AU3402301A - Azole compounds as therapeutic agents for fungal infections - Google Patents

Description

WO 01/66551 PCT/IBO1/00300 AZOLE COMPOUNDS AS THERAPEUTIC AGENTS FOR FUNGAL INFECTIONS Field of the Invention 5 The present invention relates to the derivatives of specially substituted azole compounds which have improved antifungal activity as compared to known compounds such as fluconazole and itraconazole and the processes for the preparation thereof. This invention also relates to pharmaceutical compositions containing the compounds of the present invention and their use in treating 0 and/or preventing fungal infections in mammals; preferably humans. Background of the Invention Life-threatening, systemic fungal infections continue to be a significant problem in health care today. In particular, patients who become "immuno compromised: as a result of diabetes, cancer, prolonged steroid therapy, organ 5 transplantation antirejection therapy, the acquired immune deficiency syndrome (AIDS) or other physiologically or immunologically compromising syndromes, are especially susceptible to opportunistic fungal infections. Most of these infections are caused by opportunistic pathogens, like species of Candida and Aspergillus and Cryptococcus neoformans. During the last 20 years, the incidence of sepsis 20 fungal infection caused by candida species has increased significantly in debilitated and immuno-compromised patients. In addition, the more aggressive and frequently used broad spectrum antibiotic, antineoplastic and immunosuppressive chemotherapies have also augmented fungal infections. CONFIRMATION COPY WO 01/66551 PCT/IBO1/00300 Cryptococcosis is a leading cause of morbidity among AIDS patients. The incidence of life threatening cryptococcal infection among these patients have been estimated to vary from 10 to 30%. During initial therapy, 10 to 20% of these patients die and 30 to 60% patients succumb within a year. Amphoteracin B has 5 changed disseminated cryptococcosis from uniformly fatal infection to curable infection but since Amphoteracin B penetrates the central nervous system poorly, interventricular injection may have to be administered for successful management of severe cases of patients with cryptococcal meningitis. Invasive aspergillosis has also become a leading cause of death, mainly among patients 10 suffering from acute leukaemia or after allogenic bone marrow transfusion and after cytotoxic treatment of these conditions. It also occurs in patients with condition such as AIDS and chronic granulomatous disease. At present, only Amphoteracin B and itraconazole are available for treatment of aspergillosis. Inspite of their activity in-vitro, the effect of these drugs in-vivo against Aspergillus 15 fumigatus remains low and as a consequence mortality from invasive aspergillosis remains high. In addition, the emergence of fluconazole -resistant isolates of pathogenic yeasts, particularly in HIV-positive patients, and the general nature of treating fungal infections caused by Aspergillus species, are of growing concerns among 20 infections disease specialists. The precise incidence of infections caused by Aspergillus species is difficult to determine due to lack of accurate, reliable diagnostic methodologies and poor diagnosis. The majority of Aspergillus infections in AIDS patients occur in late stage disease when immune cell functions are minimal. Impaired neutrophil and macrophage function is related to 2 WO 01/66551 PCT/IBO1/00300 increased infection rates with Aspergillus species. The most common species of Aspergillus causing disease in AIDS patients are A. fumigatus (83%), A. flavus (9%), A. niger (5%) and A. terreus (3%). Within the available drugs to treat fungal infections, the azole class 5 appears to be most promising. This class of compounds inhibits the biosynthesis of ergosterol in fungi, which is the main constituent of fungal cell membrane. Of the various representative antifungals, early azoles used were miconazole, clotrimazole and tioconazole, which were potent against a wide range of fungi pathogenic to human. However, their in-vitro activity was not well exhibited in in 0 vivo models due to poor oral bioavailability and metabolic vulnerability. Ketoconazole was the first drug that could be used against systemic fungal infection and successfully delivered through oral route. However, it was still quite susceptible to metabolic inactivation and also caused impotence and gynacomastia probably due to its activity against human cytochrome P450 15 enzymes. Fluconazole is the current drug of choice for treatment of severe infections caused by Candida species and C. neoformans. However, fluconazole has only weak activity against isolates of Aspergillus species [minimum inhibitory concen tration (MIC) values of 400 tg/ml], since the drug has low potency (IC 50 = 4.8 pM) 20 against lanosterol 14a - demethylase, the target enzyme in the fungus. Itraconazole, another triazole antifungal compound, generally is more active than fluconazole in the treatment of aspergillosis, but its activity in the clinic remains mixed as it showed variable oral availability, low solubility and caused ovarian cancer in animals. This may be due to its high protein binding properties. 3 WO 01/66551 PCT/IBO1/00300 Thus, the antifungals available in the market suffer with drawbacks such as, toxicity, narrow spectrum of activity and 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 5 immunocompromised patients and the recent trends for the steady increase of the populations of such patients, demands for new antifungal agents with broad spectrum of activity and good pharmacokinetic properties has increased. Thus, the continuing demand for safe and effective broad spectrum antifungal agent with favourable pharmacokinetic properties has spurred both the design and 0 development of new systemically active antifungal triazoles. The development of earlier compounds which were referred to as second generation triazoles and which included SCH 39304 (Genaconazole), SCH42427 (Saperaconazole) and BAY R 8783 (Electrazole) had to be discontinued as a result of safety concerns. Another promising second generation triazole, D0870, a derivative of fluconazole, 5 exhibited significant variations in plasma pharmacokinetics besides having weak antiaspergillus activity. Other fluconazole derivatives in different stages of development include voriconazole and ER 30346 (BMS 207147). Voriconazole also shows non-linear pharmacokinetics besides some concern regarding its ocular toxicity, while ER 30346's anti-aspergillus activity, both in vitro and in vivo, 20 is at best, only equal to itraconazole's activity. SCH 56592, is a hydroxylated analogue of itraconazole with potent in-vitro and in-vivo activity, but is undetectable even when the serum drug concentration after several days of treatment are 25 to 100 times above the MIC for the most resistant C. neoformans. Thus, the potent activity of SCH 56592 for C.neoformans is partially 25 negated by its low concentration at the site of infection to the central nervous 4 WO 01/66551 PCT/IBO1/00300 system. The above azole candidates are discussed in the following publications: SCH 56592; Antimicrob. Agents Chemother, 40, 1910 (1996); 3 6 th Interscience conference Antimicrob Agents Chemother, September, 1996, New Orleans, Abst. F87-F102; TAK-187; 3 6 th Interscience conference Antimicrob Agents Chemother, 5 September, 1996, New Orleans, Abst. F74; EP 567892; ER-30346: Druqs of the Future, 21, 20 (1996). Various compounds having thiol, sulphone, sulphonamides, N-di substituted sulphonamides, triazoles and tetrazoles of the second asymmetric centre of fluconazole with various side chains have been covered in U.S. Patent 10 Nos. 5,466,820; 5,371,181 and 5,371,101 assigned to Takeda. But none of them satisfies the above-described medical needs completely, either being weak in spectrum, potency, safety or having undesired pharmacokinetics. Despite the therapeutic success of fluconazole and itraconazole, there remains a significant need for improved, broad spectrum, better tolerated, less 15 toxic, more potent antifungal compounds with minimal potential for development of resistance among target fungi. SUMMARY OF THE INVENTION The present invention relates to new substituted azole compounds which can be utilized to treat and/or prevent the fungal infections in mammals, 20 preferably in humans. 5 WO 01/66551 PCT/IBO1/00300 The first aspect of the present invention provides compounds of Formula IA and its pharmaceutically acceptable salts, enantiomers, diastereomers, N oxides, prodrugs or metabolites, OHR O

R

3 X1 Y 5 N" IX OH N N-Y-N N Z N F N~ R2 Y2 R FORMULA IA wherein X is selected from the group consisting of CH 2 , CO, CS, SO 2 and 10 -N=N-; R is selected from the group consisting of (1) Cr1C4 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) C1C4 alkoxy, (3) halogen (4) formyl, (5) carboxyl (6) Cl-C 4 15 acyloxy, (7) phenyl or substituted phenyl, (8) hydroxy, (9) nitro (10) amino (11) furyl, (12) triazolyl, (13) thienyl, (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl;

R

1 and R 2 are each independently (1) hydrogen, (2) Cr-C 4 alkyl group which is unsubstituted or substituted by 1-3 substituents each 20 independently selected from the group consisting of halogen, hydroxy, C C4 alkoxy and amino; (3) nitro, (4) amino (5) cyano, (6) carboxyl or 6 WO 01/66551 PCT/IBO1/00300 protected carboxyl (7) SO 2 R' wherein R' is alkyl or aryl and (8) C-C4 alkoxy; Y is a phenyl group which is unsubstituted or substituted by substituents each independently selected from the group consisting of (1) halogen (2) 5 nitro, (3) amino, (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1C4 alkoxy and (8) SO 2 R' wherein R' is hydrogen alkyl or aryl;

R

3 is selected from the group consisting of Cr1C4 alkyl group, halogen, hydroxy, C1C4 alkoxy, nitro, amino, cyano, carboxyl and SO 2 R' wherein R' is hydrogen, alkyl or aryl; and 10 X 1 , X 2 , Y 1 , Y 2 and Z are independently selected from the group consisting of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C-C4 alkyl, C1C4 alkoxy, carboxyl or protected carboxyl. When R 1 is other than hydrogen, Formula IA has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and S.S. This invention 15 relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR. According to the second aspect of the present invention, there are provided compounds of Formula IB, and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, 20 R O R3 B (/NN-Y--N N~ N N R 5 R2 R 7 WO 01/66551 PCT/IBO1/00300 5 wherein X, R, R 1 , R 2 , Y and R 3 are the same as defined earlier,

R

4 is selected from the group consisting of hydrogen, Cr1C4 alkyl group which is unsubstituted or substituted, B is selected from oxygen and sulphur atoms; and 10 R 5 is selected from the group, (1) hydrogen, (2) C1C4 alkyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) 15 C1C4 alkyl which is unsubstituted or substituted with 1-3 substituted each independently selected from the group consisting of halogen, hydroxy, Cr C4 alkoxy and amino (b) C1C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) CC4 alkoxy (g) C1C4 alkoxycarboxyl amino (h) phenyl or naphthyl oxycarbonyl amino (i) semicarbazido (j) formamido (k) thioformamide (1) 20 hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 3 and (u) OCF 3 (4) naphthyl or naphthyl (C1C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C 25 C4 alkoxy and amino (b) halogen, (c) (C4 alkyl) halo (d) C1C4 alkoxy (e) 8 WO 01/66551 PCT/IBO1/00300 hydroxy (f) amino (g) carboxyl (h) trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (I) tetrafluoropropyl and (m) tetrafluoropropoxyl. When R 1 is other than hydrogen, Formula IA has two asymmetric centres 5 and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR. According to the third aspect of the present invention there are provided compounds of Formula 11 and its pharmaceutically acceptable salts, enantiomers, 0 diastereomers, N-oxides, prodrugs or metabolites,

R

1 B 0R4I \ NN. O -Y--N N N_<R

R

5 N F 5 R FORMULA II 20 wherein X, R, R 1 , R 4 , R 5 , B and Y have the same meanings as defined earlier. When R 1 is other than hydrogen, Formula 11 has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention 25 relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR. 9 WO 01/66551 PCT/IBO1/00300 The fourth aspect of the present invention provides compounds of Formula Ill and its pharmaceutically acceptable salts, enantiomers, diastereomers, N oxides, prodrugs or metabolites,

OHR

1 B 5 N N X OR5 F HH NF CH 3 R 0 FORMULA III wherein X, R, R 1 , Y, B and R 5 have the same meanings as defined above. When R 1 is other than hydrogen, Formula Ill has two asymmetric centres 5 and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention relates to the mixture of enantiomers as well as individual isomers and the most preferred in this situation is RR. Pharmaceutically acceptable, non-toxic, acid addition salts of the compounds of the present invention of Formulae IA, 1 B, II and Ill may be formed 20 with inorganic or organic acids, by methods well known in the art. It is further object of the invention to provide compositions containing the novel compounds of the present invention in the treatment of fungal infections. The present invention also includes within its scope prodrugs of the compounds of Formulae IA, IB, I and IlIl. In general, such prodrugs will be 25 functional derivatives of these compounds which readily get converted in vivo into 10 WO 01/66551 PCT/IBO1/00300 defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known. The invention also includes pharmaceutically acceptable salts, enantio mers, diastereomers, N-oxides, prodrugs, metabolites of the above formulae in 5 combination with pharmaceutically acceptable carriers and optional excipients. Other advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by the practice of the invention. DETAILED DESCRIPTION OF THE INVENTION 10 In order to achieve the above mentioned aspects and in accordance with the purpose of the invention as embodied and described herein, there are provided processes for the syntheses of compounds of Formulae IA,1 B, II and 111, wherein R, R 1 , R 2 , R 3 , R 4 , R 5 ,X, Y, X 1 , Y 1 , , X 2

,Y

2 , Z and B are the same as defined earlier. The compounds of Formulae IA,1B, I and Ill of the present 15 invention may be prepared by following the reaction sequences as depicted below in schemes IA, lB to IX. 11 WO 01/66551 PCT/IBO1/00300 SCHEME IA 0 5 0Y 1 X, P- H 5 N N F Z N N-Y-N + YN Y2 X2 R2 10 R. FORMULA V FORMULA IV NaH 15 OH R 1 o 3 X1 Y / N N-Y-N N / Z 20N F N V -- j F \N - =(X 2 Y 2 25 R FORMULA IA In Scheme IA there is provided a process for preparing a compound of Formula IA, as shown above, wherein 30 X is selected from the group consisting CH 2 , CO, CS, SO 2 and -N=N-, R is selected from the group consisting of (1) Cl-C 4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (2) C1C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C-C4 35 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino 12 WO 01/66551 PCT/IBO1/00300 (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl,

R

1 and R 2 are each independently selected from the group consisting of (1) hydrogen, (2) C1C4 alkyl group which is unsubstituted or substituted by 1 5 3 substituents each independently selected from the group consisting of halogen, hydroxy, Cr1C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) C1C4 alkoxy, Y is a phenyl group which is unsubstituted or substituted by substituents each independently selected from the group 0 consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) CrC4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl,

R

3 is selected from the group consisting of C1C4 alkyl group, halogen, hydroxy, C1C4 alkoxy, nitro, amino, cyano, carboxyl and SO 2 R' wherein R' 5 is hydrogen, alkyl or aryl; and

X

1 , X 2 , Y 1 , Y 2 and Z are independently selected from the group consisting of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl C-C4 alkyl, C1C4 alkoxy, carboxyl or protected carboxyl. Also, when R 1 is other than hydrogen, Formula I has two asymmetric 20 centres and there are four possible enantiomers i.e. RR, RS, SR and SS, this invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR, which comprises reacting 1-[2 (2,4-disubstituted phenyl)-2,3-epoxy derivative of 1,2,4-triazole of Formula IV, wherein X, R and R 1 , are the same as defined above, with triazol-3-one 13 WO 01/66551 PCT/IBO1/00300 derivatives of Formula V, wherein R 2 ,, R 3 , X 1 , X 2 , Y, Y1, Y 2 and Z have the same meanings, as defined above, in the presence of sodium hydride to afford the desired compound of Formula IA, wherein X, X 1

,X

2 , Y 1 , Y 2 , Z, R, R 1 , R 2 and R 3 have the same meanings as defined above. 5 SCHEME IB OHR (/ N N-Y-N NH N F N 10 R2 R FORMULA ID B=C=N-R S 15 15 OHRI O R 3 B OH / X /H / N N-Y-N N N 'F N R -- /R 5 R2 20 FORMULA IC I R 4 Z 25 R O R 3 B / N N-Y-N N JF Nz(R R5 30 R FORMULA IB 14 WO 01/66551 PCT/IBO1/00300 In Scheme IB there is provided a process for preparing a compound of Formula IB, wherein X, R, R 1 , R 2

,R

3 and Y are the same as defined above, R 4 is selected from the group hydrogen, C1 - C4 alkyl group which is unsubstituted or substituted, B is selected from oxygen and sulphur atoms, R 5 is selected from the 5 group (1) hydrogen, (2) Ci- C4 alkyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, Cr1C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1C4 alkyl which is unsubstituted or substituted with 1-3 0 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (b) C1C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1C4 acyloxy (g) C1C4 alkoxycarbonyl amino (h) phenyl or naphthyl oxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (I) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl(r) oxazolyl (s) imidazolyl (t) CF 2 15 and (u) OCF 3 (4) naphthyl or naphthyl (C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1 - C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (b) halogen (c) (C-C4 alkyl) halo, (d) C1C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoromethoxyl 20 (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (I) tetrafluoropropyl and (m) tetrafluoropropoxyl. Also, when R 1 is other than hydrogen, Formula I has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SIR and SS, this invention relates to the mixture of enantiomers as well as individual isomers and 15 WO 01/66551 PCT/IBO1/00300 the most preferred isomer in this situation is RR, which comprises reacting a compound of Formula ID wherein X, R, R 1

,R

2 , R 3 and Y have the same meanings as defined earlier, with a compound of Formula R 5 - N = C = B wherein R 5 and B are the same as defined earlier to give a compound of Formula IC, which on 5 reaction with R 4 Z wherein R 4 is the same as defined above and Z is any halogen atom, gives a compound of Formula IB wherein X, R, R 1 , R 2 , R 3 , R 4 , R 5 , Y and B have the same meanings as defined earlier. SCHEME II 10

R

1 0 R 3

X

1 Y, X N-Y-N N z F N R 15 FORMULA VI HN--N N 1 O R 3

X

1 Y 20 OH A NN N-Y-N N Z N F N R R 25 FORMULA IA In Scheme 11, there is provided a process for preparing a compound of Formula IA, wherein X, R, R1, R 2 , R 3 , Y, X1, X 2 , Y1, Y 2 and Z are the same as defined above, also when R 1 is other than hydrogen, Formula I has two 16 WO 01/66551 PCT/IBO1/00300 asymmertric centres and there are four possible enantiomers i.e. RR, RS, SR and SS, this invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR, which comprises reacting epoxide derivative of Formula VI, wherein X, R, R 1 , R 2 , R3, X 1 , X 2 , Y, Y 1 , 5 Y 2 and Z are the same as defined above with 1,2,4-triazole to afford a compound of Formula IA. SCHEME III OH (N 0-Y--N NH 0 FORMULA VII R 5 R5-N=C=B1 R1 B OH R 1 <R N "X _R5 /N -O-Y--N N N F H ?01 R FORMULA VIII 0R 4 Z

OR

4 II O-Y-1 (/N <R4 N JF I 30 R FORMULA II 17 WO 01/66551 PCT/IBO1/00300 There is provided a process for preparing a compound of Formula II, wherein X, R, R 1 , R 4 , R 5 , Y and B have the same meanings as defined earlier, also when R 1 is other than hydrogen, Formula II has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS, this invention 5 relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR, which comprises reacting a compound of Formula VII, wherein R, R 1 , X and Y are same as defined earlier with a compound R 5 -N=C=B, wherein R 5 and B are the same defined earlier to give a compound of Formula Vill, wherein R, R 1 , R 5 , X, Y and B have the same 10 meanings as defined earlier. The compound of Formula VIII, on reaction with

R

4 Z, wherein R 4 is C1-C4 alkyl and Z is any halogen atom, gives a compound of Formula 11, wherein R, R 1 , R 4 , R 5 , X, Y and B are the same as defined earlier. SCHEME IV 15 -X F m R 20 FORMULA IX B=C=N-R 25 NY X- -R /F C H H R FORMULA III 18 WO 01/66551 PCT/IBO1/00300 In scheme IV there is provided a process for the preparation of a compound of Formula Ill, wherein R, R 1 , R 5 , X, Y and B are the same as defined above, also when R 1 is other than hydrogen, Formula IlIl has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS , this 5 invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR, which comprises reacting a compound of Formula IX with a compound of Formula B=C=N-R 5 wherein B and

R

5 are the same as defined earlier, to give the desired compound of Formula Ill. 19 WO 01/66551 PCT/IBO1/00300 SCHEME V F c N N R X N + Cl CI Al 3 F 1,2,4-Triazole FNN I-~. .~ TMSL . 0 F 5 F F R FORMULA X FORMULA XI FORMULA XI FORMULA M FORMULA IV Y, X Y (R=F, X=CH,, RIH) Z N NH C Z N N NO 2 Reduction 2 X2K 2

C

3

IN

2' X2 10 FORMULA XIV FORMULA XV Y, X, Yl X, 0 Z NN NH2 cz--OC6HS N N NH 2 Y2 X2 Y2 X2 FORMULA XVI FORMULA XVII 15 Y, ,0 R H y, X, O3 0 N Z NN NH NHNH NH2 Z N N N H -- a Y2 X, Y2 X 2 R2 FORMULA XVIII FORMULA V (R3=H, Y=C 6

H

4 -) O N Y X 1 0 20 R1 N R 3 H F:-N +Z N N-Y N N2 X R2 R FORMULA V (R 3 =H, Y=C 6

H

4 ) FORMULA IV (R=F, RI 1 -H, X=CH,) Nal 25 9R NN NZ H N F N R 2 N 30 R FORMULA IA (X=CH 2 , R=F, R 1 =H, Y=C 6

H

4 -, R 3 =H) 20 WO 01/66551 PCT/IBO1/00300 In Scheme V 1,3-difluorobenzene of Formula X, on treatment with chloroacetyl chloride of Formula XI, in the presence of a Lewis acid catalyst such as aluminium trichloride gives a-choro-2, 4-difluoroacetophenone of Formula XII. This compound of Formula XII is further reacted with 1,2,4-triazole to obtain 2 5 (1 H-1,2,4-triazol-1 -yl)-2'-4'-difluoroacetophenone of Formula XIII. This compound of Formula XIII is further reacted with trimethyl sulphoxonium iodide (TMSI) to afford 1-[2-(2,4-difluorophenyl)-2, 3-epoxypropylj-lH-1,2,4-triazole of Formula IV (R=F, X=CH 2 , R 1 =H). The procedure as described in US Patent 4,404,216 is followed to prepare compound of Formula IV. 10 The triazol-3-one derivatives of Formula V (R3 = H, Y=C 6

H

4 -), wherein R 2 ,

X

1 , X 2 , Y 1 , Y 2 and Z are the same as defined earlier, are prepared by reacting substituted phenyl piperazine of Formula XIV, wherein X 1 , X 2 , Y 1 , Y 2 and Z are the same as defined earlier, is reacted with 4-chloronitrobenzene to give the corresponding nitroaryl compound of Formula XV, which on catalytic reduction 15 affords the anilino derivative of Formula XVI. The compound of Formula XVI, is acylated with phenyl chloroformate to afford phenyl carbamate derivatives of Formula XVII. Reaction of these carbamate derivative of Formula XVII, with hydrazine hydrate yields semicarbazide derivative of Formula XVIII, which on cyclization with formamidine derivatives gives the triazol-3-one derivatives of 20 Formula V(R 3 = H, Y=C 6

H

4 -). The reaction of compound of Formula V, with the compound of Formula IV (R=F, R 1 =H, X=CH2) is carried out in the presence of sodium hydride to afford the desired compound of Formula IA (X=CH 2 , R=F,

R

1 =H, Y=C 6

H

4 -, R 3 =H), wherein R 2 , X 1 , X 2 , Y 1 , Y 2 and Z are the same as defined earlier. 21 WO 01/66551 PCT/IBO1/00300 SCHEME VI F GCH, Y 1

X

1

R

3 0 A+ H3Cd COCl AIC1 3 Z N N-Y-N NH + 3 O 1 - - F Y 2 X 2 FF 5 FORMULA V F (R 3 =H, Y= C 6

H

4 -) FORMULA X FORMULA XIX NaH F FORMULA XX

CH

3 O X Y, O A* TMSJ 0 F N N Z RX Y2 F FORMULA XXI R 0 R 3

X

1 05 N-Y-N N/1,2,4-Triazole 15 FN - Z R FORMULA VI (X=CH 2 , R=F, RI=CH 3 , Y=C 6 H4-, R 3 =H) 0N-X

R

1 O R 3 Xi Y N-X N, N-Y-N Z HO N-Y-N N

R

2 R FORMULA IA 25 (X=Cli , R=F, R I = CH 3 , Y= C 6

H

4 -, R 3 =H) The compounds of Formula IA (X=CH 2 , R=F, R 1 = CH 3 , Y=CH 4 -, R 3 =H) wherein R 2 , X 1 , Y 1

,X

2 , Y 2 and Z have the same meanings as defined earlier, are 30 synthesized following the reaction sequence embodied in Scheme VI. Thus, 1, 3 difluorobenzene of Formula X is reacted with racemic (±) 2-chloropropionyl 22 WO 01/66551 PCT/IBO1/00300 chloride of Formula XIX to give a compound (±) 2-chloro-2-methyl-2', 4'-difluoro acetophenone of Formula XX. The intermediate of Formula V which in turn is prepared by following the reaction sequence as described in Scheme V wherein

R

2 , X 1 , X 2 , Y 1 , Y 2 and Z have the same usual meanings, is condensed with (±)2 5 chloro-2-methyl-2', 4'-difluoroacetophenone of Formula XX in the presence of sodium hydride to afford compound of Formula XXI, wherein R 2 , X 1 , X 2 , Y 1

,Y

2 and Z have the same meanings as defined earlier. The compound of Formula XXI is epoxidized with trimethylsulphoxonium iodide (TMSI) in dimethylsulfoxide (DMSO) to give an epoxide derivative of Formula VI (X=CH 2 , R=F, R 1

=CH

3 , 10 Y=C 6

H

4 -, R 3 =H), which is then condensed with 1,2,4-triazole to give a compound of Formula IA (X=CH 2 , R=F, R 1 = CH 3 , Y=C 6

H

4 -, R 3 =H), wherein R 2 , X 1 , Y 1 , X 2 , Y 2 and Z are the same as defined earlier. 23 WO 01/66551 PCT/IBO1/00300 SCHEME VII OH R, O-Y-N N-H

CH

3 CN 5 N F B=C=N-R 5 R FORMULA VII (X=CH 2 , R=F, Ri=H, Y=C 6

H

4 ) OH R 1 B I-I -\ 1 Nail 10 N O-Y-N N-C-N-R 5 NaH F H R 4 Z R FORMULA VIII (X=CH 2 , R=F, RI=H, Y=C 6

H

4 ) 15

OR

4 R1 B N 0-Y-N N-C-N-R F I 0 R4 20 R FORMULA II (X=CH 2 , R=F, Ri=H, Y=C 6

H

4 ) The compounds of Formula I (X=CH 2 , R=F, R 1 =H, Y=C 6

H

4 -) wherein R 4 ,

R

5 , and B have the same meanings as defined earlier, are synthesized by 25 following the reaction sequence as depicted above in Scheme VII. Thus, 2-(2,4 difluorophenyl)-3-(1H-1, 2,4-triazolyl)-1-[4-(piprazinyl) phenoxy]-propan-2-ol of Formula VII (X=CH 2 , R=F, R 1 =H, Y=C 6

H

4 -) (prepared by the process as disclosed in US Patent No. 5,023,258, assigned to Pfizer) on treatment with the compound of Formula B=C=N-R 5 , wherein B and R 5 are. the same as defined earlier gives a 30 compound of Formula VIII (X=CH 2 , R=F, R 1 =H, Y=CH 4 -) wherein R 5 and B are 24 WO 01/66551 PCT/IBO1/00300 the same as defined earlier. This compound of Formula VillI (X=CH 2 , R=F, R 1 =H,

Y=C

6

H

4 -) is further reacted with R 4 Z in the presence of sodium hydride gives the required compound of Formula II (X=CH 2 , R=F, R 1 =H, Y=CH 4 -), wherein R 4 , R 5 and B are the same as defined earlier. 25 WO 01/66551 PCT/IBO1/00300 SCHEME VIII

CH

3 0 C KCO,/DMF + HO N CH 3 + F \ _60 C 0 60' 5 F FORMULA XXIII FORMULA XXII

CH

3 0 0 CH3 O0 0 ~ ~~ N CH3DS ) O (CH 3

)

3 SOI \___ 0 O Q N CR 3 F 0 F DMSO 0 F F FORMULA XXIV FORMULA XXV

OCH

3 0 N aHD N OH N N CH 3 NaOH/Dioxane-H 2 0 N/NaH/DMF N-- -,'kH 15 \:::=- F 5- N F FORMULA XXVI N OH R \T'rx' Rs - N=C=-B O-Y--N N-H R__-_N=C=B 20 N F R FORMULA VII (X=CH 2 , R=F, Ri=CH 3 , Y=C 6

H

4 -) 25 N1 N lX O-- N N-R F R FORMULA II (X=CH 2 , R=F, Ri=CH 3 , R 4 =H, Y=C 6

H

4 -) 30 In Scheme Vill, 2-chloro-methyl-2',4'-difluoroacetophenone of Formula XXII, on treatment with 1-acetyl-4-hydroxyphenylpiperazine of Formula XXIII, 26 WO 01/66551 PCT/IBO1/00300 gives 2-[4-(4-acetylpiperazine)phenoxy]-2-methyl-2',4'-difluoroacetophenone of Formula XXIV in the presence of potassium carbonate in dimethylformamide, which on treatment with trimethyl sulphoxonium iodide (TMSI) in DMSO gives the corresponding epoxide of Formula XXV. This compound of Formula XXV is 5 reacted with 1,2,4-triazole to yield a compound of Formula XXVI, which in turn on hydrolysis with sodium hydroxide in dioxane gives a compound of Formula VII

(X=CH

2 , R=F, R 1

=CH

3 , Y=C 6

H

4 -). The compound of Formula VII on reaction with

R

5 -N=C=B gives a compound of Formula II (X=CH 2 , R=F, R 1

=CH

3 , R 4 =H) wherein R 5 and B have the same meanings as defined earlier. 27 WO 01/66551 PCT/IBO1/00300 SCHEME IX N O OH FR NO2N FN ( NO 2 HCOONH4 0 801C RNN 9 ~N /F

CH

3 H OO H 5 CH3 8 R F FORMULA IV FORMULA XXVII FORMULA XXVM (R=F, X=CH 2 , RI=H) OH R. 10 N

N-Y-NH

2 F CH 3 B=C=N-Rs 0 R FORMULA IX (X=CH,, R=F, R,=H, Y=C 6

H

4 -) 15 N OH R 1 B NX N-Y-N-C-N-R 0 \ H I F CH 3 H R 20 FORMULA M (X=CH 2 , R=F, R 1 =H, Y=C 6

H

4 -) In Scheme IX 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1 H-1,2,4-triazole of Formula IV (R=F, X=CH 2 , R 1 =H) on treatment with N-methyl-4-nitroaniline of Formula XXVII gives 3-[N-Methyl-N-(4-nitrophenyl)]-2-(2,4-difluorophenyl)-1-(1H 25 1,2,4-triazolyl)-propan-3-amino-2-o of Formula XXVIII which on reduction with palladium on charcoal gives 3-[N-Methyl-N-(4-aminophenyl)]-2-(2,4-difluoro phenyl)-1-(1H-1,2,4-triazolyl)-propane-3-amino-2-o of Formula IX, (X=CH 2 , R=F,

R

1 =H, Y=C 6

H

4 -) which on reaction with B=C=N-R 5 gives a compound of Formula Ill (X=CH 2 , R=F, R 1 =H, Y=C 6

H

4 -) wherein B and R 5 are the same as defined 30 earlier. 28 WO 01/66551 PCT/IBO1/00300 In the above schemes where specific acids, bases, solvents, catalysts, oxidising agents, reducing agents etc. are mentioned, it is to be understood that the other acids, bases, solvents, catalysts, oxidising agents, reducing agents etc. may be used. Similarly, the reaction temperature and duration of the reaction 5 may be adjusted according to the need. An illustrative list of particular compounds according to the invention and capable of being produced by Schemes IA, IB to IX include: Compound No. Chemical Name 10 1. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(4-chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone 2. 2-{[ R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 15 yl) propyl}-4-{4-[4-(4-chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone 3. 2-{[ R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 -yl) propyl}-4-{4-[4-(2,4-dinitrophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone 20 4. 2-{[i R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(2,4-dinitrophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone 5. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-[4-(1-phenylpiperazinyl)phenyl]-3-(2H,4H)-1,2,4-triazolone 25 6. 2-{[i R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(1-phenylpiperazinyl) phenyl}-3-(2H,4H)-1,2,4-triazolone 7. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(3,4-dichlorophenyl)-1-piperzinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone 30 8. 2-{[i R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(3,4-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone 29 WO 01/66551 PCT/TBO1/00300 9. 2-{[l R2RI1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-i ,2,4-triazol-i yI) propyl}-4-{4-[4-(3-trifluoromethylphenyl)-1 -piperazinyl]phenyl}-3-(2H ,4H)-1 ,2,4 triazolone 10. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hyd roxy-1 -methyl-3-(l1H-i ,2,4-triazol-1 5 yI) propyl}-4-{4-[4-(3-trifluoromethylphenyl)-1 -piperazinyl]phenyl}-3-(2H ,4H)-1 ,2,4 triazolone 11. 2-{[l R2R/i S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-I ,2,4-triazol-1 yl) propyl)-4-{4-[4-(4-fluorophenyl)-l1-piperazinyljphenyl}-3-(2H,4H)-1 ,2,4 triazolone 10 12. 2-{[l R2SI1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-i ,2,4-triazol-1 yI) propyl}-4-{4-[4-(4-fluorophenyl)-1 -piperazinyllphenyl}-3-(2H ,4H)-1 ,2,4 triazolone 13. 2-{[l R2R/i S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-i ,2,4-triazol-i yI) propyl}-4-{4-[4-(4-methoxypheny)-1 -piperazinyl]phenyl}-3-(2H,4H)-1 ,2,4 15 triazolone 14. 2-{[l R2SI S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-i ,2,4-triazol-i yI) propyl}-4-{4-[4-(4-methoxyphenyl)- I-piperazinyl]phenyl}-3-(2H ,4H)- 1,2,4 triazolone 15. 2-{[l R2R/i S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-i -methyl-3-(i H-i ,2,4-triazol-i ?oyI) propyl}-4-{4-[4-(3-chloro-4-fluorophenyl)-i -piperazinyl]phenyl}-3-(2H ,4H)-i ,2,4 triazolone 16. 2-{[i R2S/i S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-i -methyl-3-(i H-I ,2,4-triazol-i yI) propyl}-4-{4-[4-(3-chloro-4-fluorophenyl)-i -piperazinyl]phenyl}-3-(2H ,4H)-i ,2,4 triazolone ?517. 2-{[i R2R/i S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(i H-i ,2,4-triazol-i yI) propyi}-4-{4-[4-(3-chloro-4-methylphenyl)-l1-piperazinyljphenyl)-3-(2H,4H) 1 ,2,4-triazolone 18. 2-{[l R2S/i S2RJ-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(I H-I ,2,4-triazol-i yI) propyl}-4-{4-[4-(3-chloro-4-methylphenyl )- 1-pi perazinyl] phenyl}-3-(2H ,4H) 30I ,2,4-triazolone 19. 2-{[l R2RII S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-i -methyl-3-(i H-I ,2,4-triazol-i yI) propyl}-4-{4-f4-(2,4-d imethylphenyl)-i -piperazinyljphenyl}-3-(2H,4H)-l1,2,4 triazolone 20. 2-{[1 R2S/i S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(i H-I ,2,4-triazol-1 35 ~yI) propyl)-4-{4-[4-(2,4-d imethylp hen yl)- 1 -p iperazi nyl]phenyt)-3-(2H,4 H)- 1,2,4 triazolone 30 WO 01/66551 PCT/IBO1/00300 21. 2-{[1 R2R/l S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H) 1,2,4-triazolone 22. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 5 y) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H) 1,2,4-triazolone 23. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(3,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl 1,2,4-triazolone 10 24. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(3,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl 1,2,4-triazolone 25. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 y) propyl}-4-{4-[4-(2-fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-5-methyl 15 1,2,4-triazolone 26. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 y) propyl}-4-{4-[4-(2-fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-5-methyl 1,2,4-triazolone 27. 2-{[l R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 20 yl) propyl}-4-{4-[4-(2-methoxy-5-fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-5 methyl-1,2,4-triazolone 28. 2-{[IR2S/IS2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(2-methoxy-5-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5 methyl-1,2,4-triazolone 25 29. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(3,5-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl 1,2,4-triazolone 30. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(3,5-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl 30 1,2,4-triazolone 31. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(2-ethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4 triazolone 32. 2-{[l R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 35 yl) propyl}-4-{4-[4-(2-ethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4 triazolone 31 WO 01/66551 PCT/IBO1/00300 33. 2-{[1 R2R/l S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(2,4-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl 1,2,4-triazolone 34. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 5 yl) propyl}-4-{4-[4-(2,4-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl 1,2,4-triazolone 35. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2 methoxyphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone 36. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 10 fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone 37. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(3,4 dichlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 38. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2,4 diaminophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 5 39. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 40. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2,4 dinitrophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 41. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-(4 20 methoxyphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 42. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2 methoxyphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 43. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 25 44. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 hydroxyphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 45. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-[4-[1 phenylpiperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 46. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-I -yl)propyl]-4-{4-[4-(4 30 chlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone 47. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 chlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 48. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(5 chloro-2-methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 35 49. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(3 chloro-4-methylphenyl)-1 -piperazinyljphenyl}-3-(2H,4H)-1,2,4-triazolone 32 WO 01/66551 PCT/IBO1/00300 50. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2,4 dichlorophenyl)-1 -piperazinyJphenyl}-3-(2H,4H)-1,2,4-triazolone 51. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(3 trifluoromethylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 5 52. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2,4 diffuorophenyl)-1 -piperazinyl]pheny}-3-(2H,4H)-1,2,4-triazolone 53. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(3 chloro-4-fluorophenyl)-1 -piperaziny]phenyl}-3-(2H,4H)-1,2,4-triazolone 54. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2,4 10 dimethylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 55. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(3,4 difluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 56. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(3,4 dimethylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 15 57. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4 {4-[4-(3-chlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 58. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4 {4-[4-(2-chloro-4-fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 59. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4- (2 20 methoxy-5-fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 60. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4 {4-[4-(2-ethylphenyl)-1 -piperazinyljphenyl}-3-(2H,4H)-1,2,4-triazolone 61. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4 {4-[4-(3,5-dichlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 25 62. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4 {4-[4-(2-fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 63. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4 {4-[4-(2,3;4-trifluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 64. 3-{4-[4-(p-Tolylthioureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1 -(1 H-1,2,4 30 triazol-1 -yi)-propan-2-ol. 65. 3-{4-[4-(Isopropylaminothiocarbonylamino)piperazinyl]phenoxy}-2-(2,4 difluorophenyl)-1 -(1 H-1,2,4-triazol-1 -yi)-propan-2-ol. 66. 3-{4-[4-(4-Chlorophenylthioureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1 (1 H-1,2,4-triazol-1 -yi)-propan-2-ol. 35 67. 3-{4-[4-(4-Chlorophenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1 -(1 H 1,2,4-triazol-1 -yl)-propan-2-ol. 33 WO 01/66551 PCT/IBO1/00300 68. 3-{4-[4-(1 -Napthylthioureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1 -(I H 1,2,4-triazol-1 -yl)-propan-2-ol. 69. 3-{4-[4-(1 -Napthylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1 -(1 H-1,2,4 triazol-1 -yl)-propan-2-ol. 5 70. 3-{4-[4-(4-Trifluoromethylpheny thioureido)piperazinyl]phenoxy}-2-(2,4 difluorophenyl)-1 -(1 H-1,2,4-triazol-1 -yl)-propan-2-ol. 71. 3-{4-[4-(4-Methoxyphenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1 (1 H-1,2,4-triazol-1 -yl)-propan-2-ol. 72. 3-{4-[4-(2,4-Dichlorophenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1 0 (1 H-1,2,4-triazol-1 -yl)-propan-2-ol. 73. 3-{4-[4-(4-Chlorophenyl-N-ethylureido)-piperaziny ]-phenoxy)-2-(2,4 difluorophenyl)-1 -(1 H-1,2,4-triazolyl)-propan-3-amino-2-o 74. 3-{4-[4-(4-Chlorophenyl-N-ethylureido)-piperazinyl ]-phenoxy)-2-(2,4 difluorophenyl)-1 -(1 H-1,2,4-triazolyl)-2-ethoxy-3-propane. 5 75. 3-{4-[4-N-(4-Chlorophenyl)-N-(methylureido)-piperazinyl]-phenoxy}-2-(2,4 difluorophenyl)-1-(1H-1,2,4-triazolyl)-2-methoxypropane. 76. 3-{4-[4-(4-Aminophenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1 -(1 H 1,2,4-triazol-1 -yl)-propan-2-ol. 77. [1 R2R/1 S2S] 1 -{4-[4-(4-Chlorophenylureido)-piperaziny ]-phenoxy}-2-(2,4 O difluorophenyl)-1 -methyl -3-(1 H-1,2,4-triazolyl)-propan-2-ol 78. [1 R2S/1 S2R] 1 -{4-[4-(4-Chlorophenylureido)-piperazinyl ]-phenoxy}2-(2,4 difluorophenyl)-1 -methyl -3-(1 H-1,2,4-triazolyl)-propan-2-ol 79. 1 -{4-[4-(4-Trifluoromethylphenylureido)piperazinyl]phenoxy}-2-(2,4 difluorophenyl)-1 -methyl-3-(1 H-1,2,4-triazol-1 -yl)-propan-2-ol. 25 80. 3-{4-[4-(Phenylureido)-piperaziny ]-phenoxy}-2-(2,4-difluorophenyl)-1 -(1 H-1,2,4 triazol-1 -yl)-propan-2-ol. 81. 3-{N-[4-(Phenylthioureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1 -(1 H-1,2,4 triazolyl)-propan-3-amino-2-ol 82. 3-{N-[4-(Isopropylthioureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1 -(1 H 30 1,2,4-triazolyl)-propan-3-amino-2-oI 83. 3-{N-[4-(p-Tolylthioureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1 -(1 H-1,2,4 triazolyl)-propan-3-amino-2-ol 84. 3-{N-[4-(p-Fluorophenylureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1 -(1 H 1,2,4-triazolyl)-propan-3-amino-2-ol 35 85. 3-{N-[4-(p-Nitrophenyltureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1 -(1 H 1,2,4-triazolyl)-propan-3-amino-2-o 34 WO 01/66551 PCT/IBO1/00300 86. 3-{N-[4-(p-Chlorophenylureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1 -(1 H 1,2,4-triazolyl)-propan-3-amino-2-ol 87. 3-{N-[4-(Carboxymethyl)-phenyltureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl) 1 -(1 H-1,2,4-triazolyl)-propan-3-amino-2-o 5 88. 3-{N-[4-(2-Methoxy-2-oxoethyl)-phenyltureido)-phenyl]- N-methyl}-2-(2,4 difluorophenyl)-1 -(1 H-1,2,4-triazolyl)-propan-3-amino-2-o 89. 3-{N-[4-(p-Chlorophenylthiouredo)-phenyltureido)-phenyl]- N-methyl}-2-(2,4 difluorophenyl)-1 -(1 H-1,2,4-triazolyl)-propan-3-amino-2-o 90. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4 0 (isopropylthiouredio)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 91. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -y!)propyl]-4-{4-[4-(4 chlorophenyluredio)-1 -piperazinyl]phenyl}-3-(2H,4H)- 1,2,4-triazolone 92. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 chlorophenylthiouredio)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 5 93. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4-(2 methoxy-2-oxoethyl)phenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 94. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 (carboxyethyl)-phenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 95. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4-(2 20 hydroxyethyl)phenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone Preferred group of compounds belonging to the compounds of Formulae IA, IB, 11 and Ill of the present invention are exemplified in Table I to Table IV though the present invention is not limited to the compounds given there. 35 WO 01/66551 PCT/IBO1/00300 TABLE I FORMULA IA (X=CH 2 , R=F, Y=C 6

H

4 -, R 3 =H) A. LIST OF a-METHYL ANALOGUES Compound R 1

R

2 X1 Y 1 Z Y 2

X

2 Comments m.p No. * (oC) 1 CH 3 H H H CI H H (RR, SS) 192-196 2 CH 3 H H H CI H H (RS, SR) 220-222 3 CH 3 H NO 2 H NO 2 H H (RR, SS) 155-160 4 CH 3 H NO 2 H NO 2 H H (RS, SR) 153-155 5 CH 3 H H H H H H (RR, SS) 212-214 6 CH 3 H H H H H H (RS, SR) 205-207 7 CH 3 H H C C H H (RR, SS) 102-105 8 CH 3 H H C C H H (RS, SR) 233-240 9 CH 3 H H CF 3 H H H (RR, SS) 182-186 10 CH 3 H H CF 3 H H H (RS, SR) 170-172 11 CH 3 H H H F H H (RR, SS) 174-177 12 CH 3 H H H F H H (RS, SR) 218-219 13 CH 3 H H H OCH 3 H H (RR, SS) 180-185 14 CH 3 H H H OCH 3 H H (RS, SR 106-111 15 CH 3 H H CI F H H (RR, SS 148-150 16 CH 3 H H CI F H H (RS, SR 194-197 17 CH 3 H H Cl CH 3 H H (RR, SS) 156-158 18 CH 3 H H Cl CH 3 H H (RS, SR 148-150 19 CH 3 H CH 3 H CH 3 H H (RR, SS 201-202 20 CH 3 H CH 3 H CH 3 H H (RS, SR) 92-94 21 CH 3 H CH 3 H H CI H (RR, SS) Foam 22 CH 3 H CH 3 H H CI H (RS, SR) Foam 23 CH 3 H H CH 3

CH

3 H H (RR, SS Gummy 24 CH 3 H H CH 3

CH

3 H H (RS, SR) Gummy 25 CH 3 H F H H H H (RR, SS) Gummy 26 CH 3 H F H H H H (RS, SR) 179-181 27 CH 3 H OCH 3 H H F H (RR, SS) 83-85 28 CH 3 H OCH 3 H H F H (RS, SR) 90-93 29 CH 3 H H CI H Cl H (RR, SS) 188-191 30 CH 3 H H CI H Cl H (RS, SR) 207-210 31 CH 3 H C 2

H

5 H H H H (RR, SS) 142-145 32 CH 3 H C 2

H

5 H H H H (RS, SR) 177-178 33 CH 3 H CI H CI H H (RR, SS) Foam 34 CH 3 H CI H CI H H (RS, SR) Foam 5 36 WO 01/66551 PCT/IBO1/00300 B. LIST OF non- a-METHYL ANALOGUES Compound R 1

R

2 X1 Y 1 Z Y 2

X

1 m.p No. (OC) 35 H CH 3

OCH

3 H H H H 144-149 36 H CH 3 H H F H H 188-189 37 H H H Cl Cl H H 194-196 38 H H NH 2 H NH 2 H H 215-222 39 H H H H CH 3 H H 146-148 40 H H NO 2 H NO 2 H H 120-123 41 H H H H OCH 3 H H 183-186 42 H H OCH 3 H H H H 95-97 43 H H H H F H H 173-177 44 H H H H OH H H 246-248 45 H H H H H H H 170-172 46 H CH 3 H H CI H H 88-94 47 H H H H Cl H H 207-208 48 H H CH 3 H H Cl H 82-87 49 H H H H CH 3 CI H 189-201 50 H H Cl H Cl H H 97-99 51 H H H CF 3 H H H 166-168 52 H H F H F H H 157-158 53 H H H CI F H H 182-85 54 H H CH 3 H CH 3 H H 76-77 55 H H H F F H H 117-118 56 H H H CH 3

CH

3 H H 136-137 57 H H H C H H H 177-78 58 H H C1 H F H H Oil 59 H H OCH 3 H H F H Gummy 60 H H C 2

H

5 H H H H 148-150 61 H H H Cl H CI H 222-225 62 H H F H H H H 74-76 63 H H F F F H H 186-187 5 37 WO 01/66551 PCT/IBO1/00300 TABLE - II (FORMULA II) (X =CH 2 , R= F, Y= C 6

H

4 -) Compound No. R 4 B RI R 4

R

5 m.p.

0 C MIC (og/ml) (A.funigatus s 1008) 64 H S H H 192-194 3.12 5 H HCH 65 H S H H 75-78 >12.5

-CH(CH)

2 66 H S H H ca 138 >12.5 67 H 0 H H 136-137 6.25 68 H S H H 109-111 >12.5 69 H 0 H H 138-139 >12.5 70 H S H H C 150-151 >12.5 71 H O H H Gummy >12.5 72 H 0 H H Gummy >12.5 73 H 0 H C 2

H

5 a Gummy >12.5 74 C 2

H

5 0 H C 2

H

5 Gummy >12.5 75 CH 3 0 H CH 3 a Gummy >12.5 76 H 0 H H N, Gummy >12.5 77 H 0 CH 3 H , 106-108 2 78 H 0 CH 3 H a 105-107 0.5 79 H 0 CH 3 H Gummy 8 80 H S H H 154-156 >12.5 5 38 WO 01/66551 PCT/IBO1/00300 TABLE - III (FORMULA 111) (X =CH 2 , R= F, Y= C 6

H

4 -) Compound B RI R 5 m.p.oC MIC (ug/ml) No. (A.funigatus s 1008) 81 S H 147-150 >12.5 82 S H -CH(CH,) 2 76 >12.5 83 S H H 174 >12.5 84 0 H F 160-164 >12.5 85 0 H N 87-88 >12.5 86 0 H - 174-176 >12.5 87 0 H C Gummy >12.5 88 0 H Gummy >12.5 89 S H 0 C, 162-164 >12.5 5 TABLE - IV (FORMULA IB) (X = CH 2 , R= F, Y= C 6

H

4 -, R 1 , R 2 , R 3 and R 4 =H) Compoun B RI R 5 m.p.

0 C MIC (og/ml) d No. (A.fmigatus s 1008) 90 S H -CH(CH,) 2 Gummy >12.5 solid 91 0 H , 149-153 >12.5 92 S H 142-144 >12.5 93 0 H C COOCH, 66-69 >12.5 94 0 H 235-239 >12.5 95 0 H CHz.CH,-OH 114-115 >12.5 39 WO 01/66551 PCT/IBO1/00300 All compounds mentioned in the above list as well as the compounds mentioned in formulae IA, IB, Il and Ill with a variety of substituents were prepared using the methods described earlier depending upon whether they are mixtures of a-methylated isomers, mixtures of non a-methylated isomers or pure 5 RR isomers. The examples mentioned below demonstrate the general synthetic procedure as well as the specific preparation for the preferred compound. The examples are given to illustrate the details of the invention and should not be constrained to limit the scope of the present invention. 0 Most of the compounds were characterized using NMR, IR and were purified by chromatography. Crude products were subjected to column chromatographic purification using silica gel (100 -200 or 60-120 mesh) as stationary phase. EXAMPLE 1 5 Preparation of 2-{2-[(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1 yl)propyl]}-4-{[4-[4-(substitutedlunsubstituted phenyl)-1 piperazinyl]phenyl]}-3-(2H, 4H)-1,2,-substituted triazol-4-one. Step 1: Preparation of 2-chloro-2', 4'-difluoro acetophenone. 20 Into the solution of 1,3-difluorobenzene in 1,2-dicholoroethane (DCE) was added anhydrous aluminium chloride (1.2 molar equivalent of' 1,3 difluorobenzene) at 25-30 0 C and stirred for 30 minutes. The reaction mixture was then cooled to 00C and chloroacetyl chloride (1.1 molar equivalent of 1,3 40 WO 01/66551 PCT/IBO1/00300 difluorobenzene), in DCE, was then added into it over a period of 30-60 min keeping the reaction temperature below 200C. After the addition was over, the reaction mixture was stirred at 25-300C for 5-7 hours. The reaction mixture was then diluted with DCE and poured into dil. hydrochloric acid (5%) at 0-50C. The 5 mixture was then extracted with DCE. The combined organic layer was washed successively with 5% aq. sodium bicarbonate solution and water. Evaporating DCE from the organic layer under reduced pressure gave an oil which on triturating with n-Hexane gave the title compound as white crystalline material (Yield 75% of theory). 10 Step 2: Preparation of 2-(IH,2,4-triazol-1-y)-2',4'-difluoro acetophenone The product obtained in Step -1 was reacted with 1,2,4-triazole (1.2 molar equivalent) in the presence of sodium bicarbonate as base and toluene as solvent under refluxing condition. After the reaction was over, the reaction 15 mixture was poured into crushed ice and extracted with toluene. The combined organic layer was then washed with water and concentrated under reduced pressure to give brown semisolid compound which was recrystallized from ethyl acetate - hexane mixture to give light yellow solid compound which was then used as such in the next step. 20 Step 3: Preparation of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4 triazole Step 2 product was dissolved in toluene, followed by the addition of trimethylsulfoxonium iodide (TMSI), cetramide and 20% aq. sodium hydroxide 25 solution. This mixture was then heated at 600 C for 4 hrs. After the reaction was 41 WO 01/66551 PCT/IBO1/00300 over, it was diluted with toluene and poured into chilled water. The organic layer was washed with water and concentrated under reduced pressure to give light brown oil which was used after column chromatographic purification (silica gel) in the next step. 5 Step 4: Preparation of 1-(substituted phenyl)-4-(4-nitrophenyl) piperazine. Substituted phenyl piperazine was reacted with 4-chloronitrobenzene (1.1 molar equivalent of phenyl piperazine) in dimethylsulphoxide [DMSO] (5 times) using anhydrous potassium carbonate (1.5 molar equivalent) at a temperature 135-1400 C for 6 to 8 hrs. The reaction mixture was poured into crushed ice and 10 the compound was isolated either as a solid or by extracting with chlorinated organic solvent. After drying under vacuum at 30-351C for 6-8 hrs, the compound was used as such for next step. Step 5: Preparation of 1-(substituted phenyl)-4-(4-aminophenyl)piperazine 15 The nitro compound was then reduced to amine by two methods: Method 1: The compound of Step 4 was dissolved in methanol and Palladium on charcoal (wet, 10% w/w) was added under nitrogen followed by the addition of ammonium formate (5 molar equivalent). The reaction mixture was then stirred at a temperature ranging from 45 to 70 OC until the reaction went to 20 completion. After the reaction was over, the reaction mixture was then cooled to 25-30 0 C and filtered. The filtrate was then concentrated under reduced pressure to give a residue which was again dissolved in dichloroethane and washed with water. The organic layer on concentration gave the desired product. 42 WO 01/66551 PCT/IBO1/00300 Method 2: The compound of Step 4 was refluxed in ethyl acetate in the presence of 5.0 molar equivalent stannous chloride dihydrate for 6-8 hrs. After completion of the reaction, the reaction mixture was poured into 10% aq. sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was 5 then washed with water dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired product. Step 6: Preparation of [4-(4-(substituted/unsubstituted phenyl) -1-piperazinyl] phenyl carbamate 10 The amine obtained from Step 5 was dissolved in a mixture of dichloroethane (DCE) and pyridine and cooled to 50C. A solution of phenylchloroformate (1.4 molar equivalent) in DCE was added into the solution of amine at such a rate that reaction temperature remained below 350C. After the addition was over, reaction mixture was stirred at 25-30 0 C for 3-5 hours. Solvent 5 was evaporated off under reduced pressure to give brownish residue which on triturating with n-hexane gave brown solid. It was then obtained was washed with 5% aq. solution of sodium bicarbonate and water. It was then dried under vacuum at 40 OC for 3 to 5 hrs to give the corresponding carbamate. Step 7: Preparation of N-[4-[(4-substituted phenyl) 1-piperazinyl]phenyl]hydrazine 20 carboxamide. The carbamate obtained in Step 6 was stirred in 1,4-dioxane followed by the addition of hydrazine hydrate (2.5 molar equivalent 98%) at room temperature. After refluxing the reaction mixture for 4 to 6 hrs, solvent was 25 evaporated off to give solid residue which was triturated with 10% methanol in 43 WO 01/66551 PCT/IBO1/00300 diethyl ether, filtered the separated solid and dried under vacuum at 35 -400C for 4 to 6 hrs to give corresponding semicarbazide. Step 8: 4-(4-Substituted phenyl)-1 -piperazin]phenyl-3H-1,2,4-triazol-3-ones. 5 The semicarbazide so obtained was dissolved in dry dimethylformamide (DMF) followed by the addition of formamidine acetate (4.5 molar equivalent). After heating at 120 - 130*C for 3 to 5 hrs, reaction mixture was poured into chilled saturated aq. solution of sodium bicarbonate with stirring. Solid so obtained was filtered, washed with water and dried under vacuum at 400C for 7 0 hrs. to give corresponding triazolone. Step 9: Preparation of 2-[(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl) propyl]-4-[4-[4-substitutedphenyl-1-piperazinyl]phenyl]-3-(2H,4H)-1,2,3 substituted triazol-4-one. 15 Hexane washed sodium hydride (0.015 mg, 1.0 mmol) was added into a stirred solution of compound obtained from Step -8 (0.4g, 1.12 mmol) in dimethyl formamide (DMF) (10 ml) maintaining nitrogen atmosphere. After stirring at 25 300C, a solution of the compound obtained from Step 3 (1.68mmol) in DMF was added drop-wise into the reaction mixture at 400C, temperature was raised to 20 800C and maintained at this temperature for about 4 hr. After the reaction was over, reaction mixture was cooled to 35-400C, poured it into chilled water (50 ml) and extracted with ethyl acetate (3x 100ml). The combined organic layer was washed with water (4x50ml), dried over anhydrous sodium sulphate and concentrated under vacuum to give an oily residue (0.3 gm). The oil was purified 25 by column chromatography (silica gel 100-200 mesh) using hexane-ethyl acetate 44 WO 01/66551 PCT/IBO1/00300 (1:1) followed by ethyl acetate or by crystallisation from suitable solvent to give the required compound. EXAMPLE 2 Preparation of 2-{[1 R,2R/1 S,2S/1 R,2S/1 S,2R]2-[(2,4-Difluorophenyl)-2 5 hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 -yI) propyl]}-4-{[4-[4-substituted /unsubstituted)phenyl-I -piperazinyl]phenyl]}- 3- (2H, 4H)-1, 2, 3- substituted triazol -4-one. Step 1: Preparation of 2-chloro-2-methyl-2',4'-difluoro acetophenone 10 Into the solution of 1,3-Difluorobenzene in 1,2-dicholoroethane (DCE) was added anhydrous aluminium chloride (1.2 mol eqnt.) at 25-300C and stirred for 30 minutes. The reaction mixture was then cooled to 00C and (+) 2-chloropropionyl chloride (1.1 molar equivalent), diluted in DCE , was then added into it over a 15 period of 30-60 min keeping the reaction temperature below 200C. After the addition was over, reaction mixture was stirred at room temperature for 5-7 hours. For workup, reaction mixture was diluted with DCE and poured into chilled aq. hydrochloric acid solution (5%). The mixture was extracted with DCE and the combined organic layer was washed with 5% aq. sodium bicarbonate solution 20 and water. The solvent was evaporated off under reduced pressure to afford an oil. 45 WO 01/66551 PCT/IBO1/00300 Step 2: Preparation of 2-{[4-[4-[4-(substituted/unsubstituted phenyl)piperazin yl]phenyl-(2H,4H)-1,2,4-triazol-3-one-2-yl]}-2(R/S)-methyl-2',4' difluoroacetophenone 5 Hexane washed sodium hydride (1.2 molar equivalent) was added into a stirred solution of compound of Formula XII (1.0 molar equivalent) in dimethylsulphoxide (DMSO) maintained under nitrogen atmosphere. After stirring at 25-30 0 C for 1 hr, a solution of the compound of Formula XIV (2 molar equivalent) in DMSO was added dropwise into the reaction mixture at about 10 151C. The reaction mixture was then stirred at 25-30"C for 2 hrs and slowly the temperature was raised to 60 oC and maintained this temperature for 3-4 hrs. After the reaction was over, reaction mixture was cooled to 25-301C, poured into chilled water and extracted with ethyl acetate. The combined organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated to 15 give an oily residue under vacuum. The crude product was purified by column chromatography (silica gel 100-200 mesh) using hexane-ethyl acetate (1:1) followed by using ethyl acetate to give the required compound. Step 3: Preparation of 2-{[1(R/S)-methyl-2-(2',4'-difluorophenyl)-2,3-epoxy propyl]-4-[4-(substituted phenyl)piperazinyl]phenyl]}-3-(2H,4H)-1,2,4-substituted 20 thiazolone. Hexane washed sodium hydride was stirred in DMSO followed by the addition of trimethylsulfoxonium iodide (TMSI) at 15 OC. The reaction mixture was stirred at 25-30 0 C under nitrogen atmosphere for 1-2 hrs. A solution of the 25 compound obtained in Step 2 in DMSO was added into the above mixture at 25 300C and then heated to 80 to 90 OC for 1-2 hrs. Due to the generation of 46 WO 01/66551 PCT/IBO1/00300 second chiral center in the molecules two pairs of diasteromers were formed which were detected both by TLC as well as by HPLC methods. After the reaction was over the reaction mixture was cooled to 25-30*C, poured into chilled brine and extracted with ethyl acetate. The combined organic layer was washed 5 with water, dried over sodium sulfate and concentrated under vacuum to give either an oil or a fluffy solid which was then used as such for the next step. Step 4: Preparation of 2-{[1 R,2R/1 S,2S/1 R,2S/1 S,2R]2-[(2,4-Difluoro phenyl)-2 hydroxy-3-methyl-3-( 1-H-1,2,4-triazol-1 -yl)propyl]}-4-{4-[4 (substituted/unsubstituted phenyl)-1-piperazinyl]phenyl]}-3-(2H,4H)-1,2,3 0 substituted triazol-4-one]. 1,2,4-Triazole was stirred with sodium hydride in dimethylformamide (DMF) at 25-30*C for about 1 hr. The solution of epoxide obtained from step-3 in DMF was then added into this reaction mixture at 25-30 0 C and stirred the 5 reaction mixture at 1000C. After the reaction was over the reaction mixture was cooled to 25-30*C, poured into chilled brine and extracted with ethyl acetate. The combined organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum to give either an oil or a fluffy solid. Compound so obtained was actually a mixture of four isomers showing two spots 20 on TLC. The mixtures of diastereomers was then separated by preparative HPLC. 47 WO 01/66551 PCT/IBO1/00300 EXAMPLE 3 Preparation of 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(IH-1,2,4-triazol-1 yl)propyl]-4-{4-[4-(5-chloro-2-methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H) 1,2,4-triazolone 5 5-Chloro-2-methyl-phenylpiperazine (20.0g) was reacted with 4 chloronitrobenzene (16.0g) in dimethylsulphoxide (DMSO) (110ml) in the presence of anhydrous potassium carbonate (19.9g) at a temperature of 135 140 0 C for 8 hours. After the reaction was over (TLC monitoring), the reaction 10 mixture was poured into crushed ice and the compound was isolated as an orange solid. After drying under vacuum at 25-30 0 C for 6-8 hours, the nitro compound (29.0g, orange solid; m.p. 146-1500C) was used as such for the next step. The nitro compound (18.0g) was refluxed in ethyl acetate (150ml) in the 15 presence of stannous chloride dihydrate (55.5g) for 8 hours. After completion of the reaction, the reaction mixture was poured into 10% aqueous sodium bicarbonate (500ml) and extracted with ethyl acetate (3 x 150ml). The combined organic layer was washed with water (3 x 100ml) and then dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum to give the 20 desired amine (15.3g, brown oil; yield:93%). The amine (15.0g) was dissolved in a mixture of dichloroethane (DCE) (80ml) and pyridine (30ml). The reaction mixture was cooled to about 150C. A solution of phenylchloroformate (11.67g) in DCE (10ml) was added into the solution of amine at such a rate that reaction temperature remained below 200C. 25 After the addition was over, reaction mixture was stirred at 25-30"C for about 3 48 WO 01/66551 PCT/IBO1/00300 hours. Solvent was evaporated off under reduced pressure to give brownish residue which on triturating with n-hexane (150ml) gave brown solid. Solid was washed with n-hexane (2x100ml), 5% aq. solution of sodium bicarbonate (2 x 1 00ml) and distilled water (2x1 50ml) followed by drying under vacuum at 400C for 5 5 hours to give 10gm of corresponding carbamate (Yield 86%) m.p.201-205 0 C. The carbamate (18.0g) was stirred in 1,4-dioxane (130ml) followed by the addition of hydrazine hydrate (98%) (5.32g) at 25-301C. After refluxing the reaction mixture for 4 hours, solvent was evaporated off to give solid residue which was triturated with 10% methanol in diethyl ether (1 50ml). The separated 10 solid was filtered, washed and dried under vacuum at 350C for 4 to 6 hours to give corresponding semicarbazide (15.5g) mp 177-1820C. The semicarbazide (5.0g) was stirred in dry DMF (25ml) followed by the addition of formamidine acetate (6.5g). After heating at 120*C for 3 to 5 hours, the reaction mixture was poured into a chilled saturated aq. solution of sodium 15 bicarbonate (100ml) with stirring. Solid so obtained was filtered, washed with water (3 x 50ml) and dried under vacuum at 404C for 5 hours to give corresponding triazolone derivative (4.3g, 84%) as a brown amorphous solid; mp 258-262oC. Hexane washed sodium hydride (0.057g, 60% suspension in oil) was 20 added into a stirred suspension of the above triazolone intermediate (0.5g) in DMF (10ml) maintained under nitrogen atmorphere. After stirring at 25-301C, a solution of the epoxide interemdiate (0.48igm) in DMF (5ml) was added dropwise into the reaction mixture at 400C. Temperature was then raised to 800C and 49 WO 01/66551 PCT/IBO1/00300 maintained for about 4 hr. Reaction mixture then was cooled to 25-30 0 C, poured into chilled water (50ml) and extracted with ethyl acetate (3 x 100ml). The combined organic layer was washed with water (4x50ml), dried over anhydrous sodium sulphate and concentrated under vacuum to give an oily residue (0.3gm). 5 The oily residue was subjected to column chromatography (silica gel 100 200mesh) using hexane-ethyl acetate (1:1, 300ml) followed by ethyl acetate (500ml) to give the required compound. (0.481gm, 57%) mp 82-914C. EXAMPLE 4 2-{[I R2R/I S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(I H-1,2,4 10 triazol-1-yl) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl} 3-(2H,4H)-1,2,4-triazolone (Compound No. 21) 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl} 3-(2H,4H)-1,2,4-triazolone (Compound No. 22) 15 Step 1: Preparation of 2-{4-[4-[4-(2-methyl-5-chlorophenyl)piperazinyl]phenyl} (2H,4H)-1,2,4-triazol-3-one-2-yl}-2(R/S)-methyl-2,4-difluoroacetophenone. Hexane washed sodium hydride (0.311 g) was added into a stirred solution 20 of triazolone intermediate (4-[4-(2-methyl-5-chlorophenyl)-1-piperazinyl]phenyl-1 (3-(2H,4H)-1,2,4 triazolone (2.5g) in DMSO (25ml) maintained under nitrogen atmosphere. After stirring at 25-30 0 C for 1 hour, a solution of the intermediate of Formula XIV (2.77g) in DMSO (5ml) was added dropwise into the above reaction mixture at 15'C. The reaction mixture was then stirred at 25-300C for 2 hours, 25 slowly the temperature was raised to 600C and maintained for 3-4 hours. Reaction mixture was cooled to 25-30*C, poured into chilled brine (150ml) and 50 WO 01/66551 PCT/IBO1/00300 extracted with ethyl acetate (3 x 100ml). The combined organic layer was washed with water (4 x 50ml), dried over anhydrous sodium sulphate and concentrated to an oily residue under vacuum. The crude oil was subjected to column chromatography (silica gel 100-200mesh) using hexane -ethyl acetate 5 (1:1) followed by ethyl acetate to give required compound in pure form (2.6gm; 71%) mp 125-1284C. Step 2: Preparation of 2-[1-(R/S)-methyl-2-(2'-4'-difluorophenyl)-2,3-epoxy propyl]-4-{4-[4-(5-chloro-2-methylphenyl)piperazinyl]phenyl]}-3-(2H,4H)-1,2,4 triazolone. 10 Hexane washed sodium hydride (0.128g) was stirred in DMSO (15ml) followed by the addition of trimethylsulfoxonium iodide (TMSI) (0.736g) at 150C. The reaction mixture was stirred at 25-300C under nitrogen atmosphere for 1 hr. A solution of Step I product (0.9g) in DMSO (5ml) was added into the above 15 reaction mixture at 25-304C and then heated to 80 to 900C for about 1 hr. Due to generation of second chiral centre in the molecule, two pairs of diastereomers were formed which were detected by the TLC and by HPLC analyses. After the reaction was over, the reaction mixture was cooled to 25-30*C, poured into chilled brine and extracted with ethyl acetate (3 x 75ml). The combined organic 20 layer was the washed with water (2 x 50ml), dried over sodium sulfate and concentrated under vacuum to give an oil (0.93gm, 100%) which was then used as such immediately for next step. 51 WO 01/66551 PCT/IBO1/00300 Step 3: 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 21) 2-{[1 R2S/I S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4-triazol- 1 5 yl) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H) 1,2,4-triazolone (Compound No. 22) 1,2,4-Triazole (0.232g) was stirred with anhydrous potassium carbonate (0.465g) in DMF (10ml) at 25-301C for 1-2 hours. A solution of epoxide obtained 10 from Step-2 (0.925g) in DMF (3.Oml) was then added into the above mixture at 25-300C followed by heating the reaction mixture at 90 to 100*C for 1 hr. After the reaction was over, reaction mixture was cooled to 25-30*C, poured into chilled brine (70.Oml) and extracted with ethyl acetate (3 x 75ml). The combined organic layer was washed with water (2x250ml), dried over sodium sulfate and 15 concentrated under vacuum to give an oil. Compound obtained actually was a mixture of two pairs of diastereomers showing two spots on TLC (Ethyl acetate). The mixture of diastereomers (0.613g, 59%) was then separated by column chromatography to get compound no.21) (faster moving spot on TLC) (35mg), compound no.22 (slower moving spot on TLC) and 550mg of mixture of the two 20 spots. 52 WO 01/66551 PCT/IBO1/00300 EXAMPLE 5 Preparation of 3-[4-(4-Chlorophenylthioureido)N-methyl-N-phenyl]-2-(2,4 difluorophenyl)-1 -(I H-1,2,4-triazolyl)-propan-3-amino-2-oI (Compound No. 89) 5 Step 1: Preparation of 3-[N-methyl-N-(4-nitrophenyl)]-2-(2,4-difluorophenyl)-1 (1 H-1,2,4-triazolyl)- propan-3-amino-2-ol. Into a stirred suspension of sodium hydride (42 mg) in dry 10 dimethylformamide (DMF) (5.0 ml) was added N-methyl-p-nitroaniline (1.5 gm) at 5-100C. The resulting suspension was stirred at 300C for 1 hour followed by the addition of a solution of epoxide (Formula IV) in DMF (2.0 ml) at 5-100C. Reaction mixture was then stirred at 300C for 30 min, heated to 60-650C for 12 hrs and was cooled to 300C. Poured the reaction mixture into ice-water mixture 15 and extracted with dichloromethane (3x1 00 ml). The combined organic layer was washed with DM water (2 x 70 ml), dried over sodium sulphate and concentrated under reduced pressure to give a yellow solid (2.1 g, m.p. 248-500C). Step 2: Preparation of 3-[N-methyl-N-(4-aminophenyl)]-2-(2,4-difluoropheny)-1 (1 H-1,2,4-triazolyl)- propane-3-amino-2-ol. 20 Into a stirred solution of Step 1 product in methanol was added palladium on carbon (10%) (50% w/w) (0.5 g) under nitrogen atmosphere. The suspension was then cooled to 100C followed by the addition of ammonium formate (1.2 g) in portions over a period of 15 min. The reaction mixture was then heated to reflux 25 and stirred at reflux for 5 hours. Reaction mixture was cooled to 300C and filtered through a celite pad. The combined filtrate was concentrated under 53 WO 01/66551 PCT/IBO1/00300 vacuum to give a yellow semi-solid which was redissolved in dichloromethane (200 ml). The organic layer was washed with DM water (3 x 100 ml), dried over sodium sulfate and concentrated under reduced pressure to give semi-solid amine which was subjected to next step without further purification. 5 Step 3: Preparation of 3-[4-(4-Chlorophenylthioureido)N-methyl-N-phenyl]-2-(2,4 difluorophenyl)-1 -(1 H-1,2,4-triazolyl)-propan-3-amino-2-ol (Compound No. 89) Dissolved the amine (Step-Il product) (400 mg) in anhydrous acetonitrile (5 ml) and added p-chlorophenyl isothiocyanate (227 mg, 1.2 eqm) to it. Stirred for 10 4 hours at 25-30oC and the solvent was evaporated off to afford residue which was purified using column chromatography (Yield: 200 mg, 34%). EXAMPLE 6 Preparation of 3-{4-[4-N-(4-chlorophenyl)-N-(methylureido)-piperazinyl ] phenoxy}-2-(2,4-difluorophenyl)-1 -(1 H-1,2,4-triazolyl)-2-methoxypropane 15 (Compound No. 75) Dissolved the amine of Formula VII (prepared by following the process as described in US Patent No. 5,023,258) (9 g) in anhydrous acetonitrile (50 ml) and added p-chlorophenyl isocyanate (4 g) to it. Stirred the reaction mixture for 1 hr 20 at 25-30 0 C and evaporated the solvent to afford crude oil which was purified using column chromatography (Yield: 8.3 g, 75%). 54 WO 01/66551 PCT/IBO1/00300 EXAMPLE 7 Preparation of [1R2R/1S2S] 1-{4-[4-(4-chlorophenylureido)-piperazinyl ] phenoxy}-2-(2,4-difluorophenyl)-1-methyl -3-(1H-1,2,4-triazolyl)-propan-2-ol (Compound No. 77) and 5 [1R2SI1S2R] 1-{4-[4-(4-chlorophenylureido)-piperazinyl ]-phenoxy}-2-(2,4 difluorophenyl)-1 -methyl -3-(1 H-1,2,4-triazolyl)-propan-2-ol (Compound No. 78) 0 Step 1: Preparation of 2-{4-[4-acetyl-1-piperazinyl]-phenyl]-2(R/S)-methyl-2,4 difluoroacetophenone A solution of 2-chloro-2(R/S)-methyl-2,4-difluoroacetophenone(10.5 g) (1.5 molar equivalent) in dry dimethylformamide (DMF) was added into a stirred 5 suspension of 1-acetyl-4-hydroxyphenylpiperazine (8.0 g) and potassium carbonate (12.16 g) in dimethylformamide (DMF) at 5-100C. Reaction mixture was then stirred at 300C for 20 min, heated to 600C and stirred at 601C for about 5 hrs. Reaction mixture then was cooled to 25-304C, poured into ice-water mixture and extracted with ethyl acetate (3 x 200 ml). The combined organic 20 layer was washed with water (3 x 100 ml), dried over sodium sulfate and concentrated under reduced pressure to get foamy product (8.0 g; 71%). Step 2: Preparation of 1-(R/S)-methyl-2,3-epoxypropyl-2-{4-[(4 acetylpiperazinyl)] phenoxy}-2-(2',4'- difluorobenzene) 25 Into a stirred suspension of sodium hydride (1.97 g) in dry dimethylsulphoxide (DMSO) under nitrogen atmosphere was added trimethylsulfoxomium iodide (9.075 g) at 10-15 0 C. The foaming suspension was 55 WO 01/66551 PCT/IBO1/00300 stirred at 300C for 1 hr followed by the addition of a solution of Step-I product (8.0 g) in DMSO at 10-150C over a period of 10 min. Reaction mixture was then heated to 900C and stirred at 900C for about 4 hours. Cooled the reaction mixture, poured it into ice-water mixture and extracted with ethyl acetate (3 x 200 5 ml). The combined organic layer was then washed with water (3x150 ml), dried over sodium sulphate and concentrated under reduced pressure to give foamy product (7.0 g; 85%). Step 3: Preparation of 1-{4-[4-Acetylpiperazinyl)-phenyl]-2-(2,4-difluorophenyl) 1 (R/S)- methyl-3-(1 H-1,2,4- triazolyl)-propane-2-ol)] 0 Into a stirred suspension of sodium hydride(1.67 g) in dry dimethylformamide (DMF), was added 1,2,4-triazole (2.4 g) under nitrogen atmosphere and stirred at 300C for 1 hour. A solution of Step 2 product (7.0 g) in DMF was then added into the above suspension at 300C followed by heating to 15 80-850C and stirred at 80-85*C for 8 hrs. Reaction mixture was then cooled to 300C, poured into ice-water mixture and the suspension was extracted with ethyl acetate (3x200 ml). The combined organic extract was washed with DM water (3 x 150 ml), dried over sodium sulfate and concentrated under reduced pressure to give semisolid compound (6.0 g, 73%). 20 Step 4: Preparation of 1-[4-(4-(piperazinyl)phenoxy]-2-(2,4-difluorophenyl) 1 (R/S)-methyl-3-(1 H-1,2,4-triazolyl)- propan-2-ol Step 3 product (6.0 g) was dissolved in 1,4-dioxane (50 ml) followed by the addition of a solution of sodium hydroxide (1.0 g) in water (50 ml). Heated the 56 WO 01/66551 PCT/IBO1/00300 reaction mixture to reflux, stirred it at reflux for about 5 hrs and concentrated under reduced pressure to give a brown semi-solid residue. This brown semi solid was redissolved in ethyl acetate (200 ml), washed with DM water (2x100 mi), dried over sodium sulphate and concentrated to get a pure brown semi-solid 5 (4.5 g; 81%). Step 5: Preparation of [I R2R/1 S2S) I -{4-[4-(4-chlorophenylureido)-piperaziny] phenoxy}-2-(2,4- difluorophenyl)-1 -methyl-3-(1 H-1,2,4-triazolyl)-propan-2-ol. (Compound No. 77) and 10 [1 R2R/1 S2S]-1 -{4-[4-(4-chlorophenylureido)-piperazinyl]-phenoxy}-2-(2,4 difluorophenyl)-1-methyl-3-(1 H-1,2,4-triazolyl)propane-2-ol. (Compound No. 78). Dissolved the amine obtained as Step 4 product (Formula VII) (800 mg) in anhydrous acetonitrile (5 ml) followed by the addition of p-chlorophenyl 15 isocyanate (3.44 mg). The reaction mixture so obtained was stirred for 1 hour at room temperature and after the reaction was over, the solvent was evaporated off to give brown semi solid residue which was purified using column chromatography. The two spots observed on TLC were separated by preparative HPLC (Upper spot, 50mg, 30%, compound No. 77; Lower spot, 25mg, 20%, 20 Compound No. 78) 57 WO 01/66551 PCT/IBO1/00300 EXAMPLE 8 Preparation of 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 yl)propyl]-4-{4-[4-(4-chlorophenyluredio)-1 -piperazinyl]phenyl}-3-(2H,4H) 1,2,4-triazolone (Compound No. 91) 5 Dissolved the starting amine of Formula VII (following the method as described in US Patent No. 5,371,101) in anhydrous acetonitrile and added p chlorophenyl isocyanate (1.2 moler equivalent) to it and stirred for 1 hr at 25 30*C. After completion of the reaction, the solvent was evaporated off to obtain a 10 crude product which was purified using column chromatography. Assignment of RR/SS was done on the basis of 1 HNMR analysis. An illustrative list of some of the compounds of the invention which were synthesized by one or more of the above described methods is given below along with their 'HNMR data. All 'HNMR spectra were recorded on Brucker AMX 300 15 NMR machines (300 MHZ) using CDCl 3 as a solvent and TMS as an internal standard unless otherwise specified. All values are given in ppm. Symbols in the examples have the following meanings. Thus, s singlet; d:doublet; t:triplet; q:quartet; dd: double doublet; m:multiplet; br:broad; J: coupling constant: 20 Compound No. 1: 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(4-chlorophenyl)-1-piperazinyl]pheny}-3-(2H,4H)-1,2,4 triazolone

NMR(CDCI

3 ):- 8 7.96(s, IH; Ar-H), 7.72-7.67 (d, 2H; J = 14.7 Hz; Ar-H), 7.60-7.52 25 (q, 1H; Ar-H), 7.45-7.42 (d, 2H; J = 9.0 Hz; Ar-H), 7.26-7.23 (d, 2H; J = 9.0 Hz; 58 WO 01/66551 PCT/IBO1/00300 Ar-H), 7.06-7.03 (d, 2H; J = 9.0 Hz; Ar-H), 6.91-6.88(d, 2H; J = 9.0 Hz; Ar-H), 6.83-6.77(m, 2H; Ar-H), 5.56 (s, 1H; OH, D 2 0 ex.), 5.1 2 -5.05(q, 1H; -CH.CH 3 ), 5.03-4.98 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 4.38-4.33 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 3.39-3.37 (d, 8H; piperazine-CH 2 -) & 1.31-1.28(d, 3H; J = 7.2 Hz; 5 CH.CH 3 )ppm. Compound No. 2: 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(4-chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 10 triazolone

NMR(CDCI

3 ):- a 8.09(s, I H; Ar-H), 7.68 (s, I H; Ar-H), 7.39(s, I H; Ar-H), 7.36-7.30 (m, 1H; Ar-H), 7.26-7.22 (m, 3H; Ar-H), 7.16-7.13 (d, 2H; J = 9.0 Hz; Ar-H), 6.97 6.94(d, 2H; J = 9.0 Hz; Ar-H), 6.89-6.87(d, 2H; J = 9.0 Hz; Ar-H), 6.77-6.63(m, 2H; Ar-H),6.04(s, 1H;Ar-H), 5.29 (s, IH; OH, D 2 0 ex.), 5.11-5.04(q, 1H; -CH.CH 3 ), 15 4.92-4.88 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 4.63-4.59 (d, IH; J = 15.0 Hz; triazole-CH 2 ), 3.34-3.28 (q, 8H; piperazine-CH 2 -) & 1.64-1.61 (d, 3H; J = 7.2 Hz; CH.CH 3 )ppm. Compound No. 3: 20 2-{[l R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(2,4-dinitrophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone

NMR(CDCI

3 ):- 5 8.81-8.80(d, 1H; Ar-H), 8.40-8.36(dd, 1H; Ar-H),8.03(s,1H;Ar-H), 7.79-7.75 (d, 2H; Ar-H), 7.65-7.62(q, 1H; Ar-H), 7.54-7.51 (d, 2H; Ar-H), 7.25 25 7.22 (d, IH; Ar-H), 7.09-7.07 (d, 2H; J = 9.0 Hz; Ar-H), 6.91-6.85(m, 2H; Ar-H), 5.60 (s, 1H; OH, D 2 0 ex.), 5.17-5.05(qd, 2H; -CH.CH 3 & triazole-CH 2 ), 4.46-4.41 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 3.54-3.53 (d, 8H; piperazine-CH 2 -) & 1.37 1.35(d, 3H; J = 7.2 Hz; -CH.CH,)ppm. 59 WO 01/66551 PCT/IBO1/00300 Compound No. 4: 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(2,4-dinitrophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone 5 NMR(CDCIl):- 8 8.73-8.72(d, 1 H; Ar-H), 8.32-8.28(dd, 1 H; Ar-H),8.08(s, 1 H; Ar H),7.68 (s, 1H; Ar-H), 7.41(s, 1H; Ar-H), 7.35-7.32 (m, 1H; Ar-H), 7.18-7.13 (m, 3H; Ar-H), 6.76-6.74(d, 2H; J = 9.0 Hz; Ar-H), 6.73-6.63(m, 2H; Ar-H), 5.99 (s, 1H; OH, D 2 0 ex.), 5.09-5.07(q, 1H; -CH.CH 3 ), 4.93-4.88 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 4.64-4.59 (d, 1H; J = 15.0 Hz; triazole-CH2), 3.46-3.39 (q, 0 8H;piperazine-CH 2 -) & 1.64-1.61 (d, 3H; J = 7.2 Hz; -CH.CH 3 ) ppm. Compound No. 5: 2-{[1 R2R/I S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-[4-(1-phenylpiperazinyl)phenyl]-3-(2H,4H)-1,2,4-triazolone 5 NMR(CDCI 3 ):- 8 7.96(s, I H; Ar-H), 7.72-7.67 (d, 2H; J = 13.5 Hz; Ar-H), 7.60-7.52 (q, 1 H; Ar-H), 7.44-7.41 (d, 2H; J = 9.0 Hz; Ar-H), 7.33-7.26 (m, 3H; Ar-H), 7.07 6.97 (m, 4H; Ar-H), 6.93-6.88(m,1 H; Ar-H), 6,84-6.77(m, 2H; Ar-H), 5.56 (s, 1 H; OH, D 2 0 ex.), 5.12-4.98(qd, 2H; -CH.CH 3 triazole-CH 2 ), 4.38-4.33 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 3.38-3.37 (d, 8H; piperazine-CH 2 -) & 1.30-1.28(d, 3H; J= 6.9 20 Hz; -CH.CH 3 ) ppm. Compound No. 6: 2-{[1 R2S/I S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(I-phenylpiperazinyl) phenyl}-3-(2H,4H)-1,2,4-triazolone 25 NMR(CDC 3 ):- 6 8.09 (s, 1 H; Ar-H), 7.68 (s, I H; Ar-H), 7.39 (s, 1 H; Ar-H), 7.36 7.26 (m, 3H; Ar-H), 7.15-7.12 (d, 2H; J= 9.0 Hz; Ar-H), 6.97-6.87 (m, 5H; Ar-H), 6.77-6.64 (m, 2H; Ar-H), 6.05 (s, 1H; OH, D 2 0 ex.), 5.09-5.07 (q, 2H; -CH.CH 3 triazole-CH 2 ), 4.91-4.87 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 4.63-4.58 (d, 1H; J= 15.0 Hz; triazole-CH 2 ), 3.34 (s, 8H; piperazine-CH 2 -) & 1.63-1.61 (d, 3H; J = 6.9 30 Hz; -CH.CH 3 ) ppm. 60 WO 01/66551 PCT/IBO1/00300 Compound No. 7: 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(3,4-dichlorophenyl)-1-piperzinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone 5 NMR(CDCI):-6 7.96(s, 1H; Ar-H), 7.71-7.67 (d, 2H; J = 13.5 Hz; Ar-H), 7.61-7.52 (q, 1H; Ar-H), 7.45-7.42 (d, 2H; J = 9.0 Hz; Ar-H), 7.33-7.30 (d, 1H; J = 8.7 Hz; Ar-H), 7.06-7.01 (m, 3H; Ar-H), 6.84-6.77(m,3H; Ar-H), 5.56 (s, 1 H; OH, D 2 0 ex.), 5.12-5.05(q, 1H; -CH.CH 3 ), 5.03-4.98 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 4.38 4.34 (d, IH; J 15.0 Hz; triazole-CH 2 ), 3.39-3.37 (d, 8H; piperazine-CH 2 -) & 1.30 0 1.28(d, 3H; J= 7.2 Hz; -CH.CH 3 )ppm. Compound No. 8: 2-{[1 R2S/I S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(3,4-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 5 triazolone

NMR(CDCI

3 ):- 6 8.08 (s, I H; Ar-H), 7.67 (s, 1 H; Ar-H), 7.39-7.25 (m, 3H; Ar-H), 7.15-7.12 (d, 2H; J = 9.0 Hz; Ar-H), 6.99-6.93 (m, 3H; Ar-H), 6.79-6.65 (m, 3H; Ar-H), 6.01 (s, IH; OH, D 2 0 ex.), 5.10-5.05 (q, IH; -CH.CH 3 ), 4.91-4.87 (d, IH; J = 15.0 Hz; triazole-CH 2 ), 4.62-4.58 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 3.31 (s, 8H; 20 piperazine-CH 2 -) & 1.63-1.60 (d, 3H; J = 7.2 Hz; -CH.CH 3 ) ppm. Compound No. 9: 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 25 triazolone NMR(CDCl 3 ):- 7.99(s, 1H; Ar-H), 7.74-7.70 (d, 2H; J = 14.7 Hz; Ar H), 7.62-7.54 (q, 1H; Ar-H), 7.48-7.39 (m, 3H; Ar-H), 7.19-7.07 (m, 5H; Ar-H), 6.85-6.79(m, 2H; Ar-H), 5.59 (s, 1H; OH, D 2 0 ex.), 5.15-5.01(qd, IH; -CH.CH 3 & triazole-CH2), 4.40-4.35 (d, 1 H; J = 15.0 Hz; triazole-CH 2 ), 3.43 (s, 8H; piperazine-CH2-) & 1.32-1.30(d, 3H; J = 7.2 Hz; -CH.CH 3 ) ppm. 30 61 WO 01/66551 PCT/IBO1/00300 Compound No. 10: 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H) 1,2,4-triazolone NMR(CDCI 3 ):- 6 8.12(s, 1 H; Ar-H), 7.71 (s, 1 H; Ar-H), 7.43-7.32 5 (m, 3H; Ar-H), 7.15-7.11 (m, 5H; Ar-H), 7.00-6.97(d, 2H;Ar-H), 6.78-6.66 (m, 2H; Ar-H), 6.06 (s, 1H; OH, D 2 0 ex.), 5.13-5.07(q, 1H; -CH.CH3), 4.95-4.90 (d, 1H; J = 15.0 Hz; triazole-CH 2 ),4.65-4.61 (d, 1H; J= 15.0 Hz; triazole-CH 2 ), 3.39 (s, 8H; piperazine-CH 2 -) & 1.66-1.64(d, 3H; J = 9.6 Hz; -CH.CH 3 ) ppm. 10 Compound No. 11: 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone NMR(CDC1 3 ):- 7.96.09 (s, 1H; Ar-H), 7.72 (s, 1H; Ar-H), 7.67 (s, 1H; Ar-H), 7.55-7.57 (m, 1H; Ar-H), 7.41-7.44 (d, 2H; Ar-H), 6.77-7.07 (m, 8H; Ar-H), 15 5.57 (S, 1H; OH, D 2 0 ex.), 5.10-5.17 (q, 1H; J= 7 Hz; -CH), 4.98-5.03 (d, 1H; J = 14.7 Hz, -CH), 4.33-4.37 (d, 1H; J = 14.7-Hz; triazole-CH2), 3.38-3.40 (m, 4H; 2 x -CH 2 ), 3.25-3.29 (m, 4H; 2 x CH 2 -) & 1.28 (d, J = 7 Hz; 3H; CH 3 ) ppm. Compound No. 12: 20 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(4-fluorophenyl)- I -piperazinyl]phenyl}-3-(2H ,4H)- 1,2,4 triazolone

NMR(CDCI

3 ):- 68.09 (s, 1H; Ar-H), 7.68 (s, 1H; Ar-H), 6.60-7.40 (m, 12H; Ar-H), 6.02 (S, 1 H; OH, D 2 0 ex.), 5.04-5.11 (q, 1 H; J = 7 Hz; -CH), 4.87-4.92 (d, I H; J = 25 14.7 Hz, -CH), 4.58-4.63 (d, IH; J = 14.7 Hz; triazole-CH 2 ), 3.33-3.44 (m, 4H; 2 x

-CH

2 ), 3.23-3.25 (m, 4H; 2 x CH-) & 1.28 (d, J = 7 Hz; 3H; CH) ppm. Compound No. 13: 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 30 yl) propyl}-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone 62 WO 01/66551 PCT/IBO1/00300

NMR(CDC

3 ):- 8 7.97 (s, 1H; Ar-H), 7.74 (s, 1H; Ar-H), 7.67 (s, 1H; Ar-H), 7.60 7.51 (m, 1H; Ar-H), 7.44-7.41 (d, 2H; Ar-H), 7.28 (s, 1H; Ar-H), 7.07-7.04 (d, 2H; Ar-H),6.98-6.95 (m, 2H; Ar-H), 6.89-6.86 (m, 2H; Ar-H),6.82-6.77 (m, 2H; Ar H),5.59 (S, 1H; OH, D 2 0 ex.), 5.10-4.99 (q, IH; J = 7 Hz; -CH), 4.37-4.33 (d, 1H; 5 J = 14.7 Hz, -CH), 3.79(s, 3H; OCH3), 3.41-3.38 (t, 4H; 2 x -CH 2 ), 3.25-3.22 (t, 4H; 2 x CH-) & 1.30-1.25 (d, J = 7 Hz; 3H; CH,) ppm. Compound No. 15: 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol- 1 10 yl) propyl}-4-{4-[4-(3-chloro-4-fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H) 1,2,4-triazolone NMR(CDCl 3 ):- (s, IH; Ar-H), 7.73-7.69(d, 2H; Ar-H), 7.62 7.53(m, 1H; Ar-H), 7.46-7.43(d, 2H; Ar-H), 7.10-7.05(t, 3H; Ar-H),7.00-6.98 (m, 1H; Ar-H), 6.85-6.79(m, 3H; Ar-H),5.57 (s, 1H; OH, D 2 0 ex.), 5.14-5.00 (m, 2H; J = 7 Hz; -CH), 4.39-4.35 (d, 1 H; J = 14.7 Hz, -CH), 3.40-3.38 (d, 4H; 2 x -CH 2 ), 15 3.30-3.29 (d, 4H; 2 x CH 2 -) & 1.32-1.30(d, J= 7 Hz; 3H; CH 3 ) ppm. Compound No. 16: 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(3-chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H) 20 1,2,4-triazolone NMR(CDCI 3 ):- 88.02(s, I H; Ar-H), 7.61 (s, 1 H; Ar-H), 7.37 (s, I H; Ar-H), 7.33-7.23 (m, IH; Ar-H), 7.09-7.06(d, 2H; Ar-H), 6.98-6. 956(t, 1H; Ar-H), 6.90-6. 87(d, 3H; Ar-H),6.76-6.57 (m, 3H; Ar-H),5.96 (s, IH; OH, D 2 0 ex.), 5.05 4.98(q, 1 H; J = 7 Hz; -CH-CH 3 ), 4.87-4.81 (d, 1 H; J = 14.7 Hz, -CH), 4.57-4.52 (d, 1 H; J = 14.7 Hz, -CH), 3.27-3.25 (t, 4H; 2 x -CH 2 ), 3.19-3.18 (t, 4H; 2 x CH 2 -) 25 & 1.57-1.55(d, J = 7 Hz; 3H; CH) Compound No. 17: 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(I H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(3-chloro-4-m ethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H) 30 1,2,4-triazolone NMR(CDC1 3 ):- 7.98 (s, 1H; Ar-H), 7.74-7.69(d, 2H; Ar-H), 7.62 7.53(q, 1H; Ar-H), 7.46-7.43(d, 2H; Ar-H), 7.16-7.13(d, 1H; Ar-H), 7.08-7.05(d, 63 WO 01/66551 PCT/IBO1/00300 2H; Ar-H), 6.98-7.97 (m, 1H; Ar-H),6.86-7.98 (m, 3H; Ar-H), 5.59 (s, IH; OH, D20 ex.), 5.14-5.00 (m, 2H; J = 7 Hz; -CH), 4.39-4.35 (d, 1H; J = 14.7 Hz, -CH), 3.40 3.38 (d, 4H; 2 x -CH 2 ), 3.33-3.32 (d, 4H; 2 x CH 2 -), 2.31(s, 3H; Ar-CH 3 ) & 1.32 1.29 (d, J = 7 Hz; 3H; CH 3 ) ppm. 5 Compound No. 19: 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(2,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone 0 NMR(CDCl 3 ):- 6 7.48 (s, 1 H; Ar-H), 7.74 (s, 1 H; Ar-H), 7.69 (s, I H; Ar-H), 7.53 7.61 (m, I H; Ar-H), 7.42-7.45 (m, 2H; Ar-H), 6.47-7.08 (m, 5H; Ar-H), 6.78-6.85 (m, 2H, Ar-H), 5.60 (s, 1H; OH, D 2 0 ex.), 5.07-5.14 (q, 1H; J= 7 Hz; -CH), 5.00 5.05 (d, IH; J = 14 Hz, -CH), 4.34-4.39 (d, 1H; J = 14 Hz; triazole-CH 2 ), 3.37 3.40 (m, 4H; 2 x -CH 2 ), 3.05-3.09 (m, 4H; 2 x CH-), 2.33 (s, 3H, CH 3 ), 2.30 (s, 15 3H, CH) & 1.29-1.32 (d, J= 7 Hz; 3H; CH) ppm Compound No. 20: 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(2,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4 20 triazolone

NMR(CDC

3 ):- 6 8.08 (s, 1H; Ar-H), 7.67 (s, IH; Ar-H), 7.31-7.39 (m, 2H; Ar-H), 6.94-7.14 (m, 7H; Ar-H), 6.63-6.76 (m, 2H, Ar-H), 6.06 (s, IH; OH, D 2 0 ex.), 5.04 5.11 (q, 1 H; J = 7 Hz; -CH), 4.87-4.92 (d, 1 H; J = 15 Hz, -CH), 4.58-4.63 (d, 1 H; J= 15 Hz; triazole-CH 2 ), 3.31-3.34 (m, 4H; 2 x -CH 2 ), 3.02-3.03 (m, 4H; 2 x CH 2 25 ), 2.29 (s, 3H, -CH3), 2.28 (s, 3H, CH)& 1.61-1.63 (d, J= 7 Hz; 3H; CH 3 ) ppm Compound No. 21: 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 yl) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H) 30 1,2,4-triazolone NMR(CDC1 3 ):- 68.03(s, 1 H; Ar-H), 7.78-7.73(d, 2H; Ar-H), 7.62 7.60(q, 1H; Ar-H), 7.50-7.47(d, 2H; Ar-H), 7.19-7.03(m, 5H; Ar-H), 6.89-6.82 (m, 64 WO 01/66551 PCT/IBO1/00300 2H; Ar-H), 5.58 (s, 1H; OH, D20 ex.), 5.16-5.04 (m, 2H; J= 7 Hz; -CH), 4.43-4.39 (d, IH; J = 14.7 Hz, -CH), 3.45-3.41 (d, 4H;2 x-CH 2 ), 3.13-3.10 (d, 4H; 2 x CH 2 -), 2.35(s, 3H; Ar-CH) & 1.36-1.33 (d, J = 7 Hz; 3H; CH 3 ) ppm. 5 Compound No. 22: 2-{[1 R2S/I S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4-triazol-1 y) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H) 1,2,4-triazolone NMR(CDC1 3 ):- 88.15(s, 1H; Ar-H), 7.74 (s, 1H; Ar-H), 7.46 7.39(m, 1H; Ar-H), 7.31 (s, 1H; Ar-H), 7.21-7.15(t, 3H; Ar-H), 7.05-6.99(m, 4H; Ar 0 H), 6.79-7.72 (m, 2H; Ar-H), 6.12 (s, 1H; OH, D 2 0 ex.), 5.15-5.13 (q, 1H; J = 7 Hz; -CH-CH 3 ), 4.98-4.93 (d, 1 H; J = 14.7 Hz, -CH), 4.69-4.64 (d, I H; J = 14.7 Hz, -CH), 3.40-3.37 (t, 4H; 2 x -CH 2 ), 3.10-3.07 (d, 4H; 2 x CH 2 -), 2.33(s, 3H; Ar-CH 3 ) & 1.69-1.67 (d, J= 7 Hz; 3H; CH 3 ) ppm. 15 Compound No. 35: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2 methoxyphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone NMR(CDCl 3 ):- 6 8.16 (s, 1H; Ar-H), 7.81 (s, 1H; Ar-H), 7.60-7.57 (m, 1H; Ar-H), 7.02-6.79 (m, 9H; Ar-H), 6.10 (s, 1H; OH; D 2 0 ex.), 4.70 (s, 2H; triazolone-CH 2 ), 20 4.55-4.50 (d, 1H; J = 14.7 Hz; triazole-CH 2 ), 4.18-4.13 (d,IH; J = 15.0 Hz; triazole-CH 2 ), 3.89 (s, 3H; o-OCH), 3.41(s, 4H; piperazine-CH 2 -),3.21 (s, 4H; piperazine-CH 2 -) & 2.04(s, 3H; triazolone-CH 3 ) ppm. Compound No. 36: 25 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone NMR(CDC1 3 -DMSO-d 6 ):-S 8.19 (s, IH; Ar-H), 7.77 (s, 1H; Ar-H), 7.60-7.52 (m, IH; Ar-H), 7.42 (s, 1H; Ar-H), 7.32-7.30 (d, 1H; J = 8.7 Hz; Ar-H), 7.08-7.29 (m, 9H; Ar-H), 6.86-6.79 (m, 2H; Ar-H), 6.09 (s, IH; OH, D 2 0 ex.), 4.72 (s, 2H; 30 triazolone-CH 2 ), 4.50-4.60 (d, IH; J =14.7 Hz;triazole-CH 2 ), 4.19-4.15 (d, IH; J 65 WO 01/66551 PCT/IBO1/00300 14.7 Hz; triazole-CH 2 ), 3.39-3.33 (br, 4H;piperazine-CH 2 -), 3.26 (s, 4H; piperazine-CH 2 -) & 2.04 (s, 3H; triazolne-CH 3 ) ppm. Compound No. 37: 5 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(3,4 dichlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone

NMR(CDCI

3 ):-S 8.16 (s, 1H; Ar-H), 7.83 (s, 1H; Ar-H), 7.59-7.56 (m, IH; Ar-H), 7.49 (s, 1H; Ar-H), 7.32-7.26 (m, 4H; Ar-H), 6.99-6.97 (d, 3H; Ar-H), 6.85-6.76 (m, 3H; Ar-H), 4.70 (s, 2H; triazolone-CH 2 ), 4.63-4.58 (d, 1H; J = 14.7 Hz; triazole 10 CH 2 ), 4.21-4.16 (d, 1H; J = 14.7 Hz; triazole-CH 2 ), & 3.33 (s, 8H; piperazine

CH

2 -) ppm. Compound No. 38: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2,4 15 diaminophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone NMR(CDCIJ):- 5 8.19 (s, 1H; Ar-H), 7.85 (s, 1H; Ar-H), 7.63-7.55 (m, IH; Ar-H), 7.51 (s, 1H; Ar-H), 7.28-7.25 (d, 3H; Ar-H), 7.01-6.98 (d, 2H; Ar-H), 6.89-6.80 (m, 3H; Ar-H), 6.15-6.10 (m,br, 2H; Ar-H), 4.72 (s, 2H; triazolone-CH 2 ), 4.65-4.60 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 4.23-4.18 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 3.34 20 (s, br, 4H; piperazine-CH2 ) & 3.02-3.00 (d, 4H; piperazine-CH 2 -)ppm. Compound No. 39: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 25 NMR(CDCI 3 ):-6 8.18 (s, 1H; Ar-H), 7.85 (s, 1H; Ar-H), 7.64-7.55 (q, IH; Ar-H), 7.50 (s, 1H; Ar-H), 7.29-7.27 (t, 3H; Ar-H), 7.14-7.11 (d, 2H; Ar-H), 7.03-6.99 (d, 2H; Ar-H), 6.93-6.80 (m, 4H; Ar-H), 5.95 (s, 1H; OH, D 2 0 ex.), 4.72 (s, 2H; triazolone-CH 2 ), 4.66-4.61 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 4.23-4.17 (d, IH; J = 14.7 Hz; triazole-CH 2 ), 3.38-3.36 (d, 4H; piperazine-CH 2 -), 3.31-3.29(d, 4H; 30 piperazine-CH 2 -) & 2.31 (s, 3H; triazolne-CH 3 ) ppm. 66 WO 01/66551 PCT/IBO1/00300 Compound No. 40: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-(2,4 dinitrophenyl)-l -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone

NMR(CDCI

3 ):- 6 8.74-8.73 (d, 1 H; Ar-H), 8.33-8.29 (m, 1 H; Ar-H), 8.17 (s, 1 H; Ar 5 H), 7.82 (s, 1H; Ar-H), 7.60-7.53 (m, 2H; Ar-H), 7.32-7.29 (d, 3H; Ar-H), 7.19-7.16 (d, 1H; Ar-H), 6.98-6.95 (d, 2H; Ar-H), 6.85-6.79 (m, 2H; Ar-H), 5.90 (s, 1H; OH,

D

2 0 ex.), 4.72 (s, 2H; triazolone-CH 2 ), 4.62-4.57 (d, 1H; J = 14.7 Hz; triazole

CH

2 ), 4.22-4.18 (d, IH; J = 14.7 Hz; triazole-CH2), 3.46-3.43(d, 8H; piperazine

CH

2 -) ppm 10 Compound No. 41: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 methoxyphenyl)-1 -piperazinyl]pheny}-3-(2H,4H)-1,2,4-triazolone

NMR(CDC

3 ):-9 8.19 (s, 1H; Ar-H), 7.86 (s, 1H; Ar-H), 7.65-7.57 (q, IH; Ar-H), 15 7.51 (s, 1H; Ar-H), 7.31-7.28 (m, 2H; Ar-H), 7.04-6.81 (m, 8H; Ar-H), 5.96 (s, 1H; OH, D 2 0 ex.), 4.73 (s, 2H; triazolone-CH 2 ), 4.66-4.61 (d, IH; J = 15.0 Hz; triazole-CH 2 ), 4.24-4.19 (d, 1H; J = 15.0 Hz; triazole-CH 2 ), 3.81 (s, 3H, -OCH 3 ), 3.40-3.37 (d, 4H;J piperazine-CH-), & 3.26-3.23 (d, 4H; piperazine-CH 2 -) ppm. 20 Compound No. 42: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2 methoxyphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone

NMR(CDCI

3 ):-6 8.19 (s, 1H; Ar-H), 7.85 (s, 1H; Ar-H), 7.64-7.55 (q, 1H; Ar-H), 7.50 (s, 1H; Ar-H), 7.29-7.26 (t, 2H, Ar-H), 7.09-6.80 (m, 8H;Ar-H), 4.72 (s, 2H; 25 triazolone-CH 2 ), 4.66-4.61 (d, IH; J = 15.0 Hz; triazole-CH 2 ), 4.23-4.18 (d, 1H; J = 14.7 Hz; triazole-CH 2 ), 3.91 (s, 3H, -OCH 3 ), 3.43-3.39 (t, 4H; piperazine-CH-), & 3.25-3.22 (t, 4H; piperazine-CH 2 -) ppm. Compound No. 43: 30 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 67 WO 01/66551 PCT/IBO1/00300

NMR(CDCI

3 ):-8 8.17 (s, 1H; Ar-H), 7.84 (s, IH; Ar-H), 7.59-7.57 (q, 1H; Ar-H), 7.49 (s, 1H; Ar-H), 7.29-7.26 (t, 2H; Ar-H), 7.03-6.79 (s, 8H; Ar-H), 5.93 (s, 1H; OH, D 2 0 ex.), 4.71 (s, 2H; triazolone-CH 2 ), 4.64-4.59 (d, 1H; J = 14.7 Hz; triazole-CH 2 ), 4.21-4.17 (d, 1H; J = 14.7 Hz; triazole-CH 2 ), 3.38-3.34 (t, 4H; 5 piperazine-CH 2 -), & 3.27-3.24 (t, 4H; piperazine-CH 2 -) ppm. Compound No. 44: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1 -yi)propyl]-4-{4-[4-(4 hydroxyphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 10 NMR(CDCI 3 ):-S 8.86 (s, 1H; Ar-H), 8.32-8.27 (d, 2H; Ar-H), 7.72 (s, 1H; Ar-H), 7.44-7.41 (d, 2H; Ar-H), 7.33-7.30 (q, IH; Ar-H), 7.18-7.14 (t, IH; Ar-H), 7.10 7.07 (d, 2H; Ar-H), 6.94-6.84 (m, 3H; Ar-H), 6.69-6.66 (d, 2H; Ar-H), 6.19 (s, IH; OH, D 2 0 ex), 4.83-4.77 (d, 1H; J = 14.4 Hz; triazole-CH 2 ), 4.66-4.62 (d, 1H; J = 14.4 Hz; triazole-CH 2 ), 4.20 (s, 2H; triazolone-CH 2 ), 3.35-3.32 (merging with 15 DMSO-d, signal)(s, 4H; piperazine-CH-), & 3.11-3.09(d, 4H; piperazine-CH,-) ppm. Compound No. 45: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-[4-[1 20 phenylpiperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone NMR(CDCI 3 ):- 8 8.19(s, I H; Ar-H), 7.85 (s, 1H; Ar-H), 7.64-7.56 (s, 1H; Ar-H), 7.50 (s, IH; Ar-H), 7.35-7.27 (m, 5H; Ar-H), 7.03-6.80 (m, 7H; Ar-H), 5.95 (s, 1H; OH, D 2 0 ex.), 4.72 (s, 2H; triazolone-CH 2 ), 4.66-4.61 (d, 1H; J = 14.7 Hz; triazole-CH 2 ), 4.23-4.18 (d, 1H; J = 14.7 Hz; triazole-CH2), & 3.37(s, 8H; piperazine-CH 2 -) ppm. 25 Compound No. 46: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 chlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone NMR(CDCI,):-88.17 (s, 1H;Ar-H), 7.81(s, 1H;Ar-H), 7.58-7.55 (m, 1H;Ar-H), 7.32 30 7.26 (m, 2H;Ar-H), 7.06-6.78 (m, 9H;Ar-H), 6.06 (s, 1H; OH, D 2 0 ex.), 4.70 (s, 2H; triazolone-CH 2 ), 4.54-4.49 (d, 1H; J = 14.7 Hz; triazole-CH 2 ), 4.19-4.14 (d, 68 WO 01/66551 PCT/IBO1/00300 1H; J = 14.7 Hz; triazole-CH 2 ), 3.37-3.33 (t, 8H; piperazine-CH-), & 2.03 (s, 3H; triazolone-CH 3 ) ppm. Compound No. 47: 5 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 chlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone

NMR(CDCI

3 ):-S 8.17 (s, 1H; Ar-H), 7.83 (s, IH; Ar-H), 7.62-7.54 (m, 1H; Ar-H), 7.50 (s, IH; Ar-H), 7.29-7.23 (m, 4H; Ar-H), 7.01-6.98 (d, 2H; Ar-H), 6.91-6.79 (m, 8H; Ar-H), 5.96 (s, IH; OH, D 2 0 ex.), 4.72 (s, 2H; triazolone-CH 2 ), 4.63-4.59 (d, 10 1H; J = 14.7 Hz; triazole-CH 2 ), & 4.22-4.17 (d, IH; J = 14.7 Hz; triazole-CH2), & 3.37-3.30 (q, 8H; piperazine-CH 2 -) ppm. Compound No. 48: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-I -yl)propyl]-4-{4-[4-(5 chloro-2-methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 15 NMR(CDCI 3 ):-S 8.28 (s, 1H; Ar-H), 7.90 (s, 1H; Ar-H), 7.66-7.58 (m, 1H; Ar-H), 7.53 (s, IH; Ar-H), 7.32-7.29 (t, 2H; Ar-H), 7.29-7.26(d, 2H; Ar-H), 7.16-7.14 (d, IH; Ar-H), 7.04-7.02(d, 4H, Ar-H), 6.89-6.82(m, 2H, Ar-H),5.96(br, 1H; OH, D 2 0 ex.), 4.74 (s, 2H; triazolone-CH 2 ), 4.67-4.62 (d, IH; J = 14.7 Hz; triazole-CH 2 ), & 4.26-4.20 (d, IH; J = 14.7 Hz; triazole-CH 2 ), 3.40-3.33(m, 4H; piperazine-CH 2 -), 20 3.10-3.07 (m, 4H; piperazine-CH 2 -) ppm. Compound No. 49: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(3 chloro-4-methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone 25 NMR(CDCI 3 ):- S 8.20 (s, 1 H; Ar-H), 7.87 (s, 1 H; Ar-H), 7.65-7.58 (q, I H; Ar-H), 7.52 (s, IH; Ar-H), 7.31-7.29 (d, 2H; Ar-H), 7.16-7.14(d, 2H; Ar-H),7.04-6.98 (m, 3H; Ar-H), 6.88-6.80 (m, 3H; Ar-H), 5.96(s, 1H; OH, D 2 0 ex.), 4.74 (s, 2H; triazolone-CH 2 ), 4.67-4.62 (d, 1H; J = 14.7 Hz; triazole-CH 2 ), & 4.24-4.17 (d, 1H; J = 14.7 Hz; triazole-CH 2 ), & 3.3-3.33 (m, 8H; piperazine-CH 2 -) ppm. 30 69 WO 01/66551 PCT/IBO1/00300 Compound No. 50: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2,4 dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone

NMR(CDCI

3

):

8.19 (s, IH; Ar-H), 7.86 (s, 1H; Ar-H), 7.65-7.56 (m, 1H; Ar-H), 7.51 (s, 1H; Ar 5 H), 7.43-7.42(d, IH; Ar-H),7.31-7.23 (m, 3H; Ar-H), 7.03-7.01 (d, 3H; Ar-H), 6.88 6.81 (m, 2H; Ar-H), 5.93 (s, 1 H; OH, D 2 0 ex.), 4.73 (s, 2H; triazolone-CH 2 ), 4.66 4.61 (d, 1 H; J = 14.7 Hz; triazole-CH 2 ), & 4.24-4.19 (d, I H; J= 14.7 Hz; triazole

CH

2 ), 3.42-3.39 (m, 4H; piperazine-CH 2 -) , 3.22-3.18 (m, 4H; piperazine-CH 2 -) ppm. 0 Compound No. 51: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(3 trifluoromethylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone NMR(CDCI,):- 8 8.16 (s, IH; Ar-H), 7.83 (s, IH; Ar-H), 7.62-7.57 (q, IH; Ar-H), 5 7.49 (s, 1H; Ar-H), 7.40-7.35 (t, IH; Ar-H), 7.29-7.26(d, 2H; Ar-H), 7.15-7.09(m, 3H; Ar-H),7.01-6.98 (d, 2H; Ar-H), 6.84-6.78 (m, 2H; Ar-H), 5.90(s, 1H; OH, D 2 0 ex.), 4.70 (s, 2H; triazolone-CH 2 ), 4.63-4.58 (d, IH; J = 14.7 Hz; triazole-CH 2 ), & 4.21-4.16 (d, IH; J= 14.7 Hz; triazole-CH 2 ), & 3.37 (s, 8H; piperazine-CH 2 -) ppm. 20 Compound No. 52: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2,4 difluoropheny)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone

NMR(CDCI

3

):

8.16 (s, 1H; Ar-H), 7.83 (s, IH; Ar-H), 7.62-6.78 (m, 11H; Ar-H), 5.90 (s, 1H, OH), 4.70 (s, 2H; triazolone-CH 2 ), 4.63 (d, 1H; J = 14.9 Hz; triazole-CH 2 -), 4.19 25 (d, 1H; J= 14.9 Hz; triazole-CH 2 -), 3.35 (bm, 4H; piperazine-CH 2 ), 3.16 (bm, 4H; piperazine

-CH

2 ) ppm Compound No. 53: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(3 30 chloro-4-fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone NMR(CDCl 3 ):- 8.17(s, 1H; Ar-H), 7.84(s, 1H; Ar-H), 7.62-7.54 (m, 1H; Ar-H), 70 WO 01/66551 PCT/IBO1/00300 7.49 (s, 1H; Ar-H), 7.29-7.26 (m, 2H; Ar-H), 7.08-6.95 (m, 4H; Ar-H),6.83-6.98(m, 3H; Ar-H), 5.90 (s, 1 H; OH, D 2 0 ex.), 4.71 (s, 2H; triazolone-CH 2 ), 4.63-4.59 (d, 1H; J = 14.8 Hz; triazole-CH 2 ), 4.21-4.16 (d, 1H; J = 14.8 Hz; triazole-CH 2 ), 3.35-3.34 (d, 4H; 2 x piperazine-CH2-) & 3.27-3.26 (d, 4H; 2 x piperazine-CH 2 -) 5 ppm. Compound No. 54: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2,4 dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone NMR(CDCl 3

):

0 8.16 (s, 1H; Ar-H), 7.82 (s, 1H; Ar-H), 7.59-7.57 (m, 1H; Ar-H), 7.48 (s, 1H; Ar H), 7.24-7.27 (m, 3H; Ar-H), 7.02-6.78 (m, 7H; Ar-H), 5.93 (s, 1 H; OH, D 2 0 ex.), 4.63-4.70 (s, 2H; triazolone-CH 2 ), 4.47-4.58 (d, I H; J = 15 Hz; triazole-CH 2 ), 4.21-4.16 (d, IH; J= 15 Hz; triazole-CH2), 3.35-3.32 (m, 4H; 2 x piperazine-CH 2 ) , 3.04-3.01 (m, 4H; 2 x piperazine-CH 2 -) 2.30 (s, 3H; CH 3 ) & 2.28 (s, 3H, CH 3 ) 15 ppm. Compound No. 57: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yi)propyl]-4-{4-[4-(3 chlorophenyl)-1-piperaziny]phenyl}-3-(2H,4H)-1,2,4-triazolone

NMR(CDCI

3

):

20 8.16 (s, 1H; Ar-H), 7.83 (s, 1H; Ar-H), 7.59-7.57 (q, 1H; Ar-H), 7.49 (s, 1H; Ar H), 7.29-7.26(d, 2H; Ar-H), 7.22-7.17(t, 1H; Ar-H),7.00-6.97 (d, 2H; Ar-H), 6.92 6.91 (m, IH; Ar-H),6.87-6.78 (m, 4H; Ar-H), 5.90(s, IH; OH, D 2 0 ex.), 4.70 (s, 2H; triazolone-CH 2 ), 4.63-4.58 (d, 1H; J = 14.7 Hz; triazole-CH 2 ), & 4.21-4.16 (d, I H; J = 14.7 Hz; triazole-CH 2 ), & 3.34 (s, 8H; piperazine-CH 2 -) ppm. 25 Compound No. 58: 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-(2 chloro-4-fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone

NMR(CDCI

3 ):- 6 8.18(s, 1H; Ar-H), 7.84(s, 1H; Ar-H), 7.59-7.57 (m, IH; Ar-H), 30 7.49 (s, 1H; Ar-H), 7.29-6.79 (m, 9H; Ar-H), 5.92 (s, IH; OH, D 2 0 ex.), 4.71 (s, 2H; triazolone-CH 2 ), 4.64-4.59 (d, 1H; J= 14.8 Hz; triazole-CH 2 ), 4.22-4.17 (d, 71 WO 01/66551 PCT/IBO1/00300 1 H; J = 14.8 Hz; triazole-CH 2 ), 3.38-3.35 (t, 4H; 2 x piperazine-CH 2 -) & 3.23-3.20 (t, 4H; 2 x piperazine-CH 2 -) ppm. Compound No. 59: 5 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2 methoxy-5-fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone

NMR(CDCI

3 ):-S 8.19(s, IH; Ar-H), 7.85(s, 1H; Ar-H), 7.60-7.57 (m, 1H; Ar-H), 7.50 (s, 1H; Ar-H), 7.29-7.26 (m, 3H; Ar-H),7.02-6.99 (d, 2H; Ar-H), 6.85-6.78 (m, 3H; Ar-H),6.72-6.68(m, 2H; Ar-H),5.95 (s, 1 H; OH, D 2 0 ex.), 4.72 (s, 2H; 10 triazolone-CH 2 ), 4.65-4.60 (d, 1H; J = 14.8 Hz; triazole-CH 2 ), 4.22-4.17 (d, 1H; J = 14.8 Hz; triazole-CH 2 ), 3.87(s,3H;0CH 3 ), 3.41-3.38 (d, 4H; 2 x piperazine-CH 2 -) & 3.22-3.21 (d, 4H; 2 x piperazine-CH 2 -) ppm. PHARMACOLOGICAL ACTIVITY 15 Compounds of the Formulae IA, 11, I and Ill as shown herein, and their salts are useful in the curative or prophylactic treatment of fungal infections in animals, including humans. For example, they are useful in treating topical fungal infection in man caused by, among other organisms, species of candida, Trichophyton, Microsporum or Epidermophyton in mucosal infections caused by 20 C. albicans (e.g., thrush and vaginal candidiasis). They can also be used in the treatment of systemic fungal infections caused by, for example, species of Candida (e.g., Candida albicans), Cryptococcus neoformans or Aspergillus fumigatus. The compounds of the present invention have been found to have 25 unexpectedly good activity against clinically important Aspergillus species fungi. 72 WO 01/66551 PCT/IBO1/00300 The in vitro evaluation of the antifungal activity of the compounds can be performed by determining the minimum inhibitory concentration (MIC) which is the concentration of the test compound in Rosewell Park Memorial Institute (RPMI) 1640 liquid medium buffered with (3-[Morpholino]propanesulphonic acid) 5 MOPS to pH7, at which there is significant inhibition of the particular fungi In practice the National Committee for Clinical Laboratory Standard (NCCLS) M27A document for Candida and Cryptococcus and M38P for Aspergillus was used to determine the MIC against yeast and filamentous fungi with suitable modifications for dermatophytes. Two quality control strains were included each time the MIC 0 were determined and readings recorded only when the QC results fell into the acceptable range. After MIC results had been recorded, 100 [d from each of the well showing no growth was spread over Sabouraud Dextrose Aqvar (SDA) to determine the minimum fungicidal concentration. The in vivo evaluation of the compound can be carried out at a series of 15 dose levels by oral or I.V. injection to mice which are inoculated I.V. with the minimum lethal dose of Candida albicans, Cryptococcus neoformans or Aspergillus fumigatus by the tail vein. Activity is based on the survival of a treated group of mice after the death of an untreated group of mice. For Aspergilus and Cryptococcus infections target organs were cultured after 20 treatment to document the number of mice cured of the infection for further assessment of activity. For human use, the antifungal compounds of the formula and their salts can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of 73 WO 01/66551 PCT/IBO1/00300 administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring 5 agents. They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. 0 The solubility of a compound of the Formulae IA, IB, 11 and Ill in an aqueous medium may be improved by complexation with a hydroxyalkyl derivative of a cyclodextrin in the preparation of an appropriate pharmaceutical composition. For oral and parenteral administration to human patients, the daily dosage 15 level of the antifungal compounds of the Formulae IA, IB, Il and Ill and their salts will be from 0.01 to 20 mg/kg (in single or divided doses) when administered by either the oral or parenteral routes. Thus tablets or capsules of the compound will contain from 5 mg to 0.5 gm of active compound for administration one, two or more at a time, as appropriate. The physician in any event will determine the 20 actual dosage which will be most suitable for an individual patient and it will vary with age, weight and response of the particular patient. The above dosages are exemplary of the average case, there can, of course, be individual instances, where higher or lower dosage ranges are required and such are within the scope of this invention. 74 WO 01/66551 PCT/IBO1/00300 Alternatively, the antifungal compound or Formulae IA, IB, 11 and IlIl can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream consisting of an aqueous 5 emulsion of polyethylene glycols or liquid paraffin, or they can be incorporated, at a concentration between 1 and 10 % into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required. Cryptococcosis is a leading cause of morbidity and mortality among AIDS 10 patients. In many patients Cryptococcosis is the first indication of AIDS. The incidences of life-threatening cryptococcal infection among patients with AIDS has been estimated to vary from 10 - 30 %. During initial therapy, 10 - 20 % of these patients die and 30 - 60 % patients succumb within 12 months (Powderly WG: Cryptococcus meningitis and AIDS Clin. Infect. Dis. 1993; 17: 837 - 842). 15 Amphotericin B has changed disseminated cryptococcosis from uniformly fatal infection to curable infection, but since Amphotericin B penetrates the central nervous system poorly, intraventricular injection may have to be administered for successful management of severe cases of Cryptococcal meningitis. Fluconazole has excellent pharmacokinetics in CSF and performs 20 equally well in patients with Cryptococcal meningitis. However, there is a trend towards earlier deaths and longer period before sterilisation of the CSF (NIAID [National Institute of Allergy and Infection Disease] Mycoses study group and AIDS clinical trials group: comparison of Amphotericin B and Fluconazole in the 75 WO 01/66551 PCT/IBO1/00300 treatment of acute AIDS associated Cryptococcus meningitis (N Engl J Med 1992; 326: 83 - 89). Invasive aspergillosis has become a leading cause of death, mainly among patients suffering from acute leukaemia or after allogenic bone marrow 5 transfusion and after cytotoxic treatment of these conditions. It also occurs in patients with conditions such as AIDS and chronic granulomatous disease. At present, only Amphotericin B and Itraconazole are available for treatment of aspergillosis. In spite of their activity in vitro, the effect of these drugs in vivo against Aspergillus fumigatus remains low and as a consequence mortality from 10 invasive aspergillosis remains high. In vitro activity: Compounds of this invention have potent in vitro activity against a wide range of fungal pathogens tested. They are active against all species of Ca-ndida, Histoplasma capsulatum, Cryptococcus neoformans, dermatophytes, 15 Aspergillus fumigatus and A. flavus. The action on many of these strains, especially against Cryptococcus and Aspergillus is fungicidal in vitro. 76 WO 01/66551 PCT/IBO1/00300 Table containing the biological evaluation of these compounds Candida albicans C.krusei C.parap- Candida C. H. C. neoformans A. siosis tropicalis glabrata capsul- fumigatu No. Q. C. ATCC 90030 atum s 1008 A 26 1.549 Y-01-19 766-1 Q. C I M 106 1 <0.03 0.12 0.12 0.25 0.12 <0.03 <0.03 0.25 0.06 <0.03 <0.03 0.12 2 <0.03 1.00 0.25 2.00 1.00 <0.03 <0.03 0.50 <0.03 <0.03 <0.03 >16 3 <0.03 0.12 0.50 1.00 0.50 <0.03 <0.03 0.25 <0.03 <0.03 <0.03 0.25 4 <0.03 4.00 >16 >16 >16 0.25 <0.03 2.00 0.50 0.25 1.00 >16 5 <0.03 2.00 0.12 0.50 0.12 <0.03 <0.03 1.00 <0.03 <0.03 <0.03 0.50 6 <0.03 2.00 8.00 >16 16.0 0.125 <0.03 >16 0.12 0.25 2.00 >16 7 <0.03 0.25 0.12 0.25 0.12 <0.03 <0.03 0.12 0.12 <0.03 <0.03 0.25 8 <0.03 >16 > 16 >16 > 16 1.00 >16 >16 2.00 16.00 16.00 >16 9 <0.03 0.25 0.25 0.50 0.12 <0.03 <0.03 0.25 0.06 <0.03 <0.03 0.50 10 <0.03 0.50 1.00 >16 1.00 <0.03 <0.03 0.50 0.06 0.06 <0.03 >16 11 <0.03 0.06 0.12 0.25 0,12 <0.03 <0.03 0.25 <0.03 <0.03 <0.03 0.25 12 <0.03 4.00 8.00 >16 8.00 0.06 <0.03 4.00 <0.03 0.12 0.25 >16 13 <0.03 0.12 0.25 0.50 0.12 <0.03 <0.03 0.50 0.06 <0.03 <0.03 0.25 14 <0.03 2.00 2.00 >16 16.0 0.06 <0.03 2.00 0.12 0.50 <0.03 >16 15 <0.03 1.00 0.25 0.50 0.25 <0.03 <0.03 0.50 0.12 <0.03 <0.03 0.50 16 <0.03 4.00 1.00 >16 1.00 0.06 <0.03 0.50 0.50 0.12 0.12 >16 17 <0.03 0.25 0.25 0.50 0.50 <0.03 <0.03 0.50 0.25 <0.03 <0.03 0.25 18 <0.03 2.00 1.00 >16 2.00 0.25 <0.03 1.00 0.25 0.12 0.25 >16 19 <0.03 1.00 1.00 >16 0.50 0.06 <0.03 >16 0.50 <0.03 <0.03 >16 20 <0.03 8.00 2.00 >16 2.00 0.12 <0.03 2.00 0.50 0.25 0.25 >16 21 <0.03 0.25 0.25 0.50 0.25 0.06 <0.03 0.50 0.12 <0.03 <0.03 1.00 22 <0.03 2.00 1.00 8.00 1.00 0.25 <0.03 1.00 >16 0.12 0.06 >16 23 <0.03 0.25 0.50 0.50 0.25 <0.03 <0.03 0.50 0.06 <0.03 <0.03 1.00 24 <0.03 2.00 16.00 >16 16.0 0.25 <0.03 2.00 0.25 0.50 1.00 >16 25 <0.03 0.06 0.12 0.12 0.06 <0.03 <0.03 0.12 0.06 <0.03 <0.03 0.50 26 <0.03 0.25 1.00 2.00 0.50 <0.03 <0.03 1.00 0.12 <0.03 <0.03 8.00 27 <0.03 1.00 0.50 2.00 0.50 <0.03 <0.03 1.00 <0.03 <0.03 <0.03 >16 28 <0.03 8.00 4.00 >16 16.0 0.25 <0.03 4.00 2.00 0.25 1.00 >16 29 <0.03 0.25 0.25 0.50 0.25 <0.03 <0.03 0.50 0.25 <0.03 <0.03 0.50 30 <0.03 0.50 1.00 8.00 1.00 0.12 <0.03 1.00 0.50 0.12 0.25 >16 31 <0.03 >16 0.12 0.50 0.12 <0.03 <0.03 0.50 0.06 <0.03 <0.03 1.00 32 <0.03 >16 4.00 >16 4.00 0.50 <0.03 2.00 0.25 0.50 0.50 >16 33 <0.03 0.13 0.13 0.25 0.06 <0.03 <0.03 0.25 0.12 <0.03 <0.03 0.50 34 <0.03 1.00 1.00 2.00 1.00 0.25 <0.03 0.50 0.12 0.25 <0.03 >1677 35 <0.02 1.56 3.12 12.50 3.12 0.20 <0.02 12.50 0.20 0.80 3.12 >12.5 36 <0.02 0.20 0.40 3.12 1.56 <0.02 <0.02 3.12 <0.02 0.20 0.40 >12.5 37 <0.03 0.06 0.06 0.25 0.06 <0.03 <0.03 0.12 <0.03 <0.03 <0.03 >16 38 >16 >16 >16 >16 >16 >16 >16 >16 >16 >16 >16 >16 39 <0.02 0.10 0.02 0.80 0.10 <0.02 6.25 0.10 0.05 <0.02 0.05 6.25 40 <0.02 0.40 0.40 6.25 1.56 0.05 1.56 0.80 0.05 0.05 0.20 1.56 41 <0.02 0.05 0.10 1.56 0.40 <0.02 3.12 0.80 <0.02 0.10 0.40 6.25 42 0.05 0.40 12.50 3.12 1.56 <0.02 12.50 1.56 0.05 0.20 0.80 >12.5 43 <0.02 <0.02 0.05 1.56 0.20 <0.02 12.50 0.40 <0.02 0.05 0.05 >12.5 44 >12.5 >12.5 1.56 >12.5 6.25 0.20 6.25 6.25 1.56 1.56 3.12 >12.5 45 <0.02 0.05 0.05 0.80 0.10 <0.02 3.12 0.10 3.12 <0.02 0.10 >12.5 46 <0.02 0.40 0.40 3.12 0.80 <0.02 0.05 6.25 0.10 0.05 0.40 >12.5 47 <0.02 0.20 0.20 1.56 1.56 <0.02 <0.02 3.12 0.05 <0.02 0.40 3.12 48 <0.03 0.50 0.50 1.00 0.50 0.12 <0.03 1.00 0.25 <0.03 0.06 >16 49 <0.03 <0.03 <0.03 0.25 0.06 <0.03 <0.03 0.25 <0.03 <0.03 <0.03 4.00 50 <0.03 0.12 0.12 0.50 0.25 <0.03 <0.03 0.50 <0.03 <0.03 <0.03 2.00 77 WO 01/66551 PCT/IBO1/00300 Candida albicans C.krusei C.parap- Candida C. H. C. neoformans A. silosis tropicalis glabrata capsul- fumigatu No. Q. C. ATCC 90030 atum s 1008 A 26 1.549 Y-01-19 766-1 Q. C I M 106 51 <0.03 0.25 0.25 1.00 0.25 0.06 <0.03 1.00 <0.03 <0.03 <0.03 >16 52 <0.03 0.06 0.12 4.00 0.50 <0.03 <0.03 1.00 <0.03 <0.03 <0.03 >16 53 <0.03 0.06 <0.03 0.50 0.12 <0.03 <0.03 1 0.50 <0.03 <0.03 <0.03 4.00 54 <0.03 8.00 0.12 0.50 0.12 <0.03 <0.03 1.00 0.06 <0.03 <0.03 2.00 55 <0.03 0.03 0.03 1.00 0.12 <0.03 <0.03 0.25 0.004 <0.03 0.02 >16 56 <0.03 0.06 0.03 1.00 0.25 <0.03 <0.03 0.25 0.004 <0.03 0.03 >16 57 <0.03 0.25 0.12 0.50 0.25 <0.03 <0.03 0.25 0.06 <0.03 <0.03 >16 58 <0.03 0.03 0.03 1.00 0.25 <0.03 <0.03 0.25 0.004 <0.03 <0.03 2.00 59 <0.03 1.00 0.50 4.00 1.00 <0.03 <0.03 1.00 <0.03 <0.03 0.12 >16 60 <0.03 >16 0.25 1.00 0.25 <0.03 <0.03 0.50 <0.03 <0.03 <0.03 >16 61 <0.03 0.25 0.12 0.50 0.25 <0.03 <0.03 0.50 <0.03 <0.03 <0.03 >16 62 <0.03 4.00 0.50 2.00 0.50 <0.03 <0.03 1.00 <0.03 <0.03 0.12 16.00 63 <0.03 0.06 0.12 8.00 0.25 <0.03 <0.03 0.50 <0.03 <0.03 <0.03 >16 In vivo activity: Compounds of this invention have enhanced antifungal activity against the 5 important fungal pathogens of men and animals. a) Anti candida activity: A single oral dose of 12.5 mg / kg bw. (0.25 mg per mouse) is adequate to offer significant protection to mice infected via the tail vein by lethal dose of C. albicans A-26. 0 Summary of single dose studies with azoles in systemic infection with Candida albicans A-26 Example Mean survival days 1 (ped) 12.1 1 10.5 Sham treated 3.5 78 WO 01/66551 PCT/IBO1/00300 b) Anti cryptococcal activity: The compounds of this invention cross the blood brain barrier to excert their potent anti cryptococcal activity in the brain. In an animal model where lethal infection (1 million cells of C. neoformans) were injected into 5 the cranium of the animal, oral dosing with 25 mg/kg bw. BID for 8 days reduced the count by 4 logs, causing 99.99 % reduction in the fungal load. c) Anti Aspergillus activity: Doses as low as 6.25 mg / kg bw. significantly increased the survival of mice infected via the tail vein with lethal dose of Aspergillus fumigatus 10 conidia. d) Anti Dermatophyte activity: Single local application of the drug had significant effect on Trichophyton mentagrophyte infection of guinea pig skin. 79

Claims (23)

1. A compound of Formula IA R, 0 R 3 X1 Y, N N-Y-N N Z N F Nz< RX2 Y2 R FORMULA IA and its pharmaceutically acceptable salts, enantiomers, diastereomers, N oxides, prodrugs or metabolites, wherein X is selected from the group consisting of CH 2 , CO, CS, SO 2 and -N=N-, R is selected from the group consisting of (1) Cl-C 4 alkyl which is unsubstituted or substituted with . 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C-C 4 alkoxy and amino (2) C-C 4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C-C 4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl; R 1 and R 2 are each independently selected from the group consisting of (1) hydrogen,.(2) C-C 4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of 80 WO 01/66551 PCT/IBO1/00300 halogen, hydroxy, CrC4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) Cr1C4 alkoxy; Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C-C4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl; R 3 is selected from the group consisting of C1C4 alkyl group, halogen, hydroxy, C1C4 alkoxy, nitro, amino, cyano, carboxyl and SO 2 R' wherein R' is hydrogen, alkyl or aryl ; X 1 , X 2 , Y 1 , Y 2 and Z are independently selected from the group consisting of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C1C4 alkyl, C1C4 alkoxy, carboxyl or protected carboxyl.

2. A compound of Formula IB OR 4 N AN-Y-N N N F R2<R 5 R FORMULA IB 81 WO 01/66551 PCT/IBO1/00300 and its pharmaceutically acceptable salts, enantiomers, diastereomers, N oxides, prodrugs or metabolites, wherein X is selected from the group consisting of CH 2 , CO, CS, SO 2 and -N=N-, R is selected from the group consisting of (1) C1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (2) C1C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) Cl-C 4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yi; R 1 and R 2 are each independently selected from the group consisting of (1) hydrogen, (2) C1C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) Cr1C4 alkoxy; Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano- (5) carboxyl or protected carboxyl (6) hydroxy (7) C-C4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl; 82 WO 01/66551 PCT/IBO1/00300 R 3 is selected from the group consisting of C1C4 alkyl group, halogen, hydroxy, C1C4 alkoxy, nitro, amino, cyano, carboxyl and SO 2 R' wherein R' is hydrogen, alkyl or aryl ; R 4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group which is unsubstituted or substituted; B is selected from oxygen and sulphur atoms; and R 5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) CrC4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (b) C1C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) CC4 acyloxy (g) C1C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (1) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 2 and (u) OCF 3 (4) naphthyl or naphthyl (C1C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1 - C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (b) halogen (c) (C C4 alkyl) halo, (d) C1C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoro 83 WO 01/66551 PCT/IBO1/00300 methoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (1) tetra fluoropropyl and (m) tetrafluoropropoxyl.

3. A compound of Formula Il R1 B N OR4 R O-Y-N NkN N F R 5 R FORMULA II and its pharmaceutically acceptable salts, enantiomers, diastereomers, N oxides, prodrugs or metabolites, wherein X is selected from the group consisting of CH 2 , CO, CS, SO 2 and -N=N-, R is selected from the group consisting of (1) Cl-C 4 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) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl; R 1 is selected from the group consisting of (1) hydrogen, (2) C 1 -C 4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and 84 WO 01/66551 PCT/IBO1/00300 amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) C1C4 alkoxy; R 4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group which is unsubstituted or substituted; and R 5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (b) C1C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1C4 acyloxy (g) C1C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (1) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 2 and (u) OCF 3 (4) naphthyl or naphthyl (C1C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1 - C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (b) halogen (c) (C C4 alkyl) halo, (d) Cr1C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoro methoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (1) tetra fluoropropyl and (m) tetrafluoropropoxyl; 85 WO 01/66551 PCT/IBO1/00300 B is selected from oxygen and sulphur atoms; and Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C-C4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl.

4. A compound of Formula Ill OH B NN-N X OR 5 \ H H N F CH3 R FORMULA III and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, wherein R is selected from the group consisting of (1) Cr1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (2) C1C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1C4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl; 86 WO 01/66551 PCT/IBO1/00300 R 1 is selected from the group consisting of (1) hydrogen, (2) C1C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) C1C4 alkoxy; R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, Cr1C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) Cr1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, CrC4 alkoxy and amino (b) C1C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1C4 acyloxy (g) C1C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (1) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 2 and (u) OCF 3 (4) naphthyl or naphthyl (C1C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1 - C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (b) halogen (c) (Cl C4 alkyl) halo, (d) C1C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (1) tetrafluoropropyl and (m) tetrafluoropropoxyl; 87 WO 01/66551 PCT/IBO1/00300 X is selected from the group consisting of CH 2 , CO, CS, SO 2 and -N=N-; Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C-C4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl; and B is selected from oxygen and sulphur atoms.

5. A compound is selected from the group consisting of: - 2-{[1 R2R/I S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(4-chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H) 1,2,4-triazolone (Compound No. 1) - 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(4-chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H) 1,2,4-triazolone (Compound No. 2) - 2-{[I R2R/I S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(I H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(2,4-dinitrophenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 3) - 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(2,4-dinitrophenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 4) - 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-[4-(1-phenylpiperazinyl)phenyl]-3-(2H,4H)-1,2,4 triazolone (Compound No. 5) - 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(I H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(I-phenylpiperazinyl) phenyl}-3-(2H,4H)-1,2,4 triazolone (Compound No. 6) 88 WO 01/66551 PCT/IBO1/00300 - 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(3,4-dichlorophenyl)-1-piperzinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 7) - 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yi) propyl}-4-{4-[4-(3,4-dichlorophenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 8) - 2-{1[ R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 9) - 2-{[1 R2S/I S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4 triazol-1-yi) propyl}-4-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 10) - 2-{[ R2R/I S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yi) propyl}-4-{4-[4-(4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H) 1,2,4-triazolone (Compound No. 11) - 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yi) propyl}-4-{4-[4-(4-fluorophenyl)-1-piperazinyl]pheny}-3-(2H,4H) 1,2,4-triazolone (Compound No. 12) - 2-{[ R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yi) propyl}-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 13) - 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 14) - 2-{[ R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(3-chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 15) - 2-{[I R2S/I S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(3-chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 16) , 89 WO 01/66551 PCT/IBO1/00300 - 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(3-chloro-4-methylphenyl)-1-piperaziny]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 17) - 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(3-chloro-4-methylphenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 18) - 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1 -yl) propyl}-4-{4-[4-(2,4-dimethylphenyl)-1 -piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 19) - 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(2,4-dimethylphenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 20) - 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yi) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 21) - 2-{[IR2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4 triazol-1-yi) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-1,2,4-triazolone (Compound No. 22) - 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(3,4-dimethylphenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 23) - 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(3,4-dimethylphenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 24) - 2-{[ R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(2-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5 methyl-1,2,4-triazolone (Compound No. 25) - 2-{[1 R2S/I S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(2-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5 methyl-1,2,4-triazolone (Compound No. 26) 90 WO 01/66551 PCT/IBO1/00300 - 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(2-methoxy-5-fluorophenyl)-1-piperazinyl]phenyl} 3-(2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 27) - 2-{[I R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(2-methoxy-5-fluorophenyl)-1-piperazinyl]phenyl} 3-(2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 28) - 2-{[1 R2R/I S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(3,5-dichlorophenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 29) - 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(3,5-dichlorophenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 30) - 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(2-ethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5 methyl-1,2,4-triazolone (Compound No. 31) - 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(2-ethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5 methyl-1,2,4-triazolone (Compound No. 32) - 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-I -methyl-3-(1 H-1,2,4 triazol-1-yl) propyl}-4-{4-[4-(2,4-dichlorophenyl)-1-piperazinyl]phenyl}-3 (2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 33) - 2-{[ R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1 -methyl-3-(1 H-1,2,4 triazol-1-yi) propyl}-4-{4-[4-(2,4-d ichlorophenyl)-1 -piperazinyl] phenyl}-3 (2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 34) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-I -yl)propyl]-4-{4-[4-(2 methoxyphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 35) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(IH-1,2,4-triazol-1-yl)propyl]-4-{4-[4-(4 fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-5-methyl- 1,2,4-triazolone (Compound No. 36) 91 WO 01/66551 PCT/IBO1/00300 - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4 (3,4-dichlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 37) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4 (2,4-diaminophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 38) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 39) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4 (2,4-dinitrophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 40) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-i -yl)propyl]-4-{4-[4-(4 methoxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 41) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2 methoxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 42) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 fluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 43) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-I -yl)propyll-4-{4-[4-(4 hydroxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 44) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-i -yl)propyl]-4-[4-[1 phenylpiperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 45) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(l H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-(4 chlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 46) 92 WO 01/66551 PCT/IBO1/00300 - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 chlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 47) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(5 chloro-2-methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 48) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(3 chloro-4-methylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 49) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-I -yl)propyl]-4-{4-[4 (2,4-dichlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 50) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-I -yl)propyl]-4-{4-[4-(3 trifluoromethylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 51) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4 (2,4-difluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 52) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-I -yl)propyl]-4-{4-[4-(3 chloro-4-fluorophenyl)-l -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 53) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4 (2,4-dimethylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 54) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4 (3,4-difluorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 55) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4 (3,4-dimethylphenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 56) 93 WO 01/66551 PCT/IBO1/00300 - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4- (3 chlorophenyl)-l-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 57). - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2 chloro- 4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 58) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2 methoxy- 5-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 59) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2 ethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No.60). - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-I -yl)propyl]-4-{4-[4 (3,5-dichlorophenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 61) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(2 fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 62) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1-yl)propyl]-4-{4-[4 (1,2,3- trifluorophenyl)-1 -piperazinyl] phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 63) - 3-{4-[4-(p-tolylaminothiocarbonylamino)piperazinyl]phenoxy}-2-(2,4 difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol. (Compound No. 64) - 3-{4-[4-(isopropylaminothiocarbonylamino)piperazinyl]phenoxy}-2-(2,4 difluorophenyl)-1 -(I H-1,2,4-triazol-I -yi)-propan-2-ol. (Compound No. 65) - 3-{4-[4-(4-chlorophenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-I (I H-1,2,4-triazol-1 -yi)-propan-2-ol (Compound No. 66) - 3-{4-[4-(4-chlorophenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1 (I H-1,2,4-triazol-1 -yl)-propan-2-ol. (Compound No. 67) - 3-{4-[4-(I-napthyl thioureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1 (1 H-1,2,4-triazol-1 -yi)-propan-2-ol. (Compound No. 68) 94 WO 01/66551 PCT/IBO1/00300 - 3-{4-[4-(1-hapthyl thioureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-l (1 H-1,2,4-triazol-1-yl)-propan-2-ol. (Compound No. 69) - 3-{4-[4-(4-trifluoromethylphenyl thioureido)piperazinyl]phenoxy}-2-(2,4 difluorophenyl)-1-(1'H-1,2,4-triazol-1-yl)-propan-2-ol. (Compound No. 70) - 3 -{ 4 -[ 4 -(4-methoxyphenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl) 1 -(1 H-1,2,4-triazol-1-yl)-propan-2-ol. (Compound No. 71) - 3-{4-[4-(2,4-dichlorophenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl) 1 -(I H-1,2,4-triazol-I -yl)-propan-2-ol (Compound No. 72) - 3-{4-[4-(4-chlorophenyl-N-ethylureido)-piperazinyl ]-phenoxy)-2-(2,4 difluorophenyl)-1 -(1 H-1,2,4-triazolyl)-propan-3-amino-2-o (Compound No. 73) - 3-{4-[4-(4-chlorophenyl-N-ethylureido)-piperazinyl ]-phenoxy)-2-(2,4 difluorophenyl)-1 -(1 H-1,2,4-triazolyl)-2-ethoxy-3-propylamine (Compound No. 74) - 3-{4-[4-N-(4-Chlorophenyl)-N-(methylureido)-piperazinyl ]-phenoxy}-2-(2,4 difluorophenyl)-1 -(1 H-1,2,4-triazolyl)-2-methoxypropane (Compound No. 75) - 3-{4-[4-(4-aminophenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1 (I H-1,2,4-triazol-1 -yl)-propan-2-ol. (Compound No. 76) - [1 R2R/1 S2S] 1 -{4-[4-(4-chlorophenylureido)-piperazinyl ]-phenoxy}-2-(2,4 difluorophenyl)-1 -methyl -3-(1 H-1,2,4-triazolyl)-propan-2-ol (Compound No. 77) - [1 R2S/1 S2R] I -{4-[4-(4-chlorophenylureido)-piperazinyl ]-phenoxy}2-(2,4 difluorophenyl)-1 -methyl -3-(1 H-1,2,4-triazolyl)-propan-2-ol (Compound No. 78) - 1 -{4-[4-(4-Trifluoromethylphenylureido)piperazinyl]phenoxy}-2-(2,4 difluorophenyl)-1-methyl-3-(1H-1,2,4-triazol-1-yl)-propan-2-o (Compound No. 79) - 3-{4-[4-(Phenylureido)-piperazinyl ]-phenoxy}-2-(2,4-difluorophenyl)-I -(1 H 1,2,4-triazol-1-yI)-propan-2-ol(Compound No. 80) - 2 -( 2 , 4 -Difluorophenyl)-3-{4-(thioureidophenyl)N-methyl-N-phenyl}- -(I H 1,2,4-triazolyl)-propan-3-amino-2-oI (Compound No. 81) 95 WO 01/66551 PCT/IBO1/00300 - 2-(2,4-Difluorophenyl)-3-{4-(isopropylthioureido)N-methyl-N-phenyl}-1 -(1 H 1,2,4-triazolyl)-propan-3-amino-2-oI (Compound No. 82) - 3-{N-[4-(p-Tolylthioureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1 -(I H 1,2,4-triazolyl)-propan-3-amino-2-oI (Compound No. 83) - 3-{N-[4-(p-Fluorophenylureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1 (1H-1,2,4-triazolyl)-propan-3-amino-2-oI (Compound No. 84) - 3-{N-[4-(p-Nitrophenyltureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1 (1 H-1,2,4-triazolyl)-propan-3-amino-2-o (Compound No. 85) - 3-{N-[4-(p-Chlorophenylureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1 (1 H-1,2,4-triazolyl)-propan-3-amino-2-oI (Compound No. 86) - 3-{N-[4-(Carboxymethyl)-phenyltureido)-phenyl]- N-methyl}-2-(2,4 difluorophenyl)-1-(IH-1,2,4-triazolyl)-propan-3-amino-2-o (Compound No. 87) - 3-{N-[4-(2-Methoxy-2-oxoethyl)-phenyltureido)-phenyl]- N-methyl}-2-(2,4 difluorophenyl)-1 -(I H-1,2,4-triazolyl)-propan-3-amino-2-oI (Compound No. 88) - 3-{N-[4-(p-Chlorophenylthiouredo)-phenyltureido)-phenyl]- N-methyl}-2-(2,4- difluorophenyl)-1 -(1 H-1,2,4-triazolyl)-propan-3-amino-2-oI (Compound No. 89) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(I H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4 (isopropylthiou red io)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 90) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-I -yl)propyl]-4-{4-[4-(4 chlorophenyluredio)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 91) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 chlorophenylthiouredio)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 92) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 (2-methoxy-2-oxoethyl)phenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone (Compound No. 93) - 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 (carboxyethyl)-phenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 94) 96 WO 01/66551 PCT/IBO1/00300 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-4-{4-[4-(4 (2-hydroxyethyl)phenyl)-1 -piperazinyl]phenyl}-3-(2H,4H)-1,2,4 triazolone(Compound No. 95)

6. A pharmaceutical composition comprising the compound of claim 1 to 5 and a pharmaceutical acceptable carrier.

7. A pharmaceutical composition comprising a pharmaceutically effective amount of compound according to claim 1 to 5 or a physiologically acceptable acid addition salt thereof with a pharmaceutically acceptable carrier foe treating fungal infection.

8. A method of treating or preventing fungal infection in mammals comprising administering to said animal a compound of Formula IA OHR 0 R 3 XI Y, N N-Y-N N Z N F Nz | ~R2X2Y R FORMULA IA and its pharmaceutically acceptable salts, enantiomers, diastereomers, N oxides, prodrugs or metabolites, wherein X is selected from the group consisting of CH 2 , CO, CS, SO 2 and -N=N-, 97 WO 01/66551 PCT/IBO1/00300 R is selected from the group consisting of (1) Cl-C 4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (2) C1C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1C4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl; R 1 and R 2 are each independently selected from the group consisting of (1) hydrogen, (2) C1C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) C1C4 alkoxy; Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C-C4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl; R 3 is selected from the group consisting of C1C4 alkyl group, halogen, hydroxy, C1C4 alkoxy, nitro, amino, cyano, carboxyl and SO 2 R' wherein R' is hydrogen, alkyl or aryl; and 98 WO 01/66551 PCT/IBO1/00300 X 1 , X 2 , Y 1 , Y 2 and Z are independently selected from the group consisting of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, Cr1C4 alkyl, C 1 -C 4 alkoxy, carboxyl or protected carboxyl.

9. A method of treating or preventing fungal infection in an animal comprising administering to said animal a compound of Formula IB R 1 0 B NII ,X OR4 'R N-Y-N 4 N N F R2N\__/RR R FORMULA IB and its pharmaceutically acceptable salts, enantiomers, diastereomers, N oxides, prodrugs or metabolites, wherein X is selected from the group consisting of CH 2 , CO, CS, SO 2 and -N=N-; R is selected from the group consisting of (1) Cl-C 4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (2) CrC4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C-C 4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl; 99 WO 01/66551 PCT/IBO1/00300 R 1 and R 2 are each independently selected from the group consisting of (1) hydrogen, (2) Cl-C 4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) S02R' wherein R' is hydrogen, alkyl or aryl and (8) C1C4 alkoxy; Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C-C4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl; R 3 is selected from the group consisting of C1C4 alkyl group, halogen, hydroxy, C1C4 alkoxy, nitro, amino, cyano, carboxyl and SO 2 R' wherein R' is hydrogen, alkyl or aryl; R 4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group which is unsubstituted or substituted; B is selected from oxygen and sulphur atoms; and R 5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1C4 alkyl 100 WO 01/66551 PCT/IBO1/00300 which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, CrC4 alkoxy and amino (b) C1C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) CrC4 acyloxy (g) C1C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (I) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 2 and (u) OCF 3 (4) naphthyl or naphthyl (C1C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1 - C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (b) halogen (c) (C C4 alkyl) halo, (d) C1C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (1) tetrafluoropropyl and (m) tetrafluoropropoxyl.

10. A method of treating or preventing fungal infection in an animal comprising administering to said animal a compound of Formula 11 R., B Ns NX O O-Y-N N N F R 5 R FORMULA II and its pharmaceutically acceptable salts, enantiomers, diastereomers, N oxides, prodrugs or metabolites, wherein 101 WO 01/66551 PCT/IBO1/00300 X is selected from the group consisting of CH 2 , CO, CS, SO 2 and -N=N-; R is selected from the group consisting of (1) C-C 4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (2) Cr1C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) Cr1C4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl; R 1 is selected from the group consisting of (1) hydrogen, (2) Cr1C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) Cr1C4 alkoxy; R 4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group which is unsubstituted or substituted; R 5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and 102 WO 01/66551 PCT/IBO1/00300 amino (b) C-C 4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) CI-C 4 acyloxy (g) C1C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (1) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 2 and (u) OCF 3 (4) naphthyl or naphthyl (0C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1 - C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (b) halogen (c) (C C4 alkyl) halo, (d) C1C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoro methoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (1) tetra fluoropropyl and (m) tetrafluoropropoxyl; B is selected from oxygen and sulphur atoms; and Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) Cl-C 4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl. 103 WO 01/66551 PCT/IBO1/00300

11. A method of treating or preventing fungal infection in an animal comprising administering to said animal a compound of Formula Ill R B OH N ,X N-Y- R5 F\ H H CHH N CH3 R FORMULA Ill and its pharmaceutically acceptable salts, enantiomers, diastereomers, N oxides, prodrugs or metabolites, wherein R is selected from the group consisting of (1) Cl-C 4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (2) C1C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) CC4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl; R 1 is selected from the group consisting of (1) hydrogen, (2) C1C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and 104 WO 01/66551 PCT/IBO1/00300 amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) C1C4 alkoxy; R 5 is selected from the group (1) hydrogen, (2) C- C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (b) C1C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1C4 acyloxy (g) C1C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (1) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 2 and (u) OCF 3 (4) naphthyl or naphthyl (C1C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1 - C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (b) halogen (c) (C C4 alkyl) halo, (d) C1C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (1) tetrafluoropropyl and (m) tetrafluoropropoxyl; X is selected from the group consisting of CH 2 , CO, CS, SO 2 and -N=N-; 105 WO 01/66551 PCT/IBO1/00300 Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) Cl-C 4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl; and B is selected from oxygen and sulphur atoms.

12. A method of treating or preventing fungal infection in an animal comprising the step of administering to said animal the pharmaceutical composition according to claims 6 and 7.

13. A process for preparing a compound of Formula IA R 1 0 R 3 X 1 Y, OH N F N -~ R 2 R FORMULA IA wherein X is selected from the group consisting of CH 2 , CO, CS, SO 2 and N=N-; R is selected from the group consisting of (1) Cr-C 4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, Cr-C 4 alkoxy and amino (2) Cl-C 4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) ClrC4 acyloxy 106 WO 01/66551 PCT/IBO1/00300 (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl; R 1 and R 2 are each independently selected from the group consisting of (1) hydrogen, (2) Cl-C 4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C-C 4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) C-C 4 alkoxy; Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C-C 4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl; R 3 is selected from the group consisting of Cl-C 4 alkyl group, halogen, hydroxy, C-C 4 alkoxy, nitro, amino, cyano, carboxyl and SO 2 R' wherein R' is hydrogen, alkyl or aryl; and X 1 , X 2 , Y 1 , Y 2 and Z are independently selected from the group consisting of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C-C 4 alkyl, C-C 4 alkoxy, carboxyl or protected carboxyl; which comprises reacting 1-[2-(2,4-disubstituted phenyl)-2,3-epoxy derivative of 1,2,4-triazole of Formula IV 107 WO 01/66551 PCT/IBO1/00300 0 F N R FORMULA IV wherein X, R and R 1 are the same as defined above with triazol-3-one derivatives of Formula V Yi X1 R-3 O Z N N-Y-N -- N FORMULA V wherein R 2 ,, R 3 , X 1 , X 2 , Y, Y 1 , Y 2 and Z have the same meanings as defined above, in the presence of sodium hydride to afford the desired compound of Formula IA.

14. A process for preparing a compound of Formula IA R, 0 R 3 X 1 Y NN .N-Y-N N Z N F N R FORMULA IA 108 WO 01/66551 PCT/IBO1/00300 wherein X is selected from the group consisting of CH 2 , CO, CS, SO 2 and N=N-; R is selected from the group consisting of (1) C1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (2) Cl-C 4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) Cr1C4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl; R 1 and R 2 are each independently selected from the group consisting of (1) hydrogen, (2) C1C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) C1C4 alkoxy; Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C-C4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl; R 3 is selected from the group consisting of C1C4 alkyl group, halogen, hydroxy, C1C4 alkoxy, nitro, amino, cyano, carboxyl and SO 2 R' wherein R' is hydrogen, alkyl or aryl; and 109 WO 01/66551 PCT/IBO1/00300 X 1 , X 2 , Y 1 , Y 2 and Z are independently selected from the group consisting of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, Cr1C4 alkyl, C1C4 alkoxy, carboxyl or protected carboxyl; which comprises reacting epoxide derivative of Formula VI R 1 O1 R 3 X, Y1 /O X N-Y-N N Z F N~ R2X2 Y2 R FORMULA VI with 1,2,4-triazole to afford a compound of Formula IA.

15. A process for preparing a compound of Formula IB, R O R3 B /fN N-Y-N NR N FN\_/R R2 R FORMULA IB wherein X is selected from the group consisting of CH 2 , CO, CS, SO 2 and N=N-; R is selected from the group consisting of (1) C1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and 110 WO 01/66551 PCT/IBO1/00300 amino (2) Cl-C 4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) Cr1C4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl; R 1 and R 2 are each independently selected from the group consisting of (1) hydrogen, (2) C1C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, Cr1C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) C1C4 alkoxy; Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C-C4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl; R 3 is selected from the group consisting of C1C4 alkyl group, halogen, hydroxy, C1C4 alkoxy, nitro, amino, cyano, carboxyl and SO 2 R' wherein R' is hydrogen, alkyl or aryl; R 4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group which is unsubstituted or substituted; B is selected from oxygen and sulphur atoms; and 111 WO 01/66551 PCT/IBO1/00300 R 5 is selected from the group (1) hydrogen, (2) C17- C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (b) C1C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1C4 acyloxy (g) C1C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (1) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 2 and (u) OCF 3 (4) naphthyl or naphthyl (C1C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1 - C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (b) halogen (c) (C C4 alkyl) halo, (d) C1C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (1) tetrafluoropropyl and (m) tetrafluoropropoxyl, which comprises reacting a compound of Formula ID OHR O R 3 N N-Y-N NH N F R2 <I R2 R FORMULA ID 112 WO 01/66551 PCT/IBO1/00300 wherein X, R, R 1 ,R 2 , R 3 and Y have the same meanings as defined above, with a compound of Formula R 5 - N = C = B wherein R 5 and B are the same as defined above to give a compound of Formula IC OH 1 OR B OH B N N-Y-N NR N F R R FORMULA IC which on reaction with R 4 Z, gives a compound of Formula IB wherein X, R, R 1 , R 2 , R 3 , R 4 , R 5 ,Y and B have the same meanings as defined above and Z is any halogen atom.

16. A process for preparing a compound of Formula I R1 B N NX O-Y--N N F R FORMULA II wherein X is selected from the group consisting of CH 2 , CO, CS, SO 2 and N=N-; R is selected from the group consisting of (1) Cl-C 4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently 113 WO 01/66551 PCT/IBO1/00300 selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (2) CrC4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) Cr1C4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl; R 1 is selected from the group consisting of (1) hydrogen, (2) Cl-C 4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, Cr1C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) C1C4 alkoxy; R 4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group which is unsubstituted or substituted; R 5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (b) C1C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1C4 acyloxy (g) C1C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (1) hydroxy (m) nitro (n) 114 WO 01/66551 PCT/IBO1/00300 amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 2 and (u) OCF 3 (4) naphthyl or naphthyl (C1C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1 - C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, Cr1C4 alkoxy and amino, (b) halogen (c) (C C4 alkyl) halo, (d) CrC4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoro methoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (1) tetra fluoropropyl and (m) tetrafluoropropoxyl; Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C-C4 alkoxy and (8) SO 2 R' wherein R' is hydrogen, alkyl or aryl; and, B is selected from oxygen and sulphur atoms; which comprises reacting a compound of Formula VII OH N 0-Y-N NH N F R FORMULA Vil with a compound R 5 -N=C=B, wherein R, R 1 , R 5 , X and Y have the same meanings as defined above, to give a compound of Formula VIII 115 WO 01/66551 PCT/IBO1/00300 R1 B OH R N XO N 0-Y-N N N F H R FORMULA VIII and which further comprises reacting the compound of Formula VIII with R 4 Z, wherein R 4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group which is unsubstituted or substituted and Z is any halogen atom, to obtain a compound of Formula 11.

17. A process for the preparation of a compound of Formula Ill OH 1 B N N X N-Y- Rs \ H H N--r- F CH3 R FORMULA III wherein R is selected from the group consisting of (1) C1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (2) Cr1C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1C4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) 116 WO 01/66551 PCT/IBO1/00300 triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl; R 1 is selected from the group consisting of (1) hydrogen, (2) Cl-C 4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) C 1 -C 4 alkoxy; R 5 is selected from the group (1) hydrogen, (2) C 1 - C 4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C 1 -C 4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkoxy and amino (b) C 1 -C 4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C 1 -C 4 acyloxy (g) C 1 -C 4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (1) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 2 and (u) OCF 3 (4) naphthyl or naphthyl (C 1 -C 4 alkyl) which may be substituted with 1-6 substituents selected from (a) C 1 - C 5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkoxy and amino, (b) halogen (c) (C1 C 4 alkyl) halo, (d) C 1 -C 4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) 117 WO 01/66551 PCT/IBO1/00300 trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (1) tetrafluoropropyl and (m) tetrafluoropropoxyl, X is selected from the group consisting of CH 2 , CO, CS, SO 2 and -N=N-, Y is a phenyl group which is unsubstituted or substituted with substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) Cl-C 4 alkoxy and (8) S0 2 R' wherein R' is hydrogen, alkyl or aryl; and, B is selected from oxygen and sulphur atoms, which comprises reacting a compound of Formula IX OH R, / N N-Y-NH 2 N FCH3 R FORMULA IX with a compound of Formula B=C=N-R 5 , to give the desired compound of Formula Ill. 118 WO 01/66551 PCT/IBO1/00300

18. A process for preparing a compound of Formula IA wherein X=CH 2 , R=F, R 1 =H, Y=C 6 H 4 -,R 3 =H, R3 X2 NR N HO N R2 FN R FORMULA IA (X=CH 2 , R=F, R i=H, Y=C 6H4-, R3=H) and wherein R 2 is selected from the group consisting of (1) hydrogen, (2) Cl-C 4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) C1C4 alkoxy, and X 1 , X 2 , Y 1 , Y 2 and Z are independently selected from the group consisting of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, Cr-C4 alkyl, Cr1C4 alkoxy, carboxyl or protected carboxyl, 119 WO 01/66551 PCT/IBO1/00300 which involves the reaction of triazol-3-one derivatives of Formula V wherein R 3 =H, Y= C 6 H 4 -, Y1 X 1 R 3 0 Z N N-Y- N NH 22 R2 FORMULA V (R 3 =H, Y=C 6 H 4 -) wherein R 2 , X 1 , X 2 , Y 1 , Y 2 and Z are the same as defined above, with the compound of Formula IV wherein R=F, R 1 =H, X=CH 2 0 F, N F R FORMULA IV in the presence of sodium hydride.

19. A process for the preparation of triazol-3-one derivatives of Formula V wherein R 3 =H, Y= C 6 H 4 Y1 X 1 R3 O z N N-Y-N NH 2 X2 R2 FORMULA V (R 3 =H, Y=CCH 4 -) comprising reacting the substituted phenyl piperazine of Formula XIV 120 WO 01/66551 PCT/IBO1/00300 Y, X, / \ N NH -- 0 \__J/ Y2 X2 FORMULA XIV wherein X 1 , X 2 , Y 1 , Y 2 and Z are independently selected from the group consisting of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C 1 -C 4 alkyl, C-C 4 alkoxy, carboxyl or protected carboxyl, with 4 chloronitrobenzene to give the corresponding nitroaryl compound of Formula XV Y 1 X1 Z N N-C NO 2 2 X2 FORMULA XV which on catalytic reduction affords the anilino derivative of Formula XVI Y 1 X, Z N N / -NH2 Y2 X2 FORMULA XVI acylating the compound of Formula XVI with phenyl chloroformate to afford phenyl carbamate derivatives of Formula XVII 121 WO 01/66551 PCT/IBO1/00300 Y X1 0 Z N -- & NH OPh Y2 X2 FORMULA XVII reacting the carbamate derivative of Formula XVII, with hydrazine hydrate, forming semicarbazide derivative of Formula XVIII Y 1 Xi 0 Z I N/\IA NH NhNH2 Y2 X2 Formula XVIII and cyclizing the compound of Formula XVIII with formamidine derivatives to form triazol-3-one derivatives of Formula V.

20. A process for preparing a compound of Formula IA wherein X=CH 2 , R=F, R 1 = CH 3 , Y=C 6 H 4 -, R 3 =H Y 1 R32 N r X2 Y HO N F R FORMULA IA (X=CH 2 , R=F, R I=H, Y=C 6H4-, R 3 =H wherein 122 WO 01/66551 PCT/IBO1/00300 R 2 is selected from the group consisting of (1) hydrogen, (2) C1-C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO 2 R' wherein R' is hydrogen, alkyl or aryl and (8) C1-C4 alkoxy, and X 1 , X 2 , Y 1 , Y 2 and Z are independently selected from the group consisting of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C1-C4 alkyl, C1-C4 alkoxy, carboxyl or protected carboxyl, comprising reacting the 1, 3-difluorobenzene of Formula X F FORMULA X with racemic (±) 2-chloropropionyl chloride of Formula XIX Cl * H 3 - COCl FORMULA XIX to form a compound (±) 2-chloro-2-methyl-2', 4'-difluoroacetophenone of Formula XX 123 WO 01/66551 PCT/IBO1/00300 CH 3 0 * C1 F F FORMULA XX which on condensation with the intermediate of Formula V wherein R 3 =H, Y=C 6 H 4 - and R 2 , X 1 , X 2 , Y 1 ,Y 2 and Z are as defined herein Y 1 X1 0 Z / \ NN \ NANH Y 2 X 2 R2 FORMULA V (R 3 = H, Y= C 6 H 4 ) in the presence of sodium hydride, forms the compound of Formula XXI CH 3 0 X, Y, O *N Z F N=< FR2 X2 Y2 F FORMULA XXI which is then epoxidized with trimethylsulphoxonium iodide (TMSI) in DMSO to give an epoxide derivative of Formula VI wherein X=CH 2 , R=F, R 1 =CH 3 , Y=C 6 H 4 -, R 3 =H, 124 WO 01/66551 PCT/IBO1/00300 R, O R 3 X 1 I x * O0 N-Y-N N Z F N-:: RX2 Y2 R FORMULA VI (X=CH 2 , R=F, R 1 =CH 3 , Y-C 6 H 4 g, R 3 =H) which on condensation with 1,2,4-triazole forms the compound of Formula IA.

21. A process for preparing compounds of Formula 11 wherein X=CH 2 , R=F, R 1 =H, Y=C 6 H 4 N X014 R 1 B N 0-Y-N N-C-N-R F R FORMULA II (X=CH 2 , R=F, R 1 =H, Y=C 6 H 4 -) and wherein R 4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group which is unsubstituted or substituted; R 5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents 125 WO 01/66551 PCT/IBO1/00300 each independently selected from the group consisting of (a) Cr1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, Cr1C4 alkoxy and amino (b) C1C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1C4 acyloxy (g) C1C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (1) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 2 and (u) OCF 3 (4) naphthyl or naphthyl (C1C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1 - C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (b) halogen (c) (C C4 alkyl) halo, (d) C1C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoro methoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (I) tetra fluoropropyl and (m) tetrafluoropropoxyl; and B is selected from oxygen and sulphur atoms, by reacting 2-(2,4-difluorophenyl)-3-(1 H-1, 2,4-triazolyl)-1 -[4-(piprazinyl) phenoxy]-propan-2-ol of Formula VII wherein X=CH 2 , R=F, R 1 =H, Y=C 6 H 4 OH N O-Y-N N-H F R FORMULA VU (X=CH 2 , R=F, RI=H, Y=C 6 H 4 -) 126 WO 01/66551 PCT/IBO1/00300 with the compound of Formula B=C=N-R 5 , to form a compound of Formula VIII wherein X=CH 2 , R=F, R 1 =H, Y=C 6 H 4 N OH RI B N O-Y-N N-C-N-R F H OH R FORMULA VIII (X=CH 2 , R=F, R 1 =H, Y=C 6 H 4 -) wherein R 5 and B are as defined herein; and further reacting the compound of Formula Vill with R 4 Z wherein R 4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group which is unsubstituted or substituted, in the presence of sodium hydride to give the required compound of Formula 11.

22. A process for preparing a compound of Formula II wherein X=CH 2 , R=F, R 1 =CH 3 , R 4 =H, Y=C 6 H 4 R 1 B NX O-Y-N N-Rs F R R FORMULA II (X=CH 2 , R=F, Rg-CH 3 , R4=H, Y=C 6 H 4 -) wherein 127 WO 01/66551 PCT/IBO1/00300 R 5 is selected from the group (1) hydrogen, (2) C 1 - C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, Cr1C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino (b) C1C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) CC4 acyloxy (g) C1C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (1) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 2 and (u) OCF 3 (4) naphthyl or naphthyl (C1C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1 - C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (b) halogen (c) (C C4 alkyl) halo, (d) C1C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoromethoxyl (i) trifluoromethyl () tetrafluoroethyl (k) tetrafluoroethoxyl (1) tetrafluoropropyl and (m) tetrafluoropropoxyl, and B is selected from oxygen and sulphur atom, which comprises treatment of 2,4-difluoro-a-methyl-phenacyl chloride of Formula XXII, 128 WO 01/66551 PCT/IBO1/00300 CH 3 C1 F F FORMULA XXII with 1-acetyl-4-hydroxyphenylpiperazine of Formula XXIII, HO N CH3 FORMULA XXIII to form 2-[4-(4-acetylpiperazine)phenoxy]-2-methyl-2',4'-difluoroacetophen one of Formula XXIV, CH 3 0 O N -Ir CH3 0 F F FORMULA XXIV which on treatment with trimethyl sulphoxonium iodide forms the corre sponding epoxide of Formula XXV, 129 WO 01/66551 PCT/IBO1/00300 CH 3 0 F O N N CH 3 F 0 F FORMULA XXV which is then reacted with 1,2,4-triazole to yield a compound of Formula XXVI, CH3 0 N OH O NKNCH3 F F F FORMULA XXVI which on hydrolysis gives a compound of Formula VII wherein X=CH 2 , R=F, R 1 =CH 3 , Y=C 6 H 4 OH R N O O-Y-N N-H F R FORMULA VII (X=CH 2 , R=F, R 1 -CH 3 , Y=C 6 H 4 -) 130 WO 01/66551 PCT/IBO1/00300 and reacting the compound of Formula VII with R 5 -N=C=B gives the compound of Formula 11.

23. A process for preparing a compound of Formula Ill wherein X=CH 2 , R=F, R 1 =H, Y=C 6 H 4 OH R 1 B ( X~j< I I N-Y-N-C-N-P 5 NF CH3 H R FORMULA III (X=CH 2 , R=F, Ri=H, Y-=C 6 H 4 ) wherein B is selected from oxygen and sulphur atoms, and R 5 is selected from the group (1) hydrogen, (2) C 1 - C4 alkyl group which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-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) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy (g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (1) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF 2 and (u) 131 WO 01/66551 PCT/IBO1/00300 OCF 3 (4) naphthyl or naphthyl (C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1 - C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1C4 alkoxy and amino, (b) halogen (c) (C C4 alkyl) halo, (d) CrC4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (1) tetrafluoropropyl and (m) tetrafluoropropoxyl, comprising reacting 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1 H-1,2,4-triaz ole of Formula IV wherein R=F, X=CH 2 , R 1 =H N XN' O R F R FORMULA IV (R=F, X=CH 2 , R=H) with N-methyl-4-nitroaniline of Formula XXVII gives 2-(2,4-difluorophenyl)-2 hydroxy-3-(1 H,1,2,4-triazol-1 -yl)-1 -propylamino-1 N, -methyl-4-nitrobenzene of Formula XXVIII F CH3 F FORMULA XXVIII 132 WO 01/66551 PCT/IBO1/00300 which on reduction gives 2-(2,4-diflurophenyl)2-hydroxy-3-(1 H-1,2,4-triazol-1 yl)-1-propylamino-IH methyl 4-aniline of Formula IX wherein X=CH 2 , R=F, R 1 =H, Y=C 6 H 4 N OH R 1 N"XQ XN-Y-NH2 F CH3 0 R FORMULA IX (X=CH 2 , R=F, R,=H, Y=C 6 H 4 -) which on reaction with B=C=N-R 5 gives the compound of Formula Ill. 133