of methylene chloride (620 ml) and water (620 nmol) was added (+) - 3-brornocanfor-10-sulfonate of (R) -2- (2,4-d? Fluoro in? l) -3- (4-iodophen? l) -l- (lH-l, 2,4-tr? azol-l-? D-3-bute-2-ol (206.5 g, 0.27 mol) and basify with 40% NaOH The mixture was stirred for 15 minutes at room temperature and separated The aqueous phase was extracted with methylene chloride (310 i) The organic solution of the product was washed with water (620 inl) and concentrated to a volume of 245 ml Hexane (2450 rnl) was added at constant speed to the stirred concentrate and provided with seed crystals at room temperature The resulting suspension was granulated at 5 ° C for 1 hour. a white solid was obtained (117.4 g, 0.26 mmol) which was characterized by 1 H-NMR spectroscopy, 1 H-NMR 8300 MHz, CDC13): 6 = 4.55 (d, J = 15 Hz, 1 H), 4.90 (d, J = 15 Hz), 5.16 (s, 1H), 5.25 (s, 2H), 6.70 (in, 2H), 7.03 (d, 3 =. 9 Hz, 2H), 7.43 (dt, 3 = 7 and 9 H, 1H), 7.58 (d, 3 = 9 Hz, 2H), 7.79 (s, 1H), 7.80 (s) , 1H) pprn. ni) 1-Benzyl-lH-l, 2,3-tr? azol hydrochloride A mixture of 1,2,3-tpazole (79 g, 1.1 mol) and basic carbonate (138 g, 1 mol) is heated to reflux in 530 rnl of ace-ona. A solution of benzyl bromide (171 mmol, i nmol) in 250 of acetone was added to the resulting suspension over an hour and a half, maintaining reflux. The reaction mixture was stirred at reflux for 1 hour and then cooled to room temperature. 1 liter of water was added and the ketone was removed by evaporation under reduced pressure. The product was extracted with methylene chloride (700 nmol) and separated. The aqueous phase was extracted again with methylene chloride (250 nmol) and the combined organic extracts were washed with water (400 nmol). The product solution was concentrated to an oil (162 g). After a stirred solution of the oil in 805 rnl of ethyl acetate, 22% HCl in isopropyl alcohol (166 rnl, 1 mol) was added at constant speed, at room temperature. The resulting suspension was granulated at room temperature for 1 hour and for 1 hour more at 0 ° C. HPLC analysis of the filtrate (144 g, 0.74 mol), using a Dynarnax C18 column and acetonitrile / water 65:35 as eluent, gave 93.3% of the n-1 isomer. (v) Benzyl- (lH) -l, 2,3-tnazol A stirred mixture of l-benyl- (lH) -1,2,3-tpazole hydrochloride (80 g, 0.41 mol) in 320 ml of water and 320 ml of ethyl acetate was based on 20% NaOH (91%). The mixture was stirred for 10 minutes at room temperature and separated. The aqueous phase was extracted again with ethyl acetate (160 ml) and the combined organic solutions of the product were washed with water (160 nmol). The solution was concentrated at a volume of 195 nm and cooled to room temperature. Hexane (585 ml) was added over 15 minutes to the concentrate in stirred ethyl acetate. The resulting suspension, with seed crystals, granulated at 0 ° C for 1 hour. The filtered white solid (62.4 g, 0.39 mol) was characterized by iH ~ rlN spectroscopy. 1 H-NMR (300 MHz, CDC13): 6 = 5.55 (s, 2H). 7.25 (? N, 2H), 7.35 (rn, 3H), 7.45 (s, 1H), 7.70 (s, 1H) pprn. v) (R) -3- (4-p-Benzyl-lH-l, 2,3-tr-? azol-5? l] phen? l) -2- (2,4-d? -fuforofen) (l) -l- (lH-l, 2,4-tr? azol-l-? l) -3-buten-2-ol nBuLi (1.6N, 24.1 rnl, 0.04 mol) was added to a solution of 1-benzyl- (1 H) -1,2,3-tr? Azole (6.14 g, 0.04 mmol) in 370 ml of THF at -70 ° C, keeping the temperature below -60 ° C and stirring for 30 minutes. Maintaining a temperature below -40 ° C, a solution of zinc chloride (0.5N, 77.1 rnl, 0.04 mmol) was added, followed by tetrak? S (tpfen? Lfosf? Na) palad? O (15% w / w , 0.9 g). Still maintaining the temperature below -40 ° C, a solution of (R) -2- (2,4-d? Fluorophenyl) -3- (4-iodophfen? L) -l- (lH) was added at constant speed. -l, 2,4-tpazol-1-yl) -3-buten-2-ol (6.0 g, B 7 0. 13 mol) in 36 ml of THF. The reaction mixture was allowed to warm to room temperature and then heated to reflux for 2 hours. After cooling to room temperature, the reaction is quenched with acetic acid (12 rnl) and water (120 rnl) keeping the temperature below 25 ° C. The reaction mixture was evaporated under reduced pressure to remove THF. The product was extracted with methylene chloride (120 nmol) and the aqueous phase was extracted again with methylene chloride (50 nmol). The combined organic extracts were washed with water (2 x 120 ml) and concentrated to give an oil (15.6 g). In a filtered and stirred solution of the oil in ethyl acetate (100 ml), 5-sulphosalicylic acid (3.3 g, 0.13 ml) was added in 10 ml of isopropyl alcohol (IPfi). The resulting mixture was stirred at room temperature for half an hour. The resulting solid was re-suspended in ethyl acetate (50 nmol) and recrystallized from IPS (60 rnl) to give a white solid (7.2 g, 0.01 mol). The solid was added to methylene chloride (35 ml) and water (50 ml) and basified with 40% NaOH. The mixture was stirred at room temperature for 15 minutes and separated. The aqueous phase was extracted again with methylene chloride (25 nmol) and the combined organic extracts were washed with water (35 nmol). The organic solution of the product was concentrated to an oil (4.9 g) and characterized by 1 H-NMR spectroscopy. 1 H-NMR (300 MHz, CDC13): 6 = 4.62 (d, 3 = 14 Hz, 1H), 4.92 (d, 3 = 14 Hz, 1H), 5.31 (d, 3 = 26 Hz , 2H), 5.35 (s, 1H), 5.48 (s, 2H), 6.66 (rn, 2H), 6, 98 (rn, 2H), 7.10 (d, 3 = 8 Hz , 2H), 7.20 (rn, 3H), 7.28 (d, J = 8 Hz, 2H), 7.41 (m, 1H), 7.64 (s, 1H), 7.71 (s) , 1H), 7.88 (s, 1H) pprn. vi) (2R, 3S) -2- (2,4-d? fluorophenyl) -l- (lH-l, 2,4-tr? azol-1-yl) -3-riH-l, 2.3 -tr? azole-4 ~? l) phenyl] -2- ethanol (R) ~ 3- (4- [l-henn? l-lH-l, 2,3-tr? azol-5- ? l] phen? l) -2- (2,4-d? flurorfen? l) -l- (lH-l, 2,4-tr? azol-l-? l) -3-buten-2-ol (25 g, 0.05 mmol) in 2400 rnl of methanol and hydrogen at a pressure of 414 kPa with 5% palladium on carbon (0.1 g) for 20 hours at 100 ° C. After separating the catalyst by filtration, the product solution was concentrated to a white foam (19.1 g, 0.05 mmol). A sample was crystallized from ethanol / water and characterized by 1 H-NMR spectroscopy. It had a melting point of 121 ° C. 1 H-NMR (300 MHz, CDCl 3): δ = 1.16 (d, 3 = 7 Hz, 3H), 3.35 (q, 3 = 7Hz, 1H), 3.94 (d, 3 = 15 Hz, 1H), 4.70 (s, 1H9, 4.81 (d, J = 14 Hz, 1H), 6.78 (m, 2H), 7.50 (rn, 1H), 7.57 (d, 3 - 8Hz, 2H), 7.70 (s, 1H), 7.74 (s, 1H), 7.80 (d, 3 = 8 Hz, 2H), 7.95 (s, 1H) ppm EXAMPLE 67 (2R, 3S) -2- (2,4-difluorophenyl) -3- (4- [1-r-ethylpypyrazol-5-yl enyl) -! - (!, 2,4-triazol-1-yl) butan-2-ol A solution of (2R) -2- (2,4-difluorophenyl) -3- (4-Cl-methyl? Irazol-5-yl] phenyl) -1- (1, 2,4-triazol-1-yl) -3-buten-2-ol (2.0 g, 5 min. - see Preparation 53) in 50 mL of ethanol was hydrogenated at a pressure of 333 kPa on 5% palladium on charcoal. (0.2 g) for 18 hours at 50 ° C. Another batch of catalyst (0.2 g) was added and the hydrogenation was continued for 18 hours more. The mixture was filtered through "firbocel" (trademark) and the filtrate was evaporated under reduced pressure.

The residue was chromatographed on silica, eluting with a gradient of ethyl acetate / haxane / diethylamine (0: 95: 565: 33: 2). Fractions containing the desired product were combined and evaporated under reduced pressure. The residue was dissolved and reevaporated from ethyl acetate (three times) and then ether (three times) to give a colorless solid. The solid was recrystallized from aqueous ethanol to give the title compound 81.25 g, 62%) as colorless solid, m.p. 144-145 ° C, Ca] D25 - -107 ° (c = 0.1%, CH2Cl2). finalysis for C22H21F2N5O: Found: C 64.26, H 5.119, N 17.07 Calculated: C 64.54, H 5.1.1, N 17.10%.

EXAMPLE 6B (2R, 3S) -2- (2,4-Difluorophenyl) -3- (4 - [: 4-chloro-lt2,3-triazol-5-yl-yl) phenyl-1- (1,2, 4-triazol-1-yl) butan-2-ol A solution of (2R, 3S) -2- (2,4-difluorophenyl) -3- (4-Cl, 2,3-triazol-4-yl) phenyl3-l- (1, 2,4-triazole-1) -il) butan-2 ~ ol (2.0 g, 5 mmol - a product of Example 66) in 100 mL of dichloromethane was treated with N-chlorosuccinimide (0.81 g, 6 mmol). The mixture was stirred and irradiated at room temperature for 3 days and then evaporated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (50 rnl) and saturated sodium bicarbonate 820 rnl). The organic layer was washed with brine (20 ml), dried over sodium sulfate and evaporated to reduced dryness. The residue is chromatographed on silica, with a gradient of haxane / ethyl acetate (2: 13: 2). The fractions containing the desired product were combined and evaporated to give a colorless oil. The oil was recrystallized from ethanol / water to give the title compound (1.01 g, 47%) as a colorless solid, m.p. 113-115 ° C, C «] D25 = -50 ° (c = 0.1%, rnet a no L). fine i i sis for C20H17F2N6O: Found: C 55.91, H 3.84, N 19.80 Calculated: C 55.80, H 3.98, N 19.51%.

EXAMPLES 69 fi 71 The following examples were prepared by a methodology similar to that of Example 68, substituting the N-chlorosuccinimide for the appropriate halogenating agent (in Example 71, the reaction was carried out in acetomtrile at reflux) EXAMPLES 72 OR 77 The following compounds were prepared using the procedure of Example 1; in each case, only the main enantiomer (2R, 3S) was isolated. ° r EXAMPLE 78 (2R, 3S) -2- (2J -Difluorophenyl) -3- (4-Ctetrazol-5-yl] -phenyl) -l- (1,2,4-riazol-1-yl) utan-2 ol A solution of (2R, 3S) -2- (2, -di luorophenyl) -3- (4-C l ~ benzyltetra2? L ~ 5 ~ il] phenyl) -l- (1,2,4-triazole-1) ~ .il) butan -2-ol (1.00 g, 2 mmol ~ product of example 77) in 30 ml of methanol was hydrogenated at a pressure of 666 kPa on 5% palladium on charcoal (0.2 g) for 18 hours at 50 ° C. The mixture was filtered through flrbocel ™, the filtrate was evaporated under reduced pressure. The residue was chromatographed on silica, eluting with dichloromethane / methanol / acetic acid (95: 5: 1). The fractions containing the desired product were combined and evaporated under reduced pressure, the residue was presipitated in ethanol with water to give the title compound (0.68 g, 85%) as a colorless solid, e.g. f.117-120 ° C, [CÜD25 = -47 ° (c = 0.1%, CH3OH). Analysis for C19H17F2N7O.I / 4H2O: Found: C 56.82, H 4.31, N 22.84 Calculated: C 56.78, H 4.38, 24.40%.

EXAMPLE 79 (2R, 3S / 2S, 3R) -2- (2, -Dif luorophenyl) -3- (5-C? Irazol-4-yl] pi ridin-2-yl) -! - (!, 2, -triazol-l-il) butan-2-ol (2R, 3S / 2S, 3R) -2- (2,4-difluorophenyl) -3- (5- [l-tr? Phen? Lmet? I-4? Irazol? L] r? d-n-2-yl) -l- (i, 2,4-triazol-1-yl) butan-2-ol solid (0.65 g, 1 mrnol) to a mixture of tpfluoroacetic acid (0.8 nl) and water (0.3 ml) at 0 ° C. The solution was stirred at 0 ° C for one hour before quenching the reaction with a saturated sodium carbonate solution (30 rnl). The mixture was extracted three times with ethyl acetate (25 nmol) and the combined organic layers were dried over sodium sulfate and then evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a gradient of dichloroethane / ethanol (100: 095: 5). Fractions containing the desired product were combined and evaporated under reduced pressure. The crude product was dissolved in ether and evaporated to give a colorless solid. The solid was recrystallized from hexane / ethyl acetate to give the title compound (0.25 g, 63%) as a colorless solid, m.p. 186-189ßC.

Analysis for C 20 H 18 F 2 N 6 O: Found: C 60.44, H 4.10, N 21.26 Calculated: C 60.60, H 4.58, N 21.20%.

EXAMPLE 80 (2R, 3S / 2S, 3R) -2- (2, -Di luo-phenyl) -3- (5-Cimidazol-1-yl-3-pyridyl-2-yl) -l- (1, 2,4-riazole- l-il) butan-2-ol An intimate mixture of (2R, 3S / 2S, 3R) -2- (2,4-D? Fluorophen? L) -3- (5-brorno ?? r? D? N-2-? L) -1- (1, 2,4-tpazol-1-yl) butan-2-ol (0.5 g, 1.2 mmole), copper bronze (0.16 g, 2.5 mmole), irnidazole 80.42 g, 6 mrnols) potassium carbonate (0.34 g, 2.5 mmol) was heated with stirring at 140 ° C for 2 hours. The cooled mixture was suspended in a mixture of dichloromethane (100 ml) and an aqueous solution of the disodium salt of ethylenediaminetetraacetic acid (5%, 100 ml) and stirred at room temperature for one hour. The suspension was filtered through Hyflo ™ and the layers were separated. The organic phase was dried with brine (20 nmol), dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a dichloromethane / methanol gradient (100: 097: 3). Fractions containing the desired product were combined and evaporated under reduced pressure. The crude product was dissolved in ether and evaporated to give the title compound (0.17 g, 14%) as colorless solid, m.p. 161-163 ° C. Analysis for C 20 H 18 F 2 N 6 O Found: C 60.52, H 4.46, N 21.87 Calculated: C 60.60, H 4.58, N 21.20%.

EXAMPLE 81 (2R, 3S / 2S, 3R) -2- (2, -Dif luorophenyl) -3- (5-C? Irazol-1-yl] pyridin-2-yl) -! - (! 2.4 -triazol-l-il) butan-2-ol The title compound was prepared from pyrazole by a procedure similar to that of Example 80, as a colorless solid, m.p. 121-123 ° C Analysis for C20H18F2 6O.I / 2 H2O: Found: C 59.68, H 4.49, N 20.82 Calculated: C 59.63, H 4.72, N 20.73%.

EXAMPLE 82 (2R.3S / 2S, 3R) -2-2 2, -Di luo-phenyl) -3- (5- [1-ethoxymethyl-1- (1, 2,3-triazol-5-yl-3-pyridin-2-yl ) -l- (1, 2,4-riazol-1-yl) butan-2-ol A hexane solution in hexane (2.5 M, 2.7 nl, 6.8 mrnol) was added to a solution of 1-hethoxylmethyl-1,2,3-trolol (0.86). g, 6.8 mrnols) in 25 rnl of dry THF in a nitrogen atmosphere at -70 ° C. The mixture was stirred for 15 minutes and treated with a solution of zinc chloride in THF (0.5M, 3.7 ml, 6.8 mmol) and then allowed to warm to room temperature. To this mixture were added tetrakis (tpfemlfosf? Na) palad? O (0) (0.08 g, 0.1 mmoles) and (2R, 3S / 2S, 3R) -2- (2,4-d? -fluorophenyl) -3- (5-Bromop? R? Din-2-yl) -l- (1, 2,4-triazol-1-yl) butan-2-ol (0.7 g, 1.7 mmol) and the mixture was refluxed for a mean hour. Two additional batches of palladium catalyst (0.08 g) were added before conversion was achieved. Then the reaction mixture was heated to reflux for 18 hours. The cooled reaction was quenched with an aqueous solution of disodium salt of ethylenediaminetetraacetic acid (5%, 50 nmol) and the layers were separated. The aqueous phase was extracted again with ethyl acetate (2 x 50 mL) and the combined layers were dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed in silica, eluting with a dichloromethane / methanol gradient (100: 097, 5: 2.5). Fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (0.62 g, 80%) as a colorless foam. Analysis for C 22 H 23 F 2 N 7 O 2: Found: C 58.47, H 5.15, N 21.33 Calculated: C 58.02, H 5.09, N 21.53%.

EXAMPLE 83 ñ 86 The following Examples were prepared from the appropriate 1-rnethyl or 1-ethoxyrnethylhetrocycle and (2R, 3S) - or (2R, 3S / 2S, 3R) -2- (2,4-difluorophenyl) -3- (5 -bromopyridin-2-yl) -l- (1, 2,4-triazol-1-yl) butan-2-ol, using a procedure similar to that of Example 82. or EXAMPLE 84 1 H-NMR (300 MHz, CDC13): 6 = 1.14 (d, 3H), 1.26 (t, 3H), 3.80 (rn, 3H), 4.15 (d, 1H), 4.72 (d, 2H), 5.57 (s, 2H), 6.80 (rn, 2H), 7.06 (s, 1H), 7.50 (d, 1H), 7.54 (s, 1H), 7.59 (rn, 1H), 7.94 (s, 1H), 8.01 (s, IH), 8.30 (dd, IH), 9.11 (d, 1H) pprn., EXAMPLE 87 1 H-NMR (300 MHz, CDC I 3): 6 = 1.12 (d, 3 H), 3.68 (s, 3 H), 3.72 (q, 1 H), 4.17 (d, 1 H), 4 , 75 (d, 1H), 6.7-6.85 (m, 2H), 7.1-7.3 (m, 9H), 7.48 (d, 1H), 7.60 (in,? H), 7.75 (dd, 1H), 7.92 (s, 1H), 8.60 (d, 1H) ppm.

EXAMPLE 88 (2R, 3S / 2S, 3R) -2- (2,4-Di fluoroenyl) -3- (5-C 1,2,3-triazol-4-yl] pyridin-2-yl) -! - ( !, 2, -triazol-l-yl) -butan-2-ol A solution of (2R, 3S / 2S, 3R) -2- (2,4-d? Fluorophenyl) -3- (5-Cl-ethoxyrnetyltriazol-5-yl] pyridin-2-yl) -l- (1 , 2, 4-triazol-1-yl) butan ~ 2-ol (0.09 g, 0.2 mrnol - product of Example 82) in 8 ml of ethanol was diluted with 4 ml of water and treated with concentrated hydrochloric acid (1 ml). ). The mixture was heated at 80 ° C for an hour and a half, then the volume was reduced to 3 rnl and diluted with 10 rnl of water. The solution was neutralized with a saturated solution of sodium bicarbonate, with formation of a colorless precipitate. The suspension was extracted with ethyl acetate (3 x 30 mL) and the combined extracts were washed with brine (20 mL), dried over sodium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (0.05 g, 65%) as a colorless solid, m.p. 196-197 ° C. Par-a analysis C19H17F2N7O: Found: C 56.91, H 4.28, N 24.60 Calculated: C 57.43, H 4.31, N 24.67%.

EXAMPLES 89 AND 90 The following examples were prepared from (2R, 3S) ~ or (2R, 3S / 2S, 3R) -2- (2,4-difluorophen? L) -3- (1-ethoxy-methylheterocycle) -5-py? Din-2-yl) -l- (1, 2,4-triazol-1-yl) butan-2-ol, using a procedure similar to that of Example 88.

X = N or CH St 1. 07 EXAMPLE 91 (2R, 3S) -2- (2,4-Di-chlorophenyl) -3- (5-Cl-methylpyrazol-5-yl] pyridin-2-yl) -l- (1, 2,4-triazole- 1-yl) butan-2-ol and (2R, 3S) -2- (2,4-di-luo-phenyl-3- (5-C 1 -methylpi-3-yl) pyri-din-2-yl) - 1- (1, 2,4-triazol-1-yl) butan-2-ol, dihydrochloride, dihydrate c 3on? tjC? j Methyl p-toluenesulfonate (0.38 g, 2 rnrnol.es) was added to a stirred suspension of (2R, 3S) -2- (2,4-difluorophenyl) -3- (pyridin-2-yl) -l- ( 1,2,4-triazol-1-yl) butan-2-ol (0.4 g, 1 rnmolee - the product of Example 90) and potassium carbonate (0.56 g, 4 rnmoles) in DMF (10 rnl). The mixture was stirred at room temperature for 3 days and then poured into 100 mL of water and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a dichloromethane / methanol gradient (100: 0 98: 2). Fractions containing upper spot Id were pooled by TLC (dichloromethane / rnetalol 98: 2, Rf-0.50) and evaporated under reduced pressure. The oil product was dissolved in ether and precipitated by the addition of ethereal HCl. The solvent was removed under reduced pressure and the solid was suspended in ether and evaporated three times to give the (2R, 5) -2- (?, -di-fluoro-phenyl) -3 dihydrochloride (5 - Cl-meth? Razol- -? Llp? R? D? N-2-? L) -l- (l, 2,4 ~ tr? Azol ~ l-? L) butan ~ 2 ~ ol dihydrate (0.17 g, 33%) pf 163-167 ° C, Talo25 - +1?, 4 ° C (c - 0.1%, ethanol). ttnaUsis for C21H20F2NeO.2HCl.2H2O: Found: C 49.00, H 4.63, N 16.34 Calculated: C 50.31, H 4.83, N 16.70%. Fractions containing the lower spot were pooled by TLC (icloronetane / rnetanol 98: 2, Rf-0.48) and evaporated to give- (2R, 3) -2- (2,4-difluorophenyl) ~ 3 - (5-C l ~ rnet? Lp? Razol-5-? L? R? Dm-2-? L) ~ l- (1, 2, 4-tpazol-l-l) butan-2-ol (0.015 g, 3%) as a colorless foam. This product was identical to the product of Example 83 by TLC and 1 H-NMR spectroscopy.

EXAMPLE 92 AND 93 The following compounds were prepared from (2R, 3S) -2- (2,4-d? Luorophenyl) -3- (5 ~ Cp? Razol-3? L) -5- ?? r ? dm-2-? l) -l- (1, 2,4-tpazol-1-yl) butan-2-ol, using a procedure similar to that of Example 91. In each case, only derivative 3 was isolated. - ?? razol? t? co 1-sust? tuido.

EXAMPLE 94 (2R, 3S / 2S, 3R) -2- (2,4-D fluorophenyl) -3- (2-l-methylp? Razol-5-yl] pyr? D n-5-yl) -l- (1, 2,4-tnazol-1-yl) butan-2-ol A solution of (2R, 3S / 2S, 3R) -2- (2, 4-d? Fluorophen? L) -3- (2-tr? Fluorornet ilsul foniloxypyr? D? N- -? L) - l- (l, 2,4-tr? azol-1-? l) butan-2-ol (0.3 g, 0.6 rnmoles), (l-rnet? l-5-pyrazole 11) t rirneti-istanone (0.6 g, 2.4 mmol) , lithium chloride (0.08 g, 1.8 mrnoles) and tetra? s (tr? femlfosf? na) palad? o (0) (0.04 g, 0.03 rnmoles) in 15 ml of dioxane was heated in a nitrogen atmosphere for 24 hours. 20 rnl of water were added and the solution was basified with an aqueous solution of ammonia. The mixture was extracted with dichloromethane (50 nmol) and the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a gradient of dichloromethane / methanol (100: 0 99: 1). Fractions containing the desired product were combined and evaporated under reduced pressure. The crude product was triturated with ether / hexane to give the title compound (0.18 g, 70%) as a colorless solid, m.p. 158-160 ° C. final i sis for C21H20F2N6O: Found: C 6.1.46, H 4.91, N 19.58 Calculated: C 61.24, H 5.04, N 19.84%.

EXAMPLE 95 (2R, 3S / 2S, 3R) -2-C2,4-Difluorophenyl) -3-C5- (1-methylimidazol-5-illpyridin-2-yl) -! - (!, 2, -triazole-1 -il) butan-2-ol The title compound was prepared from (2R, 3S / 2S, 3R) -2- (2,4-di fluoro-phenyl) -3 ~ (5- Cl-rnethyl-2-phenylthiomidazol-5-yl] pyridine ~ 2-yl) -1- (1, 2,4-triazol-1-yl) butan-2-ol, by a procedure similar to that of Example 35, as a colorless foam. Analysis for C 21 H 20 F 2 N 6 O: Found: C 58.87, H 5.18, N 19.61 Calculated: C 58.87, H 4.85, N 19.28%.

EXAMPLE 96 (2R, 3S) -2- (2,4-D? Fluorophen I) -3- (4-C3-mercapto-4-methyl-l, 2,4-triazole-5-? 3-phenyl) -l- (1, 2,4-triazol-1-yl) butan-2-ol A solution of N-? Net? L-4- was refluxed. { 2- 2,4-d? Fluorophen? L3 -2-hydrox? -l-Cl, 2, -tr? Azol-l-? LHbut-3-ylbenzoylthiosemicarbapda (2.1 g, 4.5 rnrols) in 50 ml of ethanol and treated with a solution of sodium rnetoxide (30%, 5.5 mmol) in portions over 24 hours. The volume of the mixture was reduced to 20 rnl under reduced pressure and the mixture was partitioned between ethyl acetate (100 ml) and water (50 ml). The aqueous layer was back extracted with ethyl acetate (3 x 50 mL), the combined organic extracts were washed with brine (50 mL), dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a gradient of ethyl acetate / hexane (1: 1 3: 2). Fractions containing the desired product were combined and evaporated under reduced pressure. The crude product was triturated with ether to give the title compound (0.66 g, 33%) as colorless solid, m.p. 131-134 ° C, COÜD25 = -38 ° C (c-0.1%, methanol). 1 H-NMR (300 MHz, CÜCl 3): d = 1, 2 (d, 3H), 3.5 (q, 1H), 3.8 (d, 1H), 4.8 (d, 1H), 4.95 (d, 1H), 6.80 (rn, 2H), 7.50 (in, 1H), 7.6 (d, 2H), 7.7 (d,? H), 7.75 (s, 1H), 7.8 (s, 1H), 11.0 (s broad, 1H) pprn.

EXAMPLE 97 (2R, 3S) -2- (2,4-Difluorophenyl) -3- (4-C4-methyl-l, 2,4-triazol-3-yl] phenyl) -! - (1,2, - riazol-1-yl) butan-2-ol A solution of (2R, 3S) -2- (2,4-difluorophemethyl) -3- (4- [3-rnercapto-4-rnet] -1,2,4-triazole-5? Was heated to reflux. l3phen? l) -l- (1, 2,4-triazol-1-yl) butan-2-ol (0.6 g, 1.4 mmol) in 10 mL of acetic acid and treated dropwise with aqueous hydrogen peroxide ( 30%, 0.5 ml, 8 mmol). After a further half hour at reflux, the mixture was cooled to room temperature and evaporated under reduced pressure. The residue was partitioned between ethyl acetate (20 ml) and a saturated solution of sodium bicarbonate (20 ml). The aqueous phase was washed with brine (20 nmol), dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with dichloromethane / methanol (96: 4). Fractions containing the desired product were combined and evaporated under reduced pressure. The crude product was recrystallized from ethyl acetate / hexane to give the title compound (0.17 g, 30%) as a colorless solid, m.p. 118-120 ° C, CaJ25 - -48 ° (c = 0.1%, methanol). final i sis for C21H20F2N6O. ÍH2O: Found: C 60.14, H 5.05, N 20.00 Calculated: C 60.60, H 4.90, N 20.10% .: EXAMPLE 98 (2R, 3S) -2- (2, -Dif luoro phenyl) -3- C3-methylpi-4-phenyl-4-yl3) -I- (1, 2,4-triazol-1-yl) butan- 2-ol A solution of potassium hydroxide (0.26 g, 4. 6 mmole) in 2.8 ml of water and a solution of (2R, 3S) -2- (2,4-difluorophenyl) -3- (4-C3-methyl-5-trirnethyl-illpyrazol-4-yl] phenyl ) -l- (1, 2,4-triazol-1-yl) butan-2-ol (0.22 g, 0.45 mmol) in 12 ml of ethanol and the mixture was refluxed for 4 hours. The cooled mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (20 ml) and water (25 ml). The aqueous phase was extracted again with ethyl acetate (2 x 20 mL) and the combined organic layers were washed with brine (20 mL), dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica, eluting with a dichloromethane / methanol gradient (100: 1 96: 4). Fractions containing the desired product were combined and evaporated under reduced pressure. The crude product was recrystallized from ethyl acetate / hexane to give the title compound (0.11 g, 56%) as a colorless solid, = -50 ° (c. = 0.1%, methanol). Analysis for C22H22F2N5O: Found: C 64.2, H 4.9, N 16.7 Calculated: C 64.5, H 5.2 N 17.1% .: EXAMPLE 99 (2R, 3S / 2S, 3R) -2- (2,4-Di luoro-enyl) -3- (5- l, 2,3-triazol-2-yl] pyridin-2-yl) -l- (1, 2,4-triazol-1-yl) -butan-2-ol A solution of 2- (1-bromoetyl) -5- (1, 2, 3-tr? Azol-2? L) p? Pdma (0.75 g, 3 mmol) and l- ( 2,4-d? Fluorophen?) -2- (1, 2,4-tr? Azol-1-yl) ethanone (0.66 g, 3 11? rnrols) in 10 ml of THF to a stirred solution of zinc (0.58 g, 9 mrnol) and piorn powder (0.03 g) in 8 ml of 1 HF, in a nitrogen atmosphere. 1.5 mmol) of iodine and the mixture was stirred at room temperature for 1 hour. A solution of the disodium salt of the acid et i lendiarnmot etraaoeti co (5%, 10 rnl) was used to inactivate the reaction and the mixture < ? Continued stirring at temp a u dur'ante environment half an hour more. Ethyl acetate (30 ml) and water ('JO i) and the mixture < I filtio through? HyflotM. > < ?, r? that the layers separated. The organic phase was washed with brine (3 x 30 mL), dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a dichloromethane / methanol gradient (100: 0 98: 2). The fractions containing the desired product were combined and evaporated under reduced pressure to give an oil which was triturated with ether to give a colorless solids (0.42 g) which was characterized as a mixture of the desired product and the starting ethanone derivative. The impure product was dissolved in 30 ml of ethanol and treated with borohydride (0.05 g, 1.3 mmol), after 1 hour, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (20 ml) and a saturated sodium carbonate solution (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 mL) and the combined organic layers were washed with brine (20 mL), dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a dichloromethane / methanol gradient (100: 1: 99: 1). Fractions containing the desired product were combined and evaporated under reduced pressure. The crude product was triturated with ether to give the title compound (0.12 g, 10%) as a colorless solid, m.p. 170-171 ° C. finalysis for C19H17F2N7O: Found-a: C 57.39, H 4.10, N 25.00 Calculated: C 57.43, H 4.31, N 24.67%: The following preparations illustrate the preparation of some of the starting compounds used in the previous examples.

PREPARATION 1 2- (2, -Dif luoro phenyl) -3- (4-ci, 2,3-triazol-2-yl-phenyl) -] .- (1,2,4-triazol-1-yl) -buten -2-? ol V 2- 2-,, 4-di fluoro phenyl) -3- (4-Cl, 2,3-triazol-1-ylphenyl -1- (1,2,4- -triazol-1-yl) -3 -butan- 2-ol An intimate mixture of 2- (2,4-di-fluorophenyl) -3- (4-iodo-phenyl) -l- (1,2,4-t-riazol-1-yl) -3 was stirred at 140 ° C. for 8 hours. -buten-2-ol (2.0 g, 4.4 rnrnoles - see Preparation 20), copper powder (0.6 g, 9.4 rnrnoles), potassium carbonate (1.0 g, 7.3 rnmoles) and 1, 2,3-triazole (2.6 g, 37.6 rnmoles). The mixture was cooled to 100 ° C and treated with a suspension of the disodium salt of the etherendiaini notetraacetic acid (10 g, 26.8 mmol) in 100 ml of water. The suspension was basified with a saturated sodium carbonate solution and extracted with di chloro-methane. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with ethyl acetate / hexane (70:30). Fractions containing the stain were collected faster and evaporated under reduced pressure to give the 1,2,3-trolol-2-isomer (420 rng, 24%) as a colorless foam. , which was characterized by iH-NMR spectroscopy (300 Ml-lz, CDCI3): 6 = 4.62 (d, 1H), 4.97 (d, 1H), 5.22 (s, 1H), 5, 32 (s, 2H), 6.73 (rn, 2H), 7.42 (d, 2H), 7.48 (rn, 1H), 7.79 (s, 2H), 7.81 (d, 2H) ), 7.96 (s, 1H), 8.00 (s, 1H) pp. Continuing elution of the column with ethyl acetate, after evaporation under reduced pressure, the 1,2,3-tr? Azole-l-? L-? Sómero principal (650 ng, 37%). A sample of this product was recrystallized from ethyl acetate / hexane, m.p. 172-173 ° C. final 1 sis for C20H16F2N6O: Found: C 61.12, H 4.04, N 21.14 Calculated: C 60.91, H 4.09, N 21.31%. 1 H-NMR (300 MHz, CDCl 3): δ = 4.62 (d, 1H), 4.98 (d, 1H), 5.34 (s, 1H), 5.37 (s, 2H), 6, 76 (m, 2H), 7.47 (d, 2H), 7.49 (m, 1H), 7.66 (d, 2H), 7.83 (s, 1H), 7.86 (s, 2H), 7.98 1H) pprn, PREPARATIONS 2 TO 7 The following compounds were prepared in a manner similar to the procedure of Preparation 1, employing the appropriate heterocycle in place of 1,2,3-triazol.

Analysis (theoretical in parentheses)? - MN Prep. p.f. • C) Formula (300 MHz) n ° Molecular Het d l p] -04-205 63.98 4.31 17.79 C2? HpF, NbO (64, 12 4.36 17.80) N "^ N L = Oil CaH17F2N50 4.62 (d, 1H), 4.96 (d, 1H), 5.18 (broad s, 1H), 5.31 (s, 2h), 6.48 (m, 1H), 6, 73 (m, 2H), 7.39 (d, 211), 7.48 (m, 1H), 7.61 (d, 211), 7.72 (d.lll), 7.80 (i, lll) ), 7, ti) (: ,, lll),!, < > • (d, 1 II). I- 'Oil C21H, »F, NO), 81 (s nclio, 211), 4, 1 (d, III), 4,' i ', (d, 111), 5.30 (a, 2l?) , 6.64-6.80 (m, N <%, *** 2H), 7.25 (, 1H), 7.30 (d, 211), 7.44 (d, 2H), 7 , 45 (rtl, 1H), 7.65 (d.lll), 7.60 (s, 111), 7.81 (s, 111).

Analysis (theoretical in parentheses) '11 KMN Prep. p £. CC) Formula (100 MHz) N "Molecular Het d [ppm] NJ? PREPARATION 8 3- [4- (3-Acetam? Dopyrazol-1-yl) phenyl] -2- (2,4-di luoro-phenyl) -l- (1, 2,4-riazol-1-yl) - 3-buten-2-ol MeCOCl / Et3N The product of Preparation 4 (0.7 g, 1. 7 mmol) in dichloromethane (15 rnl) and then treated with tpetilarnine (0.25 nl, 1.8 rnmoles) followed by acetyl chloride (0.13 rnl, 1.8 mrnol). The mixture was stirred at room temperature for 18 hours, diluted with dichloromethane (50 ml) and then washed twice with water (20 ml). The organic phase was dried over magnesium sulfate and then evaporated under reduced pressure to give the title compound (0.7 g, 91%) which was characterized by 1 H-NMR spectroscopy. 1 H-NMR (300 MHz, CDC13): 6 = 2.18 (t, 3H), 4.63 (d, 1H), 4.95 (d, 1H), 5.29 (s, 3H), 6, 72 (rn, 2H), 6.93 (d, 1H), 7.35 (d, 2H), 7.42 (rn, 1H), 7.43 (d, 2H), 7.79 (d, 1H) ), 7.80 (s, 1H), 7.82 (s, 1H), 8.39 (s, 1H), pprn.

PREPARATION 9 3- [4-l3-Methylsulfonamidopyrazol-l-yl) phenyl1-2- (2,4-di luoro phenyl) -! - (1,2,4-riazol-l-yl) -3-buten-2 -ol The title compound was prepared by the procedure of Preparation 8, using rnetanosulfonyl chloride instead of acetyl chloride. The crude product was triturated with ether to give the title compound, m.p. 130-14Q ° C, which was characterized by * H-NMR spectroscopy. 1 H-NMR (300 MHz, CDC13): δ = 3.11 (s, 3H), 4.62 (d, 1H), 4.97 (d, 1H), 5.20-5.30 (rn, 3H) ), 6.42 (d, 1H), 6.70-6.80 (rn, 2H), 6.99 (s, 1H), 7.36 (d, 2H), 7.42 (rn, 2H) , 7.44 (d, 2H), 7.80 (d, 1H), 7.81 (s, 1H), 7.84 (s, 1H), ppm.

PREPARATION 10 2- (2,4-Difluorophenyl) -3- [4- [3- (3-methylureido) pyrazol-1-yl] phenyl) -! - (1,2,4-triazol-1-yl) - 3-buten-2-ol The product of Preparation 4 (0.7 g 17 rnmoles) was dissolved in dichloromethane (15 rnl) and treated with methyl isocyanate (0.15 i, 2.5 mmol). The solution was stirred at room temperature for 18 hours, and then washed twice with water (20 rnl), dried over magnesium sulfate and then evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with ethyl acetate / rnetanol (19: 1). The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (0.36 g, 45%). Analysis for C 23 H 21 F 2 N 7 O 2: Found: C 58.82, H 4.57, N 20.49 Calculated: C 58.22, H 4.46, N 20.66%.

PREPARATION 11 2- (2,4-Difluorophenyl) -3- (4- [lH-1, 2,3-triazol-4-yl] phenyl) -l- (1, 2,4-triazol-1-yl) -3-buten-2-ol (i) A mixture of 2- (2,4-difluorophenyl) -3-C4- (iodo-phenyl) -l- (1, 2,4-triazol-1-yl) -3-buten-2-ol ( 7.0 g, 15.5 mmol, see Preparation 20), trimethylsilylacetylene (2.6 mmol, 18.5 mmol), cuprous iodide (0.015 g, 0.15 mmol), bis (triphenylphosphine) palladium (II) dichloride (0.21 g, 0.3 mmol) and triethylamine ( 80 ml) was stirred at room temperature under nitrogen for 24 hours. The volatile materials were removed under reduced pressure and the residue was partitioned between dichloromethane (200 rnl) and a solution of ethylenediaminetetraacetic acid (2 g) in 100 rnl of water. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The raw product is blunt t- or graffiti in Llice, eluting with d-chloroethane / methanol (95: 5). The tractions containing the desired product were combined and evaporated under reduced pressure to give? - (2, 4-d? Fl uorof m 1) -3- (4- [rirnet-lylethyl] feni 1) -1- ( 1, 2, 4-t nazol-1-? L) - 3 -buten- 2 - oi (6.4 ng, 98%) as yellow foam that was characterized by iH-NMR (30 MHz, CDC13) spectroscopy: 6 - 0.22 (s, 9H), 4.57 (d, 1H), 4.09 ( d, 1H), 5.16 (o, ül), 5.26 (d, 2H), 6.60-6.80 (rn, 2H), 7.21 (d, 2H), 7.38 (d , 2H), 7.42 (m, IH), 7.80 (s, 2H) ppm. (11) The product of part (1) was dissolved in a mixture of aqueous potassium hydroxide (IM, 15 ml) and methanol (30 ml) and stirred at room temperature for 3 hours. The mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane (100 rnl) and water (50 ml). The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica, with ethyl acetate / methanol. The fractions containing the desired product were combined and evaporated under reduced pressure to give 2- (2,4-d? Fluorophen?) -3- (4-et? N? L phenyl) -1- (1 , 2, 4-tnazol-1-yl) -3-buten-2-ol (4.8 ng, 93%) co or yellow foam that was characterized by 1 H-NMR spectroscopy (300 MHz, CDCl 3): = 3.08 (s, 1H), 4.58 (d, 1H), 4.92 (d, 1H), 5.19 (broad s, 1H), 5.29 (s, 1H), 6.60-6.80 (m, 2H), 7.24 (d, 2H), 7.39 (d, 2H), 7.41 (rn, 1H), 7.80 (s, 1H), 7.82 (s, 1H) , ppm. (iii) A sample of the product of part (11) (2.5 g, 7 rnrols) and azidotrimethylsilane (5 ml) was heated at reflux for 20 hours by adding azidotr irnet L1 additional silane (3 x 5 ml) at 6 hour intervals . The excess of azidotri etiisi laño was then removed under reduced pressure. The residue was dissolved in 50 ml of dichloromethane and the resulting solution was washed with water (3 x 20 ml), dried over magnesium sulphate and evaporated under reduced pressure. The crude product (2.5 g) was chromatographed on silica, eluting with a gradient of d-chloro-methane / mo-t-anol (98: 2, 96: 4, 90:10). The fractions containing the desired product were evaporated under reduced pressure to give the title compound (1.0 g, 37%) as an orange colored foam which was characterized by 1 H NMR spectroscopy (300 MHz). , CDCl 3): 6 = 4.62 (d, 1H), 4.96 (d, 1H), 5.30 (s, 1H), 5.32 (d, 2H), 6.70-b, 80 ( rn, 2H), 7.38 (d, 2H), 7.46 (rn, 1H), 7.72 (d, 2H), 7.80 (s, 1H), 7.83 (s, 1H), 7.94 (s, IH), pprn.

PREPARATION 12 2- (2,4-Difluorophenyl) -3- (4-Cl-ethoxymethyl-l, 2,4-triazol-5-yl] phenyl) -! - (! 2, -triazol-1-yl) -3-buten-2-ol A solution of 1-ethoxyethyl-1,2,4-triazole (0.79 g, 6.2 nmol-see Preparation 27) in tetrahydrofuran (THF) (8 ml) stir in a nitrogen atmosphere at -70 ° C before its treatment with a solution of n-buti 11 ir. in hexane (2.5M, 2.5 nrn, 6.2 mrnol). The mixture was stirred for 15 minutes and treated with an anhydrous zinc chloride solution (1.2 g, 9.3 mrnol) in THF "(8 ml) and then warmed to room temperature. they added tet rak s- (tp feml fosMna)? alad? o (Q) (9.00 g, 0.05 mmol) and 2- (2,4-difluorophenyl) 3- (4-iodophen? l) -l- (1, 2,4-tpzol-1-yl) -3-buten-2-ol (0.7 g, 1.5 mrnol - see Preparation 20) and the mixture was refluxed for 4 hours. After cooling, a disodium salt suspension of the etiiendilarninoteet raacet LCO acid (10 g, 27 mrnol) was added and the mixture was adjusted to pH 8 with a saturated sodium carbonate solution and extracted with dichloro ethane (2 x 100 rnl). The combined extracts were dried over magnesium sulfate and evaporated under reduced pressure, the residue was chromatographed on silica, eluting with a dichloromethane / methanol gradient (98: 2, 97: 3, 95: 5). desired product, evaporated under pressure n reduced and the residue was triturated with ether to give the title compound (0.55 g, 78%) as colorless solid, m.p. 160-162 ° C. Analysis for C23H22F2N602: Found: C 61.43, H 4.82, N 18.71 Calculated: C 61.05, H 4.90, N 18.58%.

PREPARATIONS 13 TO 18 The following intermediate compounds were prepared using the procedure of Preparation 12 from the appropriate l-rnet-l or -ethoxy-methylene-heterocycle and 2- (2,4-difluoropheyl) -3- (4-iodophene? l) l- (1, 2, -tr? zol-l-1) -3-buten ~ 2-ol.

In the case of Preparation 17, the starting compound was 4-bromo-l-ethoxymethyl-lirazole.

PREPARATION 19 2- (2,4-Difluoro-enyl) -3- (4-formamidophenyl) -l- (1, 2,4-triazol-1-yl) butan-2-ol (i) Warm with stirring at 140 ° C for 2 hours, an intimate mixture of 2- (2,4-difluorophenyl) -3- (4-iodophenyl) -4-l- (1, 2,4-triazole). ~ l-il) -3 ~ buten-2-ol (12 g, 26 mmol - see Preparation 20), forrnarnide (18 rnl, 0.25 rnrnol), copper (3.6 g, 57 nmol) and potassium carbonate (6.0 g, 43 mmol). The mixture was cooled to 100 ° C and treated with a suspension of disodium salt of ethylenediarinotetraacetic acid (25 g, 6.7 mmol) in 250 ml of water. After cooling to room temperature, the mixture was extracted with dichloromethane (2 x 200 rnl). The combined organic extracts were dried over magnesium sulphate and evaporated under reduced pressure to give 2- (2, 4-difluoropheni-1) -3- (4-formaldehyde-d-phen-1) -1- (1). 2, 4-t paol-l-? L) but-3-en-2-ol (5.3 g, 55%, which was used in the rough in the next stage. (n) The crude product from step () in 150 rnl of e + anol was hydrogen on 10% palladium on charcoal (1.0 g) at a pressure of 200 I-Pa for 5 hours. The filter was filtered through the "flrbocel" (trademark) and the filtrate was evaporated under reduced pressure to give the title compound (4.4 g, 03%) as a foam. The product of es + a Preparation was used in bru + or in Example 32.

PREPARATION 20 2- < 2, 4-Difyl phenyl) -3- (4-phenyl) -! - (1,2, -t-riazol-1-yl) -3-buten-2-ol (i) 2- (2,4-D? fluorophen? l) -1- (4-iodophene Ll) ethanone Se, 2,4-d? fluorobenzyl bromide was added dropwise (23.7 rnl, 0.114 rnol) to a stirred mixture of magnesium turnings (8.1 g, 0.183 mrnol) in 300 ml of dry oil, under nitrogen. Initially the mixture was heated gently until the initiation of the reaction occurred and then the aforementioned bromide was added at a suitable rate to maintain a smooth reflux. After 1 hour, the resulting solution of the Grignard reagent was added dropwise at -78 ° C to a solution of 0, Nd? Rnet? L-4-iodobenzene hydroxanthic acid (see Preparation 30) ( 45, Pl g, 0.157 mol) in 300 ml of dry ether and the mixture was slowly extracted at room temperature during the night. The mixture was partitioned between a saturated aqueous solution of ammonium chloride and ethyl acetate and the organic solution was separated, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as white solid (38,71). g, 69%), which was characterized by ^ H-RrIN spectroscopy. 1H-RHN (300 NHz, CT) C13): 6 - 4.23 (, 2H), 6.83 (rn, 2H), 7.17 (dt, - 7 and 8, 5 H, 1H), 7, 72 (d, 3 - 9 Hz, 2H), 7.84 (d, 3 = 9 Hz, 2H) pprn. (n) 2- (2, -D? -fluoryl) -l- (4-iodo-phen ii) prop-2-enone B? s (dirnethylamine-neonate (8.78 ml, 0.075 inmol)) was added dropwise to a stirred suspension of 2 ~ (2,4-d? fluorophen? i) -l ~ (4-iodophene?) ethanone (17.73 g, 0.0495 mmol) in acetic anhydride (23.1 ml, 0.248 mol) ) at room temperature An exothermic reaction occurred and the temperature of the mixture rose to 60 ° C. Once the addition was complete, the mixture was stirred at room temperature for + 35 minutes and then ice water was added to allow the mixture to cool to room temperature. hydrolyze the excess acetic anhydride. After 30 more minutes, the product was extracted into ethyl acetate and the extracts were washed with dilute hydrochloric acid and a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as white solid (17.03 g, 93%), which was characterized by 1 H-NMR spectroscopy, 1 H-NMR, OOO 11Hz, CDC13): fi = 5.90 (s, 1H), l ?, 14 (s, 1H), 6.84 (ddd, 3 = 12, 8 and 2 H), 6.95 (dt, 3 - 2 and 8 H), 7.39 lili, 3 = 7 and 9 Hz, ll-l), 7.59 (d, -9 H, 2H), 7.83 (d, 3 = 9 Hz, 2H) pprn. (111) 2- (2, 4 -Dif 1 p or feni 1) -2- (4-iodofen l) -0 1 rano fl a «-olution of 2- (2, 4-d? f luorofe il) -l- (4-iodopheniDprop-enone (17.1 g, 100, fi rnmol) t-butyl droper ox 1 do (36.6 ml, 3 M in tripef ilpentane, 109 nmol) in 550 ml of toluene, at room temperature, hydrox do do benzyl trirnetium ammonium (3.44 nmol, 40% aqueous solution, 8.2 nmol) was added at once. washed with water (2 x 500 rnl), dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as white solid (37.6 g, 96%), which was characterized by JH-NMR spectroscopy. IH-NMR (300 MHz, CDCl 3): 6 = 3.22 (d, 3 - 5 Hz, 1H), 3.42 (d, 3 = 5 Hz, 1H), 6.80 (ddd, 3 = 12, 8 and 2 H, 1H), 6.93 (dt, 3-2 and 8 Hz, 1H), 7.47 (d +, 3 = 7 and 9 Hz, 1H), 7.70 (d, 3 = 9 Hz, 2H), 7.77 (d, 3 = 9 Hz, 2H) ppm. (1 v) 2 - (2, 4 -Di f 1 uoro f eni 1) - 2 ~ [1 - (4-iodo f em 1) -etenylJoxirane n-Butyllithium was added dropwise over 10 minutes ( 50 mL, 2.5 M in hexane, 125 INRNOL) was added to a stirred suspension of Rethyltriphenylphosphonium bromide (45.0 g, 126 mmol) in 600 mL of dry THF, under a nitrogen atmosphere at -70 ° C. The mixture was allowed to warm to -20 ° C in 20 minutes and then a solution of 2- (2,4-difluorophenyl) -2- (4-iodobenzo-1) ox) was added over 5 minutes. NaOH (37.46 g, 97 mrnol) of dry THF. The mixture was allowed to warm to ambient temperature and was stirred for 84 hours. An aqueous solution of 10% ammonium chloride (500 nmol) was added and the mixture was concentrated under reduced pressure. The product was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The solid residue was then treated with boiling hexane (3 x 500 mL) and the residual solid was discarded. The hexane solutions were combined, filtered through a small layer of silica gel and concentrated under reduced pressure to give the title compound as yellow oil (4.3 g, 92%), which was characterized by iH-NMR spectroscopy. . 1H-RI? N (300 riHz, CDC13): 6 = 3, 13 (d, 3 = 5 Hz, 1 H), 3.17 (d, 3 = 5 3z, 1H), 5.45 (rn, 2H ), 6.72 (m, 1H), 6.80 (rn, 1H), 7.14 (d, 3 = 9 Hz, 2H), 7.39 (dt, 3 = 7 and 9 H, 1H), 7.60 (d, 3 = 9 Hz, 2H) pprn. (v) 2- (2, -Dif luorophenyl) -3- (4-iodophene) -1- (1,2,4-tnazol-1-yl) -3-buten-2-ol Salt was added sodium 1, 2,4-tpazole (12.15 g, 133 nmol) to a solution of 2- (2,4-difluorophemethyl) -2-Cl- (4-iodophenyl) ethenyl] oxanthione (34.3 g, 89 mmol) in 350 mL of dry DilF or nitrogen at 70 ° C. The mixture was stirred for 5 hours, cooled and the solvent was removed under reduced pressure. The residue was partitioned in ether (80f) rnl) and water (2 x 500 rnl). The organic solution was dried over magnesium sulfate, filtered and silica gel (60-200 JJ, 75 < j) was added. The ether was removed under reduced pressure and the residual solid was applied to e. top part- of a column of silica gel (40-60 u, 300 g) and the product was eluted using hexane and increasing amounts of ethyl acetate (0-75%). The product was obtained in white foam form (23.8 g, 61%), which was characterized by iH-NMR spectroscopy. 1 H-NMR (300 MHz, CDCl 3): d-4.55 (d, 3 = 15 Hz, 1H), 4.90 (d, 3 = 15 Hz, 1H), 5.16 (s, 1H), 5 , 25 (s,? H), 6.70 (m, 2H), 7.03 (d, 3 = 9 Hz, 2H), 7.43 (dt, J = 7 and 9 Hz, 1H), 7, 58 (d, 3 = 9 Hz, 2H), 7.79 (s, 1H), 7.80 (s, 1H) pprn. The title compound was resolved by chiral HPLC using a "Chiralpak RD" column (trademark) eluting with hexane / ethanol (95: 5). The fractions containing each individual enantiomer were pooled, evaporated under reduced pressure and the residues were each chromatographed on silica, eluting with dichloromethane / methanol (95: 5) and then triturated with ether. Peak 1 (assigned to the stereochemistry 25), p.f. 110-111 ° C, Calo25 = -49 °. Analytical HPLC indicated for each enantiomer an ee > 99% The (-) enantiomer gave the following percentage analysis: Found: C 47.52, H 2.97, N 9.09 C18H14F2IN3O required: C 47, 70, H 3.11, N 9.27. The enanti om(+) gave the following percentage analysis: Found: C 47.88, H 3.02, N 9.29 C18H14F2IN3O requires: C 47.70, H 3.11, N 9.27.

PREPARATION 21 2- (2, 4-Pi fluoro phenyl) -! - (!, 2,4-triazol-l-yl-3- [4- (1,2,4-triazol-1-yl) phenyl3-3 -buten-2-ol (i) 2- (2,4-D? fluorophenyl) -l ~ C4- (l, 2,4-tr? azol-l-yl-phenyl] -l-ethanone was stirred at 100 ° C for 18 hours a mixture of 2- (2,4-difluorophenyl) -l- (4-fluorophenyl) -l-ethanone (5.0 g, 20 inino- see EP-RO, 069,442), 1,24-triazole sodium salt (2.18 g, 24 mmol) and N, N dirnethylacetarnide (1.00 rni) The mixture was diluted with full (300 ml) and concentrated under reduced pressure, The residue was dissolved in 500 ml of ethyl acetate and the residue was dissolved in 500 ml of ethyl acetate. The solution was washed with magnesium sulfate and concentrated under reduced pressure, purification by flash chromatography (elution with ethyl acetate / dichloromethane 1: 1) to obtain a white solid (1, 05 g, 10%), which was characterized by 1 H-NMR spectroscopy, 1 H-R N (300 MHz, CDCl 3): 6 = 4.31 (s, 2 H), 6.88 (in, 2H), 7.72 (rn, 1H), 7, B4 (d, 3 = 9H, 2H), 8.14 (s, 1H), 8.17 (d, 3 = 9 Hz, 2H), 8 , 66 (s, 1H) ppm. (11) 2- (2,4-D? Flurofen? L) -l-C4 - (1, 2,4-t-riazol-1-yl) -phenyl-pro-2-enone Following the procedure of Preparation 29 (FIG. ), the 2 ~ (2,4-d? flurofeml) -i-C4- (l, 2,4-tr? azol-l-? l) -fen? l] ethan-l-one (1.05 g , 3.51 nmol) was converted to 2- (2,4-d? Flurofen? L) -1- [4- (1, 2,4-tnazol-1-yl) -phen?] Pro? - 2-enone (1.03 g, 92%), as yellow solid, which was characterized by * H-MN spectroscopy. 1 H-NMR (300 MHz, CDCl 3): 6 - 5.93 (s, 1H), 6.16 (s, 1H), 6.81 (rn, 1H), 6.93 (dt, 3 = 2 and 8 Hz, 1H), 7.40 (dt, 3 = 7 and 9 Hz, 1H), 7.79 (d, 3 = 9 Hz, 2H) 8.02 (d, 3 = 9 Hz, 2H), 8, 13 (s, 1H), 8.64 (s, 1H) pprn. (lil) 2- (2,4-D? flurofen? l) -2-C4- (l, 2,4-tr? azol-l-yl) -benzoyl] 0x1 rano Following the procedure of Preparation 20 (111 ), 2- (2,4-D? flurofen? l) -1- - 1, 2, 4-tr? azol -1 -ll) -fen? L] prop-2-enone (1.04 g, 3.34 mrnol) was converted to 2- (2,4-dif lurofeml) -2-C4- (1, 2,4-triazol-1-yl) -benzole 1 lox i rano (1.01 g, 92% ), as white solid, which was characterized by iH-NMR spectroscopy. 1 H-NMR (300 MHz, CDC13): d = 3.24 (d, 3 - 4 Hz, 1H), 3.45 (d, 3 = 4 Hz, 1H), 6.80 (ddd, 1 = 2.8 and 12 Hz, 1H), 6.95 (dt, 3 = 2 and 8 H, 1H), 7.49 (dt, 3-7 and 9 Hz, 1H), 7.75 (d, 3 and 9 Hz, 2H), 8.12 (s, 1H) ), 8.17 (d, 3 = 9 Hz, 2H), 8.63 (s, 1H) ppm. (iv) 2- (2,4-D? fluorofeml) -2 ~ [l-. { 4- (1, 2,4-tr? Azol-li 1 -f em 1.} -etem 1] ox 1 rano Following the procedure of Preparation 20 (iv), the 2- (2,4-d? fluorofen? l) -2- [4- (l, 2,4-tr? azol-l-l Ibenzoyloxirane (1.00 g, 3.05 mrnol) was converted to 2- (2,4-d? fluorophen? l) -2-Cl- {4-Cl,, 4-tr? azoi-1-l) -phenyl) ethenoxy-H-heranene (570 g, 57%), in solid form, after purification by flash chromatography (hexane) / ethyl acetate 60:40), which was characterized by * H-NMR spectroscopy. 1 H-NMR (300 MHz, CDCl 3): d = 3.19 (s, 2H), 5.52 (m, 2H), 6.72 (ddd, 3 = 2.8 and 12 Hz, 1H), 6, 80 (dt, 3 = 2 and 8 Hz, 1H), 7.42 (dt, 3 = 7 and 9 Hz, 1H), 7.54 (d, 3 = 9 Hz, 2H), 7.59 (d, 3 = 9 Hz, 2H), 8.08 (s, 1H), 8.53 (s, 1H) pprn. (v) 2- (2,4-D? fluorofeml) -l- (1, 2,4-tr? azol-1-yl) -3- [4- (1, 2,4-tr? l-? l) phenol-3-buten-2-ol Following the procedure of Preparation 20 (v), 2- (2,4-d? flurofen? l) -2-Cl-. { 4- (1, 2,4-tpazol-] ~ il) -pheni l} ethanol (570 g, 1.75 mol) was treated with the sodium salt of 1, 2, 4-triazole in 10 rnl of DMF at 70 ° C for 8 hours to give 2- (2, 4-d). ? fluorophen? l) -l- (1, 2, 4-tpazol-l-? l) -3-C4-) l, 2,4-tnazol-l-lyl) phen? p-3-buten-2- ol (620 g, 89%), in solid form, which was characterized by iH-NMR spectroscopy. 1 H-NMR (300 MHz, CDCl 3): d = 4.62 (d, 3 = 13 Hz, 1H), 4.97 (d, 3 = 13 Hz, 1H), 5.32 (rn, 3H), 6 , 74 (, 2H), 7.43 (d, 3 = 9 Hz, 2H), 7.46 (rn, 1H), 7.57 (d, 3 = 9 Hz, 2H), 7.81 (s, 1H), 7.83 (s, 1H), 8.09 (s, 1H), 8.53 (s, 1H) pprn.

PREPARATION 22 - (2,4-Difluorophenyl) -l- (1, 2,4-triazol-1-yl-3- [2- (1, 2J-triazol-1-yl) pyridin-5-yl] -3 -buten-2-ol (i) 0, N-dirnethyl-2-chloropyridine-5-hydroxarnic acid. A suspension of 6-chloroacetic acid (80 g, 0.5 mmol) in 400 ml of water was heated at reflux for 3 hours. thionyl chloride to give a yellow solution. The mixture was concentrated under reduced pressure, the resin was dissolved in 600 ml of dichloromethane and treated with N, 0-dirnethylhydroxy hydrochloride 856.5 g, 0.58 mmol). The suspension was cooled on ice and then treated dropwise with triethylamine (220 mL, 1.5 mmol) and stirred for 1 hour at room temperature. The mixture was filtered and the filtrate was washed with an aqueous solution of sodium hydroxide (2N, 200 nmol), dried over magnesium sulfate and then concentrated under reduced pressure. The resulting liquid was distilled under reduced pressure to give the title compound (90 g), e.g. 106-110ßC (0.5 mrn Hg), which was characterized by? H-NMR spectroscopy. 1 H-NMR (CDC13): d = 3.38 (s), 3.56 (s), 7.18 (d), 8.00 (dd), 8.78 (d). (il) l- (2-Chloropipdn-5-yl) -2- (2,4-diflurophenyl) ethanone The title product was prepared from the product of part (1) above, by a procedure similar to that described in Preparation 20 (1), p.f. 93-95 ° C. Analysis for C 13 H 8 CF 02 NO: Found: C 58.01, H 2.99, N 5.17 Calculated: C 58.33, H 3.01, N 5.23%. (111) 2- (2,4-D? Fluorophenyl) -l-C2- (1,2,4-tr? Azol-1-yl) -p? R? Din-5-yl] ethanone Heated to 70 ° C for 4 hours a mixture of the product of part (11) (1.06 g, 4 nmol), potassium carbonate (0.54 g, 4 nrnol) and 1, 2, 4-tpazole (0.34 g) , rnrnoL) in 10 rnl of DMF. The mixture was cooled and partitioned between ethyl acetate (50 ml) and water (50 ml). The organic extract was washed with water (50 rnl), dried over magnesium sulfate and concentrated under reduced pressure. Trituration of the crude product with diethyl ether gave the title compound (0.3 g, 25%) m.p. 140-142 ° C. Analysis par-a Cis H- IOF2 N0 0: Found: C 60.31, H 3.54, N 18.1 Calculated: C 60.00, H 3.36, N 18.66%. (iv) 2- (2,4-D? fluorophen? l) -l-C2- (l, 2, 4- tpazol-1-? l) - ?? r? dm-5-yl] prop-2 enone The title compound was prepared from the product of part (111) by a procedure similar to that described in Preparation 20 (11) as a yellow solid (3.1 g, 79%), mp. 136-138 ° C. Analysis for C16H-IOF2H4O. Found: C 61.10, H 3.25, N 17.76 Calculated: C 61.54, H 3.23, N 17.94%. (v) 2- (2,4-D? fluorophen?) -2-C2- (l, 2,4-tr? azol-l-? Dp? r? d? n-5-carbon? lHox? rano The title compound was prepared from the product of part (v) by a procedure similar to that described in Preparation 20 (n?) As a yellow solid (3.1 g. 96%), p.f. 122-124 ° C. fl na 11 s i o pa ra C 16 H i or F N «O: Found: C 58.86, ti 2.94, N 16.92 Calculated: C 50.54, H 3.07, N 17.07%. (vi) 2- (2,4-D? fluorofon? D-2-C1- (2- (l, 2, 4-tr? azol-l-yl) pi p din- 5- l) etem 1 lox 1 The title compound was prepared from the product of part (v) by a procedure similar to that described in Preparation 20 (? v) as a colorless solid (2.8 g, Ü6%), mp 120-122 ° C Analysis for C17H12F2N4O: Found: C 62.87, H 3.68, N 17,18 Calculated: C 62.58, H 3.71, N 17.17% (vn) 2-82.4 ~ D? luorofen? l) -l- (l, 2,4-tr? azol-l-? l) -3- [2- (1,2,4-tr? azol-1-yl)? ndin-5- L-3-buten-2-ol The title compound was prepared from the product of part (vi) by a procedure similar to that described in Preparation 20 (v) as colorless solid (2.5 g, 75 %), pf 153-156 ° C. Analysis for C19H15F2N7O: Found: C 58.11, H 3.46, N 24.42 Calculated: C 57.72, H 3.82, N 24.80%.

PREPARATION 23 (2R, 3S / 2S, 3) -4-C2- (2,4-Difluoro-enyl) -2-hydroxy-1- (1,2,4-triazol-1-yl) but-3-yl] benzoylhydrazide H2Pd (i) 4- [2- (2,4-Di-fluoro-phenyl) -2-hydroxy-l- (1, 2, 4-triazol-1-yl) -3-buten-3-.11 methyl ester ] benzo ico. A mixture of 2- (2,4-difluorophenyl) -3- (4-iodophenyl) -1- (1,2,4-triazol-1-yl) -3-buten-2- was dissolved in 20 ml of methanol. ol (2.0 g, 4.4 mrnol - see Preparation 20), palladium acetate (0.3 g), triphenylphosphine (0.23 g) and triethyl amine (2 rnl). The mixture was heated to 100 ° C under 344.7 kPa carbon monoxide for 4 hours and then partitioned between dichloromethane (50 rnl) and water (20 rnl). The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with a dichloromethane / methanol gradient (100: 0-> 98: 2-> 96: 4). The fractions containing the desired product were pooled and evaporated under reduced pressure for < The methyl ester of the acid 4-C2 (2, 4-di-fl uoro-phenyl) 2-hydroxy? -1- (1, 2, 4-t pa ol-1-? l) -3-huten- 3-? 1 J-benzoic (1.7 g, 99%), in the form of foam.

This intermediate compound was characterized by 1 H-NMR spectroscopy. 1 H-NMR (300 MHz, CDCl 3): d = 3.90 (s, 3H), 4.59 (d, IH), 4.92 (d, 1H), 5.25 (s, LH), 5, 31 (s, 1H), 5.35 (s, 1H), 6.70 (? N, 1H), 6.74 (m, 1H), 7.36 (d, 1H), 7.44 (q, l \ - \), 7.80 (d, IH), 7.02 (s, 1H), 7.94 (s, 1H) pprn. (II) Acid methyl ester (2R, 3S / 2S, 3R) -4-C2- (2, -di fluorophen? L) -2-hydrox? -l- (1, 2, - r? Azol) -l-? l) but-3-? i] -benzoic acid The product of part (1) is hydrogenated following the procedure of Example 1. The crude product was triturated with ether to give the title compound as a colorless solid. Analysis for C20H19F2N3O3: Found: C 61.90, H 4.88, N 10.79 Calculated: C 62.01, H 4.94, N 10.85%. (III) (2R, 3S / 2S, 3R) -4-C2 ~ (2,4-d? Fluorophen? L) -2-h? Dr'ox? - L "l- (l, 2,4- tr? azol-l-? l) but-3-? ll-benzo? lh? draz? da A solution of the product from part di) (0.5 g, 1.3 mmol) in 5 ml of methanol was treated with hydrazma hydrate (0.25 mmol, 8 mmol). The mixture is refluxed for 36 hours. The mixture was then cooled to room temperature and diluted with ether. The title compound (0.3 g, 60%) was collected by filtration and characterized by * H-NMR spectroscopy (300 MHz, CDC13): d = 1.12 (d, 3H), 3.38 (q , 1H), 3.80 (d, 1H), 4.13 (broad s, 2H), 4.79 (d, 1H), 4.84 (s, 1H), 6.76 (n, 2H), 7.37 (s, 1H), 7.46 (rn, 1H), 7.60 (d, 2H), 7.74 (m, 4H) ppm.

PREPARATION 24 2- (2,4-Difluorophenyl) -3- (2- [imidazol-1-yl] pyridin-5-yl-1- (1, 2,4-triazol-1-yl) -3-buten- 2-ol \ \ (i) 0, N-dirnethyl-2- (imidazol-1-yl) pyridine-5-hydroxanic acid. A suspension of 0, N-drnet acid was stirred at 140 ° C for 24 hours. L-2-chlorop? ri d-n-5-hydroxamic (10.0 g, 50 mrnol see Preparation 22 (?)), irnidazole (4.1 g, 60 mol) and basic carbonate (6.9 g, 50 rnrnol) in 200 rnl of N, N-dimethiacetamide. The mixture was evaporated under reduced pressure and the residue was partitioned between di chloronetano (100 rnl) and water (100 ml).

The organic lase was washed with water (100 ml) and brine (50 ml), then dried over magnesium sulphate and evaporated under reduced pressure. The crude product or crude was purified by chromatography on a silica column, eluting with a gradient of ethyl acetate / hexane (1: 1, 1: 0). The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (8.2 g, 71%) as an orange oil. A sample was triturated with ether to give a colorless solid, m.p. 69-70 ° C. Analysis for C? Hi2N «? 2: Found: C 56.94, H 5.17, N 23.77 Calculated: C 56.89, H 5.21, N 24.12%. di) 2- (2,4-D? fluorophen?) -l- (2 ~ [? rn? dazol-l-? l3p? r? d? n-5 ~? l) ethanone A solution of the product of the part (i) (6.5 g, 28 nmol) in 100 ml of THF was stirred under a nitrogen atmosphere at -70 ° C and treated with a solution of 2,4-difluorovencil agnesium bromide [obtained from bromide of 2,4-difluorobenzyl (8.1 g, 39 mmol) and magnesium (1.0 g, 42 mmol) following the procedure of Preparation 20 (i) 1 in 100 ml of ether. The mixture was stirred at -70 ° C for half an hour and then allowed to warm to room temperature before the addition of dilute hydrochloric acid (2N, 100 rnl). The layers were separated and the aqueous phase was extracted with dichloromethane (100 nmol). The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to give the title compound as pale yellow solid which was characterized by? HR N spectroscopy (300 MHz, ODCI3): d = 4.28 (s, 2H ), 6.85 (in, 2H), 7.23 (in, 2H), 7.40 (d, 2H), 7.71 (s, 1H), 8.41 (dd, 1H), 8.50 (s, 1H), 9.11 (d, 1H) ppm. (111) 2- (2, 4 -Difluorofeml) -l- (2-E? Rn? Dazol-l- 1 llpí r? D? N-5-? L) -2-? Ro? En-l-ona The title compound was prepared from the product of part (11) by a procedure similar to that described in Preparation 20 (11), as yellow solid, mp. 115-116 ° C. Analysis for C 17 H 11 F 2 N 3 O: Found: C 65.43, H 3.71, N 13.54 Calculated: C 65.59, H 3.56, N 13.50%. (iv) 2- (2,4-D? fluorophen? l) -2- (2 - [? rn? dazol-l-? l3p? r? d? n ~ 5-carbon? l) 0x1 rano The compound of title was prepared from the product of part dii) by a procedure similar to that described in Preparation 20 (? n), in the form of orange oil, which was characterized by iH-NMR spectroscopy (300 MHz, CDCl 3): d-3.08 (d, 1H), 3.41 (d, 1H), 6.83 (m, 1H), 6.97 (rn, 1H), 7.39 (d, 1H), 7.49 (m, 1H), 7.64 (s, 1H), 0.39 (broad s, 1H), 8.40 (s, H \), 8.43 (dd, 1H), 9.12 (d, 1H), pprn. (v) 2 ~ (2,4-D? fluorophen? l) -2- [l- (2 - [? rn? dazol-l-illpipdin-5-? hete? l loxane The title compound was prepared from the product of part (v) by a procedure similar to that described in Preparation 20 (? v) in the form of yellow oil, which was used crude in the next stage. (vi)? - (2,4-) D? Fluorophen?) -3- (2 - [?? n? Dazol-l-yl] pyr? Din-5 ~? L) -l- (1, 2, 4-t pazol -l-il) - 3-buten-2 -ol The title compound was prepared by a procedure similar to that described in Preparation 20 (v) as a colorless solid, mp 145-148 ° C. Analysis for C20H16F2N60.1 / 5 ethyl acetate: Found: C 60.37, H 3.55, N 19.92 Calculated: C 60.63, H 4.31, N 20.40% The presence of ethyl acetate was confirmed by iH-NMR spectroscopy (300 MHz, CDCl3): d = 1.29 (t, partial H), 2.02 (s, partial H), 4.12 (q, partial H), 4.64 (d, 1H), 5.09 (d, 1H), 5.40 (s, 1H), 5.45 (s, 1H), 5.52 (s, 1H), 6.75 (rn, 2H), 7.20 (s, 1H), 7.23 (d, 1H), 7.45 (m, 1H), 7.61 (S, 1H), 7.84 (dd) , 1H), 7.85 (s, 1H), 7.88 (s, 1H), 8.35 (s, 1H), 8.37 (d, 1H) ppm.

PREPARATION 25 2- (2,4-Difluoro-enyl) -3- (4- [5-amino-1,3,4-thiadiazol-2-yl] phenyl-1- (1,2,4-triazole-1- il) -3-buten-2-ol (i) (COO) 2 (ü) HJNCNHNHJ S (i) A solution of 4- (2- (2,4-d? fluorofeml-2-h? drox? -l- (1,2,4-triazole-1) methyl ester is refluxed for 3 hours. -yl) -3-buten-3-yl) benzoic acid (see Preparation 23 part (i)) (3.44 g, 9 mmol) in a mixture of methanol (50 mmol) and aqueous sodium hydroxide solution (2M, 9 nm, 18 mmol) The cooled solution was evaporated under reduced pressure and the residue was dissolved in 30 mL of water The aqueous solution was extracted with ethyl acetate (3 x 30 mL) before acidifying with 2M hydrochloric acid. The aqueous phase was extracted again with ethyl acetate (3 x 30 nl). washed with brine (3 x 20 rnL), dried < -Over sodium sulphate and evaporated under reduced pressure to give 4- acid. { 2-r2,4-d? Tluoro in? P-2-h? Drox? -l- (1,2,4-tpazol-1-yl) -3-bu-3-yl) -benzoic acid (3,2 g, 96%). By cross-linking a sample in ethyl acetate / hexane / methanol, an off-white solid was obtained, m.p. 1B9-190 ° C. Par-a Analysis C H 9 H 15 F N 3 O 3: Found: C 61.41, H 3.99, N 11.21 Calculated: C 61.45, H 4.07, N 11.32%. (11) A sample of the product of part (1) (370 g, 1 mmol) was suspended in 15 ml of di-chloromethane and treated with one drop of dimethylformamide and 0.1 ml (1.1 mmol) of oxalyl chloride. The solution was stirred at room temperature for 1 hour and then evaporated under reduced pressure. The residue was dissolved in 15 ml of dichloromethane and treated with thiosernicarbazide (0.1 g, 1 mmol) and sodium carbonate (0.1 g, 1 mmol). The mixture was stirred at room temperature for 24 hours and then filtered. The filtrate was absorbed on silica and chromatographed graphite eluting with a gradient of ethyl acetate / methanol (97: 3, 95: 5, 94: 6). The fractions containing the desired product were combined and evaporated under reduced pressure. The crude product was triturated with ether to give 4-. { 2- [2,4-d? Fluorophen? L] -2-hydrox? L- [l, 2,4-tr? Azol-l-? L3-3-buten-3-? L} -benzoylthiosernicarbazide (0.21 g, 47%) as a colorless solid, which was characterized by 1 H-NMR spectroscopy (300 MHz, DMSO): d = 4.83 (Abq, 2H), 5.32 (s, 1H), 5.58 (ß, 1H), 6.57 (s, 1H), 6.77 (? N, 1H), 6.98 (in, 1H), 7.11 (rn, 1H), 7.30 (d, 2H), 7.50 (broad s, 1H), 7.60 (s, 1H), 7.62 (d, 2H) ), 7.78 (broad, LH), 8.19 (s, LH), 9.22 (broad s, 1H), 10.22 (broad s, 1H), pprn. (ni) The product of part di) (0.15 g, 0.3 inmol) in 8 ml of toluene was treated with rnetanosul fóm co acid (0.04 ml) and the mixture was heated to reflux for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned in a saturated solution of sodium carbonate (10 ml) and dichloromethane / methanol (10: 1, 50 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by silica column chromatography, eluting with a gradient of dichloroethane / methanol (98: 2, 95: 5, 90:10). The fractions containing the desired product were combined and evaporated under reduced pressure to give a foam which, by trituration with ether, gave the title compound (0.03 g, 20%) as a colorless solid, m.p. 118-121 ° C. Analysis for C20H16F2N6OS: Found: C 55.98, H 3.59, N 19.40 Calculated: C 56.33, H 3.78, N 19.71%.

PREPARATION 26 l-Eoxymethyl-3-methylthio-1,2-triazole A suspension of 5-nitric-l, 2,4-triazole (6.19 g, 53 mmol) and chlorine-ethyllether (2.5 mmol, 26 mmol) in 40 mL of sodium sulfate was stirred at room temperature for 24 hours. toluene The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was chromatographed on silica, eluting with ethyl acetate / diethylamine (95: 5) to give the title compound (1.1 g, 27%), as a colorless oil, which was characterized by spectroscopy. 1 H-NMR (300 MHz, CDC13): 6 = 1.20 (+, 3H), 2.59 (s, 3H), 1.60 (q, 2H), 5.41 (s, 2H9, 8.17). (ü, 1H) ppm.

PREPARATION 27 1-Etox? Methyl-l, 2,4-triazole The title compound was prepared from 1,2,4-tpazole by a procedure similar to that of Preparation 26, as a colorless oil which was characterized by 1 H-NMR spectroscopy (300 MHz, CDCl 3): d = 1, 23 (t, 3H), 3.58 (q, 2H), 5.50 (s, 2H), 8.01 (s, 1H), 8.28 (s, 1H), ppm.

PREPARATION 28 4-Bromo-l-ethoxy-ethylpyrazole The title compound was prepared from 4-brornopyrazole by a procedure similar to that of Preparation 26, as a colorless oil that was characterized by 1 H-NMR spectroscopy (300 MHz, CDCl 3): d = 1.17 (t, 3 H), 3.50 (q, 2 H), 5.39 (s, 2 H), 7.49 (s, 1H), 7.59 (s, 1H) ppm.

PREPARATION 29 1-Ethoxymethyl-1,2,3-triazole The title compound was prepared from 1,2,3-triazole by a procedure similar to that of Preparation 26, as a colorless oil which was characterized by spectroscopy of 1 H NMR (300 MHz, CDCl 3): 6 - 1.19 (t, 3 H), 3.56 (q, 2 H), 5.71 (s, 2H9, 7.77 (ABq, 2H) pprn.

PREPARATION 30 0, N-Dimethyl-4-iodobenzenehydroxamic acid A solution of pipdma (104 g, 1.32 mol) in 150 nrn of dichloromethane was added dropwise to a suspension of 4-iodobenzoyl chloride (251 g, 0.94 mmol) and N, 0- hydrochloride. d? met? l? drox? lam? na (97 g, 0.94 mmol) in 850 ml dichloroethane at 0 ° C. The mixture was allowed to warm to room temperature and was stirred for 18 hours. The solution was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (11) and then washed with dilute hydrochloric acid (2N, 3 x 400 mL) and a saturated solution of sodium bicarbonate (300 mL) and dried over sodium sulfate. The organic extract was evaporated under reduced pressure. The residue was purified by distillation to give the title product (241 g, 93%), as yellow oil, e.g. 130 ° C (0.1 rnm Hg), which was characterized by H NMR spectroscopy (300 MHz, CDC13): d = 3.32 (s, 3H), 3.50 (s, 3H), 7.40 (d, 2H), 7.72 (d, 2H) ppm.

PREPARATION 31 (2R, 3S / 2S, 3R) -2- (2, -Di luo-phenyl) -3- (4- [5-me captole, 3,4-oxadiazol-2-yl3 enyl) -l- ( l, 2,4-riazol-l-yl) -butan-2-ol A solution of (2R, 3S / 2S, 3R) -4- (2- [2, 4-di fluorophenyl) -2-hydroxy-l- (1,2,4-tr? Azol-1-yl) ) but-3-β-D-benzoylhydrazide (0.77 g, 2mmol - see Preparation 23) in 15 nl of 1,4-dioxane was treated with thiophosgene (0.25 g, 2.4 mmol) and the mixture was stirred to the room temperature for 18 hours. The mixture was evaporated under reduced pressure and the residue was partitioned between a mixture of ethyl acetate / methanol (95: 5, 50%). rnl) and water (30 nl), after adjusting to? l-1 5 with a dilute solution of ammonium hydroxide. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on a column of silica, eluting with a gradient of dichloromethane / methanol (100: 0, 98: 2, 95: 5, 90:10). The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (0.5 g, 60%) as a pale yellow foam, which was characterized by * H-NMR spectroscopy (300 MHz, DMS0d6): d = 1.06 (d, 3H),, 59 (, 1H), 3.93 (d, 1H), 4.80 (d, 1H), 5.75 (s, 1H), 6.92 (rn, 1H), 7.10-7.30 (m, 2H), 7.60 (s, 1H), 7.62 (d, 2H), 7.88 (d, 2H), 8 , 15 (s, 1H), 14.70 (broad s, 1H) pprn.

PREPARATION 32 Acid (2R, 3S / 2S, 3R) -4-C2-γ2-difluorophenyl) -2-hydroxy-1- (1, 2, - riazol-1-yl) but-3-yl3-benzoic acid A solution of the methyl ester of (2R, 3S / 2S, 3R) -4- [2] acid was heated at reflux for 3 hours. (2,4-d? Fluorophen? L) -2-hydrox? -l- (l, 2,4-tr? Azol-l-? L) but-3-yl) benzoic acid (0.8 g, 2 mmol - see Preparation 23 (n)) in a mixture of aqueous sodium hydroxide (2N, 2.1 ml, 4 mmol) and 20 1 of methanol. The mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (50 rnl) and dilute hydrochloric acid (5 rnl). The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was triturated with ether to give the title compound (0.72 g, 94%), m.p. 243-245 ° C, solid colorless. Analysis for C19H17F2N3O3: Found 1 -ado: C 60.8, H 4.56, N 11.0 Calculated: C 61, 12, H 4.59, N 11.26%.

PREPARATION 33 5- (2,5-Dimet? Lp? Rrol-l-il) -2-et lpir dina A mixture of 2-et was heated at reflux for 24 hours. l-pd-n-5-arnine (3.2 g, 26 mmol), 2,5-hexanedione (3.0 g, 26 mmol) and acetic acid (1 ml) in 50 ml of toluene . The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (50 nl) and water (20 rnl). The aqueous phase was basified with an aqueous solution of sodium hydroxide (2M) and then extracted with dichloromethane (50 nmol). The extract was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on a silica column, eluting with dichloromethane / methanol (95: 5) to give the title compound (2.38 g, 46%) as a colorless oil, which was characterized by 1H- spectroscopy. NMR 1 H-NMR (300 MHz, DMSOdβ): d = 1.38 (t, 3H), 2.02 (s, 6H), 2.91 (q, 2H), 5.93 (s, 2H), 7, 25 (d, 1H), 7.44 (dd, 1H), 8.41 (d, 1H) ppm.

PREPARATION 34 4-Et? L-6- (1,2,4-triazol-1-yl) pyrimidine It was heated at 120 ° C with stirring to a mixture of 4-chloro-6-et? lpirnni di na (1.42, g, 10 mmol) and 1H-1, 2,4-tpazol (1.4 g, 20 mmol) will give an oil? yellow that deposited an orange solid. The mixture was kept at 120 ° C for 12 minutes, cooled to 70 ° C and dissolved in methanol (10 mL). The solution was diluted with O ml of di chloro-methane and washed with a saturated solution of sodium bicarbonate (20 ml). The aqueous phase was extracted with dichloro-methane (? X 20 rnl) and the combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on a silica column, eluting with ethyl acetate to give the title compound (1.44 g, 82%), as yellow solid, m.p. 75 ~ 76 ° C, which was characterized by ^ H-NMR spectroscopy. 1 H-NMR (100 MHz, 0DC13): d = 1.38 (t, DH), 2.90 (q, 2H), 7.74 (s, 1H), 8.13 (s, 1H), 8, 98 (s, 1H), 9.22 (s, 1H) pprn.

PREPARATION 35 2- (2-Chlorophenyl) -3- (4-iodo-enyl) -l- (1, 2,4-r? Azol-1-yl) -3- buten-2-ol (i) 2- (2-Clorofeml) -3- (4-yodofeml Jetanone.) The title compound was prepared from a, 2-dichlorotoluene and 0, N-d? met? l-4-iodobenzene hydroxamic acid. (see Preparation 30) by a procedure similar to that of the Preparation 20 (?) Co or colorless solid, m.p. 105-106 ° C, which was characterized by 1H-NMR electroscopy. 1 H-NMR (300 MHz, CDCl 3): d = 4.40 (s, 2H), 7.27 (s, 3H), 7.42 (rn, 1H), 7.74 (d, 2H), 7, 82 (d, 2H) ppm. (11) 2- (2-Clorofeml) -3- (4-iodophen? L)? Rop-2-enone. The title compound was prepared from the product of part (1), by a procedure similar to that of Preparation 20 (n), as a colorless solid, m.p. 101-103 ° C, that 1Gb it was characterized by elect oscopy iH-RMN. 1 NMR (300 MHz, CDCl 3): d -5.93 (s, 1H), 6.10 (s, 1H), 7.20-7.40 (rn, 4H), 7.65 (d,? H) , 7.03 (d, 2H) pprn. (111) 2- (-Color or phenyl) -3- (4-iodobonzoyl) ox? 1 year The title compound was prepared from the product of part (11), by a procedure similar to that of Preparation 20 (???), as a colorless foam, which was characterized by electroscopy iH- NMR 1 H-NMR (300 MHz, CDCl 3): d-3,22 (d, 1H), 3.49 (d, LH), 7.20-7.40 (m, 3H), 7.57 (? N, 1H), 7.71 (d, 2H), 7.77 (d, 2H), ppm. (? v) 2- (2-Clorofeml) -3- (1 - [4-iodophon-lloxirane The title compound was prepared from the product of section (111), by a procedure if ilar- to that of Preparation 20 (? v), as a colorless oil, which was characterized by iH-NMR electroscopy, IH-NMR (300 MHz, CDCI3): d = 3.01 (d, 1H), 3.12 (d, 1H) , 5.26 (s, 1H), 5.32 (s, 1H), 7.17 (d, 2H), 7.25 (rn, 2H), 7.34 (m, 1H), 7.52 ( m, 1H), 7.62 (d, 2H), pp. (v) 2- (2-Cloroferul) -3- (4-iodophen? l) -1- (1, 2, 4-tnazol-l- (l) -3-buten-2-ol The title compound was prepared from the product of part (v), by a procedure similar to that of Preparation 20 (v), as a colorless solid, mp 128-130. ° C. Analysis for CißHis CIIN30: Found: C 47.89, H 3.16, N 9.23 Calculated: C 47.84, H 3.33, N, 9.30%.

PREPARATION 36 2- (2-Fluorophenyl) -3- (4-iodophenyl) -l- (1, 2,4-triazol-1-yl) -3-buten-2-ol i- BuOOH (i) 2- (2-Fluoro-phenyl) -l- (4-iodo-phenyl) -ethanone. This product was prepared from 2-fluorobenzyl bromide and 0, N-dirnethyl-4-iodobenzene hydroxamic acid (see Preparative 30) by a procedure similar to that of Preparation 20 (i), co or colorless solid, m.p. 112-114 ° C. Analysis for CnvHioFIO: Found: C 49.91, H 2.98 Calculated: C 49.56, H 2.95%. (11) 2 - (-Fluorophen? L) -1 - (4-iodophene?) Pro? -2-enone The title compound was prepared from the product of part (i) by a procedure similar to that described on Preparation 20 (??), as a colorless solid, mp y2-93 ° C. Analysis for CysHIOFIO: Found: C 51.64, H 2.73 Calculated: C 51.28, H 2.85%. (111) 2- (2-Fluor-ofen? 1) -1- (4-iodophene 1) ox? r-ano The title compound was prepared from the product of part (n), by a procedure similar to that of Preparation 20 (???), as colorless solid, m.p. 75-76 ° C. Analysis for C15H10CIIN3O: Found: C 49.11, H 2.77 Calculated: C 49.05, H 2.72 (iv) 2- (2-Fluoro in α1) -3- (1- [4-iodophene? l) Oxygenate The title compound was prepared from the product of part (111), by a procedure similar to that of Preparation 20 (? v), with or colorless oil, which was characterized by 1H- electroscopy. NMR. 1 H-NMR (300 MHz, CDCl 3): <; d = 3.16 (ABq, 2H), 5.45 (d, 2H), 6.98 (t, 1H), 7.09 (t, IH), 7.16 (d, 2H), 7.23 (m, 2H), 7.45 (n, 1H), 7.60 (d, 2H), ppm. (v) 2- (2-Chlorophen? l) -3- (4-iodophene? l) -l- (1, 2,4-tpazol-1-yl) -3-buten-2-ol The title compound was prepared from the product of the part (IV), by a procedure similar to that of Preparation 20 (v), as a colorless solid, mp. 117-118 ° C. Analysis for C18H15CIIN3O: Found: C 50.35, H 3.52, N 9.66 Calculated: C 49.77, H 3.46, N, 9.70%. IH-NMR (300 MHz, CDCl 3): d = 4.58 (d, 1H), 4.96 (d, 1H), 5.1 (broad s, 1H), 5.24 (d, 2H), 6 , 90-7.05 (rn, 2H), 7.80 (s, 1H), 7.82 (s, 1H), pprn.

PREPARATIONS 37 TO 39 The following compounds were prepared following the procedure of Preparation 1 or of Preparation 12, as specified in the Table.

PREPARATION 37 LH-NMR (300 MHz, CDCl 3): d = 4.64 (d), 4.77 (d), 5.30 (S), 5.44 (S), 5.46 (D), 5 , 57 (S), 7.00-7.90 (multiple) pprn. (Note: the compound was a mixture of rotarneros.

PREPARATION 40 (Alternative to preparation 29) 1-Etox? Methyl-l, 2, 3-triazole Acetone Chloromethylethylether (125 g, 1.3 mol) was added dropwise, over the course of an hour and a half, to a mechanically stirred suspension of 1,2,3-tpazole (91.4 g, 1.3 mmol) and potassium carbonate (183 g, 1.3 mole) in 1500 rnl of acetone cooling with an ice bath. The mixture was heated to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in 1 liter of water. The aqueous solution was extracted with dichloromethane (3 x 300 ml) and the organic extracts were combined. The dichloromethane solution was washed with brine (3 x 300 ml) and the organic phase was dried over sodium sulfate and evaporated under reduced pressure to give a pale yellow oil. The oil was distilled under reduced pressure to give, initially, 2-ethoxymethyl-1, 2, 3-thiazole, (57 g, 34%), e.g. < 90 ° C (3 mm Hg). 1 H-RMM (300 MHz, CDC13): d = 17.58 (t, 3H), 3.60 (q, 2H), 5.70 (s, 2H) pprn. Analysis for C5H9N3O: Found: C 47.36, H 7.23, N 32.62 Calculated: C 47.19, H 7.14, N, 33.05%. Continuing the distillation, the title compound was obtained (73 g, 43%), e.g. 92-93 ° C (3 rnrn Hg). 1 H-NMR (300 MHz, CDCl 3): d = 1.15 (t, 3 H), 3.56 (q, 2 H), 5.70 (s, 2 H) 7.77 (s, 1 H), 7.79 (s, 1H), pprn. Analysis for C5H9N3O: Found: C 46.30, H 7.52, N 33.29 Calculated: C 47.19, H 7.14, N, 33.05%.

PREPARATION 41 2- (2,4-Difluorophenyl) -l- (1, 2,4-riazol-1-yl) -3- [4- (1- (2-methoxyethoxymethyl) -!, 2, 3- triazol-5-yl) phenyl3-3-buten-2-ol The following compound was prepared in a manner similar to the procedure of Preparation 12 using the tpazole of Preparation 42: p.f. 124-127 ° C. Analysis for C 24 H 24 F 6 MSO 3: Found: C 59.79, H 4.86, N 17,14 Calculated: C 59.75, H 5.01, N, 17.42%.

PREPARATION 42 1- (2- (2-Methoxymethoxymethyl) -1, 2, 3-riazole The title compound was prepared from 1,2,3-triazole and 2-rnetox? Ethoxy? Rnet chlorur-o? lo, by a procedure similar to that of Preparation 40, as a colorless oil that was characterized by 1 H-NMR spectroscopy (300 MHz, CDCl 3): d = 3.31 (s, 3H), 3.46 (rn, 2H), 3.62 (n, 2H), 3.62 (rn, 2H), 5.77 (s, 2H), 7.73 (s) , IH), 7.75 (s, 1H), ppm.

PREPARATION 43 2- (2,4-Di-luo-phenyl) -3- (4- [l-pencil-l, 2,3-triazol-5-yl-3-phenyl] -1- (1,2,4-t-riazol- 1-yl) phenyl 3-3-buten-2-ol The following compound was prepared as a racemate of form similar to the procedure of Preparation 12, using l-benzyl, 2,3-tpazole, mp. 105-108 ° C.

Analysis for C 27 H 22 F 2 N 6 O: Found: C 66.69, H 4.59, N 17.56 Calculated: C 66.93, H 4.58, N, 17.35%.

PREPARATION 44 2- (2J4-Difluorophenyl) -3-U- [1-hydroxyethoxymethyl} - (1, 2,3-triazol-5-yl] enyl) -! - (!, 2,4-triazol-1-yl) enyl 3 -3-buten-2-ol The following compound was prepared in a similar manner to the procedure of Preparation 12 using the tpazol of Preparation 45: The product was isolated as a colorless oil which was characterized by NMR. IH-NMR (300 MHz, CDCl 3): d = 3.6-3.0 (in, 4H), 4.64 (d, 1H), 4.96 (d, LH), 5.26 (s, 1H), 5.34 (s, 2H), 5.74 (s, 1H), 5.78 fs, 1H), 7.4-7.55 (rn, 5H), 7.7.7.8 (rn, 2H), 7.80 (m, 3H) ppm.

PREPARATION 45 1-Hydroxyethoxymethyl-1,2,3-triazole Tetrahydrofuran Tetrah1drofuran L76 A solution of l, 2, 3-tpazol-l-? 1-methoxetine rnet acetate (0.72 g, 4.2 mmol - see Preparation 46) on 10 ml of triehydrofuran was added dropwise to a suspension of lithium aluminum hydride (0.16 g). , 4.2 rnrnol), 0 ° C. The mixture was allowed to warm to room temperature overnight and was quenched by the addition of gu (0)., 32 ml) followed by an aqueous solution of sodium hydroxide (15%, 0.32 mmol) and water (1 ml). After 1 hour, the supernatant liquid was collected by filtration and the residue was washed with tetrahydrofuran (10 mL). The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography on silica, eluting with dichloromethane / netanol (19: 1). The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound as oil (0.30 g, 52%), which was characterized by NMR. IH-RMM (300 MHz, CDC13): d = 2.05 (t, 1H), 3.6-3.8 (rn, 4H), 5.80 (s, 2H), 7.78 (s, 2H) ppn .

PREPARATION 46 Methyl 1,2,3-triazole-l-yl-methoxyacetate The title compound was prepared from 1,2,3-triazole and methyl chloromethoxyacete, by a procedure similar to that of Preparation 40, as an oil colorless, which was characterized by NMR. 1 H-NMR (300 MHz, CDCl 3): d = • 3.76 (s, 3H), 4.16 (s, 2H), 5.84 (s, 2H), 7.80 (d, 2H) pprn.

PREPARATION 47 (2R, 3S / 2S, 3R) -2- (2,4-D? Fluorophen? L) -3- (4-propanoyl-phenyl3-l- (l, 2,4-triazol-1-yl) butan-2-ol A solution of N, 0-d? Met? L-4-2-l "2,4-di fluorofeml] -2-h? Drox? -l- (1,2,4-tr? Azol-l) acid -? l) but-3-? l-benzenehydroxarnico (2.70 g, 6.5 mmol - see Preparation 4g) in 100 ml of dry ether was cooled to 0 ° C under a nitrogen atmosphere and treated with a solution of ethyl bromide in ether (1MM, 15 ml, 15 nrnol) The solution was stirred at room temperature for 18 hours, quenched with a saturated solution of ammonium chloride (50 nmol) and the layers were separated. The aqueous phase was extracted with ethyl acetate (100 mL) and the organic layers were combined, dried over magnesium sulfate and evaporated under reduced pressure.The residue was purified by flash chromatography on silica, eluting with a gradient of ethyl acetate. ethyl / hexane (1: 1, 1: 0) The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (0.5 g, 20%) as a colorless solid, mp 171-172 ° C. Ana 1 i si s i > a ra C21 H21 Fe 2g O2: Found: C 65.04, H 5.63, N 10.88 Calculated: C 64.45, H 5.45, N, 10.91%.

PREPARATION 48 (2R, 3S / 2S, 3R) -2- (2, 4-Di luoro phenyl) -3- (4-acetyl phenyl) -l- (1,2,4-triazole-1-yl) butan -2-ol The title compound was prepared by a procedure similar to Preparation 47, using methylnanesorbromide, solid or colorless solid, m.p. 172-173 ° C. Analysis for C20H19F2N3O2: Found: C 64.43, H 5.09, N 11.31 Calculated: C 64.69, H 5.12, N, 11.32%. 79 PREPARATION 49 N-f-d-O-ethyl-4- (2-C 2, 4-difluoropheni 13-2-hydrox-l -1,2, 4-triazol-1-yl-butyl-3-yl) benzenehydroxamic acid In a solution of tet rahydrofuran / ethanol (1: 1, 40 ml) a mixture of N, 0-d? Met? L-4- (2-C2,4-difl uorofeml) -2-hi was suspended. droxy-1-Cl, 2,4-tnazol-1-l] -3-buten-3-D-D-benzenehydroxaic acid (0.9 g, 2.2 nrnol - see preparation 50), 10% palladium on charcoal ( 0.2 g) and ammonium formate (0.68 g, 11 mmol) and heated to ref Luxury for 3 hours. The cooled suspension was filtered through "rbocel" and the filtrate was concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate and the solution was washed with a saturated solution of sodium carbonate (20 mL) and brine (20 mL) and then dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica, eluting with a gradient of di-chloromethane followed by dichloromethane / rnetanoi (39: 1). The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (0.5 g, 55%) as a colorless foam. Analysis for C21 H22F2N4 O3: Found: C 60.17, H 5.40, N 13.11 Calculated: C 60.57, H 5.32, N, 13.45%.

PREPARATION 50 N, 0-dimethyl-4- (2- [2,4-difluorophenyl-2-hydroxy-l- [l, 2,4-triazol-l-yl-but-3-en-3-yl) benzenehydroxamic acid 4- (2-C2,4-difluorophenyl) -2-hydrox? -l-Cl, 2,4-triazol-l-yl3but-3-en-3-yl) benzoic acid (1.0 g, 2, 7 nm - see Preparation 25 (?) Was converted to acid chloride by following the procedure of Preparation 25 part (ii) This intermediate compound was dissolved in 40 ml of dry dichloromethane and treated with N, 0-dirnethylhydroxyl hydrochloride. l-arnin (0.31 g, 3.9 minol) The suspension was cooled to 0 ° C and treated with a solution of t-petilamine (0.75 nl, 5.4 minol) in die Loroethane The mixture was dried or warmed to room temperature over 18 hours before being evaporated to dryness under reduced pressure, the solvent was dissolved in ethyl acetate. (100 rnl) and washed with a saturated solution of sodium carbonate (3 x 30 ml) and brine (3 x 30 rnL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was subjected to flash chromatography on silica, eluting with a gradient of di chloro-methane followed by dichloromethane / methanol (24: 1). The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (0.5 g, 55%) as a colorless foam, m.p. 154-156 ° C. Analysis for C 21 H 20 F 2 N 4 O 3: Found: C 60.70, H 4.67, N 13.30 Calculated: C 60.86, H 4.86, N, 13.52%. 102 PREPARATION 51 2- (2,4-Difluorophenyl) -3- (4- [pyrazol-3-yl-phenyl-1- (1, 2,4-triazol-1-yl) -3-buten-2-ol (i) a mixture of 2- (2,4-di fl uorophenyl) -3- (4-iodophene) -l- (1, 2,4-tr? azol-1-yl) -3- buten-2-ol (4.0 g, 8.8 nmol see Preparation 20), 3, 3-d? et? iox? prop-l-? no (1.52 ml, .6 mmol), copper iodide (I) (0.02 g) and bis dichloride (tpfen? lfosf? na) palladium (0.12 g) in tethylaniline (40 ml) and tet rahydrofurane (13 ml) was stirred at room temperature for 18 hours. The solvents were removed under reduced pressure and solvent. it was repaired in the middle of the year (50 rnl) and water (50 rnl). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to chroma, ultra-rapid treatment on silica, and lilting with ethyl acetate. The fractions containing the desired product were combined and evaporated at reduced pressure? give 2- (2,4-d? -fluorophenyl) -3- (4-T3, -di et ox i prop-1 -i n-1-ill feml) 1 (1,2,4-tpazol-1- (l) -J-buten-2-ol as yellow (2.4 rn, 60%).

By grinding with cyclohexane an off-white solid was obtained which was characterized by 'NMR. 1 H-NMR, (300 MHz, CDC13) - d = 1.28 (t, 6H), 3.67 (q, 2H), 3.83 (q, 2H), 4.56 (d, 1H), 4 , 94 (d, 1H), 5.16 (s, 1H), 5.30 (d, 2H), 5.50 (s, 1H), 5.6-6.8 (rn, 2H), 7, 23 (d, 2H), 7.39 (d, 2H), 7.45 (rn, 1H), 7.82 (s, 2H) pprn. (11) The product of part (1) (2.4 g, 5.3 nmol) was dissolved in 30 rnl of dioxane and treated dropwise with dilute hydrochloric acid (2M, 6.6 rnl). The mixture was stirred at room temperature for 3 hours before the addition of hydrazide hydrate (98%, 0.31 mmol, 6.3 mmol) and continued stirring at room temperature overnight. The solvents were removed under reduced pressure and the residue was basified with a sodium hydroxide solution before being extracted with dichloromethane (2 x 50 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a yellow gum.

The residue was subjected to flash chromatography on silica, eluting with a gradient of hexane / ethyl acetate (1: 3, 0: 1) followed by ethyl acetate / methanol (9: 1). The fractions containing the desired product were combined and evaporated under reduced pressure to give 2- (2,4-di-f-1-chlorophenyl) -3- (4-p? Razol -3-? L-phen? L) -l - (l, 2,4-tr? azol-l-? l) -3-buten-2-ol (0.6 rng, 29%) as yellow solid, mp 182-184"C. Analysis for C 21 H 17 F 2 N 5 O: Found: C 64.51, H 4.39, N 17.81 Calculated: C 64, 12, H 4.35, N 17.80%.

PREPARATION 52 2- (2,4-D? Fl uo roten i 1) -3- (2- fl uoro-4-r 1-ethoxy rne i 1-1, 2,3-triazole-5- 1 Ifeni 1) - 1 - (1,?, 4-tpazoI -1 - l) -3- buten-2-ol (i) 0, Nd? methyl-2-fluoro-4-iodobenzene-hydroxamic acid This product was prepared from 2-fluoro-4-iodobenzoic acid (EP-A-0.327.igo) and hydrochloride 0 , Nd? Met? lhydrox Llarnin by a procedure similar to that of Preparation 30, as yellow oil, m.p. 120-122 ° C (0.5 inm Hg) which was characterized by NMR. iH-NMR (300 MHz CDCl3): d = 3.44 (s, 3H), 3.53 (s, 3H), 7.14 (t, 1H), 7.51 (d, 1H), 7.56 (dd, 1H) ppm. (11) 2 ~ (2,4-Difluorophen? L) -l- (2-fluoro-4-iodophene) -ethanone The title compound was prepared from the product of part (1) by a procedure similar to that of Preparation 20 (1), as colorless solid, e.g. F. 01-82 ° C. Analysis for C14H8F3TO Found: C 44.96, H 2.28 Calculated: C 44.71, H 2.14%. (in) 2- (2,4-D? fluorophen? l) -l- (2-fluoro-4-yodofeml) -prop-2-inone The title compound was prepared from the product of the pair. (11) by a procedure similar to that of Preparation 20 (??), as a colorless oil, which was characterized by NMR. 1 H-NMR (300 MHz, CDCl 3): d = 6.04 (s, 1H), 6.15 (s, 1H), 6.8-6.95 (rn, 2H), 7.40 (rn, 1H), 7.46 (t, 1H), 7.51 (dd, 1H), 7.63 (dd, 1H) ) pprn. (? v) 2- (2,4-D? fluorophen? l) -2- (2-fluoro-4-iodobenzoyl) -oxanhydrate The title compound was prepared from the product of part (111) by a procedure similar to that of Preparation 20 (111), such as colorless acell, which was characterized by 'PMN. 1 H-NMR (300 MHz, CDCl 3): d = 3.30 (d, 1H), 3.38 (d, IH), 6.80 (, 1H), 6.92 (rn, 1H), 7.4 -7.5 (rn, 3H),, 7.57 (dd, 1H) pprn .. (v) 2 - (2, 4 -Di f L uoro f eni 1) - 2 - (1 - L "- f 1-uoro-4-yod feni 1 Hetenyl) oxanura The title compound was prepared from the product of part (iv) by a procedure similar to that of Preparation 20 (iv) as a colorless oil, which was characterized by NMR. 1 H-NMR (300 I1I-: -, CDCl 3): d-3.07 (d, 1H), 3.19 (d, 1H), 5.40 (s, 1H), 5.51 (s, 1H), 6.74 (r, 1H), 6.03 (rn, 1H), 7.00 (t, 1H), 7.30-7.45 (m, 3H) pp. (Vi) 2 ~ ( 2,4-D? Fluorophen? L) -3- (2-fluoro-4-iodophenyl) -l- (l, 2,4-tpazoi-l-? L) -3-buten-2-ol The compound of title was prepared from the product of part (v) by a procedure similar to that of Preparation 20 (v) as a colorless solid, mp 136 ~ 138 ° C, which was characterized by 1 H NMR-NMR (300 MHz-CDCl 3). ): d = 4.54 (d, 1H), 5.08 (d, 1H), 5.18 (s, 1H), 5.28 (s, 1H), 5.53 (s, 1H), 6 , 70 (rn, 2H), 6.80 (t, 1H), 7.42 (td, 2H), 7.49 (rn, 1H), 7.81 (s, 1H), 7.95 (s, 1H) ppm. (vil) 2- (2,4-difluorophen? l) ~ 3 - (2 ~ fluoro-4-Cl-ethoxy? metii-l, 2,3-triazol-5-? l3phen?) -l- ( 1, 2,4-triazol-1-yl) -3-buten-2-oi The title compound was prepared from the product of part (vi) by a procedure similar to that of Preparation 12, as a colorless oil, which was characterized by NMR. 1 H-NMR (300 MHz, CDCl 3): d = 1.21 (, 3H), 3.73 (q, 2H), 4.60 (d, 1H), 5.08 (d, 1H), 5.30 (s, 1H), 5.36 (s, 1H), 5.56 (s, 1H), 5.65 (s, 2H), 6.6-6.8 (rn, 2H), 7.10 ( t, 1H), 7.3-7.6 (rn, 3H), 7.64 (td, 1H), 7.73 (s, 1H), 7.79 (s, 1H), 7.98 (s) , 1H) ppm.

PREPARATION 53 TO 58 The following compounds were prepared from (2R) -2-í2,4-d? Fluorophen? L) -3-C4-iodophen? L) -l- (lH-l, 2,4-triazole-l- il) -3-buten-2-ol, except in the case of Preparation 59 in which the starting compound (2RS) was used, and the appropriate heterocycle 1 -substituted, by a procedure similar to that of Preparation 12 00 • Yes ? OR 91 PREPARATION 54 1 H-NMR (300 MHz, C C 13): d = 1.41 (t, 3H), 4.15 (q, 2H), 4.63 (d, 1H), 4.97 (d, 1H), 5.14 (s, 1H), 5.32, (d, 2H), 6.26 (, 1 \), 6 , 69-6.79 (m, 2H), 7.32 (d, 2H), 7.38 (d, 2H), 7.47-7.55 (m,? H), 7.01 ("_., 1H),?, 84 (s, 1H), f > prn.

PREPARATION 55 1 H-NMR (300 MHz, CDCl 3): d = 1.46 (d, 3H), 1.48 (d, 3H), 4.53 (rn, 1H), 4.63 (d, 1H), 4.97 (d, 1H), 5.12 (s, IH), .32 (d, 2H), 6.22 (s, 1H), 6.73-6.79 (rn, 2H) 7.27-7.55 (rn, 6H), 7.8.1 (s, 1H) ), 7.84 (, 1H) ppm.

PREPARATION 56 1 H-NMR (300 MHz, CDCl 3): d = 3.99 (ß, 3H), 4.62 (d, 1H), 4.97 (d, 1H), 5.25 (s, 1H), 5.29 (ß, 1H), 5.35 (s, 1H), 6.71-6.77 (m, 2H), 7.42-7.49 (rn, 3H), 7.59-7.61 (rn, 2H), 7.81 (s, 1H), 7, 83 (s, 1H), 7.92 (s, 1H) pprn.

PREPARATION 58 1 H-NMR (300 MHz, CDCl 3): d = 4.60 (d, 1H), 4.95 (d, 1H), 5.11 (ß, 1H), 5.34 (s, 1H), 5, 38 (s, 1H), 5.60 (s, 2H), 6.65-6.80 (rn, 2H), 7.14 (m, 1H), 7.3-7.55 (rn, 9H), 7.82 (s, 19? 1H), 7.84 (s, 1H) ppm.

PREPARATION 59 1 H-NMR (300 MHz-CDC13): 6 ~ 3.61 ('',, 3H), 4.61 (d, 1H), 4.96 (d, 1H), 5.12 (, 1H), 5.30 (s, 2H), 6.7-6.8, (m, 2H), 7.18-7.4 (rn, 1H), 7.50 (q, 1H), 7.79 (s, 1H) 7.83 (s, 1H) p PREPARATION 60 2- (2,4 ~ P.? Fluorophene) -3- (4 ~ [l-rnet? Lim? Dazol-5? L] -phenyl) -l- (l, 2.4 ~ tr? azol-l ~? l) -3-buten-2-ol The title compound was prepared from 2- (2,4-di-fluoro-phenyl) -3- (4-C 1 -methyl-2-phenylthioirnidazol-5-yl] phenyl) -l- (l, 2,4-trolol-1-yl) -3-buten-2-ol, by a procedure similar to that of Example 35, as a colorless foam, which was characterized by * H-NMR spectroscopy. 1 H-NMR (300 MHz, CDCl 3): = 3.68 (s, 3 H), 4.54 (d, 1 H), 4.96 (d, 1 H), 5.31 (s, 1 H), 5.34 (s, 1H), 6.7-6.85 (m, 2H), 7.12 (s, 1H), 7.28 (s, 1H), 7.34 (d, 2H), 7.40 ( d, 2H), 7.54 (rn, 1H), 7.55 (s, 1H), 7.85 (s, 1H), 7.88 (s, 1H) ppm.

PREPARATION 61 (R, 3 / 2cJ, 3R) -? - (2,4 -O f luoro I eru 1) - - (5 T l-rifo l? Ne +? L-4- irazol i ll pin d - - 1 ) - 1 - í 1, 2, 4-t-r'iazol-1- 1) hutan-2-ol The title compound was prepared from 4-hromo-1-tp-phenyl-1-rtrole and (2R, 3S / 2S, 3R) -2- (2,4-diflorophe-ml) -3- (5-bromop? Pd? N-2- l) -! - (], 2,4 tr'iol-1-ll) b? Tan-2-ol, by a procedure similar to that of Example 82, for give the title compound as solid colorless, mp 208-209 ° C. Analysis for C29H32F2O: Found: C 73.44, H b, 25, N 13.13 Calculated: C 73.34, H 5.05, N 13.16%.

PREPARATION 62 (2R, 3S / 2C,, 3R) -? - (2, 4-D? F luorofeml) -3- (5-brornop? Ri d -? -? 1) -1 (1, 2, 4- tr? azol-1-? 1) butan-2-ol and add dropwise a solutjon of 2 ~ (1 ~ bromoeti l) -5-brorno ?? ri d na (1.32 g, 5 rnrnol) and 2- (1, 2, 4-tpazol-l-il) -2 ',' -dif 1 uoroacetophenone (1.11 y, 5 rnrno) in 12 rnl of THF to a suspension of zinc (0.85 and, 13 mmol) on 8 nl of THF at the appropriate temperature in a nitrogen atmosphere. Iodine was added at once 0.25 g (1 mmol), producing an exothermic reaction that did not moderate. When the reaction mixture returned to room temperature, it was quenched by the addition of aceUco acid (1 ml) and water (10 rnl). Ethyl acetate (30 ml) and the disodium salt of the acid et lend ammotetraacet (3.72 g, 10 mmol) were added and the organic phase was separated, dried over magnesium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (silica gel), eluyencjo with ethyl acetate / hexane (1: 1) to give, after trituration with diethyl ether, the diastereomer (2R, 3S / 2S, 3R). ) desired (0.62 g, 31%), mp 158-161 ° C. Analysis for C17H1S BrF2 * 0: Found: C 49.81, H 3.55, N 13.45 Calculated: C 49.90, H 3.69, N 13.69%. 1H-Partial RMM (300 MHz, CDCl 3): d --- 1, 08 (d, 3H), 4.05, 4.78 (AB system,? H) pprn. Continuing the elution of the previous column with ethyl acetate / hexane (2: 1), the diastereoisorium (2R, 3R / 2S, 3S) was obtained which crystallized when left at rest. (0.22 g, 11%), p. F. 82-83 ° C.

Analisys [= C17H15 BrF 2N4O: found: C 49.96, H 3.54, N 13.70 Calculated: C 49.90, H 3.69, M 13, 69%. 1 H-Partial NMR (300 MHz, CDCl 3): & = 1.50 (d, 3H), 4.66, 4.80 (AB system, 2H) pprn.

PREPARATION 63 (2R, 3S) -2- (2,4-D? Fluorophen? L) -1- (5-brornop? R? D-? - 11) - 1- (1, 2, 4- i azole - 1 - 11) but -2 -ol A solution of (2R, 3S / 2S, 3R) -2- (2, 4-d? Fluorofeml) -3- (5-bromop? R? D-2-? L) -1- (1, 2 , 4-tr? Azol-l-11) butan-2-ol (15.0 g, 37 nmol) was treated with an acid solution (-) - 3-brornocanfor-8-sulfon? Co [generated from the salt ammonia (24.0 g, 73 mrnol) by treatment of an ethanolic slurry (250 rnl) with ethanol HCl, followed by filtration of more soluble D material and stirring overnight at room temperature. The mixture was filtered and evaporated under reduced pressure. The residue was dissolved in 60 nl of acetone and stirred overnight at room temperature to give a colorless suspension. The solid was collected by filtration and recited twice in acetone to give the (-) - 3-brornocanfor-8-sulfonate salt of (2R, 3S) -? ~ (2,4-d? Fluorophen?) - 3- (5-brorno? Pd-2-? L) -l- (1, 2,4-tpazol-1-yl) -butan-? -ol (14.4 g). It was determined that the optical purity of the product was 92% e.e. by HPLC analysis using a Chiralcel ™ OD column and eluting with ethyl acetate / hexane (20:80). The solid was suspended in 100 ml of water, basified with a saturated sodium carbonate solution and extracted with ethyl acetate (3 x 100 rnl). The combined organic extracts were washed with brine (3 x 50 mL), dried over sodium sulfate and evaporated to give a colorless oil. The oil was dissolved in ether and evaporated to give the title compound in the form of foam (4.23 g, 56% of theory). Analysis for C17H15 BrF2N «0: Found: C 49.61, H 3.28, N 13.46 Calculated: C 49.90, H 3.69, N 13.69%.

PREPARATION 64 2- (1-Bromoethyl) -5-bromopi ridine f ^ YBP AIBN ^ ÍÍBr C CHj ** C? - íCICH- i.Cl * Br CBi ** J A solution of 2-et? l-5-brornopi pd? na (1.86 g, 10 mmol) and N-brunsucminitrin (1.78 g, 10 mmol) in 20 ml of 1, 2- 97 dichloroethane was refluxed before the addition of azoisobuty ronit ryl (AIBN) (20 ing). Then the solution was refluxed for 2 more hours. The cooled suspension was filtered and evaporated in vacuo. Purifying by column chromatography (silica gel), eluting with di chloro-methane / hexane (1: 1) gave the desired product as pale yellow oil (2.12 g, 80%). 1 H-RMIM (300 MH, CDC13): 6 = 2.05 (d, 3H), 5.20 (q, 1H), 7.35 (d, 1H), 7.8 (d, ll), 8, 6 (d, 1H) pprn.

PREPARATION 65 2-Ethyl-5-bromopyridine A solution of ethyl agnesium bromide in ether (100 ml, 3M, 0.3 mol) was added dropwise to a cold (5 ° C) solution of anhydrous zinc chloride (40.9 g, 0.3 mmol) in 500 g. rnl of THF, under nitrogen. After stirring for 1 hour at 0 ° C, tetrakis (triphenylphosphine) palladium (0) (1.0 g, 0.87 nmol) was added, followed by a solution of 2.5 dibrornopyridm (50 g, 0.21 mol) in 200 rnl of THF. The resulting yellow suspension was stirred at room temperature overnight, quenched by the addition of 200 ml of water and then evaporated in vacuo. The residue was treated with a suspension of ethylene diamine-acetic acid (200 g) in 1000 ml of water and 500 ml of di chloro-methane. The organic layer was separated and the aqueous layer was extracted again with 500 i of d clo or methane. The combined extracts were dried over magnesium sulfate, the solvent was evaporated in vacuo and the residue was distilled (123 ~ 124 ° C, 60 nm Hg) to give the required product as a colorless oil (28.8 g, 76%). 1 H-RMM (300 MHz, CDC13): d-1.30 (*, 3H), 2.80, (q, 2H), 7.10 (d, 1H), 7.7 (dd, ll-l) , 0.6 (d, 1H) pprn.

PREPARATION 66 l-Fto? Rnet ilpj razol The title compound was prepared by a procedure similar to that of Preparation 26 as a colorless oil, e.g. 100 ° C to 15 nm Hg (Kugelrohr), which was characterized by iH-NMR spectroscopy. 1 H-NMR (300 MHz, CDCl 3): 6 = 1.16 (t, 3H), 3.52 (q, 2H), 5.43 (s, 2H), 6.33 (t, IH), 7, 58 (rn, 2H) ppm.

PREPARATION 67 (2R, 3S / 2S, 3R) -2- (2,4-Di luoro-enyl) -3- (2-tri-luoromethylsulfonyloxypyridin-S-iD-ld ^^ -triazol-1-yl) butan-2- ol T-or ? 3 / P Ethanol (i) l- (2-Chloropyridin-5-ii) -2- (2,4-difluorophenyl) pro? -2-enone The title compound was prepared from the product of Preparation 22 part (ii) by a procedure similar to that of Preparation 20 (ii) as a colorless solid, mp 111 ~ 112 ° C, which was characterized by * H-NMR spectroscopy.

J o o 1 H-NMR (300 MHz, CDCl 3): "5.95 (s, 1H), b, 0 (s, 1H), 6.80 (m, 1H), 6.90 (rn, 1H), 7.4U (q, IH), 7.45 (d, 1H), 8.10 (dd, 1H), 8.80 (s, 1H) pprn. (II) 2 - (2-Clorop? r'i d? n -5 -carboni 1) -2- (2,4-difluoropheniDoxn ano) The title compound was prepared from the product of part (1) by a procedure described in Preparation 20 (111). ) as yellow oil, which was characterized by an IL-NMR spectroscopy, 1 H-NMR (300 MHz, CDCI 3) - d - 3,25 (d, 1 H), 3,40 (d, 1H), 6.80 (rn, 1H), 6.95 (in, 1H), 7.40 (d, 1H), 7.45 (q, 1H), 8.25 (< Jd, 1H), 9.00 (s, 1H) ppin. (III) 2- (2-Chloro-pd? N-5? L) etem.1-2- (2,4-di f 1 uo ro fen 11) ox 1 ra no The title compound was prepared Starting from the product of part (11) by a procedure similar to that described in Preparation 20 (iv), as yellow oil, which was characterized by 1 H-NMR spectroscopy. 1 H-NMR (300 MHz, CDCl 3): d = 3.15 (q, 2H), 5.50 (d, 2H), 6.70 (rn, 1H), 6.90 (rn, 1H), 7, 25 (d, 1H), 7.40 (q, 1H), 7.70 (d, 1H), 8.40 (s, 1H) pprn. (iv) (2R, 3S / 2S, 3R) -2- (2,4-D? fluorophen? l) -3 ~ (2-chloro-p? pd? n-5? l) -l- (l , 2,4-tpazol-1-yl) -3-bu ten-2-ol The title compound was prepared from the product of part (111) by a procedure similar to that described in Preparation 20 (v) , as a colorless solid, mp 116 ~ il9 ° C, which was characterized by iH-NMR spectroscopy. 1 H-RMM (300 MHz, CDCl 3): d-4.60 (d, IH), h, 00 (d, 1H), b, 35 (s, 1H), 5.40 (d, 2H), 6, 65-6.80 (rn, 2H), 7.20 (d, Ih), 7.40 (q, 1H), 7.60 (dd, 1H), 7.80 (s, 1H), 7.85 (s, 1H), 8.20 (s, 1H) pμm. (v) (2 R, 3 S / 2 S, 3 R) ~ 2 - (2, 4 - D 1 f 1 or 1 -phen 11) - 3 - (2 -rn toxi ip dm-5 -il ) -1 ~ (1, 2, 4-tr? Azol-l-yl) -3-u en- 2 -or 1 One solution (Je (2R, 3S / 2S, 3R) -2- (, 4-d) ? f 1 orotenyl) -3- (2-chloropyldi-5-yl) -1- (1, 2, 4 -peace l-1-? l) -3-but en-? -ol (10.27 g , 20 mmol) in 20 ml of ethanol was treated with a solution of sodium inetoxide [formed from sodium (1.3 g, 56 ml) and 30 ml of methanol] and the solution was refluxed for 10 hours. After 4 days at reflux, additional amounts of sodium inoxide solution were added (from 2 x 3.25 g, 0.28 mole total of sodium) The mixture was diluted with 100 nrl of water and evaporated under reduced pressure. The residue was partitioned between water (100 mL) and dichloromethane (100 mL), the organic phase was washed with water (50 mL), dried over magnesium sulfate and evaporated under reduced pressure, and the residue was chromatographed on silica, eluting with a gradient dichloromethane / ethanol (100: 098: 2). The fractions containing the desired product were combined and evaporated under reduced pressure to give a yellow oil (10.15 g, quantitative yield) which was characterized by iH-NMR spectroscopy as a 93: 7 mixture of product: starting compound. 1 H-NMR (300 MHz, CT) C 13): d-3.90 (s, 3H), 4.60 (d, 1H), 5.00 (d, 1H), 5.27 (s, 1H), 5.30 (d, 2H), 6.60 (d, 1H), 6.65-6.80 (in, 2H), 7.45 (, 1H), 7.55 (dd, 1H), 7, 80 (s, 1H), 7.85 (s, 1H), 8.05 (d, 1H) pprn. (vi) (2R, 3S / 2S, 3R) -2- (2,4-DLfluorophen? I) -3- (2-rne-t ox? p? -? d? -5-1) ~ 1- ( 1, 2, 4-tp zol-l-? L) utan -2-ol The title compound was prepared from the product of part (v) by a procedure similar to that described in Example 1, as colorless solid, p. f "94-96 ° C, which was characterized by H-NMR spectroscopy, 1 H-RMM (300 MHz CDCl 3): d = 1.10 (d, 3H), 3.30 (q, 1H), 3 , 85 (d, 1H), 3.95 (s, 3H), 4.80 (d, 1H), 4.90 (s, 1H), 6.70 (m, 2H), 6.80 (d, 1H), 7.45 (q, 1H), 7.74 (s, 1H), 7.76 (s, 1H), 7.85 (dd, 1H), 8.20 (d, 1H) pprn. vn) (2R, 3S / 2S, 3R) -2- (2,4-D? fluorophen? l) -3- (2-h? drox ??? r? -n-5-? l) -1- (1, 2, 4-t pazol-1-? L) -but n-2-ol A solution of (2R, 3S / 2S, 3R) -2- (2,4-d-luo-phenyl) -3- ( 2-methox? P? R? Dm-5-? L) -1- (1,2,4-tnazol-1-yl) butan-2-ol (7.06 g, 19.6 mmol) in 50 ml of ethanol treated with dilute hydrochloric acid (2M, 20 ml) and the mixture was heated to reflux for 84 hours.The mixture was evaporated under reduced pressure and the residue was triturated with water to give the title compound as a colorless solid (4.05 , 60%, mp 213-214 ° C, which was characterized by H-NMR spectroscopy, 1 H-NMR (300 MHz, CDCl 3): d = 0.90 (d, 3H), 3.30 (q, 1H) , 4.10 (d, 1H), 4.80 (d, 1 H), 5.55 (s, 1H), 6.30 (d, 1H), 6.85 (rn, 1 H), 7.10 (in, 1H), 7.20 (q, 1H), 7.25 (d, 1H), 7.45 (dd, 1H), 7.60 (s, 1H), 8, 15 (s, 1H), 11.50 (broad s, 1H) ppm. (VJII) (2R, 3S / 2S, 3R) -2 (2, -D? F luorophenyl) -3- (2-tnf luoromethylsuloru loxLp? R? D? N-5 ll) - 1 - (1, 2 , 4-trolol 1-11) ut an-2-ol A suspension of (2R, 3S / 2, 3R) -2- (2, 4-dii luor-or eeml) - 3- (2-hydr oxy) pi pd? n-5-? l) -l- (1,?, 4-t riazole -1-11) butan-2-ol (2.0 <j, r>, 8 mol) in 15 ml of pindine was treated with phthalate fluor fluoride (2.14 mmol, 11.6 mmol) 0 ° C. The yellow solution was stirred at 0 ° C. for 15 minutes and allowed to warm to room temperature overnight. 10 ml of water were added and the mixture was partitioned between dichloromethane (50 ml) and a saturated aqueous solution of sodium carbonate; The organic phase is dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a dichloromethane / methanol gradient (100: 098: 2). The pure fractions containing the desired product were combined and evaporated under reduced pressure to give a colorless oil which was triturated with ter to obtain the title compound in solid form (0.71 g, 26%), m.p. 172-173 ° C, which was characterized by 1 H-NMR spectroscopy. 1 H-NMR (300 MHz CDC13): d = 1.15 (d, 3H), 3.40 (q, 1H), 3.80 (d, 1H), 4.80 (d, 1H), 5.10 (s, 1H), 6.80 (rn, 2H), 7.20 (d, 1H), 7.45 (q, 1H), 7.74 (s, 1H), 7.76 (s, 1H), 0.15 (dd, 1H), 0.40 (d , 1H) ppm.

PREPARATION 68 l-Met? Lp? Razol-5-? L-tnmetilestannano Butyl lithium (2.5 M in hexane, 9.75 mmol, 24.4 mmol) was added to a stirred solution of 1-rnetylpyrazole (2.0 g, 24.4 mrnol) in 30 mL of THF at -78 ° C. After 9 minutes, a solution of chlorotrinethylenetetan (4.85 g, 24.4 mmol) was added dropwise and the mixture was allowed to warm to room temperature. The mixture was evaporated under reduced pressure and the residue was partitioned between ether (50 rnl) and water (50 rnl). The ether layer was dried over magnesium sulfate and evaporated to give the title compound or colorless oil (6.0 g, quantitative yield), which was characterized by 1 H-NMR spectroscopy. 1 H-NMR (300 MHz, CDC13): d = 0.35 (s, 9H), 3.95 (s, 3H), 6.30 (s, 1H), 7.50 (s, 1H) pprn.

PREPARATION 69 (2RJ3S) -N-riet l-4-. { 2- [2,4-di luo-phenyl] -2-hydroxy? -l- [1,2-tr azol-l-? L-l ut-3- l} benzoiltiosem? carbazide Solid methyl otiocyanate (0.30 g, 5.2 inmol) was added to a solution of (2R, 3S) -N-Met? L-4-. { 2- C2, 4-di fluorofeni 11-2-h? drox -1-Cl, 2, 4-t-riazol-1-? l] but-3? l} benzo? lh? draz? da (2.0 g, 5.2 inrnol - prepared from the product of Preparation 20 by the procedure of Preparation 23) in 20 rnl of ethanol. The mixture was refluxed overnight and evaporated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (150 rnl) and a saturated solution of sodium bicarbonate (35 rnl). The aqueous phase was extracted with ethyl acetate (50 ml) followed by dichloromethane / methanol (95.5). The organic extracts were combined, washed with brine (40 nl) and dried over sodium sulfate and then evaporated under reduced pressure. The residue is chromatographed on silica, eluting with a dichloromethane / methanol gradient (98: 292: 8). The pure fractions containing the desired product were combined and evaporated under reduced pressure to give a colorless oil which was triturated with ether to give the title compound in solid form (2.1 g, 85%), m.p. 172-173 ° C, which was characterized by iH-NMR spectroscopy. 1 H-NMR (300 MHz, CDCl 3): d = 0.9 (d, 3H), 2.8 (d, IH), 3.2 (q, 1H), 3.6 (d, 1H), 4, 6 (d, 1H), 4.8 (s, 1H), 5.1 (s, 1H), b, 5 (rn, 2H), 7.2 (in, 21-1), 7.3 (d , 2H), 7.4 (s, 1H), 7.7 (rn, 3H), 8.7 (broad s, 1H), 9.8 (broad s, 1H) pprn.

PREPARATION 70 (2R, 3S) -2- (2,4-Difluorophenyl3-3- (4- [3-methyl-5-trimethyl-silylpyrazol-4-yl] -phenol!) -! - (1,2,4-triazole) -l-illbutan-2-ol , u Hexano / TH? l -? r > **? 1? (i) (2R, E / Z) -2- (2,4-Difluoro-enyl) -3- (4-C2-cyano-l-propenyl] enyl) -l- (1, 2,4-tr? -l-yl] -3-buten ~ 2-ol A suspension of (2R) -2- (2,4-difluorophenyl) "3- (4-yodofe il) -1-Q, 2,4-tnazol-1 --il_l-3-buten-2-ol (2.0 g, 4.4 nmol - Example 66 part (I), palladium acetate (0.05 g), triethia ina (1.0 rnl) and tp (ortho-tolyl) phosphine ( 0.14 g) in 50 rnl of acetonite was treated with rnetacplomtri lo (0.74 ml, 8.8 rninol) and the mixture was heated to reflux for 70 hours.Equal amounts of each of the reagents were added and the mixture was returned. The mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (30 ml) and saturated sodium bicarbonate (20 ml), the organic phase was washed with brine (30 nl), dried Sodium sulfate and evaporated under reduced pressure The residue c & amphora on silica, eluting with a gradient of di chloromene / rnethol (98: 292: 8) The pure fractions containing the product were pooled. and evaporated under reduced pressure to give a colorless solid (1.3 g, 75%) which was characterized by mass spectroscopy, rn / z = 393. (ll) (2R) -2- (2,4-D? fluorofen? n-3- (4-C3-rnet? l ~ 5-tr? -rnenylsilyl p? razol-4-? l] phenyl) -l- (1, 2, 4-tpazol-l-? l3-3 -buten-2-ol Butylit or (2.5 M in hexanes, 4.0 i, 10 mmol) was added dropwise to a solution of tprnethylsilyldiazornetan (2.0 M in hexanes, 5.0 rnl, 10 mmol) in 20 rnl. of THF at -78 ° C. After stirring for 15 minutes, a solution of (2R) -2- (2,4-d? Fluorofeml) -3- (4-C2-c? Ano-l-? Ropeml3feml) -l was added dropwise. - (1, 2,4-tnazol-1-yl) -3-buten-2-ol (1.3 g, 3.3 nmol) to give a brown solution which is heated to room temperature overnight. The mixture of inactive with a saturated solution of ammonium chloride (20 mL) was added with dichloromethane (30 mL).VO with water (30 rnl) and brine (15 rnl) was added to sodium sulfate and evaporated under reduced pressure. The residue is cured on silica, eluting with a gradient of di chloromethane / methanol (100: 098: 2). The pure tractions containing the desired product were combined and evaporated under reduced pressure to give a colorless solid (0.65 g, 41%) which was characterized by 1 H-NMR spectroscopy with or mixed 2.1 turners. 1 H-NMR (300 MHz, CDCl 3): d -0.05 (s, 6H), 0.20 (s) 3H), 2.16 (s, 2H), 3.94 (s, 1H), 4.52 (d, 0.3H), 4.62 (d 0.7H), 4.87 (d, 0, 3H), 4.93 (d, 0.7H), 4.97 (s broad, 0.3H) 5.13 (broad s, 0.7H), 5.15 (s, 0.7H), 5, 20 (s, 0.3H), 5.30 (s 2H), 6.55-6.7 (rn, 2H), 7.10 (d, 1.4H), 7.14 (d, 0.6H) ), 7.22 (d 1.4H), 7.42 (m, 1H), 7.75 (s, 0.7H), 7.78 (s, 1.3H) ppm. (111) (2R, 3S) -2- (2,4-D? Fluorofeml) -3- (4- [3-rnethyl-5-trinetiisilylp r-azol -4-? L] phen? L) -1- (1, 2, 4-tr? Azol-l -1 Dbutan-2-oi The title compound was prepared from the product of part di) by a procedure similar to that described in Example 1, as pale yellow solid, which was characterized by 1 H-NMR spectroscopy. 1 H-NMR (300 MHZ CDCl 3): d = 0.15 (s, 9H), 2.25 (s, 3H), 3.35 (q, 1H), 3.87 (d, 1H), 4.80 (s broad, 1H), 4.87 (d, 1H), 6.75 (rn, 2H), 7.22 (d, 2H), 7.4-7.5 (rn, 3H), 7.72 (s, 1H), 7.78 (s, 1H) ppm.

PREPARATION 71 (2- (1-Bromoethyl) -5- (1, 2, 3-triazol-2-yl) pi ridine (i) 2-Et? l-5- (l, 2,3-tr? azol-2? l) ??? -? dma The title compound was prepared from 5-bromo-2-et? i ??dma (preparation 65) and 1,2,3-t-riazole by a procedure similar to that of preparation 1. The regioisomer product was separated by chromatography on a column of silica, eluting with a gradient of ethyl acetate / hexane ( 1: 11: 0). The eluted fractions were first combined containing the title compound and evaporated under reduced pressure to give an oil that was distilled, e.g. 135 ° C @ 9.05 mm Hg (Kugelrohr). (n) 2- (1-Brornoet? l) -5-) 1, 2,3-tr? azole-2? l) p? pd? na The title compound was prepared by the procedure of preparation 64 using as a solvent 1,1,1-tr? chloroethane (Gen lene), as a colorless solid, mp 72-73 ° C. Analysis for C9H9BrN-4: Found: C 42.85, H 3.68, N 22.70 Calculated: C 42.71, H 3.58, N 22.14%.

PHARMACOLOGICAL DATA Acute syndemic candidosis in immuno-normal mice Mice were ravenously infected with Candida albicans to establish a systemic infection (all untreated control animals died within 2 days after infection). The efficacy of the compound was evaluated based on survival after oral dosing (0.1-5 rng / kg, 1, 4 and 24 hours after infection) and was measured as 50% protective dose of the animals on the second day after the infection. Results: Compound of example N9 Pso (mg / kg) 3 0.32 4 0.10 6 0.04 15 (form 2R, 3S / 3S, 3R) 0.56 36 0.18 38 0.10 Safety data No it has been found that the compounds exhibit no adverse toxicity. For example, in a 7-day toxicity study (ie duration in rats (80 mg / kg po, od) the products of examples 3 and 15 (2R, 3S / 2S, 3R), had no adverse effect The components are also useful as anti-fungal agents in plants.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A cornpuos-t o de f o rmu 1 a: or a pharmaceutically acceptable salt thereof, wherein Ares a phenyl group substituted with 1 to 3 substituents each independently selected from halo and CF3 and X is a group of formulas: in Iri that Z is H or F and Het is an aromatic heterocyclic group with 5 members, < They contain nitrogen and optionally contain an oxygen or sulfur atom and are bonded to the phenyl, pyrimidyl or pyrimidyl group by a carbon or nitrogen atom and optionally substituted with 1 to 3 selected substituents each. they independently enter halo, alkyl 1-4, (alkoxy Ci-4) ethyl, 2- (to ox? C? -4) et ox nnet ilo, 2-h idroxiet ox 1 methyl, cyano et 1] or, NR R2 or -CH2CÜNRIR2, where R1 and R2 are c < one of them independently H or C1-4 alkyl; phenylthio or phenyl-C1-2alkyl in both of which the aforementioned renyl group is optionally substituted with halo, tp luororneti lo or C1-4alkyl -NHCO-C1-4alkyl, -NHSO2 -alkyl C? - ", -IMHCONRl R2, where R1 and R2 are those defined above, mercapto and -S (0) n -alkyl Ci-,., Where n is 0, 1 or 2. 2.- A component according to claim 1, wherein that Z is H. 3. A compound according to claim 1 or 2, wherein "Het" is a pyrazolone, irni, dazolyl, tpazolyl, thiadiazolyl, oxadiazole, pyrrolyl, thiazolyl or -t and razolyl group, all of which optionally substituted as defined in claim 1. 4.- A compound according to claim 3, wherein "Het" is a group? razol ~ l-? lo, pi razol-3-? lo, p? razol-4-i lo,? rn? dazol-1 -1I0,? rn? dazol-2-? lo, irnidazole -4-? lo, 1, 2, 3-tpazol-1-? io, l, 2, 3-trolol-2-yl, 1, 2, 3-tnazol-4-yl, i, 2, 4-t-riazol-1-yl, 1, 24-trolol-3-yl, 1, 2, 4-t-pazol-4-iio, 1,3,4-thiadiazol-2-lio, 1, 3, -oxad? azole -? ilo, 1, -oxadiazol -5-? lo, pir r-ol-l-ilo, -t? azol-5-? ot ottr azol -G -lio, escando all these groups optionally substituted with 1 to 3 their The components as defined in claim 1. 5. A structure according to claim 4, in which "Het" is substituted with 1 to 2 substituents each selected independently in-t-re-chlorine, bromine, fluoro, iodine, C1-3 alkyl, arní no ethoxymethio, 2-rnetoxyethoxy etiio, 2-hydrox ethoxynet? E-t-lithium, r-methanesulfonyl, r-mercapto, phenylthio, r-methanesulfonarmdo, 3-methyledido, cyanoethyl, car'barnoi lrnet 1I0, acetarnide and benzyl. 6. A compound according to claim 5, wherein "Het" is ?? r-azol-1-? io, 3-arn? no ?? razol -1 -lio, 1-ethoxyrnetilpí razol -4-1I0, 1-ethox? met? l ?? razol -5 - 1 lo, 4-bromop? razol-3-? I-methanesulf or narm dopí razol -li lo, 3- (3-rnet? lure? do) ?? razol- 1 lio, 3-acetarn? dop? razol -1 lio, 1-rnet? l ?? razol- 5-? Lo, 1-met? Lp r azol-3-? Lo, l-et? L? R-azol-5-iio, l-isopr-opiipi razol -5-? Lo, 1-etox? Met ? ip? What is the reason for this? -5 - lio, 1-carba oilrneti l ?? razol-3-? lo, 1-c? anornet? lp? razol-3-? lo, p? razol-3-? lo, p? razol-4-? lo, 3-met? lp? razol-4-? lo, 1-rnetilrní azol -2-? lo, Methiazole-1-l, 2-methylene-dazol-1, 1-ethoxyrnet-11 -2-f emitted irni-dazol-5-l, l-ethoxy-rnet? l? rn-dazol- 2-1I0, 4-methox? Dazol-l-lio, l-ethoxy? Rnet? I? Nn? Dazol-5-yl,? Rn? Dazol-2-? L, l-met? L? rn? dazoi-5-? lo, 1-et? i? n? dazol -5-? lo, 1-rnet? i-2-femlt? o? rn? dazol-5-? lo,? rn? dazol- 4-? Lo, 1,2, 3-tr? Azol-1-? Lo, 1, 2,3-tr? Azol-2 -i lo, 1, 2, 4-tr? Azol-l-? Lo, 1-Etox? Met? L-1,2,4-tpazol-5-lio, 1-ene nne 1 -3-? Net i lt? Ole, 2, 4-tr? Azol-5-j lo, 1,2,3-tpazol-4-lyo, 1- (2-nitrate-1-nitric acid L!) - 1, 2, 3-t-riazol-S-yl, 1- -bibi-1, 2,3-tr? azoL-5- lyo, 1 - (2-hydro? ethoxy? met l) -1 / 2,3-triazole-5-lyo, G-rneti 1 - 1, 2, 3-tpazol-4-? lo, 3-? Net? Lt? O- 1, 2, 4-tr? Azol-1-? Lo, 1-etho? Rnet L1 -1, 2, 3-tpazol-5-lo, 4-inethyl-1, 2 , 4-tpazol-3-lyo, 3-rnerca-to-4-rnet? L- 1, 2, 4-trolol 5-L10, 1-? Net? L ~ l, 2, 4-tr? Azol -5-? Lo, 1-ethoxy? Net? -1.2, 3-tpazol-4-? Lo, 2-et oxy ethyl - 1, 2, 3-t pazol - 4- i lo, 1, 2, 4 - t ri azoi-4-? Lo, -chloro 1,2,2-tpazol-5-1 lo, 4-bromo- 1, 2, 3 - tpazol-5-? lo, 4-iodo-1, 2, 3-triazol-5-Lio, 4-fluoro-l, 2, 3-tr? azol-5? lo, 1,2,4-tpazol -3-i lo, 5-methane sul fon 11-1,2, 4-tri azol-3-? Lo, 3-rnetanosul fon ll, 2, 4-tr? Azol-1-? Lo, 1-ethox L rne ti 1 -3-rnetanosul foni 11, 2, 4-triazol-5-? what, 5-ammo-l, 3, 4-t? ad? aolol 2-? it, 5-rnet? l- 1,3,4-oxadiazol -2-? it, 5-rnetltolut, 3, -oxad? azol-2 -? lo, 5-ethanesulfoml-1, 3,4-oxad? azol -2-? lo, 3-arn? no-l, 2, 4-oxad? Azole-5? Lo, 5-a? N? No-l, 3, 4-oxad? Azole -2-? Lo, 1-met? ltetrazol-5-lyo, .1-benzyltrite-5-yl, tetrazol-5-yl, t-azol-5-yl and 2,5-dirnethylpyrrol-l-yl. 7. A compound according to claim 1, wherein X is a group of the formula: - "wherein Z is H or F and" Het "is the one defined in any of claims 1 and J to 6. 8. A compound according to claim 7, wherein X is a group of formula: wherein "Het" is as defined in claim 7. 9. A compound according to any of claims 1 to 4, 7 and 8, wherein "Het" is selected from (a) a group 1, 2, -trαolol-1- unsubstituted, (b) a 1, 2, 4-tpazol-1-lyo or 1, 2, 4-trolol-4-unsubstituted -lio group, (c) a group 1, 2, 3-tr? Azol? or 1,2,4-tpazolyl linked to the adjacent phenyl group by a carbon atom and optionally substituted on a nitrogen atom with C 1-4 alkyl or (C 1-4 alkoxy) -rnet? io, (d)? rn? dazol-1? the unsubstituted, (e) a group pi razol- 3-? the unsubstituted, a group p? razol-4-? the unsubstituted or a group l-rnet? lp? razol-5-? and (f) a group? rn? dazol ~ 4-? lo or l-rnet? l? rn? dazol-5-? lo. 10. A compound according to any of the preceding claims, wherein Ar is a phenyl group substituted with 1 or 2 substituents each independently selected from halo and CF3. 11. A compound according to claim 10, wherein Ar is an enyl group substituted with 1 or 2 substituents each independently selected from F, Cl and Br. 12. A compound according to claim 11, wherein Ar- is 2,4-d? Fl uorophenyl, 2-chlorophenol or 2-fiuorofen? Lo. 13. A compound of formula (I) according to claim 1, which is selected from: (2R, 3S) -2- (2,4 ~ di luoro phenyl) -3- (4-C? Rn? Dazol-l) -? lH phenyl) -l- (l, 2,4-tr? azol-1-yl) butan-2-ol, (2R, 35) -2- (2,4-d? f-1-chlorophenyl) -3 - (- i 1, 2, 3-tpazol-l ~? iJfen? l) -l- (l, 2, 4-tpazol-l-? l) butan-2-ol, (2R, 3S) -2 ~ 2/4-d? fluorophen? l) -3- (4-p, 2,3-tr? azol-4? i:] phen? l) -l- (l, 2,4-triazole-1-) ?) butan-2-ol, (2R, 3S) -2- (2, 4-d? fluorofem 1) -3- (4- [l, 2,4-tr? azol-l-? pfen? l ) -l- (1, 2, 4-triazol-l-? l) butan-2-ol, (2R, 3S) -2- (2,4-d fluorofeml) -3- (4-Cl, 2, 4-tnazol ~ 3-? L] feml) -l- (1, 2,4-tpazol-1-yl) butan-2-ol, (2R, 3S) -2- (2, 4 -dif luorophenyl) -3- (4-Cl, 2,4-triazol-4-? L] phenyl) -1- (1, 2, 4-triazol-1-yl) butan-2-ol and (2R, 3S) - 2- (2, 4-difluorophenyl) -3- (4-Cl -methi ?? razol-5-? L] feml) -l- (l, 2,4-tr? Azol-l-? L) butan- 2-ol. 14. A compound of formula: wherein Ar is as defined in claim 1, and X is that defined in claim 1 but where "Het" is attached to the phenyl, pi idyl or pyrirnidyl group adjacent through a carbon atom. 15. A compound of formula: wherein Ai "is as defined in claim 1 and R is H or C 1-4 alkyl 16. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in 17.- A composition according to claim 16, wherein the compound of formula (I) is complexed with a cyclodextrin 18.- A composition according to any of claims 1 to 13, and a pharmaceutically acceptable carrier or diluent. claim 17, wherein the cyclodextrin is a hydroxyalkyl or sul-alkylic derivative of beta-cyclodextrin 19. A compound of formula (I) according to any of claims 1 to 13, or a pharmaceutically acceptable salt thereof, Use as a medication. 20. The use of a compound of formula (i) according to any of claims 1 to 13, or one of its pharmaceutically acceptable salts, for the manufacture of a medicament for the treatment of a fungal infection. 21. The use of a composition according to claims 16 to 18, for the manufacture of a medicament for the treatment of a fungal infection. 22. A process for the preparation of a compound of the formula: or a pharmaceutically acceptable salt thereof, wherein Ares a phenyl group substituted with 1 to 3 substituents each independently selected from halo and CF3 and X is a group of formulas: - € T where Het is a 5-membered aromatic heterocyclic group, which contains nitrogen and optionally contains an oxygen or sulfur atom and is linked to the phenyl group, pin di lo or pi? rn? It is optionally substituted by a carbon or nitrogen atom and is optionally substituted with 1 to 3 substituents each independently selected from halo, C 4 -4 alkyl, (1-4 alkoxy) rnet i lo, 2- (C 1 - alkoxy) 4) ethoxynethyl, 2-hydroxy ethoxy, cyanornetium, -NR * R2 or -CH2CONRIR2, where R1 and R2 are each independently H or C1-4alkyl; femltium or phenyl-C1-2alkyl in both of which the aforementioned phenyl group is optionally substituted with halo, trifluoromethyl or C1- alkyl; _NHCO-alkyl C1-4, -NHSO2-C1-4alkyl, -NHCONRi R2, where R1 and R2 are defined above, rnercapto and ~S (0) n -C1-4alkyl where n is 9, 1 or 2 and Z is H or F; process characterized by: (i) reducing a 3-buten-2-ol derivative of the formula: wherein Ar and X are those defined for the formula (I) and optionally eliminating any one of the substituents (alkoxy) -4) rnet? lo, 2- (C1-4 alkoxy) ethoxynet 1I0, 2-hydroxy-ethoxynet, phenylthio or benzyl of "Het"; (11) reduce a 3-buten 2-ol derivative of formula: wherein Ar and Z are those defined for formula (I) and Heti is a 5-membered nitrogenous aromatic heterocyclic group attached to the femyl ring by a carbon atom or nitrogen atom and substituted in a nitrogen atom of the ring by an N-protecting group, eliminating the N-protecting group at the same time with said reduction; (111) removing the N-protecting group from a compound of formula: where Ar and Z are those defined for the formula (T) and Heti is the one defined in (11) above; (iv) removing by catalytic hydrogenation a compound of formula (I) a substituent phenylthio, t) ßnc lo, (C 1-4 alkoxy) γ net, 2- (alkoxy CI-A) ethoxy? net ? io or 2-h? dr oxiet oxymethi lo, when linked to "Het"; (v) to prepare a compound of formula (E) in which "Het" is a group 1, -t-pazol- -i i, react with fopnilhidrazma ol corresponding compound of formula (I) containing a substituent forrnarnide in the femlo, pyridyl or pyrimidinyl group of X; (vi) to prepare a compound of formula (T) in which "Het" is a 5- (alkyl Cl-) -1,3,4-oxadiazole-2-yl group, make the corresponding compound of formula (I) that has a hydrazmocarbon substitute and (-CONHNH2) in the phenyl group, pipdyl or piprnidim lo of X, with an imidate of formula: (C1-4 alkyl) -C-0C2Hs, or with one of its salts; II NH (vn) remove by hydrolysis a substituent (alkoxy Ci - «)? net? lo, 2- (alkox? C1-4) ethoxy? 110, tptilo or 2-hydroxy-ethoxyrnetium linked to an atom of mtr. 'Oet of "Het" in a compound of formula (I); (vm) to prepare a compound of formula (I) in which "Het" is substituted with a C 1-4 alkyloxy group, alkylate the corresponding substituted-chain-substituted compound of formula (I); dx) to prepare a compound of formula (I) in which "Het" is substituted with a group (C 1-4 alkyl) sulfinyl or (C 1-4 alkyl) sulphide, oxidize a compound substituted with C 1-4 alkylthio of formula (I); (x) to prepare a compound of formula (I) wherein "Het" is an oxadiazolyl group of formula: wherein R 1 and R 2 are each independently H or C 1-4 alkyl, reacting the corresponding compound containing a substituent (C 1 -alkoxy) carbonyl in the corresponding ferulo group, pipdimlo or r - ?? diol of X, with a hydroxyguanidine of formula: wherein R1 and R2 are those defined above; (xi) to prepare a compound of formula (I) wherein "Het" is an oxadiazolyl group of formula: wherein R 1 and R 2 are each independently H or C 1-4 alkyl, reacting a reactive ester of the corresponding compound containing a carboxy substituent); in the phenyl group, pin di ni lo or pir irididimlo of X, with a thiose icarbazide of formula: wherein R1 and R2 are those defined above; (xn) reacting a formula ketone: e with a nucleophile of formula: X-CH-CH / tv \ or a compound of formula: M I? _CH-CH3 - (VAT) where X and Ar are those defined for formula (I) and M is Li, Zn-Hal or Mg-Hal; (xiii) to prepare a compound of formula (I) wherein "Het" is substituted with a group of formula -NHCO-C 1-4 alkyl, -NHSO? -C 1-4 alkyl or -NHCONH-alkyl CI-A, reacting a compound of formula (I) in which "Het" is substituted with an arnino group with an anhydride or acid chloride of formula (C 1-4 alkyl) C0C1 or (C 1 -4 -CO) alkyl? a (1-4C) alkane sulphonyl chloride or a C 1-4 alkyl isocyanate, as appropriate; (xiv) to prepare a compound of formula (I) in which "Het" is a 1,2,3-tpazol-4-α-lo or 5- (C 1 -4 alk) -1, 2, 3 group -tpazol-4-? lo, reacting- a compound of formula: wherein Ar is the one defined for formula (I) and R is H or C 1-4 alkyl, with a compound of formula C (R ") 2 l 3PN 3 + X- wherein R" is C 1-4 alkyl, C5 cycloalkyl -7 or each R * together with the nitrogen atom to which they are linked represents pyrrolidino or piperidino and X is a counterion, in the presence of a strong base; (xv) to prepare a compound of formula (I) in which "Het" is attached to the adjacent femly or heterocyclic ring by a carbon atom and is substituted on a nitrogen atom with a C1-4 alkyl group, (C1-alkoxy) 4-netyl, cyanornetium or carbamoylmethyl, N-alkylating the corresponding unsubstituted compound of formula (I) with a C 1-4 alkyl halide, a (C 1-4) alkoxy halide, a cyanorhexyl halide or a halide carbamoi lrnet ilo, respectively; (xvi) pair-a prepare a compound of formula (T) wherein X is a group of formula: in which Z is H or F and Het "is a 1,2,3-triazol-4-yl group, reacting a compound of the formula: (SAW) wherein Ar and Z are those defined for formula (I), first with an azido-tri (C 1-4 alkyl) silane and then with water; (xvii) to prepare a compound of formula (I) wherein "Het" is that defined for formula (I) but is linked to the adjacent phenyl group by a nitrogen atom, reacting a compound of formula: with a compound of formula Het-H in the presence of a copper catalyst and a base, where Ar 'and Z are those defined by the formula (I), "l-let" is the (He finido in this procedure and Y is CH or N; (vm) to prepare a compound in which "Het" is substituted with halogen, halogenate the corresponding unsubstituted compound; (xix) couple-to prepare a compound in which "Het" is 3-rnercapto-4- (C 1-4 alkyl) -1,2,4-tpazol-5-yl, cyclar- the corresponding compound in which the femlyl, pipdimlico or pi runi dimlico ring is substituted with -CONHNHCS-NH-C1-4alkyl; (xx) remove a rnercapto group from "Het"; (xxi) remove a trirneti 1 silyl group from "Het"; or (xxn) pair-a prepare a compound in which "Het" is linked to a phenyl, pyridine or pyridinyl group adjacent through a carbon atom, reacting the corresponding compound in which the phenyl, pyridinyl or pyrirnidinyl group is substituted with a leaving group such as Cl, Br , I u -OSO2CF2, with a compound of the formula Het-t wherein M is -Sn (lie) 3 / -Sn (n-Bu) 3, -B (Et) 2, -B (0H) 2 or - ZnCl, where Het is defined for formula (I) and N-protected, if necessary, in the presence of a palladium or nickel catalyst and, when the displaceable group is -OSO 2 CF 3, additionally in the presence of lithium chloride; the processes (i) to (xxn) being optionally followed by the conversion of the product of the formula (T) into a pharmaceutically acceptable salt. 23.-) n procedure according to claim 22, characterized in that it is used to prepare a formula (T) compound in which "Het" is a pyrazolyl group,? Rn? dazoi i lo, tpazolyl, thiadiazolyl, oxadi azolyl, pyrrolyl or tetrazolium, optionally substituted as defined by the formula (T). 24. A process according to step 22, characterized in that it is used to prepare a compound of formula (I) in which "Het" is a pyrazole-1-l, pyrazole-3-? , p? razol-4 ~? What is it, irnidazole, 1-io,? rn? dazol-2-l, irnidazol-4-? lo, 1,2,3-tpazol-l-1, 1, 2, 3-tpazol-2? 1, 2, 3-triazole-4-? lo, 1,2,4-tpazol-1-yl, 1, 2, 4-t r? azol-3? lo, 1, 2, 4-tpazol-4-? lo, l, 3,4-t? ad? azol-2-? 1, 3, 4-oxad? azole -2-? lo, 1,2,4-oxad? azole-5? lo, pyrrol-l-yl, t? azole-5? lo or tetrazole-5 - it, being all these groups optionally substituted with 1 to 3 substituents as defined in claim 1. 25.- A method according to any of claims 22 to 24, characterized in that Ar is a femlo group substituted with 1 or 2 substituents Each one of them is independently selected from F, Cl and Br. 26.- A process according to claim 22 (i) or (n), characterized in that the reduction is carried out by catalytic hydrogenation. 27. A process according to claim 22 (i), characterized in that the extraction is carried out with p-toluenosul onyl hydrazide. 28. A process according to claim 22 (vil), characterized in that the hydrolysis is an acid hydrolysis. 29. A process according to claim 22 (i), characterized in that it is prepared (2R, 3S) -2- (2) , 4-d? Fluorophen? L) -3- (4- C l-met I lpi razol -5 ~? L3fen? L) -l- (l, 2, 4-tpazol -1 -ll) butan ~ 2- by reduction of (2R) -2- (2,4-d? -fluoroenyl) -3- (4-Cl-methyl-pyrazole-5-? l] fonyl) - 1 - (1, 2, 4- tp azol-1-? 1) ~ 3-L > uten-2 -ol. 30. A process according to claim 29, characterized in that the reduction is carried out by catalytic hydrogenation. SUMMARY OF THE INVENTION An antimicrobial agent of formula: or of their pharmaceutically acceptable salts, wherein Ar is a femlo group substituted with 1 to 3 substituents each independently selected from halo and CF3; and X is a group of formulas: wherein Z is H or F and Het is a 5-membered heteroaryl aromatic group, which is nitrogen and optionally contains an oxygen or sulfur atom and is linked to the feml ?, pipdiio or? imidinyl by a carbon atom or nitrogen and optionally is substituted with 1 to 3 substituents each selected independently from halo, alkyl Cl-4, (alkoxy 1-4)? net Lio, 2- (alkoxy? C1-4) et oxymethyl, 2-hd? oxetane-1-oxymethyl, cyclohexane-1, -NRiR2 or -OH2 CONRi R2, where RI R2 are each independently H or C1-4alkyl; iltium or f-C1-C2-alkyl ester in both of which the aforementioned phenyl group is optionally substituted with halo, trifluor-orne 1I0 or C1-4 alkyl; -NHCO-C 1-4 alkyl, -NHSO 2 -alkyl CI-A, -NHCONRiR 2, where R 1 and R 2 are as defined above, rnercapto and -S (0) n -C 1- alkyl- where n is 0, 1 or 2, use of the same, components that the Leñen and procedure trust to prepare them. P97 / 1056F PF / lss * amm * fac * elt * amp * rnmm * lpm * blrn * l * ca *