BACKGROUND OF THE INVENTION Recently the incidence of serious fungal infection has become very prominent in patients undergoing chemotherapy for cancer, organ transplants and patients with AIDS. Most of these infections are caused by opportunistic pathogens like Candida spp., Aspergillus spp., Pneumocystis camii and Cryptococcus neoformans. The antifungal agents available in the market suffer with draw backs such as, toxicity, narrow spectrum of activity, fungistatic profile rather fungicidal. Some of them also exhibit drug-drug interactions and, as a result, therapy becomes very complex. In view of the high incidence of fungal infections in immunocompromised patients and the recent trend for the steady increase of the populations of these patients, demands for new antifungal agents with broad spectrum of activity and good pharmacokinetic properties have increased.

Within the available drugs to treat fungal infections, the azole class appears to be more promising. This class of compounds inhibit the biosynthesis of ergosterol in fungi, which is the main constituent of fungal cell membrane. Fluconazole and itraconazole are routinely used for maintenance of fungal infections. Although fluconazole is highly bioavailable, it is not active against filamentous fungi and emergence of fungal resistance has been reported recently (Antimicrob. Agents Chemother. 1995, 39, 1-8).

Itraconazole is active against filamentous fungi, but it shows inconsistent results, maybe due to its high protein binding properties and less

bioavailability. During the last few years, several research groups have been actively searching for new azoles with optimum pharmacokinetic properties.

As a result, a number of candidate azoles have emerged, and some of them are undergoing preclinical and clinical evaluation. Some of the candidate azoles are disclosed in the following publications: Sch 51048 (Drugs of the Future, 1995, 20,241-247).

Sch 56592; Antimicrob. Agents Chemother. (1996, 40, 1910-1913; 36th Interscience Conference Antimicrob. Agents Chemother. Sept. 1996, New Orleans, Abst. F87-F102).

UK-109,496 (Drugs of the Future, 1996, 21, 266-271; EP 440372).

TAK-1 87; 36th Interscience Conference Antimicrob. Agents Chemother. Sept.

1996, New Orleans, Abst. F74; EP 567982).

KP-103 (36th Interscience Conference Antimicrob. Agents Chemother. Sept.

1996, New Orleans, Abst. F78, WO 94126734).

ER-30346 (Drugs of the Future, 1996, 21, 20-24) In the present invention, we report new triazoles with broad spectrum antifungal activity. The triazoles are particularly effective against systemic and lung invasive fungal infections.

SUMMARY OF THE INVENTION The present invention relates to new triazole derivatives which can be utilised to treat or prevent fungal infections in animals, preferably in humans.

In accordance to the present invention, there is provided an antifungal triazole of the general formula I, i.e. 2-aryl-3-(4-substituted piperazin-1-yl)-1- <BR> <BR> (1 H-1,2,4-triazol-1-yl)-2-ols and and pharmaceutically acceptable salts thereof,

wherein: Ar is a phenyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, CF3 and OCF3; R, and R2 are each independently hydrogen or C,-C4 alkyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, with the proviso that where R, is hydrogen, R2 is other than hydrogen, and vice versa; R3 and R4 are each independently hydrogen or C,-C4 alkyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, or R3 and R4 together form =S; R5 and R6 are each independenly hydrogen or C,-C4 alkyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, or R5 and R6 together form =S; X is selected from the group consisting of a direct bond, CO, CS, SO2 and -N=N-; R7 is selected from the group consisting of i) hydrogen, ii) CN iii) CHO iv) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (1) C1-

C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, (2) C1-C4 alkoxy, (3) halogen, (4) formyl, (5) carboxyl, (6) C1-C4 acyloxy, (7) C1-C4 alkoxycarbonylamino, (8) phenyl- or naphthyl- oxycarbonylamino, (9) semicarbazido, (10) formamido, (11) thioformamido, (12) hydroxy, (13) nitro, (14) amino, (15) furyl, (16) triazolyl, (17) thienyl, (18) oxazolyl, (19) imidazolyl and (20) triazolone-yl, v) a 5- or 6-membered monocyclic or 8- to 10-membered bicyclic heterocycle having 1-4 heteroatoms each independently selected from the group consisting of N, 0 and S, which heterocycle is unsubstituted or ring- substituted with 1-3 substituents each independently selected from the group consisting of (1) C1-C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (2) benzyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of C1- C4 alkyl, CF3, halogen and OCF3, (3) halogen, (4) hydroxy, (5) nitro, (6) amino, (7) C,-C4 acylamino, (8) formyl, (9) formamido, (10) thioformamido, (11) C1-C4 alkoxycarbonylamino, (12) phenyl- or naphthyl-oxycarbonylamino and (13) semicarbazido, vi) NHR6 wherein R8 is selected from the group consisting of (1) Cr-C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, (2) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1- C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, (b) C,-C4 alkoxy, (c) halogen, (d) formyl, (e) carboxyl, (f) C,-C4 acyloxy, (g) C1-C4 alkoxycarbonylamino, (h) phenyl- or naphthyl- oxycarbonylamino, (i) semicarbazido, t) formamido, (k) thioformamido, (I) hydroxy, (m) nitro, (n) amino, (o) furyl, (p) triazolyl, (q) thienyl, (r) oxazolyl, (s) imidazolyl and (t) triazolone-yl, and (3) a 5- or 6-membered monocyclic or 8-

to lO-membered bicyclic heterocycle having 1-3 heteroatoms each independently selected from the group consisting of N, 0 and S, which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of hydroxy, halogen, amino and carboxyl, vii) OR9 wherein R9 is selected from the group consisting of (1) C,-C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, (2) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1- C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, (b) C1-C4 alkoxy, (c) halogen, (d) formyl, (e) carboxyl, (f) C,-C4 acyloxy, (g) C1-C4 alkoxycarbonylamino, (h) phenyl- or naphthyl- oxycarbonylamino, (i) semicarbazido, t) formamido, (k) thioformamido, (I) hydroxy, (m) nitro, (n) amino, (o) furyl, (p) triazolyl, (q) thienyl, (r) oxazolyl, (s) imidazolyl and (t) triazolone-yl and (3) a 5- or 6-membered monocyclic or 8- to 10-membered bicyclic heterocycle having 1-3 heteroatoms each independently selected from the group consisting of N, 0 and S, which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C,-C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (A) C,-C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (B) C,-C4 alkoxy, (C) halogen, (D) formyl, (E) carboxyl, (F) C,-C4 acyloxy, (G) C,-C4 alkoxycarbonylamino, (H) phenyl- or naphthyl-oxycarbonylamino, (I) semicarbazido, (J) formamido, (K) thioformamido, (L) hydroxy, (M) nitro, (N) amino, (0) furyl, (P) triazolyl, (Q) thienyl, (R) oxazolyl, (S) imidazolyl and (T) triazolone-yl, (c) naphthyl which is unsubstituted or substituted with 1-3

substituents each independently selected from the group consisting of (A) C1- CA alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, (B) C1-C4 alkoxy, (C) halogen, (D) formyl, (E) carboxyl, (F) C,-C4 acyloxy, (G) C,-C4 alkoxycarbonylamino, (H) phenyl- or naphthyl- oxycarbonylamino, (I) semicarbazido, (J) formamido, (K) thioformamido, (L) hydroxy, (M) nitro, (N) amino, (0) furyl, (P) triazolyl, (Q) thienyl, (R) oxazolyl, (S) imidazolyl and (T) triazolone-yl, (d) a 5- or 6-membered monocyclic or 8- to 10-membered bicyclic heterocycle having 1-3 heteroatoms each independently selected from the group consisting of N, 0 and S, (e) (C,-C4 alkyl)phenyl, (f) (C,-C4 alkyl)naphthyl, (g) hydroxy, (h) halogen, (i) amino and 0) carboxyl, and viii) a group of the formula wherein R is selected from the group consisting of (1) hydrogen, (2) C,-C,0 alkyl which is unsubstituted or substituted by 1-5 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1-C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) C,-C4 alkoxy, (c) halogen, (d) formyl, (e) carboxyl, (f) C1-C4 acyloxy, (g) C,-C4 alkoxycarbonylamino, (h) phenyl- or naphthyl-oxycarbonylamino, (i) semicarbazido, formamido, (k) thioformamido, (I) hydroxy, (m) nitro, (n) amino, (o) furyl, (p) triazolyl, (q) thienyl, (r) oxazolyl, (s) imidazolyl, (t) trizolone-yl, (u) CF3 and (v) OCF3, (4) a 5- or 6-membered monocyclic or 8- to 1 0-membered bicyclic heterocycle having 1-3 heteroatoms each independently selected from the group

consisting of N, 0 and S, which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1- C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, (b) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (A) C1- C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, (B) C1-C4 alkoxy, (C) halogen, (D) formyl, (E) carboxyl, (F) Cr-C4 acyloxy, (G) C,-C4 alkoxycarbonylamino, (H) phenyl- or naphthyl- oxycarbonylamino, (I) semicarbazido, (J) formamido, (K) thioformamido, (L) hydroxy, (M) nitro, (N) amino, (0) furyl, (P) triazolyl, (Q) thienyl, (R) oxazolyl, (S) imidazolyl and (T) triazolone-yl, (c) naphthyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (A) C1-C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (B) C,-C4 alkoxy, (C) halogen, (D) formyl, (E) carboxyl, (F) C1-C4 acyloxy, (G) C,-C4 alkoxycarbonylamino, (H) phenyl- or naphthyl-oxycarbonylamino, (I) semicarbazido, (J) formamido, (K) thioformamido, (L) hydroxy, (M) nitro, (N) amino, (0) furyl, (P) triazolyl, (Q) thienyl, (R) oxazolyl, (S) imidazolyl and (T) triazolone-yl, (d) a 5- or 6- membered monocyclic or 8- to 1 0-membered bicyclic heterocycle having 1-3 heteroatoms each independently selected from the group consisting of N, O and S, (e) (C,-C4 alkyl)phenyl, (f) (C,-C4 alkyl)naphthyl, (g) hydroxy, (h) halogen, (i) amino and t) carboxyl, (5) phenyl(C,-C4 alkyl) which is unsubstituted or ring-substituted with 1-3 substituents each independently selected from the group consisting of (a) C,-Cs alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, (b) halogen, (c) halo(C,-C4 alkyl), (d) C1-C4 alkoxy, (e) hydroxy, (f) amino, (g) carboxyl, (h) trifluormethoxyl, (i) trifluoromethyl, t) tetrafluoroethyl, (k) tetrafluoroethoxyl,

(I) tetrafluoropropyl and (m) tetrafluoropropoxyl, (6) naphthyl(C,-C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C,-C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C,-C4 alkoxy and amino, (b) halogen, (c) (C,-C4 alkyl)halo, (d) C,-C4 alkoxy, (e) hydroxy, (f) amino, (g) carboxyl, (h) trifluormethoxyl, (i) trifluoromethyl, t) tetrafluoroethyl, (k) tetrafluoroethoxyl, (I) tetrafluoropropyl and (m) tetrafluoropropoxyl, (7) methoxyl, (8) trifluormethoxyl, (9) trifluoromethyl, (10) trifluoroethyl, (11) tetrafluoroethyl, (12) tetrafluoroethoxyl, (13) tetrafluoropropyl and (14) tetrafluoropropoxyl.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the above definition of formula I, halogen is fluorine, chlorine, bromine or iodine. Preferred halogens are fluorine and chlorine.

C,-C4 alkyl is, for example, methyl, ethyl, propyl, 1-methylethyl, n-butyl, 1-methylethyl, isopropyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl and cyclobutyl. Preferred alkyls are methyl and ethyl.

Examples of Ar groups include, 4-fluorophenyl, 2-4-difluorophenyl, <BR> <BR> <BR> <BR> 2,4,6-trifluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 4-trifluoromethylphenyl and 4-trifluoromethoxyphenyl. Preferred Ar groups are phenyl group having 1 or 2 substituents each independently selected from fluorine, chlorine, trifluoromethyl and trifluromethoxy. Most preferably, Ar is 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-trifluromethylphenyl or 4- trifluoromethoxypheny1.

Examples of 5-or 6-membered monocyclic rings are 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-imidazolyl, 4- imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1 -(1 H)-1 ,2,4- triazolyl, 3-(1H)-1 ,2,4-triazolyl, 3-(4H)-1 ,2,4-triazolyl, 5-(1 H)-1 2,4-triazolyl, 4- (4H)-1 ,2,4-triazolyl, 1,2,3-triazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 1 ,2,4-oxadiazol-3-yl, 1 ,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1,3,4-

thiadiazol-2-yl, 5-( 1 H)-tetrazolyl, 5-(2H)-tetrazolyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidyl, 4-pyrimidyl and 5-pyrimidyl.

Examples of 8- to 10-membered bicyclic heterocycle groups are 2- benzimidazolyl, 5-benzimidazolyl, 2-benzoxazolyl, 5-benzoxazolyl, 6- benzoxazolyl, 2-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, imidazolo[4 , 5-b]pyrid in-2-yl, imidazolo[4 , 5-b]pyridin-5-yl, oxazolo[5,4-b]pyridin- 2-yl, oxazolo[5,4-b]pyridin-5-yl, oxazolo[5,4-b]pyridin-6-yl, thiazolo[5,4- b]pyridin-2-yi, thiazolo[5 ,4-b]pyrid in-5-yl and thiazolo[5,4-b]pyridin-6-yl.

Triazolone-yl may be 2- or 5-substutitued 1 ,2,4-triazol-3-one, such as 2H-1 ,2,4-triazol-3-oneA-yl or 4H-1 ,2,4-triazol-3-one-2-yl.

Examples of R, include hydrogen, methyl, ethyl, propyl, hydroxymethyl, alkoxymethyl, fluoromethyl and trifluoromethyl. Preferably, R1 is alkyl. Most preferably, R, is methyl.

Examples of R2 include hydrogen, methyl, ethyl, propyl, hydroxymethyl, alkoxymethyl, fluromethyl and trifluoromethyl. Preferably, R2 is hydrogen.

Depending on the substituents in formula I, the compound may have one or more than one asymmetric centers, resulting in possible stereoisomers. This invention relates to single individual isomers as well as mixture of isomers.

When R1 and R2 are the same, formula I has one asymmetric center and there are two possible isomers, i.e. 2R and 2S isomers. This invention relates to mixtures as well as individual isomers. The most preferable isomer is the 2R isomer.

When R, and R2 are different, formula I has two asymmetric centers, and there are four possible isomers, i.e. 2R,3R; 2R,3S; 2S,3R and 2S,3S.

This invention relates to the mixture of isomers as well as individual isomers.

The most preferred isomer in this situation is 2R,3R.

It is more preferred that R, is a group

wherein R is as described above, and most preferred that the other groups additionally are as follows: Ar is 2,4-difluorophenyl, R, is methyl, and R2 through R6 are each hydrogen.

Specifically, the more preferred embodiments of the present invention include the compounds that are disclosed in Table 3. Those disclosed in Example Nos. 36-51 are more preferred, with Example Nos. 43, 47, 50 and 51 being the most preferred.

The compounds of formula I can be prepared by a convergent approach from the epoxide of formula II and the piperazino compound of formula Ill (see Scheme 1). The epoxides were prepared following the synthetic routes described in the literature (Chem. Pharm. Bull., 1993, 41, 1035-1042).

The synthetic routes for the preparation of certain piperazino compounds of the formula Ill are disclosed in Schemes 4-6 and 8. The Scheme 7 describes a linear synthetic route for preparing certain compounds of formula I. The epoxide of formula Il and the piperazino compound of formula Ill were reacted in the presence of base such as sodium carbonate, potassium carbonate, cesium carbonate and the like. This reaction was also performed in the presence of lithium perchlorate and sodium perchlorate. The suitable solvents were chosen from acetonitrile, DMF, DMSO, THF, dichloromethane, chloroform, methanol, ethanol, isopropanol and tert-butanol.

The most preferred solvents were DMF and acetonitrile. The temperature of the reaction varied from 60-180 "C, depending on the solvent and reactants.

The most preferred temperature was 80-140 "C. The reactants were allowed to react to the completion or near to the completion of the reaction. The length of reaction time varied from few hours to several hours depending on the reactants, temperature, and the solvent.

Scheme-1 Scheme-2

Certain compounds of formula I were prepared from a common intermediate, which forms Example 2 of this invention as described in Scheme 3. Example 2 was prepared from epoxide IV by two synthetic routes as depicted in Scheme 2. In the first route, a 1:1 molar ratio of epoxide and ethyl piperazine-1-carboxylate were reacted in the presence of potassium carbonate or lithium perchlorate in a suitable solvent. The obtained ester was hydrolysed with strong base such as sodium hydroxide or potassium hydroxide to give piperazinyl compound 2. In this reaction the resulting N- carboxylic acid undergoes in-situ decarboxylation to give the piperazino compound 2. In an alternate route, the piperazino compound was obtained in a single step from the reaction of epoxide IV with piperazine. In a typical procedure, the epoxide and excess piperazine were reacted in the presence of lithium perchlorate in a suitable solvent and at a desired temperature.

Certain compound of formula I wherein X is CO, SO2, CS, or -N=N- were prepared as described in Scheme 3.

The compounds of formula I wherein X is CO were produced from the reaction of piperazinyl compound 2 with acid chloride (R7COCI) in the presence of a base such as triethylamine, N-methylmorpholine, N,N- diisopropylethylamine. The reaction was carried out in an inert solvent at -20 "C to 80 OC. The most preferred solvents were dichloromethane, chloroform, tetrahydrofuran and acetonitrile. Most preferably the reaction was carried out at 0-25 OC. Certain compounds of formula I wherein X is SO2 were prepared from the reaction of 2 and R7-SO2-CI. In these reactions, R7 is as described above.

Certain compounds of formula I wherein X is CO or CS and R7 is OR were prepared from the reaction of piperazinyl compound 2 and isocyanates and isothiocyanates. In a typical reaction, a 1:1 molar ratio of compound and isocyanate or isothiocyanate were reacted in a suitable solvent at -15 to 45 "C. The preferred solvents were acetonitrile, ethyl acetate and dichloromethane. The preferred temperature was 0 to 25 CC. The reaction time varied from few hours to several hours depending on the reactants, solvent and temperature.

Scheme-3

The reaction of 1 H or 2H-1 ,2,4-triazol-3-diazonium salt with the piperazinyl compound 2 gave the N-azo compound of formula VIII. This reaction was conducted at suitable temperature in suitable solvent in the presence of base like sodium hydroxide, potassium hydroxide and potassium carbonate.

Certain compounds of formula I wherein X is bond and R7 is unsubstituted or substituted azole were prepared according to Scheme 1 The synthetic routes followed for the preparation of piperazinyl azoles X, XI, XII, XIII and XVI are described in Schemes 4-6. In a typical procedure, piperazinyl azole and epoxide were heated in a suitable solvent in the presence of lithium perchlorate or potassium carbonate for 2448 h. The molar ratio of the reactants varied from 1:1 to 1:5. After usual workup the product was purified by column chromatography.

Scheme-4 Scheme-5 Fm N) Sealed tube/EtOH /7 N) H-N N-H + N ,N . HN H-N N4 YN ½J Br N mi 1N H H XI Nm- -2Br/OO3 N N Br N BrN' N H Ar Ar A H -N N-H Sealed tube/EtOH Fm ANiffiN Nm H-N NN \ 1)N NN Ñ ) J HN / Ar Ar XII XIII Scheme-6 Certain compounds of formula I wherein X is a bond and R7 is a 4-[2- substituted-l ,2,4-triazol-3-one-4-yl]phenyl group were prepared in two independent synthetic routes. The first route involves the linear approach as described in Scheme 7. The intermediates formed during this synthesis are compounds of formula I, wherein X is bond and R7 is phenyl group with substitution.

Scheme-7 oi o 3 N /ysar- a Nm,N 2 \= N $" F H2. a% Pt-C Acetonitrile F 30 N F o'Q HO 3N7'N Ro / a0 N mj - a ~~ N H a P F Phenylchlorof h=8 v 33 31 F f 33 HO 3N7'N/\NtNMH1 Hydrazineloimethoxyethane NN < a \sN F I F HO Formaildifle acetate N triethylamine/ethoxyethanol N 110°C. 18 h \=N N \/F 9 35 F 0 Rer or aoles/caco or L4CO, N/Uf-N, 8,00 I uj - In F F The second synthetic route involves a more efficient convergent approach (Scheme 1). In a typical procedure, an appropriate epoxide of formula II and an appropriate piperazinyl derivative XXIII were reacted in the presence of lithium perchlorate in a suitable solvent and at a suitable temperature. The reactants were allowed to react to the completion of the reaction. The reaction time varied from few hours to several hours depending on the reactants. The epoxides used in this invention are known and were prepared by following the reported procedures. The piperazino compounds of formula XXIII were prepared as described in Scheme 8.

Scheme-8 H-N oil Di-tert-butyldi- < W NO2 carbonate BOC N < N02 ½' - mi - X x X.H or F XVIII X.H or F Phenyl chloroformate/ H2/10 Pd-C 80C - N N Hz7' triethylamine ~~~~~~~~ SOC-N N NH I x XVIIIa X.R or F 0 o Y~,.NH, < ,Ph , Ph BOC--N N )=/ NN BOC - N N X NH ° Hydrazine k -H H mi -H x x XXI X.H or F XIXI X.H or F Formamidine acetate/ 0 Base/RX or triethylamine / N,H epoxide BOC--N > N W N X=Bromo or OMs or mi are. x XX1, X-R or F 0 BOC < X N N 3M HC1 R BOC - ~~~~~~~~ e X N SOC-N N t H-N N-</ - N x XXIII DH or F X XXIII I X.H or F

Pharmaceutically acceptable salts of formula I were prepared by mixing the solution of the free base with excess of acid at 0-25 OC. The precipitated salt was collected by filtration. In some cases the solvent was evaporated to dryness and the resulting crude salt was recrystallized in a suitable solvent.

For the preparation of these acid addition salts, acids were selected from hydrochloric acid, hydrobromic acid, sulphuric acid, tartaric acid, succinic acid, fumaric acid, methanesulphonic acid or p-toluenesulphonic acid.

The compounds of the present invention were evaluated in vitro for their antifungal activity and were assessed based on minimum inhibitory concentration of the test compound, i.e. the concentration of the test compound at which growth of particular organism fails to occur. The MIC was determined after incubating the test compound with the strain for 48 h at 37 "C in an appropriate medium. The microorganisms used in this test include Candida albicans, C. tropicalis, C. kefyr, C. krusei, C. guilliermondii, C. glabrata, Cryptococcus neoformans, Aspergillus niger and A. fumigatus. In vitro data of certain representative compounds is provided in the following Table.

Table 1 In vitro activity of compounds of formula I Fungal MIC ofcompounds offormula I, pg/ml strains # 36 # 40 # 41 # 42 # 43 # 44 # 46 Fluco- Itraco- nazole nazole Candida 0.09 0.09 0.09 0.09 0.048 0.048 0.048 0.78 0.09 albicans C. tropicalis 0.09 0.048 0.09 0.09 0.048 0.048 0.048 0.39 0.09 C. ketr 0.048 0.048 0.48 0.048 0.048 0.048 0.048 0.39 0.09

C. krusei 0.09 0.19 1.56 1.56 0.09 0.09 0.19 50 0.39 C. guillier- 0.048 0.048 0.048 0.09 0.09 0.048 0.048 1.56 0.19 mondii C. glabrata 0.09 0.39 0.78 12.5 0.78 1.56 0.39 12.5 0.19 Cryptococcu 0.048 0.48 0.48 0.19 0.048 0.048 0.048 1.56 0.39 S neoformans Saccheromyces 0.19 0.09 0.19 0.39 0.09 0.048 0.09 6.25 0.39 cerevisiae A. niger 0.78 0.78 3.12 3.12 0.19 0.19 0.09 >100 0.39 Aspergillus 0.39 0.39 0.78 0.39 0.19 0.048 0.048 >100 0.19 fumigates Certain selected compounds were evaluated in-vivo for their antifungal efficacy. Series of doses of test compounds were administered by oral, i.v and s.c. routes to infected mice, i.e mice that are inoculated with a strain of Candida albicans or Aspergillus fumigatus. Efficacy of test compound was determined based on survival oftreated mice compared to control. The in vivo efficacy was assessed based on EDso of the test compound. The following table provides EDso of certain compounds for systemic infections of C. albicans and A. fumigatus in mice models.

Table 2 In-vivo activity of compounds of formula I Therapeutic efficacy (ED50 mg/kg) in mice systemic infectinons Example &num C. albicans A. fumigatus 36 8.01 >45 40 4.68 67.05 41 8.01 89.28 42 >90 71.14 43 1.57 42.3 46 56.02 >45

The compounds of formula I and their salts are antifungal agents, useful to treat or prevent topical, lung invasive, as well as systemic fungal infections in mammals including humans. For example they are useful in treating topical infections in man caused by species of Candida, Trichophyton, Microsponim, mucosal infections caused by species of Candida, and systemic infections caused by species of Candida, Aspergillus, Cryptococcus, Pneumocystis, Histoplasma or Blastomyces. The above compounds have shown impressive in vivo efficacy against mice systemic candidiosis, systemic aspergillosis and lung invasive aspergillosis.

When the compounds of the present invention or their pharmaceutically acceptable salts are used for treatment or prophylaxis of fungal infections in mammals including humans, they can be administered alone, but generally it is more preferred to administer the compounds in a pharmaceutical formulation. This formulation varies with intended route of administration. For example the compounds can be administered orally in the form of tablets, coated tablets, capsules, suspensions, solutions and the like. These oral preparations which contain the present compounds are prepared with excipients, binders, coloring agents, flavors, etc. which can be formulated in a manner known in the art.

The present compounds can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. These injections are sterile aqueous solutions which contain the antifungal agent with other substances, such as salts, glucose or an isotonic agent, and can be formulated in a conventional manner.

The amount of the present compounds incorporated into the pharmaceutical composition varies depending on the physical and chemical properties of the drug, dosage and route of administration. Preferably the oral formulations are prepared with 1 to 25% (w/w) antifungal agent and the injection formulation is prepared with 0.1 to 5% (w/w) of antifungal agent.

Alternatively, the antifungal agents also can be administered in the form of a suppository or pessary, or they may be applied topically in the form of lotion, solution, ointment, cream or dusting powder. Suppositories and ointments which contain 1-10% of active ingredient with a base, stabilizer or surfactant can be prepared in a conventional manner.

The dosage of the compound of formula I or its pharmaceutically acceptable salt can be suitably determined depending on the indivdual cases, taking symptoms, age, sex, disease status, patient condition, route of administration and the like into consideration. Usually the dosage can be 0.01-20 mg /kg in single or divided daily doses.

Table-3 Ts I Configuration # X-R, c, and C, 1 1 j H 3 R,R 5 --CH, --CH, 1 --H 1 R,R 1 6 --CY --CH3 COOEt R,R 0 R,R { 7 i H | H | ot Example Configuration at It X-R7 C2 and C3 8 o ANt R,R OH 9 + N ~ CH R,R N 10 R,R H 0 11 JTN CH3 R,R H o r R,R \ 12 t O F R,R 13 ¼ R,R I CF, 1 14 R,R NO, 0 is ¼ , R,R 0 16 5CB3 R,R 0 Example X R Configuration at # X-R7 7 C2 and C3 CHO Hz CH3 R,R 17 Jj 0 18 Oso::¼¼$NO R,R NH 01N2 R.R 19 'L/ 20 -N=N i\ ,No R,R R,R 21 S R,R N 23 ,N R,R H Example X=bond; Configuration at # R, C, and C, N N 5 N CF, R,R 25 N R, R 26 Nw R,R 27 NTh ¼ R, R N 28 ½y CF, N 29 ¼ R, R 30 C - NO2 R,R 31 e NHz R,R Example X-bond; Configuration at # R, C2 and C3 NHCOOEt R,R 33 < -NHCOOPh R,R 34 9 NHCONHNH2 R,R 35 9 S N R,R 36 o R 37 so 0 38 O s,s 39 R,S - VH

Example X=bondi Configuration at # 7 C2 and C3 CH 40 R,R 40 NNi R, R CH 4 l 4 \S N R,R 41 0 42 9 N I CH3 R,R - \&H N OHOH 0 43 -N ICF, RR 44 ½ CF, R,R CF2H 45 < ~ N CF, R, R o F 46 3 \S N\, R,R -" IR,R CCF, Example X=bond; Configuration at R7 R7 C2 and C3 0 48 Ni¼½ R,R OCH, 0 49 N¼NI¼{)3I R,R CF3 a 50 R,R OC,CF2CF,H 0 51 < \fin N < of R,R - CF3 F EXAMPLES: Example I (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-ethoxycarbonylpiperazin- 1-yl)-1- (1H-1,2,4-triazol-1-yl)butan-2-ol:

A mixture of (2R,3S)-2-(2,4-difluorophenyl).3-methyl-2-(1 H-l ,2,4-triazol-l - yl)methyloxirane IV (1.0 g, 4.0 mmol), ethyl piperazine-l -carboxylate (1.2 ml, 8 mmol) and potassium carbonate in DMF (5 ml) was heated at 120 °C for 18 h. After cooling the reaction mixture was poured onto crushed ice and extracted with ethyl acetate (3X30 ml). The combined extract was washed with water, brine, dried (MgSO4) and concentrated and the resulting product was purified on a column of silica gel (hexane/EtOAc, 1:1) to give the title compound as off-white solid (400 mg, 24%). m.p.: 182-183°C.

'H NMR (CDCl3) b: 0.90 (d, 3H, CH3), 1.26 (t, 3H, CH3), 2.31-2.49 (m, 2H, CH2), 2.78-3.07 (m, 3H, CH2and CH), 3.40-3.59 (m, 4H, 2XCH2), 4.15 (q, 2H, OCH2), 4.9 (AB q, 2H, CH2), 5.05 (s, 1H, OH), 6.66-6.84 (m, 2H, Ar-H), 7.36-7.51 (m, 1H, Ar-H), 7.78 (s, 1H, Het-H), 7.92 (s,1H, Het-H).

FAB-MS: 410.2 (MH+), calcd. C'gH25F2N503 409.44.

Example 2 (2R,3R)-2-(2,4-Difluorophenyl)-3-(piperazin-1-yl)-1-(1H-1,2, 4-triazole-1- yl)butan-2-ol: A mixture of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol- 1- yl)methyloxirane (1.0 g, 4.0 mmol), piperazine (860 mg, 10 mmOl) and lithium perchlorate (625 mg, 6 mmol) in acetonitrile (15 ml) was heated under reflux for 48 h. The solvent was removed under reduced pressure, the residue was treated with crushed ice and extracted with ethylacetate (3X30 ml). The combined organic extract was washed with water, brine, dried (Na2SO4) and concentrated to give the title compound as thick viscous gum (1.5 g, 78%).

The title compound was also prepared by hydrolysis of 2R,3R-2-(2,4- <BR> <BR> <BR> <BR> difluorophenyl)-3-(4-ethoxycarbonylpiperazin-I -yl)-I -(I H-1,2,4-triazol-1 - yl)butan-2-ol 1 with 2M sodium hydroxide solution.

'H NMR (CDCI3) b: 0.97 (d, 3H, CH3), 2.32-2.42 (m, 2H, CH2), 2.66-2.90 (complex, 8H, 3XCH2, CH and NH), 4.85 (AB q, 2H, CH2), 6.68-6.83 (m, 2H, Ar-H), 7.42-7.55 (m, 1H, Ar-H), 7.78 (s, 1H, Het-H), 8.0 (s, 1H, Het-H).

FAB-MS: 338.1 (MH+), calcd. C,6H2,F2N5O 337.38.

Example 3 (2R.3R)-3-(4-Cyanopiperazin-1 -yl)-2-(2,4-diflurophenyl)-1 -(1 H-1.2.4- triazol-1-yl)butan-2-ol: To a cooled (0 °C) mixture of (2R,3R)-2-(2,4-difluorophenyl)-3-(piperazin-1-yl)- 1-(1H-1,2,4-triazol-1-yl)butan-2-ol 2 (250 mg, 0.74 mmol) and triethylamine (0.42 ml, 3 mmol) in acetonitrile (15 ml) was added cyanogen bromide (160 mg, 1.5 mmol) in acetonitrile (0.5 ml). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. To the resulting residue water was added and extracted with ethyl acetate (3X20 ml). The combined organic extract was washed with water, brine and dried over magnesium sulphate. The solvent was removed and the product was purified on a column of silica gel (hexane/EtOAc, 1:1) to give the title compound as a colorless solid (150 mg, 56%). m.p: 220 °C (decomp).

IR (Nujol) Vmax: 2210 cm-1.

'H NMR (CDCl3) b: 0.89 (d, 3H, CH3), 2.52-2.61 (m, 2H, CH2), 3.0-3.31 (m, 7H, 3XCH2 and CH), 4.88A.91 (m, 3H, CH2 and OH), 6.66-6.78 (m, 2H, Ar-H), 7.3-7.5 (m, 1H, Ar-H), 7.78 (s, 1H, Het-H), 7.87 (s, IH, Het-H).

FAB-MS: 363.0 (MH+), calcd. C17H20F2N6O 362.39.

Example 4 (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-formylpiperazin-1-yl)-1- (1H-1,2,4- triazol-1-yl)butan-2-ol: A mixture of compound 2 (200 mg, 0.6 mmol) and potassium carbonate (248 mg, 1.8 mmol) in DMF (5 ml) was heated at 120 °C for 24 h. The contents

were poured into cold water and extracted with ethyl acetate (3X20 ml). The combined organic extract was washed with water, brine and dried over sodium suphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (EtOAc/MeOH; 98:2) to give the title compound as colorless solid (80 mg, 36%). m.p: 118-120 °C.

'H NMR (CDCl3) b: 0.90 (d, 3H, CH3), 2.44-2.52 (m, 2H, CH2), 2.93-3.11 (m, 3H, CH2 and CH), 3.39-3.59 (m, 4H, 2XCH2), 4.93A.97 (m, 3H, CH2 and OH), 6.66-6.81 (m, 2H, Ar-H), 7.36-7.48 (m, lH, Ar-H), 7.79 (s, 1H, Het-H), 7.91 (s, 1H, Het-H), 8.02 (s, 1H, CHO).

FAB-MS: 366.1 (MH+), calcd. C,7H2,F2NsO2 365.39.

Example 5 (2R,3R)-2-(2,4-Difluorophenyl)-3-(2,5-dimethylpiperazin-1-yl )-1-(1H- 1,2.4-triazol-1-yl)butan-2-ol: The title compound 5 was obtained as a thick viscous oil in 58% yield from the reacton of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol- 1- yl)methyloxirane IV and 2,5-dimethylpiperazine, by a similar method described in example 2.

'H NMR (CDCl3) b: 0.85-0.96 (3 d merged, 9H, 3XCH3), 1.85-1.96 (m, 2H), 2.4-2.59 (m, 2H), 2.64-2.96 (m, 3H), 3.27-3.38 (m, 1H), 4.81 (AB q, 2H, CH2), 5.50 (brs, 1 H, OH), 6.69- 6.84 (m, 2H, Ar-H), 7.45-7.58 (m, 1 H, Ar-H), 7.81 (s, 1H, Het-H), 8.02 (s, 1H, Het-H).

FAB-MS: 366.1 (MH+), calcd. C,8H25F2NsO 365.43.

Example 6 (2R,3R)-2-(2,4-Difluorophenyl)-3-(2,5-dimethyl-4- ethoxycarbonylpiperazin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan -2-ol:

To a mixture of compound 5 (228 mg, 0.62 mmol) and triethylamine (0.18 ml, 1.24 mmol) in dichloromethane (10 ml) at 0 °C was added dropwise ethyl chloroformate (135 mg, 1.24 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at 0 °C for 30 minutes and 1 h at room temperature. The contents were diluted with 30 ml of dichloromethane, washed with water, brine and dried over magnesium sulphate. The solvent was removed under reduced pressure and the resulting oil was chromatographed on a column of silica gel.

Elution with hexane/EtOAc (1:1) gave the title compound as an off-white solid (210 mg, 80%). m.p: 57-59 °C.

'H NMR (CDCl3) b: 0.94 (d, 3H, CH3), 1.07-1.10 (m, 6H, 2XCH3), 1.28 (t, 3H, CH3), 2.34-2.46 (m, 1H), 2.76-2.82 (m,1H), 2.96-3.09 (m, 2H), 3.21-3.31 (m, 1H), 3.67 (m, lH), 3.984.27 (m, 3H), 4.80 (AB q, 2H), 5.13 (s, 1H, OH), 6.67- 6.82 (m, 2H, Ar-H), 7.39-7.52 (m, 1H, Ar-H), 7.78 (s, 1H, Het-H), 7.94 (s, 1H, Het-H).

FAB-MS: 438.3 (MH+), calcd. C21H29F2N5O3 437.49.

Example 7 (2R,3R)-3-(4-tert-BOC-Piperazin-1-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4- triazol-I -yl)butan-2-ol: To a mixture of compound 2 (150 mg, 0.44 mmol) and triethylamine (1.0 ml, 0.72 mmol) in dichloromehane (15 ml) was added di-tert-butyldicarbonate (110 mg, 0.48 mmol) at °C. The reaction mixture was stirred for 1h at 0 °C and 3 h at room temperature. Then diluted with chloroform (20 ml), washed with water, brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (EtOAc/hexane) to give the title compound as a colorless solid (160 mg, 82%). m.p.: 138-139 "C.

1H NMR (CDCl3) 5: 0.92 (d, 3H, CH3), 1.46 (s, 9H, 3XCH3), 2.34-2.40 (m, 2H, CH2), 2.79-2.92 (m, 2H, CH2), 2.97 (m, IH, CH), 3.43 (m, 4H, 2XCH2), 4.88 (AB q, 2H, CH2), 5.11 (s, 1H, OH), 6.66-6.80 (m, 2H, Ar-H), 7.38-7.51 (m, IH, Ar-H), 7.78 (s, 1H, Het-H), 7.94 (s, 1H, Het-H).

FAB-MS 438.2 (MH+); calcd. C2,H29F2N503 437.49.

Example 8 (2R,3R)-3-(4-Anilinocarbonylpiperazin-1-yl)-2-(2,4-difluorop henyl)-1- (1 H-1,2,4-triazol-1 -yl)butan-2-ol: To a ice cooled solution of (2R,3R)-2-(2,4-diflurophenyl)-3-(piperazin-1-yl)-1- (1H-1,2,4-triazole-1-yl)butan-2-ol 2 (150 mg, 0.44 mmol) in acetonitrile (10 ml) was added phenylisocyanate (60 mg, 0.5 mmol) in acetonitrile (4 ml). The reaction mixture was stirred at 0 °C for 2 h, diluted with 20 ml of ethyl acetate and successively washed with water, brine and dried over sodium sulphate.

This organic extract was concentrated and the residue was purified by passing through a column of silica gel (hexane/EtOAc) to give the title compound as a colorless solid (170 mg, 84%). m.p.: 98-100 °C (decomp).

1H NMR (CDCl3) b: 0.92 (d, 3H, CH3), 2.5 (m, 2H, CH2), 3.02 (m, 3H, CH2 and CH), 3.52 (m, 4H, 2XCH2), 4.8-5.1 (AB q and S merged, 3H, CH2 and OH), 6.31 (brs, 1H, NH), 6.65-6.85 (m, 2H, Ar-H), 7.0-7.1 (m, 1H, Ar-H), 7.25-7.5 (m, 5H, Ar-H), 7.78 (s, 1H, Het-H), 7.92 (s, 1H, Het-H).

MS (FAB): 457.0 (MH+), calcd. C23H26F2N6O2 456.49.

Example 9 (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-ethylaminocarbonylpipera zin-1-yl)- 1-(1H-1,2,4-triazol-1-yl)butan-2-ol: The tiltle compound was prepared similarly to example 8 starting from same piperazine derivative and ethylisocyanate. The product was obtained as a colorless solid in 75 % yield.

m.p.: 103-105 OC.

'H NMR (CDCI3) 5:0.9 (d, 3H, CH3), 1.14 (t, 3H, CH3), 2.42 (m, 2H, CH2), 2.8- 3.1 (m and q merged, 3H, CH2 and CH), 3.2-3.5 (m, 6H, 3XCH2), (4.4 brs, 1 H, NH), 4.88 (AB q, 2H, CH2), 5.06 (s, 1H, OH), 6.7-6.9 (m, 2H, Ar-H), 7.45 (m, 1H, Ar-H), 7.78 (s, 1H, Het-H), 7.93 (s, 1H, Het-H).

FAB-MS: 409.1 (MH+), calcd. C19H26F2N6O2 408.45.

Example 10 (2R,3R)-3-(4-Anilinothiocarbonylpiperazin-1-yl)-2-(2,4-diflu orophenyl)- 1-(1H-1,2,4-triazol-1-yl)butan-2-ol: The title compound was prepared similarly to example 8 starting from same piperazine derivative 2 and phenylisothiocyanate. The product was obtained as a colorless solid in 80% yield. m.p.: 106-108 OC.

'H NMR (CDCI3) : 0.88 (d, 3H, CH3), 2.5 (m, 2H, CH2), 2.9-3.1 (m, 3H, CH2 and H), 3.84 (m, 4H, 2XCH2), 4.8-5.1 (AB q and s merged, CH2 and OH), 6.7- 6.85 (m, 2H, Ar-H), 7.1-7.5 (m, 7H, 6 Ar-H and 1 NH), 7.77 (s, 1H, Het-H), 7.88 (s, 1H, Het-H).

FAB-MS: 473.3 (MH+), calcd. C23H26F2N6OS 472.56.

Example 11 (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-ethylaminothiocarbonylpi perazin- 1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol: The title compound was prepared similarly to example 8 starting from same piperazine derivative 2 and ethylthioisocyanate. The product was obtained as a colorless solid in 85% yield. m.p.: 96-98 OC.

1H NMR (CDCl3) b: 0.88 (d, 3H, CH3), 1.25 (t, 3H, CH3), 2.5 (m, 2H, CH2), 3.06 (m, 3H, CH2 and CH), 3.6-4.0 (q and m merged, 6H, 3XCH2), 4.8-5.0 (AB q and s merged, 3H, CH2 and OH), 5.39 (s, 1H, NH), 6.7-6.9 (m, 2H, Ar-H), 7.4-7.5 (m, 1H, Ar-H), 7.78 (s, 1H, Het-H), 7.89 (s, IH, Het-H).

FAB-MS: 425.1 (MH+), called. C1gH26F2N6OS 424.51.

Example 12 (2R.3R)-3-[4-(2.4-Difluorobenzoyl)piperazin-1 -yll-2-(2.4- difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.

To a mixture of compound 2 (674 mg, 2 mmol) and triethylamine (0.55 ml, 4 mmol) in tetrahydrofuran (10 ml) was added dropwise 2,4-difluorobezoyl chloride (440 mg, 2.5 mmol) in 5 ml tetrahydrofuran at 0 °C The reaction mixture was stirred at 0 °C for 30 minutes and at room temperature for 18 h.

The solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (50 ml). The organic phase was washed with brine, dried over sodium sulphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (EtOAc/hexane, 9:1) to give the title compound as colorless prisms (448 mg, 47%). m.p.= 63-65 °C.

1H NMR (CDCl3) : 0.88 (d, J = 6.1 Hz, 3H), 2.04-2.59 (m, 2H); 2.99-3.09 (m, 4H); 3.35 (s, 2H); 3.72-4.10 (m, 1H) 4.91 (s, 2H); 5.01 (s, 1H); 6.65-7.00 (m, 5H); 7.34-7.48 (m, 1H); 7.77 (s, 1 H); 7.9 (s, 1 H).

FAB-MS: 478.3 (MH+), calcd. C23H23F4N5O2 477.46.

Example 13 (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[ 4-(4- trifluoromethylbenzoyl)piperazin-1-yl]butan-2-ol.

The example 13 was prepared form the reaction of piperazino derivative 2 and 4-(trifluoromethyl)benzoyl chloride by following the similar procedure described for the example 12.

Colorless prisms, m.p.: 88-90 °C, Yield 87%.

1H NMR (CDCI3) b: 0.88 (d, J = 6.5 Hz, 3H); 2.39-2.59 (m, 2H) 3.00-3.10 (m, 4H); 3.41-3.73 (m, 4H); 4.83 (AB q, 2H) 6.65-6.79 (m, 2H); 7.35-7.47 (m, 1H); 7.49 (d, J=8.0 Hz, 2H) 7.66 (d, J=8.0 Hz, 2H); 7.78 (s, 1H), 7.91 (s, 1 H).

FAB-MS: 510.1 (MH+), Calcd. C24H24F5N5O2 509.48.

Example 14 <BR> <BR> <BR> <BR> (2R.3R)-2-(2.4-Difluorophenyl)-3-14-(4-nitrobenzoyl)piperazi n-1 -yll-1 - (1 H-1.2.4-triazol-1 -yl)butan-2-ol The example 14 was prepared form the reaction of piperazino derivative 2 and 4-nitrobenzoyl chloride by following the similar procedure described for the example 12. After column purification the product was obtained as brown prisms in 92% yield. m.p. 90-92 "C.

'H NMR (CDCI3) b: 0.88 (d, J = 6.5 Hz, 3H), 2.42-2.61 (m, 2H) 3.05-3.08 (m, 4H); 3.39-3.73 (m, 3H); 4.92 (s, 3H) 6.66-6.78 (m, 2H); 7.34-7.47 (m, 1H); 7.55 (d, J = 8.6 Hz, 2H) 7.77 (s, 1H); 7.88 (s, 1H); 8.26 (d, J = 8.6 Hz, 2H).

FAB-MS: 487.0 (MH+) , C23H24F2N6O4 486.42.

Example 15 (2R,3R)-3-[4-(4-Aminobenzoyl)piperazin-1-yl]-2-(2,4-difluoro phenyl)-1- (1H-1,2,4-triazol-1-yl)butan-2-ol A solution of nitrocompound 14 (487 mg, 1.0 mmol) in ethyl acetate (95 ml) was hydrogenated over 10% Pd-C (50 mg) at 45 psi pressure and room

temperature for 6 h. The catalyst was removed by filtration and the filtrate was concentrated to give the amino compound 15 as a colorless solid (330 mg, 72%). m.p.: 100-102 °C.

1H NMR (CDCl3) #: 0.89 (d, J = 5.8 Hz, 3H); 2.42-2.47 (m, 2H) 2.88-3.06 (m, 3H); 3.63 (br, 4H); 3.09 (br, 2H) 4.82 (t, J = 16.3 Hz, 2H); 5.02 (br, 1H); 6.61 (d, J = 8.5 Hz, 2H) 6.73-6.79 (m, 2H); 7.22 (d, J = 8.5 Hz, 2H); 7.30-7.48 (m, 1H) 7.77 (s, 1H); 7.92 (s, 1H).

FAB-MS: 457.1 (MH+), calcd. C23H26F2N6O2 456.46.

Example 16 (2R,3R)-2-(2,4-Difluorophenyl)-3-[4-(p-toluenesulphonyl)pipe razin-1- yl]-1-(1H-1,2,4-triazol-1-yl)butan-2-ol: To a mixture of piperazinyl compound 2 (146 mg, 0.43 mmol) and triethylamine in dichloromethane (5 ml) was added p-toluenesulphonyl chloride (51 mg, 0.45 mmol) in dichloromethane (1 ml) at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes and 2 h at room temperature. Then the reaction mixture was diluted with chloroform (15 ml), washed with water, brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (CHCl3/MeOH; 98:2 ) to give the title compound as a colorless solid (75 mg, 16%). m.p.: 81-83 0C.

'H NMR (CDCI3) b: 0.88 (d, J = 6.9 Hz, 3H), 2.44 (s, 3H), 2.48-2.57 (m, 2H), 2.92-3.08 (m, 7H), 4.74 (s, 2H), 4.83 (s, 1H), 6.64-6.76 (m, 2H), 7.29-7.36 (m, 3H), 7.63 (s, 1H), 7.68 (s, 1H), 7.74 (s, 1H), 7.80 (s, 1H).

FAB-MS: 491.9 (MH+), calcd. C23H27F2N5O3S 491.55.

Example 17 (2R,3R)-2-(2,4-Difluorophenyl)-3-[4-methanesulphonyl)piperaz in-1-yl]- 1-(1H-1,2,4-triazol-1-yl)butan-2-ol: The epoxide IV (300 mg, 1.19 mmol) and LiC104 (235 mg, 1.43 mmol) were dissolved in 12 mL dry acetonitrile and 1-methanesulfonylpiperazine (190 mg, 1.79 mmol) was added. The mixture was heated to reflux for 4 days, cooled and the solvent evaporated. The residue was dissolved in dichloromethane and then washed with water and brine. The solution was dried over Na2SO4 and the solvent evaporated. The crude reaction products were eluted through a silica gel column using 3% MeOH/97% EtOAc as eluent to give the title compound (180 mg, 36%) as a colorless solid. m.p.: 83-85 "C.

'H NMR (CDCI3) b: 0.91 (d, J = 6.4 Hz, 3H), 2.56-2.61 (m, 2H), 2.80 (s, 3H), 3.02-3.18 (m, 3H), 3.22-3.30 (m, 4H), 4.89 (s, 2H), 4.93 (s, IH), 6.66-6.79 (m, 2H), 7.35-7.48 (m, 1H), 7.79 (s, 1H), 7.88 (s, 1H).

FAB-MS: 415.9 (MH+), C,7H23F2N503S 415.45 Example 18 (2R,3R)-2-(2,4-Difluorophenyl)-3-[4-(4-nitrophenylsulphonyl) piperazin- 1 -yl]-1-(1 H-1.2.4-triazol-1 -yl)butan-2-ol.: The title compound was prepared from piperazinyl compound 2 and p- nitrobenzenesulphonyl chloride by following the similar procedure described for example 12. The product was obtained as tan needles in 38% yield after purification on a column of silica gel (CHCl31MeOH; 96:4) followed by recrystalization in ether. m.p.: 160-162 °C.

'H NMR (CDCl3) b: 0.87 (d, J = 6.7 Hz, 3H), 2.51-2.66 (m, 2H), 2.96-3.20 (m, 7H),4.74 (s, 2H), 4.81 (s, 1H), 6.62-6.76 (m, 2H), 7.29-7.41 (m, 1H), 7.72 (s, 1 H), 7.77 (s, H), 7.94-7.98 (m, 2H), 8.39-8.43 (m, 2H).

FAB-MS: 523.2 (MH+), calcd. C22H24F2N6O5S 522.52.

Example 19 (2R,3R)-3-[4-(4-aminophenylsulphonyl)piperazin-1-yl]-2-(2,4- difluorophenyl)-1 -(1 H-1,2,4-triazol-1 -yl)butan-2-ol: A solution of nitrocompound 18 (230 mg, 0.44 mmol) in ethanol (10 ml) was hydrogenated over 10% Pd-C (25 mg) at 45 psi pressure and room temperature for 18 h. The catalyst was removed by filtration and the filtrate was concentrated and the resulting product was purified on a column of silica gel (CHCI3/MeOH; 57:43) to give the amino compound 19 as a colorless solid (165 mg, 76%). m.p.: 95-97 °C.

'H NMR (CDCl3) #: 0.88 (2, J = 6.1 Hz, 3H), 2.48-2.58 (m, 2H), 2.96-3.09 (m, 7H), 4.14 (br, 2H), 4.75 (s, 2H), 4.86 (s, 1H), 6.63-6.77 (m, 4H), 7.31- 7.43 (m, 1H), 7.52-7.57 (m, 2H), 7.74 (s, 1 H), 7.83 (s, H).

FAB-MS: 493.5 (MH+), calcd. C22H26F2NsO3S 492.54.

Example 20 (2R,3R)-2-(2,4-Difluorophenyl)-3-[4-(3-azo-1H-1,2,4-triazoly l)piperazin- 1-yl]-1-(1H-1,2,4-triazol-1-yl)butan-2-ol: To a cooled solution of 3-amino-1H-l ,2,4-triazole (378 mg, 4.5 mmol) in concentrated hydrochloric acid (1 ml) was added sodium nitrite (310 mg, 4.5 mmol) in portions. The resulting diazonium salt was transferred to a flask containing compound 2 (1 9, 3.0 mmol) in 20 ml of 3:1 mixture of 10% sodium hydroxide solution and tetrahydrofuran. The resulting reaction mixture was stirred at room temperature for 2 h and extracted with chloroform (3X25

ml). The combined organic extract was washed with water, brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel to give the title compound as thick viscous gum (100 mg, 8%).

1H NMR (CDCl3) #: 0.92 (d, 3H, CH3), 2.65 (m, 2H, CH2), 3.1-3.3 (m, 3H, CH2 and CH), 4.0 (m, 4H, 2XCH2), 4.95 (m, 3H, CH2 and OH), 6.72-6.81 (m, 2H, Ar-H), 7.4-7.49 (m, IH, Ar-H), 7.79 (s, 1H, Het-H), 7.91 (s, 1H, Het-H), 7.97 (s, 1H, Het-H).

FAB-MS: 433.2 (MH+), calcd. C'8H22F2N10O 432.43.

Example 21 Ethyl 4-(2-thiazolyl)piperazine-1-carboxylate: A mixture of 2-bromothiazole (1.64 g, 10 mmol), ethyl 1 -piperazinecarboxylate (1.896, 12 mmol) and sodium iodide (1.498, 10 mmol) in N,N- dimethylformamide (10 ml) was heated at 1200C for 18 h. After cooling, the solvent was removed under reduced pressure and the residue was treated with crushed ice. The desired product was precipitated as colorless solid, was isolated by filtration (2.2 g, 91%).

1H NMR (CDCl3) 5:1.28 (t, 3H, CH3), 3.48 (m, 4H, 2XCH2), 3.62 (m, 4H, 2XCH2), 4.17 (q, 2H, OCH2), 6.60 (d, 1H, Het-H, J=3.5 Hz), 7.20 (d, 1H, Het- H, J=3.5 Hz) 2-(Piperazin-1 -ylthiazole: To a methanolic solution of ethyl 4-(2-thiazolyl)piperazine-1-carboxylate (2 g, 8 mmol), 20 ml of 10% sodium hydroxide solution was added. The resulting mixture was heated under reflux for 5 h. After cooling, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water and extracted with chloroform (3 X 30 ml). The combined extract was washed

with water, brine, dried (Na2SO4) and concentrated to give the title compound as a thick viscous liquid (1.2 g, 86%).

1H NMR (CDCl3) b: 1.68 (br s, 1H, NH), 2.98 (m, 4H, 2XCH2), 3.46 (m, 2XCH2), 6.56 (d, 1H, Het-H, J=3.5 Hz), 7.2 (d, 1H, Het-H, J=3.5 Hz).

(2R,3R)-2-(2,4-Difluorophenyl)-3-[4-(2-thiazolyl)piperazi n-1-yl]-1-(1H-1,2,4- triazol-1-yl)butan-2-ol: To a mixture of (2 R,3S)-2-(2,4-d ifluorophenyl)-3-methyl-2-( 1 H-1,2,4-triazol-1 - yl)methyloxirane IV (502 mg, 2 mmol) and lithium perchlorate (320 mg, 3 mmol) in acetonitrile (10 ml), 2-(piperazin-1-yl)thiazole (X)(507 mg, 3 mmol) was added. The resulting mixture was heated under reflux for 48 h. The reaction mixture was cooled, concentrated under reduced pressure. The residue was disolved in chloroform, washed with water, brine, dried (Na2SO4) and concentrated. The resulting product was purified on a column of silica gel using ethyl acetate and hexane (4:1) as eluent to give the title compound as colorless solid (650 mg, 77%). m.p.: 180-181 °C.

'H NMR (CDCl3) b: 0.93 (d, 3H, CH3), 2.57 (m, 2H, CH2), 3.05 (m, 3H, CH2and CH) 3.51 (m, 4H, 2XCH2), 4.92 (AB q, 2H, CH2), 5.05 (s,1 H, OH), 6.58 (d, 1 H, Het-H, J=3.5 Hz), 6.7-6.8 (m, 2H, Ar-H), 7.2 (d, 1H, Het-H, J=3.5 Hz), 7.4-7.5 (m, 1H, Ar-H), 7.78 (s, 1H, Het-H), 7.93 (s, 1-H, Het-H).

FAB-MS: 421.0 (MH+), calcd. C1gH22F2N6OS 420.482.

Example 22 (2R,3R)-2-(2,4-Difluorophenyl)-3-[4-(1H-1,2,4-triazol-3-yl)p iperazin-1- yl]-1-(1H-1,2,4,triazol-1-yl)butan-2-ol: The title compound was prepared in 48% yield from (2R,3S)-2-(2,4- difluorophenyl)-3-methyl-2-(1 H-1,2,4-triazoi-l -yl)methyloxirane and 3- (piperazin-l-yl)-l H-1,2,4-triazole (Xl) in the presence of lithium perchlorate

following the similar procedure described for example 21. m.p.: 71-73 °C.

H NMR (CDCl3) #: 0.91 (d,3H, CH3), 2.48-2.60 (m, 2H, CH2), 2.90 -3.03 (m, 3H, CH2 and CH), 3.32-3.51 (m, 4H, 2XCH2), 4.81-5.04 (m, 2H, CH2), 5.20 (br, 2H), 6.67-6.86 (m, 2H, Ar-H), 7.35-7.58 (m, 1H, Ar-H), 7.72 (s, 1H, Het-H), 7.78 (s, 1H, Het-H), 8.01 (s, 1H, Het-H) FAB-MS: 405.0 (MH+), calcd. C,8H22F2N8O 404.36.

Example 23 (2R,3R)-2-(2,4-difluorophenyl)-3-[4-(1H-5-tetrazolyl)piperaz in-1-yl]-1- (1H-1,2,4,triazol-1-yl)butan-2-ol: A mixture of compound 3 (140 mg, 0.39 mmol), sodium azide (31 mg, 0.47 mmol) and ammonium chloride (25 mg, 0.47 mmol) in DMF (5 ml) was heated at 90 °C for 48 h. Solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (3X10 ml). Combined organic extract was washed with water, brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel to give the title compound as a off-white solid (30 mg, 19%). m.p.: 104-105 °C.

'H NMR (CDCl3) b: 0.93 (d, 3H, CH3), 2.63 (m, 2H, CH2), 3.07 (m, 3H, CH2 and CH), 3.56 (m, 4H, 2XCH2), 4.93 (AB q and s merged, 3H, CH2 and OH), 6.70-6.77 (m, 2H, Ar-H), 7.42-7.45 (m, IH, Ar-H), 7.80 (s, 1H, Het-H), 7.96 (s, 1H, Het-H).

FAB-MS: 406.3 (MH+), calcd. C17H2,F2NgO 405.42 Example 24

(2R,3R)-2-(2,4-Difluorophenyl)-3-{4-[2-(4-tert-butylbenzyl)- 2H-tetrazol- 5-yl]piperazin-1-yl}-1-(1H-1,2,4-triazol-1yl)butan-2-ol: The title compound was prepared from the epoxide IV and tetrazolylpiperazine XVI (Am4-tetrt-butylphenyl) by following the similar procedure described for example 21.

After usual workup and column purification the title compound was obtained as a colorless solid in 36% yield. m.p.: 99-101 OC.

'H NMR (CDCl3) #: 0.94 (d, 3H, CH3), 1.30 (s, 9H, 3XCH3), 2.47-2.59 (m, 2H, CH2), 2.91-3.01 (m, 3H, CH2 and CH), 3.50 (m, 4H, 2XCH2), 4.88 (AB q, 2H, CH2), 5.12 (brs, 1H, OH), 5.53 (s, 2H, CH2), 6.67-6.81 (m, 2H, Ar-H), 7.29- 7.48 (m, 5H, Ar-H), 7.79 (s, 1H, Het-H), 7.95 (s, 1H, Het-H).

FAB-MS: 552.2 (MH+); calcd. C28H3sF2NgO 551.61.

Example 25 (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{ 4-2-(4- trifluoromethylbenzyl)-2H-tetrazol-5-yl]piperazin-1 byl}butan-2-ol: The title compound was prepared from the epoxide IV and tetrazolylpiperazine XVI (Ar = 4-(trifluoromethyl)phenyl) by following the similar procedure described for example 21. After usual workup and column purification the title compound was obtained as a colorless solid in 30% yield. m.p.: 71-72 °C.

'H NMR (CDCl3) 5: 0.93 (d, 3H, CH3), 2.51-2.56 (m, 2H, CH2), 2.96-3.02 (m, 3H, CH2 and CH), 3.49 (m, 4H, 2XCH2), 4.90 (AB q, 2H, CH2), 5.07 (s, iH, OH), 5.62 (s, 2H, CH2), 6.68-6.77 (m, 2H, Ar-H), 7.43-7.65 (m, 5H, Ar-H), 7.78 (s, 1H, Het-H), 7.93 (s, 1H, Het-H).

FAB-MS: 564.1 (MH+), calcd. C25H26F5NgO 563.54.

Example 26

(2R,3R)-2-(2,4-Difluorophenyl)-3-{4-[2-(4-tert-butylbenzyl)- 2H-1,2,4- triazol-3-yl]piperazin-1-yl}-1-(1H-1,2,4-triazol-1yl)butan-2 -ol: The title compound was prepared from the epoxide IV and triazolylpiperazine XII (Ar = 4-tert-butylphenyl) by following the similar procedure described for example 21. After usual workup and column purification the title compound was obtained as a colorless solid in 45% yield. m.p.: 73-75 OC.

'H NMR (CDCl3) #: 0.93 (d, 3H), 1.30 (s, 9H), 2.49-2.59 (m, 2H), 2.95-3.07 (m, 3H), 3.12-3.14 (m, 4H), 4.78-4.95 (m, 2H), 5.04 (s, 1H), 5.15 (s, 2H), 6.66-6.80 (m, 2H), 7.12 (d, 2H, J=8.3 Hz), 7.34 (d, 2H, J=8.3 Hz), 7.35-7.49 (m, IH), 7.69 (s,IH), 7.76 (s, 1H), 7.92 (s, IH).

FAB-MS: 551.4 (MH+), calcd. C29H36F2N8O 550.66 Example 27 (2R,3R)-2-(2,4-Difluorophenyl)-3-{4-[1-(4-tert-butylbenzyl)- 1H-1,2,4- triazol-3- yl]piperazin-1 -y}-1 -(1H-1,2,4-triazol-1 yl)butan-2-ol: The title compound was prepared from the epoxide IV and triazolylpiperazine XIII (Ar = 4-tert-butylphenyl) by following the similar procedure described for example 21. After usual workup and column purification the title compound was obtained as a colorless solid in 46% yield. m.p.: 84-86 OC.

'H NMR (CDCl3): b: 0.94 (d, 3H, CH3), 1.30 (s, 9H, 3XCH3), 2.45-2.55 (m, 2H), 2.83- 3.01 (m, 3H), 3.42-3.48 (m, 4H), 4.79-4.97 (m, 2H), 5.11 (s, 2H), 5.22 (s, 1H), 6.67-6.81 (m, 2H), 7.16 (d, 2H, J=8.2 Hz), 7.36 (d, 2H, J=8.2 Hz), 7.41-7.53 (m, 1H), 7.66 (s, 1H), 7.78 (s, H), 7.97 (s, H).

FAB-MS: 551.3 (MH+), calcd. C29H36F2N8O 550.66.

Example 28

(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1yl)-3-{4 -[1-(4- trifluoromethylbenzyl)-1H-1,2,4-triazol-3-yl]piperazin-1-y}b utan-2-ol: The title compound was prepared from the epoxide IV and triazolylpiperazine XIII (Ar = 4-(trifluoromethyl)phenyl) by following the similar procedure described for example 21. After usual workup and column purification the title compound was obtained as a colorless solid in 18% yield. m.p.: 69-72 °C 'H NMR (CDCl3) b: 0.96 (d, 3H, CH3), 2.49-2.54 (m, 2H, CH2), 2.88-2.99 (m, 3H, CH2 and CH ), 3.43 (m, 4H, 2XCH2), 4.93 (AB q, 2H, CH2), 4.98 (2 s merged , 3H, CH2 and OH), 6.69-6.80 (m, 2H, Ar-H), 7.32-7.64 (m, 5H, Ar-H), 7.78 (2 s merged, 2H, Het-H), 7.98 (s, 1 1H, Het-H).

FAB-MS: 562.9 (MH+), calcd. C20H27F5N8O 562.56.

Example 29 (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-phenylpiperazin-1-yl)-1- (1H- 1,2,4,triazol-1-yl)butan-2-ol: The title compound was prepared by opening of the epoxide IV with 1- phenylpiperazine in the presence of lithium perchlorate by following similar procedure described to example 21. After column purification the compound was obtained as a colorless solid. m.p.: 103-105 OC.

1H NMR (CDCl3) b: 0.99 (d, 3H, CH3), 2.6 (m, 2H, CH2), 2.9-3.05 (m, 3H, CH2 <BR> <BR> <BR> and CH), 4.89 (AB q, 2H, CH2), 5.23 (s, IH, OH), 6.7-7.0 (complex, 5H, Ar-H), 7.2-7.3 (m, 2H, Ar-H), 7.5 (m, IH, Ar-H), 7.79 (s, 1H, Ar-H), 7.79 (s, 1H, Het- H), 7.97 (s, IH, Het-H).

FAB-MS: 414.1 (MH+), calcd. C22H25F2N5O 413.47.

Example 30

(2R,3R)-2-(2,4-Difluorophenyl)-3-[4-(4-nitrophenyl)piperazin -1-yl]-1- (I H-I .2.4.triazol-I -yl)butan-2-ol: The title compound was prepared similarly to example 21 using the oxirane IV(600 mg, 2.4 mmol), 4-nitrophenylpiperazine (660 mg, 3.2 mmol) and lithium perchlorate (383 mg, 3.6 mmol) as starting materials. After usual workup, the crude reaction product was purified on a column of silica gel (EtOAc/hexane) to give the desired compound as light yellow solid (920 mg, 84%). m.p. 148-150 °C 'H NMR (CDCl3) b: 0.94 (d, 3H, CH3), 2.58-2.64 (m, 2H,), 3.06-3.13 (m, 3H), 3.4-3.5 (m, 4H), 4.93 (AB q, 2H, CH2), 5.04 (s, 1H, OH), 6.7-6.85 (m and d merged, 4H, Ar-H), 7.38-7.51 (m, 1H, Ar-H), 7.79 (s, 1H, Het-H), 7.91 (s, 1H, Het-H), 8.13 (d, 2H, Ar-H).

FAB-MS: 459.2 (MH+), calcd. C22H24F2N6O3 458.47 Example 31 (2R,3R)-3-[4-(4-Aminophenyl)piperazin-1-yl]-2-(2,4-difluorop henyl)-1- (1H-1,2,4,triazol-1-yl)butan-2-ol: To a solution of nitrocompound 30 (600 mg, 1.3 mmol) in 50 ml of ethyl acetate, 120 mg of 5% platinum on charcoal was added. The reaction mixture was hydrogenated in Parr hydrogenator at room temperature and 45 psi pressure for 18 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The pure amino compound 31 was obtained by dissolving the product in ethyl acetate and precipitating by addition of hexane (530 mg, 95%). m.p.: 150-151 °C.

'H NMR (CDCl3) 5 : 0.98 (d, 3H, CH3), 2.53-2.59 (m, 2H, CH2), 2.89-3.04 (complex, 7H, 3XCH2 and CH), 4.87 (AB q, 2H, CH2), 6.6-6.9 (2d and m merged, 6H, Ar-H), 7.43-7.55 (m, IH, Ar-H), 7.79 (s, IH, Het-H), 7.98 (s, 1H, Het-H).

FAB-MS: 429.2 (MH+), calcd. C22H26F2N6O 428.487.

Example 32 (2R,3R)-2-(2,4-Difluorophenyl)-3-[4-(4- ethoxycarbonylaminophenyl)piperazin-1-yl]-1-(1H-1,2,4-triazo l-1- yl)butan-2-ol: To a cooled (0 °C) mixture of amine 31 (300 mg, 0.7 mmol) and triethylamine (0.4 ml) in dichloromethane (30 ml) was added ethyl chloroformate (160 mg, 1.5 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at 0 °C for 2 h, then diluted with 30 ml of chloroform, washed with water, brine and dried over sodium sulphate. The solvent was removed under reduced pressure, the residue was purified on a column of silica gel (hexane/EtOAc, 1:1 and 1:2) to give the title compound as amorphous solid (330 mg, 94%). m.p. 90-92 OC.

'H NMR (CDCl3)5: 0.99 (d, 3H, CH3), 1.29 (t, 3H, CH3, J=7 Hz), 2.58 (m, 2H, CH2), 2.95 (m, 3H, CH2 and CH), 4.2 (q, 2H, CH2, J=7 Hz), 4.88 (AB q, 2H, CH2), 5.21 (s, lH, OH), 6.44 (s, IH, NH), 6.7-6.85 (m, 2H, Ar-H), 6.87 (d, 2H, Ar-H, J=8.9 Hz), 7.26 (d, 2H, Ar-H, J=8.9 Hz), 7.41-7.54 (m, lH, Ar-H), 7.78 (s, 1H, Het-H), 7.97 (s, 1H, Het-H).

FAB-MS: 501.0 (MH+), calcd. C25H30F2N6O3 500.55.

Example 33

(2R,3R)-2-(2,4-Difluorophenyl)-3-[4-(4- phenoxycarbonylaminophenyl)piperazin-1-yl]-1-(1H-1,2,4,triaz ol-1- yI)butan-2-oI: The title compound was prepared similarly to the above procedure using the amine 31(428 mg, 1 mmol) and phenyl chloroformate (235 mg, 1.5 mmol) in the presence of triethylamine (0.4 ml). After usual workup and purification on a silica gel column, the product was obtained as a colorless solid (475 mg, 89%). m.p.: 95-97 OC.

'H NMR (CDCl3) #: 0.98 (d, 3H, CH3), 2.58 (m, 2H, CH2), 2.98 (m, 3H, CH2 and CH), 3.15 (m, 4H, 2XCH2), 4.88 (AB q, 2H, CH2), 5.19 (s, 1H, OH), 6.7- 7.0 (d and m merged, 4H, Ar-H), 7.2-7.6 (complex, 8H, Ar-H), 7.78 (s, 1H, Het-H), 7.96 (s, 1H, Het-H).

FAB-MS: 549.3 (MH+), calcd. C2gH30F2N6O3 548.594.

Example 34 (2R.3R)-2-(2.4-Difluorophenyl)-3i4-14-(semicarbazid-4- yl)phenyl]piperazin-1-yl}-1-(1H-1,2,4,triazol-1-yl)butan-2-o l: To a solution of compound 33 (400 mg, 0.73 mmol) in dimethoxyethane (10 ml) was added hydrazine (1 ml) dropwise at room temperature and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was treated with crushed ice. The precipitated product was isolated by filtration and washed with water and hexane to give the title compound as a colorless solid (300 mg, 85%). m.p.: 180-182°C.

1H NMR (CDCl3) : 0.99 (d, 3H, CH3), 2.54-2.60 (m, 2H, CH2), 2.90-3.0 (m, 3H, CH2 and CH), 3.10 (m, 4H, 2XCH2), 3.8 (br s, 2H, NH2), 4.88 (AB q, 2H,

CH2), 5.7 (br s,1 H, OH), 6.09 s, 1H, NH), 6.7-6.9 (d and m merged, 4H, Ar-H), 7.3-7.6 (d and m merged, 3H, Ar-H), 7.8 (s, 1H, Het-H), 7.93 (br s, H, NH), 8.0 (s, 1H, Het-H).

FAB-MS: 487.0 (MH+), calcd. C23H28F2N8O2 486.527.

Example 35 (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{ 4-[4-(2H- 1,2,4-triazol-3-one-4-yl)phenyl]piperazin-1-yl}butan-2-ol.

To a mixture of semicarbazide 34 (486 mg, 1 mmol) and formamidine acetate (416 mg, 4 mmol) in methoxyethanol (5 ml), triethylamine (0.8 ml) was added.

The reaction mixture was heated at 110 °C for 18 h. Solvent was removed under reduced pressure and the residue was treated with crushed ice, extracted with ethyl acetate (3 X 30 ml). The combined extract was successively washed with water and brine and dried over sodium sulphate.

The solvent was removed under reduced pressure, the crude product was purified on a column of silica gel (EtOAc/MeOH, 9:1) to give the triazolone 35 as a crystaline solid (320 mg, 65%). m.p.: 223-225 °C.

'H NMR (CDCl3) 6: 0.98 (d, 3H, CH3, J=6.4 Hz), 2.57-2.63 (m, 2H, CH2), 2.95- 3.1 (m, 3H, CH2 and CH), 4.9 (AB q, 2H, CH2), 5.14 (s, 1H, OH), 6.7-6.82 (m, 2H, Ar-H), 6.98 (d, 2H, Ar-H, J=8.9 Hz), 7.37 (d, 2H, J=8.9, Ar-H), 7.4-7.5 (m, 1H, Ar-H), 7.62 (s, 1H, Het-H), 7.79 (s, 1H, Het-H), 7.95 (s, IH, Het-H).

FAB-MS: 497.0 (MH+), calcd. C24H26F2N8O2 496.522 Example 36 (2R,3R)-2-(2,4-Difluorophenyl)-3-[4-{4-[2-(3-pentyl)-2H-1,2, 4-triazol-3- one-4-yl]phenyl]}piperazin-1-yl]-1-(1H-1,2,4-triazol-1-yl)bu tan-2-ol.

To a mixture of triazolone 35 (248 mg, 0.5 mmol) and cesium carbonate (326 mg, 1 mmol) in DMF, 3-bromopentane (226 mg, 1.5 mmol) was added. The

reaction mixture was heated at 80 °C for 18 h and concentrated in vacuo. The residue was treated with crushed ice, extracted with ethyl acetate (3 X 30 ml).

The combined extract was washed with brine, dried (Na2SO4) and the solvent was removed under rduced pressure. The resulting crude product was purified on a column of silica gel (hexane/EtOAc) to give the title compound 36 as a crystaline solid (240 mg, 85%).

The title compound was also prepared in an alternate method in a convergent approach according to Scheme. Thus a mixture of (2R,3S)-2-(2,4- difluorophenyl)-3-methyl-2-( 1 H-1,2,4-triazol-1 -yl)methyloxirane IV, piperazino compound XXIII (R= 3-pentyl) and lithium perchlorate were heated in acetonitrile for 48 h. After usual workup and chromatographic purification, the title compound was obtained in 75% yield. m.p.: 143-145 OC.

IH NMR (CDCl3)5: 0.88 (t, 6H, 2XCH3), 0.98 (d, 3H, CH3), 1.65-1.8 (m, 4H, 2XCH2), 2.60 (m, 2H, CH2), 3.1 (m, 3H, CH2 and CH), 3.2 (m, 4H, 2XCH2), 4.12 (m, 1H, CH), 4.9 (AB q, 2H, CH2), 5.18 (s, 1H, OH), 6.7-6.8 (m, 2H, Ar- H), 6.97 (d, 2H, Ar-H, J=9 Hz), 7.4-7.6 (d and m merged, 3H, Ar-H), 7.64 (s, 1H, Het-H), 7.79 (s, 1H, Het-H), 7.96 (s, 1H, Het-H).

FAB-MS: 567.3 (MH+), calcd. C29H36F2N8O2 566.657.

Example 37 (2S,3R)-2-(2,4-Difluorophenyl)-3-[4-{4-[2-(3-pentyl)-2H-1,2, 4-triazol-3- one-4-yl]phenyl}piperazin-1-yl]-1-(1H-1,2,4-triazol-1-yl)but an-2-ol.

The title compound was prepared from (2S,3S)-2-(2,4-difluorophenyl)-3- methyl-2-(l H-1,2,4-triazol-l -yl)methyloxirane and piperazino compound XXIII (R = 3-pentyl) by following the similar procedure described for the example 36.

Yield 70%, colorless solid.

m.p.: 83-85 OC.

'H NMR (CDCl3) b: 0.88 (t, 6H, 2XCH3), 1.25 (d, 3H, CH3), 1.65-1.84 (m, 4H, 2XCH2), 2.46 (m, 2H, CH2), 2.75 (m, 2H, CH2), 2.93 (m, 4H, 2XCH2), 3.19 (q, 1H, CH), 4.05 (m, 1H, CH), 4.44 (d, 1H, J=14 Hz), 4.95 (d, 1H, J=14 Hz), 4.98 (s, 1H, OH), 6.64-6.77 (m, 2H, Ar-H), 6.74 (d, 2H, Ar-H), 7.29-7.43 (m, 3H Ar-H), 7.59 (s, 1H, Het-H), 7.77 (s, 1H, Het-H), 7.93 (s, 1H, Het-H).

FAB-MS: 567.2 (MH+), calcd. C29H36F2N8O2 566.657.

Example 38 (2S,3S)-2-(2,4-Difluorophenyl)-3-[4-{4-[2-(3-pentyl)-2H-1,2, 4-triazol-3- one-4-yl]phenyl}piperazin-1-yl]-1-(1H-1,2,4-triazol-1-yl)but an-2-ol.

The title compound was prepared from (2S,3R)-2-(2,4-difluorophenyl)-3- methyl-2-(1 H-1,2,4-triazol-l -yl)methyloxirane and piperazino compound XXIII (R=3-pentyl) by following the similar procedure described for the example 36.

Yield 87%, off-white solid. m.p.: 218-220 OC.

1H NMR(CDCl3) 5 : 0.88 (t, 6H, 2XCH3), 0.97 (d, 3H, CH3), 1.70-1.84 (m, 4H, 2XCH2), 2.63 (m, 2H, CH2), 3.01 (m, 3H, CH2 and CH), 3.22 (m, 4H, 2XCH2), 4.12 (m, IH, CH), 4.90 (AB q, 2H, CH2), 5.14 (s, 1H, OH), 6.69-6.82 (m, 2H, Ar-H), 6.96 (d, 2H, Ar-H), 7.40-7.49 (m and d merged, 3H, Ar-H), 7.63 (s, 1H, Het-H), 7.79 (s, 1H, Het-H), 7.95 (s, 1H, Het-H).

FAB-MS: 567.4 (MH+), calcd. C29H3eF2N8O2 566.657.

Example 39 (2R,3S)-2-(2,4-Difluorophenyl)-3-[4-{4-[2-(3-pentyl)-2H-1,2, 4-triazol-3- one-4-yl]phenyl}piperazin-1-yl]-1-(1H-1,2,4-triazol-1-yl)but an-2-ol.

The title compound was prepared from (2R,3R)-2-(2,4-difluorophenyl)-3- methyl-2-( 1 H-1,2,4-triazol-l -yl)methyloxirane and piperazino compound XXIII (R= 3-pentyl) by following the similar procedure described for the example 36.

Yield 60%, colorless solid. m.p.: 110-113 °C.

'HNMR (CDCl3) #: 0.87 (t, 6H, 2XCH3), 1.25 (d, 3H, J=7 Hz), 1.69-1.87 (m, 4H, 2XCH2), 2.46 (m, 2H, CH2), 2.75-2.95 (m, 6H, 3XCH2), 3.19 (q, 1H, J=7 Hz), 4.07 (m, IH, CH), 4.45 (d, 1H, J=15 Hz), 4.94 (d, 1H, J=15 Hz), 5.03 (s, 1H, OH), 6.66-6.76 (m, 2H, Ar-H), 6.87 (d, 2H, Ar-H), 7.34-7.39 (d and m merged, 3H, Ar-H), 7.60 (s, 1H, Het-H), 7.77 (s, 1H, Het-H), 7.93 (s, 1H, Het- H).

FAB-MS: 567.1 (MH+), calcd. C29H36F2N8O2 566.657.

Example 40 (2R,3R)-3-[4-{4-[2-(2-Butyl)-2H-1,2,4-triazol-3-one-4- yl]phenyl}piperazin-1-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4 -triazol-1- yl)butan-2-ol.

The example 40 was prepared similarly to the above procedure by alkylation of triazolone 35 with 2-bromobutane in the presence of cesium carbonate.

After column chromatography the product was obtained as a colorless solid.

Yield 88%. m.p.: 156-157 °C.

'H NMR (CDCl3) #: 0.90 (t, 3H, CH3), 0.98 (d, 3H, CH3), 1.6-1.9 (m, 2H, CH2), 2.60 (m, 2H, CH2), 3.0 (m, 3H, CH2 and CH), 3.22 (m, 4H, 2XCH2), 4.29 (m, 1H, CH), 4.9 (AB q, 2H, CH2), 5.14 (s, 1H, OH), 6.65-6.85 (m, 2H, Ar-H), 6.96 (d, 2H, Ar-H, J=8.9 Hz), 7.5 (m, 1H, Ar-H), 7.61 (s, 1H, Het-H), 7.79 (s, 1H, Het-H), 7.95 (s, 1H, Het-H).

FAB-MS: 553.1 (MH+), calcd. C28H34F2N8O2 552.573.

Example 41 (2R,3R)-2-(2,4-Difluorophenyl)-3-[4-{4-[2-(2-propyl)-2H-1,2, 4-triazol-3- one-4-yl]phenyl}piperazin-1-yl]-1-(1H-1,2,4-triazol-1-yl)but an-2-ol.

The title compound 41 was prepared by alkylation of triazolone 35 with 2- bromopropane in the presence of cesium carbonate following the procedure similar to the above described for example 36.

Yield 80%. m.p.: 166-167 °C.

'H NMR (CDCl3) b: 0.97 (d, 3H, CH3), 1.40 (d, 6H, 2XCH3), 2.60 (m, 2H, CH2), 3.0 (m, 3H, CH2 and CH), 3.22 (m, 4H, 2XCH2), 4.55 (m, IH, CH), 4.9 (AB q, 2H, CH2), 5.15 (s, 1H, OH), 6.7- 6.85 (m, 2H, Ar-H), 6.96 (d, 2H, Ar-H, J=9 Hz), 7.38 (d, 2H, Ar-H, J=9 Hz), 7.5 (m, IH, Ar-H), 7.59 (s, 1H, Het-H), 7.79 (s, IH, Het-H), 7.95 (s, 1H, Het-H).

FAB-MS: 539 (MH+), calcd. C27H32F2N8O2 538.6.

Example 42 (2R,3R)-2-(2,4-Difluorophenyl)-3-[4-{4-[2-(2-hydroxypropyl)- 2H-1,2,4- triazol-3-one-4-yl]phenyl)piperazin-l -yl]-1-(1 H-1,2,4-triazol-1 -yl)butan- 2-01.

To a mixture of triazolone 35 (248 mg, 0.5 mmol) and potassium carbonate (138 mg, 1 mmol) in DMF (6 ml), 1,2-epoxypropane (870 mg, 15 mmol) was added. The reaction mixture was heated at 60 °C for 18 h and concentrated in vacuo. The residue was treated with crushed ice, extracted with ethyl acetate (3 X 30 ml). The combined extract was washed with brine, dried (Na2SO4) and the solvent was removed under reduced pressure. The resulting crude product was purified on a column of silica gel (EtOAc/MeOH, 9:1) to give the hydoxypropyltriazolone 42 as a colorless solid (200 mg, 72%). m.p.: 110-112 °C (decomp).

'H NMR (CDCl3) 5: 0.97 (d, 3H, CH3), 1.28 (d, 3H, CH3), 2.60 (m, 2H, CH2), 2.9-3.1 (m and q merged, 3H, CH2 and CH), 3.23 (m, 4H, 2XCH2), 3.74.0 (m,

2H, CH2), 4.8-5.0 (AB q, 2H, CH2), 5.12 (s, 1H, OH), 6.65-6.85 (m, 2H, Ar-H), <BR> <BR> <BR> 6.96 (d, 2H, Ar-H, J=9 Hz), 7.37 (d, 2H, Ar-H, J=9 Hz), 7.5 (m, 1H, Ar-H), 7.63 (s, IH, Het-H), 7.78 (s, 1H, Het-H), 7.94 (s, 1H, Het-H).

FAB-MS: 555.3 (MH+), calcd. C27H32F2N8O3 554.60 tert-Butyl 4-(4-nitrophenyl)piperazine-I -carboxylate (XVII: X=H): To a solution of 1-(nitrophenyl)piperazine (20.7, 0.1 mol) and triethylamine (21 ml) in dichloromethane (250 ml) at 0-5 "C was added dropwise a solution of di-tert-butyld icarbonate in dichloromethane (50 ml). The resulting mixture was stirred at 0-5 oC for 2 h and at room temperature for 18 h. Then the reaction mixture was diluted with 100 ml of chloroform, washed with water, brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was triturated with hexane and hexane/ethyl acetate mixture to give the title compound as a yellow solid (29 g, 94%).

'H NMR (CDCl3) 5:1.5 (s, 9H, 3XCH3), 3.43 (t, 4H, 2XCH2), 3.6 (t, 4H, 2XCH2), 6.8 (d, 2H, Ar-H, J=9 Hz), 8.15 (d, 2H, Ar-H, J=9 Hz). tert-Butyl 4-(4-Aminophenyl)pi perazi ne-1 -carboxylate (XVIII: X=H): A solution of butyl 4-(4-nitrophenyl)piperazine (60 g, 0.195 mol) in ethyl acetate (800 ml) was hydrogenated in the presence of 10% palldium on charcoal (6.0) at room temperature and 45 psi pressure in the Parr hydrogenator for 18 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound as a offwhite solid (50 g, 93%).

'H NMR (CDCl3) 5:1.49 (s, 9H, 3XCH3), 3.0 (t, 4H, 2XCH2), 3.4 (br s, 2H, NH2), 3.5 (t, 4H, 2XCH2), 6.65 (d, 2H, Ar-H), 6.85 (d, 2H, Ar-H). tert-Butyl 4-(4-Phenoxycarbonylaminophenyl)piperazine-I -carboxylate (XIX: X=H):

To a solution of terf-butyl 4-(4-aminophenyl)piperazine-l -carboxylate (50 g, 0.18 mol) and triethylamine (39 ml, 0.27 mol) in dichloromethane (400 ml) was added dropwise a solution of phenyl chloroformate (36.65 g, 0.23 mol) in dichloromethane (100 ml) at 0 oC. The resulting reaction mixture was stirred for 2 h at 0 OC and additional 3 h at room temperature. Then diluted with chloroform (100 ml), washed with water, brine and dried over sodium sulphate. The solvent was removed under reduced pressure, the crude product was purified on a column of silica gel (hexane/EtOAc, 1:1) to give the tiltle compound as colorless solid (60 g, 84%). m.p.: 158-160 OC.

'H NMR (CDCl3) b: 1.48 (s, 9H, 3XCH3), 3.0-3.2 (m, 4H, 2XCH2), 3.6 (m, 4H, 2XCH2), 6.8 (brs, 1H, NH), 6.92 (d, 2H, Ar-H), 7.1-7.5 (complex, 7H, Ar-H).

4-(4-(4-t-BOC-piperazin-I -yl)phenylsemicarbazide (XX: X=H).

To a solution of tert-butyl 4-(phenoxycarbonylaminophenyl)piperazine-1 - carboxylate (36 g, 90 mmol) in dimethoxyethane (300 ml), anhydrous hrazine (40 g, 1.25 mol) was added. The resulting reaction mixture was stirred at room temperature for 3-5 h. Solvent was removed under reduced pressure and the residue was treated with crushed ice and left overnight at room temperature. The precipitated solid was collected, washed with water and hexane to give the title compound as a offwhite solid (25 g, 82%).

'H NMR (CDCl3) b: 1.48 (s, 9H, 3XCH3), 3.06 (t, 4H, 2XCH2), 3.58 (t, 4H, 2XCH2), 3.82 (s, 2H, NH2), 5.98 (s, 1H, NH), 6.89 (d, 2H, Ar-H, J=8.9 Hz), 7.36 (d, 2H, Ar-H, J=8.9 Hz), 7.95 (s, 1H, NH).

4[4-(4-t-BOC-Piperazin-1-yl)phenyl-2H-1,2,4-triazol-3-one (XXI; X=H): A mixture of 4-[4-(4-t-BOC-piperazin-1-yl)phenylsemicarbazide (25 g, 75 mmol), formamidine acetate (31.2 g, 300 mmol) and triethylamine (50.5 ml,

360 mmol) in methoxyethanol (250 ml) was heated at 110 °C for 18 h. The solvent was removed under reduced pressure, the residue was treated with crushed ice and extracted with ethyl acetate (3X250 ml). Combined extract was successively washed with water and brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the product was purified on a column of silica gel to give the title compound as a colorless solid (16.7 g, 65%). m.p.: 195-197 OC.

1H NMR (CDCI3) 5:1.48 (s, (H, 9H, 3XCH3), 3.16 (t, 4H, 2XCH2), 3.59 (t, 4H, 2XCH2), 6.98 (d, Ar-H, J=9 Hz), 7.38 (d, 2H, Ar-H), 7.62 (s, 1H, Het-H), 9.7 (brs, 1H, NH).

2-(3-Pentyl)-4-[4-(4-t-BOC-piperazin-1-yl)phenyl-2H-1,2,4 -triazol-3-one (XXI I: X=H. R= 3-pentyl): A mixture of 4(4-(4-t-BOC-piperazin-1 -yl)phenyl-2H-I ,2,4-triazol-3-one XXI (3.45 g, 10 mmol), 3-bromopentane (4.53 g) and potassium carbonate (2.76 g, 20 mmol) in DMF (30 ml) was heated at 80 °C for 18 h. The solvent was removed under reduced pressure, the residue was diluted with water, extracted with ethyl acetate (3X50 ml). The combined extract was washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The resulting product was purified on a column of silica gel (2.9 g, 70%) to give the title compound as a colorless solid. m.p.: 96-97 "C.

'H NMR (CDCl3) b: 0.88 (t, 6H, 2XCH3), 1.48 (s, 9H, 3XCH3), 1.7-1.9 (m, 4H, 2XCH2), 3.15 (t, 4H, 2XCH2), 3.59 (t, 4H, 2XCH2), 4.05 (m, 1H, CH), 6.98 (d, 2H, Ar-H, J=9 Hz), 7.44 (d, 2H, Ar-H, J=9 Hz), 7.63 (s, IH, Het-H).

2-(3-Pentyl)-4-[4-(piperazin-1-yl)phenyl]-2H-1,2,4-triazo l-3-one (XXIII: X=H: R=3-pentyl):

To a solution of 2-(3-pentyl)4-[4-(4-t-BOC-piperazin-1-yl)phenyl-1H-1,2,4- triazol-3-one (2.5 g, 6 mmol) in ethyl acetate (30 ml), 30 ml of 10% hydrochloric acid was added. The resulting heterogenious mixture was stirred at room temperature for 5 h. Solvent was removed under reduced pressure, the residue was diluted with water, basified with potassium carbonate and extracted with chloroform (3X50 ml). The combined extract was washed with water, brine, dried (Na2SO4) and concentrated to give the title compound as colorless solid (1.8 g, 95%). m.p.: 135-137 °C.

1H NMR (CDCI3) 5:0.88 (t, 6H, 2XCH3), 1.7-1.9 (m, 4H, 2XCH2), 3.07 (m, 4H, 2XCH2), 3.18 (m, 4H, 2XCH2), 4.05 (m, 1H, CH), 6.95 (d, 2H, Ar-H), 7.42 (d, 2H, Ar-H), 7.63 (s, 1H, Het-H).

2-(2-Butyl)-4[4-(4-t-BOC-piperazin-1-yl)phenyl]-2H-1,2,4- triazol-3-one (XXII: X=H. R=2-butyl): The title compound was obtained by alkylation of triazolone XXI with 2- bromobutane in the presence of potassium carbonate. m.p.: 134-135 °C.

1H NMR (CDCI3) b: 0.90 (t, 3H, CH3), 1.39 (d, 3H, CH3), 1.48 (s, 9H, 3XCH3), 1.8 (m, 2H, CH2), 3.15 (t, 4H, 2XCH2), 3.59 (t, 4H, 2XCH2), 4.3 (m, 1H, CH), 6.97 (d, 2H, Ar-H, J=8.9 Hz), 7.42 (d, 2H, Ar-H, J=8.9 Hz), 7.61 (s, 1 H, Het-H).

2-(2-Butyl)-4-[4-(piperazin-1-yl)phenyl]-2H-1,2,4-triazol -3-one (XXIII: X=H, R=2-butyl): The title compound was obtained by removal of t-BOC group of 2-(2-butyl)- 4[4-(4-t-BOC-piperazin-1-yl)phenyl]-2H-1,2,4-triazol-3-one with 3M hydrochloric acid. m.p.: 91-93 OC.

'H NMR (CDCI3) b: 0.90 (t, 3H, CH3), 1.39 (d, 3H, CH3), 3.04 (m, 4H, 2XCH2), 3.17 (m, 4H, 2XCH2), 4.29 (m, 1H, CH), 6.98 (d, 2H, Ar-H, J=8.9 Hz), 7.4 (d, 2H, Ar-H, J=8.9 Hz), 7.61 (s, 1H, Het-H).

4-[4-(4-t-BOC-Pi perazin-1 -yl)phenyll-2-(2-propyl)-2H-1 .2.4-triazol-3-one (XXII: X=H. R=2-propyl): The title compound was obtained by alkylation of triazolone XXI with 2- bromopropane in the presence of potassium carbonate. m.p: 166-167 °C.

'H NMR (CDCl3) 5:1.41 (d, 6H, 2XCH3), 1.49 (s, 9H, 3XCH3), 3.16 (t, 4H, 2XCH2), 3.59 (2XCH2), 4.55 (m, 1H, CH), 6.97 (d, 2H, Ar-H, J=8.9 Hz), 7.40 (d, 2H, Ar-H, J=8.9 Hz), 7.59 (s, 1H, Het-H).

4-[4-(Piperazin-1-yl)phenyl]-2-(2-propyl)-2H-1,2,4-triazo l-3-one (XXIII: X=H. R=2-propyl): The title compound was obtained by removal of t-BOC <BR> <BR> <BR> <BR> group of 4-[4-(4-t-BOC-piperazin- 1 -yl)phenyl]-2-(2-propyl)-2H-l ,2,4-triazol-3- one with 3M hydrochloric acid. m.p.: 120-121 °C.

'H NMR (CDCl3) 5:1.41 (d, 6H, 2XCH3), 3.04 (m, 4H, 2XCH2), 3.17 (m, 4H, 2XCH2), 4.55 (m, 1H, CH), 6.97 (d, 2H, Ar-H, J=9 Hz), 7.38 (d, 2H, Ar-H, J=9 Hz), 7.59 (s, 1H, Het-H).

2-(2-Hydroxypropyl)-4-[4-(4-t-BOC-piperazin-1-yl)phenyl]- 2H-1,2,4-triazol- 3-one (XXII: X=H. R=2-hydroxypropyl): The title compound was obtained by alkylation of triazolone XXI with 1,2- epoxypropane in the presence of potassium carbonate m.p: 168-170 OC.

'H NMR (CDCl3) b: 1.28 (d, 3H, CH3), 1.48 (s, 9H, 3XCH3), 3.17 (t, 4H, 2XCH2), 3.4 (brs, 1H, OH), 3.59 (t, 4H, 2XCH2), 3.70 (dd, 1H), 3.96 (dd, 1H), 4.2 (m, 1H, CH), 6.98 (d, 2H, Ar-H, J=8.9 Hz), 7.39 (d, 2H, Ar-H, J=8.9 Hz), 7.63 (s, IH, Het-H).

2-(2-Hydroxypropyl)-4-[4-(piperazin-1-yl)phenyl]-2H-1,2,4 -triazol-3-one (XXIII: X=H. R=2-hydroxypropyl): The title compound was obtained by removal of t-BOC group of 2-(2- hydroxypropyl)-4-[4-(4-t-BOC-piperazin-1-yl)phenyl]-2H-1,2,4 -triazol-3-one with 3M hydrochloric acid.

'H NMR (CDCl3) b: 1.28 (d, 3H, CH3), 3.0 (m, 4H, 2XCH2), 3.2 (m, 4H, 2XCH2), 3.84.0 (m, 2H, CH2), 4.2 (m, 1H, CH), 6.98 (d, 2H, Ar-H, J=9 Hz), 7.3 (d, 2H, Ar-H, J=9 Hz), 7.62 (s, 1H, Het-H) Example 43 4-[4-(4-t-BOC-Piperazin-1-yl)phenyl]-2-[(4-trifluoromethyl)b enzyl]-2H- 1,2,4-triazol-3-one (XXII: X=H. R=4-trifluoromethylbenzyl): The title compound was prepared by alkylation of triazolone XXI (X=H) with 4-(trifluoromethyl)benzyl bromide in the presence of potassium carbonate.

After usual workup and purification on a column of silica gel, the title compound was obtained in 95% yield as a colorless solid.

'H NMR (CDCI3) b: 1.49 (s, 9H, 3 x CH3); 3.16 (t, 4H, 2 x 2); 3.59 (t, 4H, 2 x <BR> <BR> <BR> <BR> CH2); 5.06 (s, 2H, CH2); 6.98 (d, 2H, J = 8.9 Hz, Ar-H), 7.39 (d, 2H, J = 8.9 Hz, Ar-H); 7.5-7.60 (m, 6H, Ar-H); 7.64 (s, 1H, Het-H).

4-[4-(Piperazin-1-yl)phenyl]-2-[(4-trifluoromethyl)benzyl ]-2H-1,2,4-triazol- 3-one (XXIII; X=H. R=4-trifluoromethylbenzyl):

The title compound was obtained by removal of t-BOC group of 4-t4-(4-t- BOC-piperazin-1-yl)phenyl]-2-[(4-trifluoromethyl)benzyl]-2H- 1,2,4-triazol-3-one with 3M hydrochloric acid. After usual workup the product was obtained as a colorless solid in 95% yield.

'H NMR (DMSO-de) #: 2.81-2.84 (m, 4H, 2 x CH2); 3.04-3.07 (m, 4H, 2 x CH2); 5.05 (s, 2H, CH2); 7.0 (d, 2H, J = 9 Hz, Ar-H); 7.43-7.53 (m, 4H, Ar-H); 7.73 (d, 2H, J = 8 Hz, Ar-H); 8.38 (s, 1H, Het-H).

(2R.3R)-2-(2.4-Difluorophenyl) -1-(1 H-1,2,4-triazol-1 -yl)-3-[4g4-[2-(4- trifluoromethylbenzyl)-2H-1,2,4-triazol-3-one-4-yl]phenyl]}p iperazin-1- yl]butan-2-ol (43): The title compound was prepared from (2R,3S)-2-(2,4-difluorophenyl)-3- methyl-2-(l H-1,2,4-triazol-l -yl)methyloxirane IV and piperazino compound XXIII (R= 4-trifluoromethylbenzyl; X=H) by following the similar procedure described for the example 36.

Colorless solid, 189-191 °C, yield 65%.

'H NMR (CDCI3) b: 0.98 (d, 3H, J = 5.5 Hz, CH3), 2.57-2.63 (m, 2H, CH2); 3.0- 3.05 (m, 3H); 3.08 -3.23 (m, 4H, 2 x CH2); 4.81-4.99 (q, 2H, CH2); 5.07 (s, 2H, CH2); 5.15 (s, 1H); 6.68-7.64 (m, 12H); 7.79 (s, 1H, Het-H); 7.95 (s, 1H, Het- H).

FAB-MS: 657.3 (MH+); calcd. C32H3'O2F5N8 656.64.

Example 44 4-[4-(4-tert-BOC-Piperazin-1-yl)phenyl]-2-(2,2,3,3-tetrafluo ropropyl)- 2H-1,2,4-triazol-3-one (XXII: X=H, R=2,2,3,3-tetrafluoropropyl): The title compound was obtained by alkylation of triazolone XXI (X=H) with 2,2,3,3-tetrafluropropyl methanesulphonate in the presence of potassium carbonate. The product was obtained as light yellow solid in quantitative yield.

1H NMR (CDCI3) : 1.48 (s, 9H, 3 x CH3); 3.18 (t, 4H, 2 x CH2); 3.59 (t, 4H, 2 x CH2); 4.344.48 (m, 2H) 5.71-6.28 (m, 1H, CHF2); 6.98 (d, 2H, Ar-H) 7.39 (d, 2H, Ar-H); 7.69 (s, 1H, Het-H).

4-[4-(Piperazin-1-yl)phenyl]-2-(2,2,3,3-tetrafluoropropyl )-2H-1,2,4-triazol- 3-one (XXIII: X=H. R=2.2.3.3-tetrafluoropropyl): The title compound was obtained by the deprotection of the BOC group of the above compound with 3N hydrochloric acid. The product was obtianed as light yellow solid in quantitative yield. This was used in the following step without further purification.

'H NMR (CDCI3) 5: 3.01-3.21 (m, 8H); 4.33-4.62 (m, 3H, CH2 and N-H); 5.67- 6.29 (m, 1 H, CHF2); 6.97 (d, 2H, Ar-H); 7.37 (d, 2H, Ar-H); 7.70 (s, 1H, Het-H).

2R,3R)-2-(2,4-Difluorophenyl)-3-[4-{4-[2-(2,2,3,3-tetrafl uoropropyl)-2H- 1,2,4-triazol-3-one-4-yl]phenyl}piperazin-1-yl]-1-(1H-1,2,4- triazol-1- yl)butan-2-ol.

The title compound was prepared from (2R,3S)-2-(2,4-difluorophenyl)-3- methyl-2-(l H-1,2,4-triazol-l -yl)methyloxirane IV and piperazino compound XXIII (R=2,2,3,3,-tetrafluoropropyl; X=H) by following the similar procedure described for the example 36.

Colorless solid, Yield 55%. m.p.: 155-157 °C.

'H NMR (CDCl3) 6: 0.97 (d, 3H, J = 5.4 Hz, CH3); 2.57-2.65 (m, 2H, CH2); 3.00-3.23 (m, 7H); 4.35-4.48 (m, 2H, CH2); 4.82-5.00 (m, 2H, CH2); 5.13 (s, 1H); 5.71-6.28 (m, 1H, -CHF2); 6.69-6.83 (m, 2H, Ar-H); 6.96 (d, 2H, J = 9 Hz; Ar-H); 7.35-7.53 (m, 3H, Ar-H); 7.68 (s, 1H, Het-H); 7.79 (s, 1H, Het-H); 7.95 (s, 1H, Het-H).

FAB-MS: 611.2 (MH+), calcd. C27H28O2F6N8 610.56.

Example 45 4-[4-(4-t-BOC-Piperazin-1-yl)phenyl]-2-(2,2,2-trifluoroethyl )-2H-1,2,4- triazol-3-one (XXII: X=H. R=2,2,2-trifluoroethyl): The title compound was prepared from the reaction of triazolone XXI (X=H) with 2,2,2-trifluroethyl bromide in a sealed vessel in the presence of potassium carbonate. After usual workup and purification on a column of silica gel, the alkylated compound was obtained as a colorless solid in 21% yield.

'H NMR (CDCl3) b: 1.49 (s, 9H, 3 x CH3); 3.18 (t, 4H, 2 x CH2); 3.59 (t, 4H, <BR> <BR> <BR> 2 x CH2); 4.44 (q, 2H, CH2); 6.98 (d, 2H, J = 7 Hz, Ar-H); 7.38 (d, 2H, J = 7 Hz, Ar-H); 7.69 (s, 1H, Het-H).

4-[4-(Piperazin-1-yl)phenyl]-2-(2,2,2-trifluoroethyl)-2H- 1,2,4-triazol-3-one (XXIII; X=H, R=2,2,2-trifluoroethyl): The title compound was obtained by deprotection of BOC group of the above compound with 3M hydrochloric acid.

'H NMR (CDCI3) 5:1.73 (s, 1 H, N-H); 3.00-3.20 (m, 8H, 4 x CH2); 4.44 (q, 2H, CH2); 6.95-7.00 (m, 2H, Ar-H); 7.34-7.39 (m, 2H, Ar-H); 7.68 (s, 1H, Het-H).

(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[ 4-{4-[2-(2,2,2- trifluoroethyl)-2H-1,2,4-triazol-3-one-4-yl]phenyl]}piperazi n-1-yl]butan-2- ol.

The title compound was prepared from (2R,3S)-2-(2,4-difluorophenyl)-3- methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane IV and piperazino compound XXIII (R= 2,2,2-trifluoroethyl, X=H) by following the similar procedure described for the example 36.

Colorless solid, yield: 59%. m.p.: 95-97 °C.

'H NMR (CDCl3) b: 0.90 (d, 3H, J = 6.3 Hz, CH3); 2.50-2.56 (m, 2H, CH2); 2.93-3.16 (m, 7H); 4.37 (q, 2H, CH2); 4.83 (m, 2H, CH2); 6.61-6.91 (m, 4H, Ar- H); 7.27-7.46 (m, 3H, Ar-H); 7.61 (s, 1H, Het-H); 7.71 (s, 1H, Het-H); 7.88 (s, 1H, Het-H).

FAB-MS: 579.2 (MH+), calcd. C26H27O2F5N8 578.55.

Example 46 2-(2,4-Difluorobenzyl)-4-[4-(4-tert-BOC-piperazin-1-yl)-2H-1 ,2,4-triazol- 3-one (XXII: X=H. R=2.4-difluorobenzyl): The title compound was prepared by alkylation of triazolone XXI (X=H) with 2,4-difluorobenzyl bromide in the presence of potassium carbonate. After usual workup the product was obtained in quantitative yield as a colorless solid.

'H NMR (CDCl3) #: 1.49 (3, 9H, 3 x CH3); 3.17 (t, 4H, 2 x CH2); 3.59 (t, 4H, 2 x CH2); 5.04 (s, 2H, CH2); 6.78-7.01 (m, 4H, Ar-H); 7.29-7.45 (m, 3H, Ar-H); 7.63 (s, 1H, Het-H).

2-(2,4-Difluorobenzyl)-4-[4-(4-piperazin-1-yl)-2H-1,2,4-t riazol-3-one (XXIII: X=H. R=2.4-difluorobenzyl): The title compound was obtained by deprotection of BOC group of the above compound with 3N hydrochloric acid.

Colorless solid, 70% yield.

'H NMR 3) #: 1.70 (s, 1H, N-H); 2.92-3.10 (m, 8H, 4 x CH2); 4.96 (s, 2H, CH2); 6.71-6.91 (m, 4H, Ar-H); 7.21-7.37 (m, 3H, Ar-H); 7.54 (s, 1H, Het-H).

(2R,3R)-3-[4-{4-[2-(2,4-Difluorobenzyl)-2H-1,2,4-triazol- 3-one-4- yl]phenyll}piperazin-1 -yli -2-(2.4-difluorophenyl) -1-(1H-1,2,4-triazol-1- yl)butan-2-ol.

The title compound was prepared from (2R,3S)-2-(2,4-difluorophenyl)-3- methyl-2-(1 H-1,2,4-triazol-l -yl)methyloxirane and piperazino compound XXIII (R= 2,4-difluorobenzyl, X=H) by following the similar procedure described for the example 36.

Colorless solid, yield 53% m.p.: 161-163 "C.

1H NMR (CDCl3) b: 0.91 (d, 3H, J = 5.6 Hz, CH3); 2.49-2.57 (m, 2H, CH2); 2.91-3.14 (m, 7H); 4.734.91 (m, 2H, CH2); 4.97 (s, 2H, CH2); 5.09 (s, 1H); 6.60-6.90 (m, 6H, Ar-H); 7.25-7.45 (m, 4H, Ar-H); 7.54 (s, 1 H, Het-H); 7.70 (s, 1H, Het-H); 7.87 (s, 1H, Het-H).

FAB-MS: 623.1 (MH+); calcd. C30H30 F4O2N8 622.63.

Example 47 4-[4-(4-tert-BOC-Piperazin-1-yl)phenyl-2-(4-trifluoromethoxy )benzyl- 2H-1 .2.4-triazol-3-one (XXII: X=H. R=4-trifluoromethoxybenzyl): The title compound was prepared by alkylation of triazolone XXI (X=H) with 4-(trifluoromethoxy)benzyl bromide in the presence of potassium carbonate.

After usual workup the product was obtained in 90% yield as a colorless solid.

1H NMR (CDCl3) b: 1.49 (s, 9H, 3 x CH3), 3.13-3.18 (m, 4H, 2 x CH2); 3.56- 3.61 (m, 4H, 2 x CH2); 5.00 (s, 2H, CH2); 6.94-6.99 (m, 2H, Ar-H); 7.17-7.22 (m, 2H, Ar-H) 7.38-7.47 (m, 4H, Ar-H); 7.63 (s, 1H, Het-H).

4-[4-(Piperazin-1-yl)phenyl-2-(4-trifluoromethoxy)benzyl- 2H-1,2,4-triazol- 3-one (XXIII: X=H. R=4-trifluoromethoxybenzyl): The title compound was obtained by removal of t-BOC group of the aboove compound with 3M hydrochloric acid.

Colorless solid, quantitative yield.

'H NMR (CDCl3) b: 1.64 (s, 1H, N-H); 3.01-3.20 (m, 8H, 4 x CH2); 5.01 (s, 2H, CH2); 6.95-6.99 (m, 2H, Ar-H); 7.18-7.22 (m, 2H, Ar-H), 7.34-7.47 (m, 4H, Ar- H); 7.61 (s, 1H, Het-H).

(2R,3R)-2-(2,4-Difluorophenyl)-3-[4-{4-[2-(4-trifluoromet hoxybenzyl)-2H- 1.2.4-triazol-3-one-4-yl]phenyl}piperazin-1-yll-1 -(1 H-1,2,4-triazol-1 = yl)butan-2-ol: The title compound was prepared from (2R,3S)-2-(2,4-difluorophenyl)-3- methyl-2-(1 H-1,2,4-triazol-l -yl)methyioxirane and piperazino compound XXIII [R=4-(trifluoromethoxy)benzyl; X=H] by following the similar procedure described for the example 36.

Colorless solid, 91% yield m.p.: 175-177 °C.

'H NMR (CDCI3) b: 0.98 (d, 3H, J = 5.7 Hz, CH3); 2.57-2.65 (m, 2H, CH2); 2.99-3.22 (m, 7H); 4.824.92 (m, 2H, CH2) 5.01 (s, 2H, CH2); 5.15 (s, 1H); 6.68-7.54 (m, 11H, Ar-H); 7.62 (s, 1H, Het-H); 7.79 (s, 1H, Het-H); 7.95 (s, 1H, Het-H).

FAB-MS: 671.3 (MH+), calcd. C32H3'O3F5N8 670.64.

Example 48 2-(4-Methoxybenzyl)-4-[4-(4-tert-BOC-piperazin-1-yl)phenyl-2 H-1,2,4- triazol-3-one (XXII: X=H. R=4-methoxybenzyl): The title compound was prepared by alkylation of triazolone XXI (X=H) with 4-methoxybenzyl bromide in DMF in the presence of potassium carbonate.

Colorless solid, 96% yield.

'H NMR (CDCl3) 5:1.49 (s, 9H, 3 x CH3); 3.12-3.17 (m, 4H, 2 x CH2); 3.55- 3.61 (m, 4H, 2 x CH2); 3.77 (s, 3H, OCH3); 4.94 (s, 2H, CH2); 6.83-6.99 (m, 4H, Ar-H); 7.32-7.41 (m, 4H, Ar-H); 7.59 (s, 1H, Het-H).

2-(4-Methoxybenzyl)-4-(4-(pi perazin-1 -yl)phenyl-2H-1 .2.4-triazol-3-one (XXIII: X=H. R=4-methoxybenzyl): The title compound was obtained by deprotection of t-BOC group of 2-(4- methoxybenzyl)-4-[4-(4-tert-BOC-piperazin-1-yl)phenyl-2H-1,2 ,4-triazol-3-one with 3M hydrochloric acid.

Colorless solid, 94% yield.

'H NMR (CDCI3) b: 1.62 (s, 1H, N-H); 3.01-3.19 (m, 8H, 4 x CH2); 3.79 (s, 3H, OCH3); 4.95 (s, 2H, CH2); 6.86-6.99 (m, 4H, Ar-H); 7.35-7.39 (m, 4H, Ar-H); 7.57 (s, 1H, Het-H).

(2R,3R)-2-(2,4-Difluorophenyl)-3-[4-{4-[2-(4-methoxybenzy l)-2H-1,2,4- triazol-3-one-4-yl]phenyl}piperazin-1-yl]-1-(1H-1,2,4-triazo l-1-yl)butan-2- ol: The title compound was prepared from (2R,3S)-2-(2,4-difluorophenyl)-3- methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane IV and piperazino compound XXIII (R= 4-methoxybenzyl; X=H) by following the similar procedure described for the example 36.

Colorless solid, yield 69%. m.p. 178-179°C 'H NMR (CDCl3) T: 0.96 (d, 3H, J = 6.8 Hz, CH3); 2.56-2.62 (m, 2H CH2); 2.99- 3.21 (m, 7H); 3.79 (s, 3H, OCH3); 4.89-4.99 (m, 2H, 2); 4.95 (s, 2H, CH2); 5.14 (s, 1 H); 6.68-6.97 (m, 6H, Ar-H); 7.35-7.53 (m, 5H, Ar-H), 7.58 (s, 1 H, Het-H); 7.78 (s, 1H, Het-H); 7.95 (s, 1H, Het-H).

FAB-MS: 617.0 (MH+), calcd. C32H34O3F2N8 616.67.

Example 49 2-(2,4-Bis-trifluoromethyl)benzyl-4-[4-(4-tert-BOC-piperazin -1- yl)phenyl]-2H-1,2,4-triazol-3-one (XXII: X=H. R=2.4-bis- trifluoromethylbenzyl): The title compound was prepared by alkylation of triazolone XXI (X=H) with 2,4-bis(trifluoromethyl)benzyl bromide in the presence of potassium carbonate. After usual workup the product was obtained in 76% yield as a colorless solid.

'H NMR (CDCl3) 5:1.49 (s, 9H, 3 x CH3); 3.15-3.20 (m, 4H, 2 x CH2); 3.57- 3.63 (m, 4H, 2 x CH2); 5.31 (s, 2H, CH2); 6.98-7.02 (m, 2H, Ar-H); 7.40-7.53 (m, 3H, Ar-H); 7.72 (s, IH, Het-H); 7.77-7.95 (m, 2H, Ar-H). <BR> <BR> <BR> <BR> <BR> <BR> <P>2-(2.4-Bis-trifluoromethyl)benzyl4-[4-(piperazin-1 -yl)phenyl]-2H-I .2.4- triazol-3-one (XXIII: X=H. R=2.4-bis-trifluoromethylbenzyl): The title compound was obtained by deprotection of t-BOC group of 4[A-(4- tert-BOC-piperazin-1-yl)phenyl]-2-(2,4-bis-trifluoromethyl)b enzyl-2H-1,2,4- triazol-3-one with 3M hydrochloric acid.

Colorless solid, 91% yield.

'H NMR (CDCI3) 5:1.88 (s, 1H, NH); 3.02-3.21 (m, 8H, 4 x CH2); 5.31 (s, 2H, CH2); 6.96-7.01 (m, 2H, Ar-H); 7.39-7.95 (m, 5H, Ar-H); 7.70 (s, 1H, Het-H).

(2R,3R)-3-[4-{4-[2-(2,4-Bis-trifluoromethylbenzyl)-2H-1,2 ,4-triazol-3-one-4- yl]phenyl}piperazin-1-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4 -triazol-1-yl)- butan-2-ol: The title compound was prepared from (2R,3S)-2-(2,4-difluorophenyl)-3- methyl-2-(l H-1,2,4-triazol-l -yl)methyloxirane IV and piperazino compound XXIII [R= 2,4-bis(trifluromethyl)benzyl; X=H] by following the similar procedure described for the example 36.

Colorless solid, yield: 70%. m.p.: 146-148°C.

'H NMR (CDCI3) b: 0.99 (d, 3H, J = 6.8 Hz, CH3); 2.58-2.66 (m, 2H, CH2); 3.01-3.24 (m, 7H); 4.82-5.00 (m, 2H, CH2); 5.14 (s, 1H); 5.31 (s, 2H, CH2), 6.69-6.83 (m, 2H, Ar-H); 6.96-7.00 (m, 2H, Ar-H) 7.40-7.53 (m, 4H, Ar-H); 7.72 (s, 1H, Het-H) 7.77-7.81 (m, 2H, Ar-H & Het-H); 7.95 (s, 2H, Ar-H & Het- H).

FAB-MS: 723 (MH+), called. 722.64.

Example 50 4-[4-(4-tert-BOC-Piperazin-1-yl)phenyl]-2-[4-(2,2,3,3- tetrafluoropropoxy)benzyl]-2H-1,2,4-triazol-3-one [XXII: X=H. R=4- (2.2.3.3-tetrafluoropropoxy)benzyl]: The title compound was prepared by alkylation of triazolone XXI (X=H) with 4-(2,2,3,3-tetrafluoropropoxy)benzyl bromide in the presence of potassium carbonate. After usual workup the product was obtained in 81% yield as a colorless solid.

'H NMR (CDCl3) 5:1.49 (s, 9H, 3XCH3), 3.12-3.17 (m, 4H, 2XCH2), 3.55- 3.60 (m, 4H, 2XCH2), 4.26-4.37 (m, 2H, OCH2), 4.94 (s, 2H, CH2), 5.76-6.36 (m, 1H, CF2H), 6.86-6.98 (m, 4H, Ar-H), 7.37 (m, 4H, Ar-H), 7.60 (s, 1H, Het- H).

4-[4-(Piperazin-1-yl)phenyl]-2-[4-(2,2,3,3-tetrafluoropro poxy)benzyl]-2H- 1.2.4-triazol-3-one [XXIII: X=H. R=4-(2.2.3.3-tetrafluoropropoxy)benzyl]: The title compound was obtained by deprotection of t-BOC group of the above compound with 3M hydrochloric acid. After usual workup the product was obtained in 98% yield as colorless solid.

'H NMR (CDCI3) 5:1.87 (s, 1H, NH), 3.01-3.19 (m, 8H, 4XCH2), 4.274.39 (m, <BR> <BR> <BR> <BR> 2H, OCH2), 4.96 (s, 2H, CH2), 5.77-6.35 (m, 1 H, CF2H), 6.89-6.99 (m, 4H, Ar- H), 7.33-7.42 (m, 4H, Ar-H), 7.58 (s, 1H, Het-H).

(2R.3R)-2-(2.4-Difluorophenyl)-3-[4-{4-[2-((4-(2.2.3.3 - tetrafluoropropoxy)benzyl))-2H-1,2,4-triazol-3-one-4-yl]phen yl}piperazin- 1-yl]-1-(1H-1,2,4-triazol-1-yl)butan-2-ol: The title compound was prepared from (2R,3S)-2-(2,4-difluorophenyl)-3- methyl-2-(l H-1,2,4-triazol-l -yl)methyloxirane IV and piperazino compound XXIII [R=4-(2,2,3, 3-tetrafluoropropoxy)benzyl ; X=H] by following the similar procedure described for the example 36.

Yield 86%, colorless prisms. m.p.: 83-85 OC. rH NMR(CDCI3) b: 0.97 (d, 3H, CH3), 2.57-2.62 (m, 2H, 2), 2.99-3.22 (m, 7H), 4.27-4.38 (m, 2H, CH2), 4.81-4.99 (m, 2H, CH2), 4.96 (s, 2H, CH2), 5.15 (s, 1 H, OH), 5.77-6.35 (ml H, CF2H), 6.68-6.98 (m, 6H, Ar-H), 7.35-7.53 (m, 5H, Ar-H), 7.59 (s, 1H, Het-H), 7.78 (s, 1H, Het-H), 7.95 (s, 1H, Het-H).

FAB-MS: 717.3 (MH+), calcd C34H34F6O3N8 716.69.

Example 51 4-[3-Fluoro-4-(4-tert-BOC-piperazin-1-yl)phenyl]-2-[4- (trifluoromethyl)benzyl]-2H-1,2,4-triazol-3-one (XXII: X=F. R=4- trifluoromethylbenzyl): The title compound was prepared by alkylation of triazolone XXI (X=F) with (trifluoromethyl)benzyl bromide in the presence of potassium carbonate. After usual workup and purification on a column of silica gel, the title compound was obtained in 95% yield as a colorless solid.

'H NMR (CDCI3) 5:1.48 (s, 9H, 3XCH3), 3.04 (m, 4H, 2XCH2), 3.60 (m, 4H, 2XCH2), 5.06 (s, 2H, CH2), 6.99 (m, 1H, Ar-H), 7.2-7.4 (m, 2H, Ar-H), 7.49- 7.62 (m, 4H, Ar-H), 7.64 (s, 1H, Het-H).

4-[3-Fluoro-4-(piperazin-1-yl)phenyl]-2-[4-(trifluorometh yl)benzyl]-2H- 1.2.4-triazol-3-one (XXIII: X=F. R=4-trifluoromethylbenzyl): The title compound was obtained in 96% yield by deprotection of BOC group of the above compound with 3M hydrochloric acid.

'H NMR (CDCI3) b: 3.0 (s, 8H, 4XCH2), 5.05 (s, 2H, CH2), 7.0 (m, 1H, Ar-H), 7.2-7.38 (m, 2H, Ar-H), 7.48-7.62 (m, 4H, Ar-H), 7.65 (s, 1H, Het-H).

(2R,3R)-2-(2,4-Difluorophenyl)-3-[4-{3-fluoro-4-[2-(4- trifluoromethyl)benzyl-2H-1,2,4-triazol-3-one-4-yl]phenyl}pi perazin-1-yl]- 1-(1H-1,2,4-triazol-1-yl)butan-2-ol: The title compound was prepared from (2R,3S)-2-(2,4-difluorophenyl)-3- methyl-2-(l H-1,2,4-triazol-l -yl)methyloxirane IV and piperazino compound XXIII [R = 4-(trifluoromethyl)benzyl; X=F] by following the similar procedure described for the example 36.

Colorless solid, Yield 69%. m.p.: 189-191 °C.

'H NMR (CDCl3) b: 0.99 (d, 3H, CH3), 2.65 (m, 2H, CH2), 2.95-3.2 (m, 7H, 3XCH2 and CH), 4.90 (AB q, 2H, CH2), 5.07 (s, 2H, CH2), 5.15 (s, 1H, OH), 6.7-6.85 (m, 2H, Ar-H), 7.04 (m, 1H, Ar-H), 7.2-7.62 (m, 7H, Ar-H), 7.64 (s, 1H, Het-H), 7.79 (s, 1H, Het-H), 7.95 (s, 1H, Het-H).

FAB-MS: 673.8 (MH+), calcd. C32H30F6NBO2 672.634