WO1995006047A1

WO1995006047A1 - Antimicrobial quinolinyl-(1h-1,2,4-triazol-1-yl)alkanol derivatives

Info

Publication number: WO1995006047A1
Application number: PCT/JP1994/001378
Authority: WO
Inventors: Hideko Nakamura; Hidenori Ohki; Akira Yamada; Kohji Kawabata
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1993-08-23
Filing date: 1994-08-22
Publication date: 1995-03-02
Also published as: JP3550686B2; EP0715626A1; GB9317491D0; CN1133041A; KR960703895A; ZA946218B; JPH09501690A; AU7467594A; CA2170031A1

Abstract

A compound of formula (I) in which R?1 and R2¿ are each hydrogen or lower alkyl, R3 is optionally substituted quinolyl or oxide thereof, and X and Y are each hydrogen, halogen, cyano or lower alkyl, or pharmaceutically acceptable salts thereof, which has antimicrobial acivity.

Description

DESCRIPTION

ANTIMICROBIAL QUIN0LINYL-(lH-1,2,4-TRIAZ0L-l-YL)ALKAN0L DERIVATIVES

TECHNICAL FIELD

The present invention relates to a new compound and a pharmaceutically acceptable salt thereof-

More particularly, it relates to a new quinoline derivative and a pharmaceutically acceptable salt thereof, which have antimicrobial activities (especially antifungal activities), to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a method for treating or preventing infectious diseases in a human being or an animal.

Accordingly, one object of the present invention is to provide the quinoline derivative and a pharmaceutically acceptable salt thereof, which are highly active against a number of pathogenic microorganisms in a human being or an animal.

Another object of the present invention is to provide a process for the preparation of the quinoline derivative and a salt thereof.

A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said quinoline derivative or a pharmaceutically acceptable salt thereof.

Still further object of the present invention is to provide a method for treating or preventing infectious diseases caused by pathogenic microorganisms, which comprises administering said quinoline derivative to a human being or an animal.

DISCLOSURE OF INVENTION

The object quinoline derivative of the present invention is novel and can be represented by the following general formula (I) :

in which R-'- and R² are each hydrogen or lower alkyl,

R is optionally substituted quinolyi or oxide thereof, and X and Y are each hydrogen, halogen, cyano or lower alkyl, or a pharmaceutically acceptable salts thereof.

The compound (I) of the present invention can be prepared by the processes as illustrated in the following schemes. Process 1

(ID (I) or a salt thereof or a salt thereof

Process 2 oxidation of the optionally substituted quinolyi

(I-a) (I-b) or a salt thereof or a salt thereof

Process 3

hydrolysis of the lower alkoxy-substi- tuent of optionally substituted quinolyi

d-d)

(I-c) or a salt thereof or a salt thereof Process 4 oxidation of the lower alkylthio- or lower alkylsulfinyl-substituent of optionally substituted quinolyi

(I-e) ( i-f ) or a salt thereof or a salt thereof

Process 5

hydrolysis of the cyano-substituent of optionally substituted quinolyi

(I-h)

(i-g) or a salt thereof or a salt thereof

in which R¹, R², R , X and Y are each as defined above, R-³ is optionally substituted quinolyi,

3.

R, is N-oxide of optionally substituted b . quinolyi, R is quinolyi substituted by lower alkoxy and optionally by suitable substituent (s) , R^ is quinolyi substituted by hydroxy and optionally by suitable substituent (s) , R_g is quinolyi substituted by lower alkylthio or lower alkylsulfinyl and optionally by suitable substituent (s) , R is quinolyi substituted by lower alkylsulfinyl or lower alkylsulfonyl and optionally by suitable substituent (s) , R_g is quinolyi substituted by cyano and optionally by suitable substituent (s) , and quinolyi substituted by carboxy and optionally by suitable substituent (s) .

Some of the starting compound (II) or a salt thereof may be novel and can be prepared by a conventional manner.

And also the starting compound (III) or a salt thereof may be novel and can be prepared in a similar manner as that of Preparations mentioned below or by a conventional manner. Suitable pharmaceutically acceptable salt of the object compound (I) is conventional non-toxic salts and may include a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g. trimethylamine salt, triethyla ine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, etc.] an organic acid addition salt [e.g. formate, acetate, trifuloroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.], a salt with an amino acid [e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.], and the like.

In the above and subsequent description of this specification, suitable examples of the various definitions are explained in detail as follows :

The term "lower" is intended to mean 1 to 6, preferably 1 to 4 carbon atom(s), unless otherwise indicated.

Suitable "lower alkyl" may include a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like, in which the most preferred example may be methyl.

Suitable "optionally substituted quinolyi" means quinolin-1- (or 2- or 3- or 4- or 5- or 6- or 7- or 8-)yl optionally substituted by one or more, preferably one or two suitable substituent(s) such as :

-hydroxy;

-protected hydroxy, in which the hydroxy group is protected by a conventional hydroxy-protective group such as acyl, tri (lower) alkylsilyl (e.g. t-butyldimethylsilyl, etc.) , etc.;

-halogen (e.g. chlorine, bromine, iodine or fluorine);

-lower alkoxy, which may be straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc., more preferably Cχ-C4 alkoxy (e.g. methoxy, etc.);

-halo(lower)alkyl, which is aforementioned lower alkyl group substituted by one or more, preferably one to three halogen as mentioned below (e.g. trifluoromethyl, etc.);

-halo(lower) alkoxy, which is hydroxy group substituted by aforementioned halo(lower)alkyl (e.g. trifluoromethoxy, etc.) ;

-lower alkyl as mentioned above, more preferably C1-C4 alkyl (e.g. methyl, t-butyl, etc.);

-lower alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc, more preferably ^-C^ alkylthio (e.g. methylthio, etc. ) ;

-lower alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl, etc, more preferably -^-C^ alkylsulfinyl (e.g. methylsulfinyl, etc.);

-lower alkylsulfonyl, such as methylfulfonyl, ethylsulfonyl, prcpylsulfonyl, isopropylsulfonyl, butylsulfonyl, per.rylsulfonyl, hexylsulfonyl, etc, more preferably Cχ-C₄ alkylsulfonyl (e.g. methylsulfonyl, etc.); amino; nitro; cyano; carboxy; and the like.

Preferable examples of optionally substituted quinolyi may be quinolyi optionally substituted by hydroxy, halogen, lower alkoxy, halo (lower)alkyl, halo (lower)alkoxy, lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano or carboxy, in which the most preferable one may be quinolin-2- (or 4-)yl optionally substituted by hydroxy, fluorine, chlorine bromine, methoxy, trifluoro ethyl, trifluoromethoxy, t-butyl, methylthio, methylsulfinyl, methylsulfonyl, cyano or carboxy.

Suitable oxide of "optionally substituted quinolyi" means N-oxide of aforementioned optionally substituted quinolyi, in which more preferable example may be N-oxide of quinolyi which is optionally substituted by the group consisting of hydroxy, halogen, lower alkoxy, halo(lower)alkyl, halo(lower)alkoxy, lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl and cyano, halo(lower) alkyl, halo(lower)alkoxy, and the most preferable one may be N-oxide of quinolin-2- (or 4-)yl or N- oxide of 6-fluoroquinolin-2-yl.

Suitable "quinolyi substituted by lower alkoxy and optionally by suitable substituent(s) " means aforementioned optionally substituted quinolyi, wherein said quinolyi is substituted at least by lower alkoxy as mentioned above, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4-)yl, etc.) substituted at least by lower alkoxy (e.g. methoxy, etc.).

Suitable "quinolyi substituted by hydroxy and optionally by suitable substituent (s) " means aforementioned optionally substituted quinolyi group, wherein said quinolyi is substituted at least by hydroxy, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4- )yl, etc.) substituted at least by hydroxy.

Suitable "quinolyi substituted by lower alkylthio or lower alkylsulfinyl and optionally by suitable substituent(s) " means aforementioned optionally substituted quinolyi, wherein said quinolyi is substituted at least by lower alkylthio or lower alkylsulfinyl as mentioned above, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4-)yl, etc.) substituted at least by lower alkylthio (e.g. methylthio, .etc.) or lower alkylsulfinyl (e.g. methylsulfinyl, etc.).

Suitable "quinolyi substituted by lower alkylsulfinyl or lower alkylsulfonyl and optionally by suitable substituent(s) " means aforementioned optionally substituted quinolyi, wherein said quinolyi is substituted at least by lower alkylsulfinyl or lower alkylsulfonyl as mentioned above, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4-)yl, etc.) substituted at least by lower alkylsulfinyl (e.g. methylsulfinyl, etc.) or lower alkylsulfonyl (e.g. ethylfulfonyl, etc.).

Suitable "quinolyi substituted by cyano and optionally by suitable substituent(s) " means aforementioned optionally substituted quinolyi, wherein said quinolyi is substituted at least by cyano, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4-)yl, etc.) substituted at least by cyano.

Suitable "quinolyi substituted by lower alkoxy and optionally by suitable substituent (s) " means aforementioned optionally substituted quinolyi, wherein said quinolyi is substituted at least by lower alkoxy as mentioned above, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4-)yl, etc.) substituted at least by lower alkoxy (e.g. methoxy, etc.).

One preferable embodiment of R¹, R², R³, X and Y are as follows.

R! and R² are each hydrogen or lower alkyl,

R³ is quinolyi optionally substituted by the group consisting of hydroxy, halogen, lower alkoxy, halo (lower) alkyl and halo (lower) alkoxy, and X and Y are each hydrogen or halogen.

Another preferable embodiment of R , R², R , X and Y are as follows.

R^x and R^ are each hydrogen or lower alkyl, R^J is quinolyi or its N-oxide which is optionally substituted by the group consisting of hydroxy, halogen, lower alkoxy, halo (lower) alkyl, halo (lower)alkoxy, alkylsulfinyl, lower alkylsulfonyl, cyano and carboxy, and X and Y are each hydrogen or halogen.

The processes for preparing the object compound (I) or a salt thereof of the present invention are explained in detail in the following.

Process 1

The object compound (I) or a salt thereof can be prepared by reacting a compound (II) or a salt thereof with a compound (III) or a salt thereof. Suitable salts of the compounds (II) and (III) can be referred to the ones as exemplified for the compound (I) .

The present reaction may be carried out in a conventional solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, N,N- dimethylformamide, ethanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent which does not adversely affect the reaction.

This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal (e.g. lithium, sodium, potassium, etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride (e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal, hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodium-bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium tert- butoxide, etc.), alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkylamine (e.g. triethylamine, etc.), pyridine compound (e.g. pyridine, lutidine, picoline, 4- dimethylaminopyridine, etc.), quinoline, lithium diisopropylamide, and the like. The reaction temperature is not critical, and the reaction is usually carried out under cooling to under heating.

Process 2 The object compound (I-b) or a salt thereof can be prepared by oxidizing the optionally substituted quinolyi of a compound (I-a) or a salt thereof.

Suitable salts of the compounds (I-a) and (I-b) can be referred to the ones as exemplified for the compound (I) . Suitable oxidizing agent used in this reaction may be a conventional one which is capable of converting a nitrogen or sulfur atom to its oxide such as potassium permanganate, chrc ic compound (e.g. chromium trioxide, chromic acid, sodium chromate, dichromic acid, sodium dichro ate, pyridinium dichromate, etc.), peroxy acid (e.g. 3-chloroperbenzoic acid, etc.), and the like.

The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction can be carried out at room temperature or under warming.

Process 3

The compound (I-d) or a salt thereof can be prepared by hydrolyzing the lower alkoxy-substituent of optionally substituted quinolyi of the compound (I-c) or a salt thereof.

Suitable salts of the compounds (I-c) and (I-d) may be the same as those for the compound (I) . The hydrolysis is preferably carried out in the presence of a base or an acid. Preferable base may include an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), an alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), and the like.

Preferable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.). The acidic hydrolysis using trifluoroacetic acid is usually accelerated by addition of cation trapping agent (e.g. phenol, anisole, etc.).

In addition, hydrolysis using trihaloborane (e.g. tribromobrane, etc.) in halo(lower) alkane (e.g. dichloromethane, etc.) can also be used in this reaction. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof. A liquid base or acid can be also used as the solvent.

The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.

Process 4

The compound (I-f) or a salt thereof can be prepared by oxidizing the lower alkylthio- or lower alkylsulfinyl- substituent of optionally substituted quinolyi of the compound (I-e) or a salt thereof. Suitable salts of the compounds (I-e) and (I-f) can be referred to the ones as exemplified for the compound (I) .

This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction condition [e.g. reactive derivatives, solvents reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 2

Process 5

The compound (I-h) or a salt thereof can be prepared by hydrolyzing the cyano-substituent of optionally substituted quinolyi of the compound (I-g) or a salt thereof.

Suitable salts of the compounds (I-g) and (I-h) can be referred to the ones as exemplified for the compound (I) .

This reaction can be carried out in substantially the same manner as Process 3. and therefore the reaction mode and reaction condition [e.g. reactive derivatives, solvents reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 3.

The object compounds obtained according to the above Processes can be isolated and purified in a conventional manner for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, high performance liquid chromatography, and the like, and also can be converted into its salt by a conventional manner.

Especially the compound having the following formula is more preferable.

in which R¹, R², R³, X and Y are each as defined above. Further, the compound having the following formula is the most preferable.

in which R , X and Y are each as defined above, and R^ is lower alkyl.

In order to show the usefulness of the compound (I) of the present invention, a biological datum of the representative compound is shown in the following.

Test Antimicrobial activity

1. Test Method

In vitro antimicrobial activity of the test compound was determined by the two-fold agar-plate dilution method as described below.

One loopful of an overnight culture of a microorganism in Sabouraud broth containing 2 % Glucose (10^ viable cells per ml) was streaked on yeast nitrogen base dextrose agar (YNBDA) containing graded concentrations of the test compound, and the minimal inhibitory concentration (MIC) was expressed in terms of μg/ml after incubation at 30°C for 45 hours.

2. Test Compound

The enantiomeric pair A of Example 1-2) 3. Test Result

organism MIC (μg/ml)

Cryptococcus neoformans FPl^'-35 0.39

From the test result, it is realized that the compound (I) of the present invention has an anti-microbial activity (especially, antifungal activity) .

The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation) , nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation. The active ingredient may be compounded, for example, with the u~ual non-toxic, pharmaceutically acceptable carriers _; r tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. And, if necessary, in addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The compound (I) or a pharmaceutical acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the ~-ired antimicrobial effect upon the pro ΪSS or condition c iiseases.

For applying the composition to a human being or an animal, it is preferable to apply it by intravenous, intramuscular, pulmonary, or oral administration, or insufflation. While the dosage of therapeutically effective amount of the compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 20 g of the compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.1 - 20 mg of the compound (I) per kg weight of a human being or an animal, in case of oral administration, a daily dose of

0.5 - 50 mg of the compound (I) per kg weight of a human being or an animal is generally given for treating or preventing infectious diseases.

The following Preparations and Examples are given for the purpose of illustrating .the present invention in more detail.

EXAMPLES

Preparation 1 To a refluxing mixture of p-fluoroaniline (3.0 ml) and

6N hydrochloric acid (15.9 ml) was added trans-2-pentenal (3.26 ml) over 1 hour. After the addition, the solution was stirred for 1.5 hours under reflux, and then cooled down to room temperature. The solution was neutralized with 4N aqueous sodium hydroxide and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solution was evaporated and the residue was chromatographed on silica gel (110 g, eluent : ethyl acetate - hexane, 1:15, V/V) to give 2- ethyl-6-fluoroquinoline (2.2 g) .

IR (Neat) : 1600, 860, 825 cm^"1

NMR (CDC1₃, δ) : 1.39 (3H, t, J=7.6Hz), 2.99 (2H, q, J=7.6Hz), 7.27-7.50 (3H, m) , 8.00-8.07 (2H, m) The following compound was obtained by the similar manner to that of Preparation 1.

Preparation 2

2-Ethyl-8-fluoroquinoline

IR (Neat) : 1720, 1600 cm^-1

NMR (CDC1₃, δ) : 1.41 (3H, t, J=7.6Hz), 3.06 (2H, q,

J=7.6Hz), 7.31-7.46 (3H, m) , 7.52-7.59 (1H, m) ,

8.07-8.12 (1H, m)

Preparation 3

To a stirred solution of lithium diisopropylamide in a mixture of n-hexane and tetrahydrofuran (1.55M, 8.2 ml) in tetrahydrofuran (8.0 ml) was added dropwise over 20 minutes a solution of 2-ethylquinoline (2.0 g) in tetrahydrofuran (4.0 ml) at -70°C under an atmosphere of nitrogen. After stirring at -75°C for 20 minutes, to the solution was added methyl iodide (2.5 ml) and the resultant mixture was allowed to warm to ambient temperature over 30 minutes. To the mixture was added water (10 ml) , and solvents were removed by evaporation to give a residue, which was chromatographed on silica gel (150 ml) eluting with a mixture of n-hexane and ethyl acetate (10:0-8:2, V/V) to give 2- (1-methylethyl) - quinoline (1.58 g) .

NMR (CDCI3, δ) : 1.40 (6H, d, J=7.0Hz), 3.27 (1H, sept, J=7.0Hz), 7.34 (1H, d, J=8.5Hz), 7.41-7.55 (1H, m) , 7.60-7.82 (2H, m) , 8.05 (1H, d, J=7.5Hz), 8.09 (1H, d, J=8.5Hz)

Preparation 4

2- (1-Methylethyl) -6-methylthioquinoline (1.96 g) was obtained in substantially the same manner as that of Preparation 3. NMR (CDCI3, δ) : 1.38 (6H, d, J=6.9Hz), 2.58 (3H, s), 3.23 (1H, sept, J=6.9Hz), 7.32 (1H, d, J=8.6Hz), 7.46-7.66 (2H, m) , 7.85-8.08 (2H, ) APCI-Mass : e/z = 218 (M+H)⁺

Example 1-1)

2-Ethylquinoline (704 mg) was added over 5 minutes to a stirred solution of lithium diisopropylamide (2.89 ml of 1.55 M solution in tetrahydrofuran) in tetrahydrofuran (4.5 ml) at -70°C under an atmosphere of nitrogen. The solution was stirred at -70°C for 1 hour. Then a solution of 1-

(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone (1.0 g) in tetrahydrofuran (5.0 ml) was added with stirring at - 70°C over 5 minutes, after the addition, the solution was stirred for 3 hours. To the solution was added water (5 ml) at 0°C and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel (60 g, eluent : ethyl acetate - hexane, 1:2, V/V) to give an enantiomeric pair A of 2- (2, 4- difluorophenyl) -3- (quinolin-2-yl) -1- (1H-1, 2, -triazol-l- yl)butan-2-ol (288 mg) and an enantiomeric pair B of the same (232 mg) .

enantiomeric pair A :

IR (Nujol) : 3050, 1590 cm^"1

NMR (DMSO-d₆, δ) : 1.08 (3H, d, J=7.1Hz), 3.91 (1H, q, J=7.1Hz), 4.12 and 4.80 (2H, ABq, J=14.3Hz), 6.95-7.01 (1H, m) , 7.13 (1H, s) , 7.17-7.86 (6H, m) , 8.01-8.13 (2H, ) , 8.19 (1H, s) , 8.45 (1H, d,

J=8.4Hz)

enantiomeric pair B :

IR (Neat) : 3100, 1590 cm^-1 NMR (DMSO-d₆, δ) : 1.56 (3H, d, J=6.8Hz), 3.95 (1H, q, J=7.0Hz), 4.82 (2H, s), 6.53-6.58 (1H, m) , 6.89-7.94 (8H, m) , 8.17 (1H, d, J=8.3Hz), 8.30 (1H, s)

The following compounds were obtained in substantially the same manner as that of Example 1-1) .

Example 1-2)

Dihydrochloride of enantiomeric pair A of 2- (2, 4- difluorophenyl) -3- (6-fluoroquinolin-2-yl) -1- (1H-1, 2, 4- triazol-l-yl)butan-2-ol

NMR (DMSO-d₆, δ) : 1.21 (3H, d, J=7.0Hz), 4.35-4.42 (1H, m) , 4.38 and 5.09 (2H, ABq, J=14.3Hz), 6.97-7.05 (1H, m) ,- 7.25-7.42 (2H, ) , 7.94-8.17 (4H, m) , 8.59-8.66 (2H, m) , 8.79 (1H, br s) ,

8.92 (1H, d, J=8.8Hz)

Dihydrochloride of enantiomeric pair B of 2- (2, 4- difluorophenyl) -3- (6-fluoroquinolin-2-yl) -1- (1H-1,2, 4- triazol-l-yl)butan-2-ol

NMR (DMSO-d₆, δ) : 1.64 (3H, d, J=6.8Hz), 4.20 (1H, q, J=6.9Hz), 4.95 and 5.05 (2H, ABq, J=14.3Hz), 6.58-6.65 (1H, m) , 6.97-7.11 (1H, ) , 7.74 (1H, d, J=8.7Hz), 7.76-7.93 (2H, m) , 8.02 (1H, s) , 8.29-8.36 (1H, m) , 8.58 (1H, d, J=8.7Hz), 8.97

(1H, s)

Example 1-3)

Enantiomeric pair A of 2- (2, 4-difluorophenyl) -3- (quinolin-4-yl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol IR (Nujol) : 3150, 1580 cm^"1

NMR (DMSO-d₆, δ) : 1.53 (3H, d, J=6.8Hz), 4.58 (1H, q, J=6.8Hz), 4.86 and 5.04 (2H, ABq, J=14.5Hz), 6.24 (1H, s), 6.49-6.59 (1H, m) , 6.67-6.79 (1H, ) , 6.99-7.11 (1H, m) , 7.49-7.69 (4H, m) , 7.86 ( 1H, dd, J=1 . 2Hz and 8 . 4Hz ) , 8 . 17 ( 1H, d,

J=8 . 5Hz ) , 8 . 35 ( 1H, s ) , 8 . 65 ( 1H, d, J=4 . 6Hz )

Enantiomeric pair B of 2- (2, 4-difluorophenyl) -3- (quinolin-4-yl) -1- (1H-1,2, 4-triazol-l-yl)butan-2-ol IR (Nujol) : 3070, 1570 cm^"1 NMR (DMSO-d₆, δ) : 1.16 (3H, d, J=6.9Hz), 3.78 and

4.76 (2K, ABq, J=14.2Hz), 4.48 (1H, q, J=7.0Hz), 5.91 (1H, s), 6.92-7.02 (1H, m) , 7.22-7.41 (2H, m) , 7.60 (1H, s) , 7.65 (1H, d, J=4.6Hz), 8.07-

8.15 (2H, m) , 8.27-8.32 (1H, m) , 8.96 (1H, d, J=4.6Hz)

Example 1-4) 2- (2, 4-Difluorophenyl) -3- (quinolin-2-yl) -1- (1H-1,2,4- triazol-1-yl)propan-2-ol

IR (CHC1₃) : 3050, 1590 cm^-1

NMR (DMSO-d₆, δ) : 3.40 and 3.67 (2H, ABq, J=14.8Hz), 4.64 and 4.77 (2H, ABq, J=14.2Hz), 6.72-6.82 (2H, m) , 7.10-7.29 (2H, m) , 7.33 (1H, d, J=8.4Hz),

7.49-7.57 (1H, m) , 7.66-7.74 (1H, m) , 7.79 (1H, s), 7.86-7.90 (1H, m) , 8.19 (1H, d, J=8.4Hz), 8.37 (1H, s)

Example 1-5)

Enantiomeric pair A of 2- (2, 4-difluorophenyl) -3- (8- fluoroquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol IR (CHCI3) : 3150, 1590 cm^"1

NMR (CDCI3, δ) : 1.17 (3H, d, J=7.0Hz), 3.92 (1H, q, J=7.0Hz), 3.28 and 4.76 (2H, ABq, J=14.2Hz),

6.77-6.89 (2H, m) , 7.36-7.71 (5H, m) , 7.99 (1H, s), 8.08 (1H, s), 8.23-8.28 (1H, m)

Enantiomeric pair B of 2- (2, 4-difluorophenyl) -3- (8- fluoroquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol IR (CHCI3) : 3250, 1590 cm^"1

NMR (CDCI3, δ) : 1.65 (3H, d, J=7.0Hz), 4.01 (1H, q, J=6.9Hz), 4.77 and 4.88 (2H, ABq, J=13.7Hz), 6.32-6.42 (1H, m) , 6.53-6.64 (1H, m) , 7.09-7.64 (6H, m) , 7.96-8.01 (1H, m) , 8.12 (1H, s)

Example 2-1)

To a solution of the enantiomeric pair A of 2- (2, 4- difluorophenyl) -3- (quinolin-2-yl) -1- (1H-1,2, 4-triazol-l- yl)butan-2-ol (192 mg) in dichloromethane (2 ml) was added 80% 3-chloroperbenzoic acid (131 mg) . The solution was stirred at room temperature for 16 hours. Then the solvent was evaporated and the residue was stirred with diethyl ether and filtered. The sol-id was dried in vacuo to give an enantiomeric pair A of 2- [2- (2, 4-difluorophenyl) -2- hydroxy-l-methyl-3- (1H-1, 2, 4-triazol-l-yl)propyl] quinoline N-oxide (170 mg) .

IR (KBr) : 1614, 1274, 962 cm^"1

NMR (DMSO-d₆, δ) : 1.06-1.13 (3H, m) , 3.34-3.40 (1H, m) , 4.12 (1H, d, J=14.3Hz), 5.00-5.25 (1H, m) ,

6.27 (1H, br s) , 6.90-6.98 (1H, ) , 7.20-7.31 (1H, m) , 7.61-8.21 (7H, m) , 8.68 (1H, d, J=8.6Hz)

Example 2-2)

To a solution of the enantiomeric pair A of 2- (2, 4- difluorophenyl) -3- (6-fluoroquinolin-2-yl) -1- (1H-1, 2, 4- triazol-1-yl)butan-2-ol dihydrochloride (30 mg) in water (2 ml) and ethyl acetate (2 ml) was added sodium hydrogen carbonate (5.8 mg) . After stirring for 1 minute, the organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give an enantiomeric pair A of 2- (2, 4- difluorophenyl) -3- (6-fluoroquinolin-2-yl) -1- (1H-1, 2, 4- triazol-l-yl)butan-2-ol . The following enantiomeric pair A was obtained by the similar manner to that of Example 2-1) from the above- obtained enantiomeric pair A.

2- [2- (2, 4-Difluorophenyl) -2-hydroxy-l-methyl-3- (1H-

1, 2, 4-triazol-l-yl)propyl] -6-fluoroquinoline N-oxide IR (KBr) : 1616, 1286, 966 cm^-1

NMR (DMS0-d₆, δ) : 1.05-1.15 (3H, m) , 3.34-3.40 (1H, m) , 4.08 (1H, d, J=14.6Hz), 5.05-5.20 (lH,- m), 6.13 (1H, br s) , 6.90-6.97 (1H, m) , 7.19-7.31

(2H, m) , 7.59-7.99 (5H, m) , 8.18 (1H, s), 8.68-

8.76 (1H, m)

Example 3-1)

Enantiomeric pair A of 2- (2, 4-difluorophenyl) -1- (1H- 1,2, 4-triazol-l-yl) -3- (6-trifluoromethoxyquinolin-2-yl) - butan-2-ol

IR (KBr) : 3159, 1601 cm^"1

NMR (CDC1₃) : 1.17 (3H, d, J=7.1Hz), 3.90 (1H, q, J=7.1Hz), 4.17 and 4.77 (2H, ABq, J=14.1Hz), 6.78-6.89 (2H, m) , 7.52-7.68 (5H, m) , 7.97 (1H, s), 8.13 (1H, d, J=9.0Hz), 8.23 (1H, d, J=8.5Hz)

Mass : M+l = 465

Dihydrochloride of enantiomeric pair B of the same NMR (DMSO-d₆, δ) : 1.57 (3H, d, J=6.9Hz), 4.03 (1H, q, J=7.1Hz), 4.91 (2H, s) , 6.54-6.63 (1H, m) ,

6.94-7.11 (2H, ) , 7.54 (1H, d, J=8.6Hz), 7.73-

7.77 (1H, m) , 7.87 (1H, s) , 7.99 (1H, s), 8.13 (1H, d, J=9.2Hz), 8.40 (1H, d, J=8.6Hz), 8.66 (1H, s) Example 3-2 )

Enantiomeric pair A of 2- (2, 4-difluorophenyl) -3- (6- methoxyquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol IR (KBr) : 3140, 1599 cm^"1 NMR (CDC1₃, δ) : 1.16 (3H, d, J=7.0Hz), 3.84 (1H, q,

J=7.0Hz), 3.96 (3H, s), 4.15 and 4.78 (2H, ABq, J=14.1Hz), 6.75-6.80 (2H, m) , 7.11 (1H, d, J=2.7Hz), 7.38-7.66 (3H, m) , 7.53 (1H, s) , 7.99 (1H, d, J=9.0Hz), 8.00 (1H, s) , 8.12 (1H, d, J=9.0Hz)

Mass : M+l = 411

enantiomeric pair B of the same IR (KBr) : 3236, 1601 -cm^"1 NMR (CDCI3, δ) : 1.63 (3H, d, J=6.9Hz), 3.88 (3H, s) ,

3.85-3.98 ' (1H, m) , 4.76 and 4.89 (2H, ABq, J=13.8Hz), 6.26-6.37 (1H, m) , 6.54-6.60 (1H, m) , 6.93-7.05 (3H, m) , 7.30-7.36 (1H, m) , 7.64 (1H, s), 7.81 (1H, s), 7.85 (1H, d, J=1.7Hz), 8.09 (1H, s)

Mass : M+l = 411

Example 3-3)

Enantiomeric pair A of 2- (2, 4-difluorophenyl) -3- (7- fluoroquinolin-2-yl)-l- (1H-1,2, 4-triazol-l-yl)butan-2-ol IR (KBr) : 3217, 1601 cm^"1

NMR (CDCI3, δ) : 1.16 (3H, d, J=7.1Hz), 3.87 (1H, q, J=7.1Hz), 4.16 and 4.77 (2H, ABq, J=14.0Hz), 6.77-6.89 (2H, m) , 7.33-7.98 (5H, ) , 7.45 (1H, s), 8.09 (1H, s), 8.22 (1H, d, J=8.4Hz)

Mass : M+l = 399

enantiomeric pair B of the same

NMR (CDCI3, δ) : 1.63 (3H, d, J=6.9Hz), 3.97 (IH, q, J=6.9Hz), 4.75 and 4.88 (2H, ABq, J=13.9Hz), 6.30-6.39 (1H, m) , 6.54-6.66 (1H, m) , 6.98-7.10 (2H, m) , 7.40-7.73 (4H, m) , 7.93 (1H, d, J=8.4Hz), 8.09 (1H, s) Mass : M+l = 399

Example 3-4)

Enantiomeric pair A of 2- (2, 4-difluorophenyl) -1- (1H- 1,2, 4-triazol-l-yl) -3- (6-trifluoromethylquinolin-2- yl)butan-2-ol NMR (CDC1₃, δ) : 1.18 (3H, d, J=7.1Hz), 3.93 (1H, q,

J=7.1Hz), 4.20 and 4.77 (2H, ABq, J=14.2Hz), 6.79-6.88 (2H, m) , 7.50 (1H, s) , 7.59 (1H, d, J=8.5Hz), 7.65-7.69 (1H, m) , 7.92-7.97 (2H.m) , 8.18-8.30 (2H, m) ,- 8.32 (1H, d, J=8.4Hz) Mass : M+l = 449

Example 4-1)

To a stirred solution of enantiomeric pair A of 2- (2, 4-difluorophenyl) -3- (6-methoxyquinolin-2-yl) -1- (1H- 1,2, -triazol-l-yl)butan-2-ol (800 mg) in dichloromethane

(8 ml) was added dropwise a solution of boron tribromide in dichloromethane (IN, 11.7 ml) at -78°C, and the resulting mixture was allowed to warm to ambient temperature. After stirring for one hour at ambient temperature, the reaction mixture was taken up into cold aqueous sodium hydroxide.

The organic layer was separated, washed in turn with water and brine, dried over magnesium sulfate. Evaporation of the solution gave a residue, which was chromatographed on silica gel (40 ml) eluting with a mixture of n-hexane, ethyl acetate and methanol (1:2:0 to 0:10:1, V/V) to give enantiomeric pair A of 2- (2, 4-difluorophenyl) -3- (6- hydroxyquinolin-2-yl) -1- (1H-1,2, 4-triazol-l-yl)butan-2-ol (573 mg) .

NMR (DMSO-d₆, δ) : 1.04 (3H, d, J=7.0Hz), 3.83 (1H, q, J=7.0Hz), 4.08 and 4.76 (2H, ABq, J=14.4Hz), 6.91-7.00 (1H, m) , 7.15-7.25 (2H, m) , 1.32-1.46 (2H, m) , 7.54-7.58 (2H, m) , 7.95 (1H, d, J=9.1Hz) , 8.18 (1H, s) , 8.22 (1H, d, J=8.5Hz)

Example 4-2)

Enantiomeric pair B of 2- (2, -difluorophenyl) -3- (6- hydroxyquinolin-2-yl) -1- (1H-1,2, 4-triazol-l-yl)butan-2-ol was obtained in substantially the same manner as that of Example 4-1) . IR (KBr) : 3120, 1601 cm^"1

NMR (CDC1₃, δ) : 1.61 (3H, d, J=6.8Hz), 3.89 (1H, q, J=6.9Hz), 4.77 and 4.90 (2H, ABq, J=13.8Hz), 6.17-6.21 (1H, m) , 6.52-6.63 (1H, m) , 6.90-6.98 (3H, m) , 7.23-7.29 (1H, ) , 7.68 (1H, s) , 7.71- 7.81 (2H, ) , 8.18 (1H, s)

Mass : M+l = 397

Example 5-1)

Lithium diisopropylamide (27.0 ml of 1.55M solution in tetrahydrofuran) was added over 40 minutes to a solution of 6-chloro-2-ethylquinoline (8.00 g) in tetrahydrofuran (42 ml) at -70°C under an atmosphere of nitrogen. The solution was stirred at -70°C for 30 minutes. Then a solution of 1- (2, 4-difluorophenyl) -2- (1H-1, 2, 4-triazole-l-yl) ethanone (6.21 g) in tetrahydrofuran (60 ml) was added with stirring at -70°C over 2 hours. After the addition, the solution was stirred for 4 hours. To the solution was added saturated aqueous ammonium chloride (50 ml) at -70°C and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel (600 g) (eluent : ethyl acetate : hexane = 2:3, V/V) to give an enantiomeric pair A of 3- (6-chloroquinolin-2-yl) -2- (2, 4-difluorophenyl) - l-(lH-l,2,4-triazol-l-yl)butan-2-ol (1.64 g) and an enantiomeric pair B (1.57 g) of the same.

enantiomeric pair A mp : 144-151°C IR (KBr) : 3159, 1595, 1497 cm^-1

NMR (CDC1₃, δ) : 1.16 (3H, d, J=7.0Hz), 3.87 (1H, q, J=7.0Hz), 4.18 and 4.76 (2H, ABq, J=14.7Hz), 6.77-6.89 (2H, m) , 7.49 (1H, d, J=8.4Hz), 7.51 (1H, s), 7.55-7.67 (1H, m) , 7.71 (1H, dd, -J=2.3Hz - and J=9.0Hz), 7.76 (1H, br s), 8.84 (1H, d,

J=2.3Hz), 7.97 (1H, s) , 8.01 (1H, d, J=9.0Hz), 8.14 (1H, d, J=8.4Hz) Mass : M+l = 415

enantiomeric pair B

NMR (CDCI3, δ) : 1.63 and 1.64 (total 3H, two d,

J=6.9Hz), 3.98 (1H, q, J=6.9Hz), 4.75 and 4.88 (2H, ABq, J=13.8Hz), 6.30-6.38 (1H, m) , 6.54-6.66 (1H, m) , 6.96-7.09 (1H, m) , 7.08 (1H, d, J=8.4Hz), 7.44 (1H, br s) , 7.58-7.68 (3H, m) ,

7.86 (1H, d, J=8.4Hz), 7.87 (1H, d, J=8.9Hz), 8.07 (1H, s) Mass : M+l = 415

The following compounds were obtained in substantially the same manner as that of Example 5-1) .

Example 5-2)

Enantiomeric pair A of 3- (6-bromoquinolin-2-yl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol mp : 138-149°C

IR (KBr) : 3217, 1595, 1500 cm^"1

NMR (CDCI3, δ) : 1.16 (3H, d, J=7.1Hz), 3.87 (1H, q, J=7.1Hz), 4.20 and 4.76 (2H, ABq, J=14.7Hz), 6.78-6.89 (2H, m) , 7.49 (1H, d, J=8.4Hz), 7.51 (IH, s) , 7.55-7.67 (IH, ) , 7.75 (IH, br s), 7.84 (IH, dd, J=2.1Hz and J=9.0Hz), 7.95 (IH, d, J=9.0Hz), 7.97 (IH, s) , 8.02 (IH, d, J=2.1Hz), 8.14 (IH, d, J=8.4Hz) MAss : M⁺ = 459, M+2 = 461

enantiomeric pair B of the same

IR (KBr) : 3220, 1595, 1497 cm^-1

NMR (CDC1₃, δ) : 1.63 (3H, d, J=6.9Hz), 3.98 (IH, q, J=6.9Hz), 4.75 and 4.88 (2H, ABq, J=13.9Hz),

6.29-6.38 (IH, m) , 6.54-6.66 (IH, ) , 6.96-7.08 (IH, m) , 7.08 (IH, d, J=8.4Hz), 7.43 (IH, br s) , 7.64 (IH, s), 7.71-7.88 (4H, m) , 8.07 (IH, s) Mass : M⁺ = 459, M+2 =^■ 461

Example 5-3)

Enantiomeric pair A of 3- (6-tert-butylquinolin-2-yl) - 2- (2, -difluorophenyl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol IR (KBr) : 3178, 1597, 1500 cm^"1 NMR (CDC1₃, δ) : 1.15 (3H, d, J=7.1Hz), 1.45 (9H, s) ,

3.84 (IH, q, J=7.1Hz), 4.14 and 4.78 (2H, ABq, J=14.3Hz), 6.75-6.88 (2H, m) , 7.42 (IH, d, J=8.4Hz), 7.52-7.65 (IH, m) , 7.54 (IH, s), 7.77 (IH, d, J=2.1Hz), 7.88 (IH, dd, J=2.1Hz and J=8.9Hz), 8.00 (IH, s) , 8.03 (IH, d, J=8.9Hz),

8.18-8.22 (IH, br s) , 8.20 (.IH, d, J=8.4Hz) Mass : M+l = 437

enantiomeric pair B of the same IR (KBr) : 3260, 1597, 1498 cm¹

NMR (CDCI3, δ) : 1.38 (9H, s), 1.62 (3H, d, J=6.9Hz), 3.94 (IH, q, J=6.9Hz), 4.76 and 4.88 (2H, ABq, J=13.8Hz), 6.29-6.38 (IH, ) , 6.55-6.66 (IH, m) , 7.00-7.13 (IH, m) , 7.02 (IH, d, J=8.3Hz), 7.59 (IH, d, J=2.1Hz), 7.64 (IH, s), 7.77 (IH, dd, J=2.1Hz and J=9.0Hz), 7.85-8.03 (3H, ) , 8.09 (IH, s) Mass : M+l = 437

Example 5-4)

Enantiomeric pair A of 2- (2, 4-difluorophenyl) -3- (5- methoxyquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol mp : 133-138°C

IR (KBr) : 3197, 1593, 1500 cm^"1 NMR (CDC1₃, δ) : 1.15 (3H, d, J=7.0Hz), 3.85 (IH, q,

J=7.1Hz), 4.04 (3H, s) , 4.16 and 4.77 (2H, ABq, J=14.3Hz), 6.75-6.83 (2H, m) , 6.89 (IH, dd, J=2.9Hz and J=5.9Hz), 7.41 (IH, d, J=8.6Hz), 7.53 (IH, s), 7.56-7.7.3 (3H, m) , 8.01 (IH, s) , 8.18 (IH, s), 8.63 (IH, d, J=8.6Hz)

Mass : M+l = 411

enantiomeric pair B of the same mp : 115-117°C IR (KBr) : 3217, 1595, 1497 cm^"1

NMR (CDC1₃, δ) : 1.63 (3H, d, J=6.3Hz), 3.94 (3H, s), 3.98 (IH, q, J=6.3Hz), 4.76 and 4.88 (2H, ABq, J=13.8Hz), 6.27-6.36 (IH, m) , 6.54-6.66 (IH, m) , 6.78 (IH, dd, J=l .3Hz and 7.3Hz), 6.98-7.10 (2H, m) , 7.47-7.62 (2H, m) , 7.64 (IH, s), 7.90 (IH, s), 8.09 (IH, s), 8.34 (IH, d, J=8.6Hz) Mass : M+l = 411

Example 5-5) Enantiomeric pair A of 2- (2, -difluorophenyl) -3- (6- methylthioquinclin-2-yl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2- ol mp : 120-125°C

IR (KBr) : 3120, 1591, 1504 cm^"1 NMR (DMSO-d₆, δ) : 1.07 (3H, d, J=7.0Hz), 3.34 (3H, s), 3.87 (IH, q, J=7.0Hz), 4.78 and 4.10 (2H, ABq, J=14.3Hz), 6.91-7.00 (IH, m) , 7.03 (IH, s) , 7.16-7.28 (IH, m) , 7.33-7.46 (IH, m) , 7.56 (IH, s), 7.66 (IH, d, J=8.5Hz), 7.68 (IH, dd, J=2.2Hz and J=8.9Hz), 7.80 (IH, d, J=2.2Hz), 8.00 (IH, d,

J=8.9Ez), 8.19 (IH, s), 8.34 (IH, d, J=8.5Hz) Mass : M+l = 427

enantiomeric pair B of the same IR (KBr) : 3255, 1591, 1497 cm^"1

NMR (CDC1₃, δ) : 1.61-1.65 (3H, m) , 2.54 (3H, s) , 3.88-3.98 (IH, m) , 4.75 and 4.88 (2H, ABq, J=14.3Hz), 6.28-6.37 (IH, m) , 6.54-6.66 (IH, m) , 6.96-7.09 (2H, m) ,- 7.38 (IH, d, J=2.1Hz), 7.54 (IH, dd, J=2.1Hz and J=8.8Hz), 7.64 (IH, s) , 7.68

(IH, br s), 7.811 (IH, d, J=8.8Hz), 7.812 (IH, d, J=8.5Hz), 8.08 (IH, s) Mass : M-l = 427

Example 5-6)

Enantiomeric pair A of 3- (6-cyanoquinolin-2-yl) -2- (2, 4-difluorophenyl)-l- (1H-1,2, -triazol-l-yl)butan-2-ol mp : 136-144°C

IR (KBr) : 3260, 2229, 1620, 1597, 1500 cm^'1 NMR (CDCI3, δ) : 1.18 (3H, d, J=7.1Hz), 3.94 (IH, q,

J=7.1Hz), 4.21 and 4.76 (2H ABq, J=14.4Hz), 6.78-6.89 (2H, m) , 7.40 (IH, s) , 7.49 (IH, s) , 7.57-7.70 (2H, m) , 7.89-7.94 (2H, m) , 8.16 (IH, d, J=8.8Hz), 8.26-8.30 (2H, m) Mass : M+l = 406

Example 5-7)

Enantiomeric pair A of 2- (2, 4-dichlorophenyl) -3- (6- fluoroquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol mp : 140-150°C

IR (KBr) : 3140, 1606, 1506 cm^"1

NMR (CDC1₃, δ) : 1.12 (3H, d, J=7.1Hz), 4.44 (IH, q, J=7.1Hz), 4.20 and 5.22 (2H, ABq, J=14.2Hz), 7.20 (IH, dd, J=2.2Hz and J=8.6Hz), 7.41 (IH, d,

J=2.2Hz), 7.45-7.54 (3H, m) , 7.58 (IH, dd, J=2.8Hz and J=8.3Hz), 7.80 (IH, d, J=8.6Hz), 7.98 (IH, s), 8.01 (IH, br s), 8.08 (IH, dd, J=5.2Hz and J=9.1Hz), 8.18 (IH, d, J=8.5Hz) Mass : M⁺ = 431

enantiomeric pair B of the same p : 136-142°C

IR (KBr) : 3255, 1605," 1504 cm^"1 NMR (CDCI3, δ) : 1.64 (3H, d, J=6.9Hz), 4.57 (IH, q,

J=6.9Hz), 4.78 and 5.34 (2H, ABq, J=13.9Hz), 6.68 (IH, dd, J=2.2Hz and J=8.7Hz), 7.11 (IH, d, J=8.4Hz), 7.16-7.21 (2H, m) , 7.31 (IH, dd, J=2.7Hz and J=8.8Hz), 7.40-7.50 (IH, m) , 7.64 (IH, s), 7.70 (IH, br s) , 7.89 (IH, d, J=8.4Hz),

7.92 (IH, dd, J=5.4Hz and J=9.2Hz), 8.09 (IH, s) Mass : M⁺ = 431

Example 5-8) Enantiomeric pair A of 3- (6-chloroquinolin-2-yl) -2-

(2,4-dichlorophenyl)-l-(lH-l,2,4-triaz-ol-l-yl)butan-2-ol mp : 154-160°C

IR (KBr) : 3236, 1595, 1493 cm^"1

NMR (CDCI3, δ) : 1.11 (3H, d, J=7.1Hz), 4.20 and 5.21 (2H, ABq, J=14.2Hz), 4.44 (IH, q, J=7.1Hz), 7.20

(IH, dd, J=2.2Hz and J=8.7Hz), 7.41 (IH, d, J=2.2Hz), 7.50 (IH, d, J=8.4Hz), 7.51 (IH, s) , 7.71 (IH, dd, J=2.3Hz and J=9.0Hz), 7.80 (IH, d, J=8.7Hz), 7.85 (IH, d, J=2.3Hz), 7.93 (IH, br s) , 7.98 (IH, s), 8.02 (IH, d, J=9.0Hz), 8.15 (IH, d, J=8.4Hz) Mass : M⁺ = 447, M+2 = 449

enantiomeric pair B of the same IR (KBr) : 3260, 1597, 1493 cm^"1

NMR (CDC1₃, δ) : 1.64 (3H, d, J=6.9Hz), 4.58 (IH, q, J=6.9Hz), 4.78 and 5.34 (2H, ABq, J=13.9Hz), 6.68 (IH, dd, J=2.2Hz and J=8.6Hz), 7.10-7.20 (3H, m) , 7.58-7.68 (4H, m) , 7.84 (IH, s) , 7.88 (IH, s), 8.09 (IK, s)

Mass : M⁺ = 447, M+2 = 449

Example 5-9)

Enantiomeric pair A of -3- (6-bromoquinolin-2-yl) -2- (2, 4-dichlorophenyl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol mp : 156-161^βC

IR (KBr) : 3275, 1593, 1489 cm^-1

NMR (CDC1₃, δ) : 1.11 (3H, d, J=7.1Hz), 4.43 (IH, q, J=7.1Hz), 4.20 and 5.20 (2H, ABq, J=14.2Hz), 7.20 (IH, dd, J=1.8Hz and J=8.6Hz), 7.41 (IH, d,

J=1.8Hz), 7.48-7.52 (2H, m) , 7.80 (IH, d, J=8.'6Hz), 7.82-7.86 (IH, ) , 7.93-8.03 (4H, m) , 8.14 (IH, d, J=8.4Hz) Mass : M+l = 493

enantiomeric pair B of the same

IR (KBr) : 3255, 1593, 1491 cm^"1

NMR (CDCI3, δ) : 1.63 (3H, d, J=6.9Hz), 4.57 (IH, q, J=6.9Hz), 4.78 and 5.33 (2H, ABq, J=13.9Hz), 6.68 (IH, dd, J=2.1Hz and J=8.7Hz), 7.09-7.20 (3H, m) ,

7.64-7.87 (6H, m) , 8.09 (IH, s) Mass : M+l = 493

Example 5-10) Enantiomeric pair A of 2- (2, 4-dichlorophenyl) -3- (6- methylthioquinolin-2-yl) -1- (1H-1, 2, 4-triazo.l-l-yl)butan-2- ol mp : 159-164°C

IR (KBr) : 3178, 1589, 1488 cm^"1 NMR (CDC1₃, δ) : 1.11 (3H, d, J=7.1Hz), 2.61 (3H, s),

4.18 and 5.22 (2H, ABq, J=14.1Hz), 4.40 (IH, q, J=7.1Hz), 7.19 (IH, dd, J=2.2Hz and J=8.6Hz), 7.40-7.45 (2H, m) , 7.52 (IH, s) , 7.55 (IH, d, J=2.1Hz), 7.65 (IH, dd, J=2.1Hz and J=8.9Hz), 7.80 (IH, d, J=8.6Hz), 7.96 (IH, d, J=8.9Hz),

7.99 (IH, s), 8.11 (IH, d, J=8.5Hz), 8.15 (IH, s) Mass : M⁺ = 459

enantiomeric pair B of the s^'ame IR (KBr) : 3255, 1589, 1488 cm^"1

NMR (CDCI3, δ) : 1.53 (3H, d, J=6.9Hz), 2.54 (3H, s) , 4.53 (IH, q, J=6.9Hz), 4.77 and 5.34 (2H, ABq, J=13.9Hz), 6.67 (IH, dd, J=2.1Hz and J=8.7Hz), 7.05 (IH, d, J=8.4Hz), 7.16-7.21 (2H, m) , 7.38 (IH, d, J=2.1Hz), 7.54 (IH, dd, J=2.1Hz and

J=8.9Hz), 7.64 (IH, s) , 7.78-7.83 (3H, m) , 8.13 (IH, s) Mass : M⁺ = 459

Example 5-11)

Enantiomeric pair A of 3- (6-cyanoquinolin-2-yl) -2- (2, 4-dichlorophenyl)-l- (1H-1,2, 4-triazol-l-yl)butan-2-ol mp : 152-156°C

IR (KBr) : 3142, 2229, 1593, 1462 cm^"1 NMR (DMSO-d₆, δ) : 1.05 (3H, d, J=7.1Hz), 4.14 and

5.28 (2H, ABq, J=14.3Hz), 4.52 (IH, q, J=7.1Hz), 6.70 ^'(IH, s), 7.32 (IH, dd, J=2.2Hz and J=8.6Hz), 7.53 (IH, s), 7.59 (IH, d, J=8.6Hz), 7.60 (IH, d, J=2.2Hz), 7.87 (IH, d, J=8.6Hz), 8.09 (IH, dd, J=1.8Hz and J=8.8Hz), 8.18 (IH, s) , 8.26 (IH, d. J=8.8Hz), 8.57 (IH, d, J=8.6Hz), 8.70 (IH, d, J=1.8Hz) Mass : M⁺ = 438, M+2 = 440

Example 5-12)

Enantiomeric pair A of 3- (6-bromoquinolin-2-yl) -2- (4- fluorophenyl)-l- (1H-1,2, 4-triazol-l-yl)butan-2-ol mp : 132-137°C

IR (KBr) : 3255, 1593, 1510 cm^"1

NMR (CDC1₃, δ) : 1.15 (3H, d, J=7.0Hz), 3.66 (IH, q, J=7.0Hz), 4.16 and 4.43 (2H, ABq, J=14.1Hz), 7.01 (2H, t, J=8.7Hz), 7.27-7.36 (2H, m) , 7.52 (IH, d, J=8.5Hz), 7.59 (IH, br s), 7.63 (IH, s) , 7.74 (IH, s), 7.82 (IH,^' dd, J=2.0Hz and J=9.0Hz), 7.93 (IH, d, J=9.0Hz), 8.02 (IH, d, J=2.0Hz), 8.14

(IH, d, J=8.5Hz) Mass : M⁺ = 441

enantiomeric pair B of the same IR (KBr) : 3255, 1593, 1510 cm^"1

NMR (CDCI3, δ) : 1.69 (3H, d, J=6.9Hz), 3.80 (IH, q, J=6.9Hz), 4.48 and 4.68 (2H, ABq, J=13.9Hz), 6.69 (2H, t, J=8.6Hz), 7.04-7.11 (3H, m) , 7.39 (IH, br s), 7.72-7.90 (6H, m) Mass : M⁺ = 441

Example 5-13)

Enantiomeric pair A of 2- (4-fluorophenyl) -3- (6- methylthioquinolin-2-yl)-l- (1H-1,2, -triazol-l-yl)butan-2- ol mp : 121-127°C

IR (KBr) : 3199, 1591, 1510 cm^"1

NMR (DMSO-d₆,δ) : 1.05 (3H, d, J=7.0Hz), 2.62 (3H, s), 3.77 (IH, q, J=7.0Hz), 4.12 and 4.72 (2H, ABq, J=14.2Hz), 6.78 (IH, s) , 7.10 (2H, m) , 7.45 (2H, dd, J=5.5Hz and J=8.8Hz), 7.57 (IH, d, J=8.4Hz), 7.61 (IH, s), 7.67 (IH, dd, J=2.2Hz and J=8.8Kz), 7.78 (IH, d, J=2.2Hz), 7.97 (IH, d, J=8.8Hz), 8.04 (IH, s), 8.31 (IH, d, J=8.4Hz) Mass : M+l = 409

enantiomeric pair B of the same

IR (KBr) : 3260, 1591, 1508 cm^"1

NMR (CDC1₃, δ) : 1.68 (3H, d, J=6.9Hz), 2.53 -(3H, s) , 3.76 (IH, q, J=6.9Hz), 4.49 and 4.68 (2H, ABq,

J=13.9Hz), 6.64-6.73 (2H, m) , 7.00 (IH, d, J=8.5Hz), 7.04-7.12 (2H, m) , 7.38 (IH, d, J=2.1Hz), 7.52 (IH, dd, J=2.1Hz and J=8.9Hz), 7.61 (IH, br s), 7.75-7.83 (4H, m) Mass : M+l = 409

Example 5-14)

Enantiomeric pair A of 2- (4-chlorophenyl) -3- (6- cyanoquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l-yl) utan-2-ol mp : 139-144°C

IR (KBr) : 3257, 2229, 1600, 1497 cm^"1 NMR (DMSO-d₆, δ) : 1.09 (3H, d, J=7.0Hz), 3.83 (IH, q, J=7.0Hz), 4.19 and 4.77 (2H, ABq, J=14.2Hz), 6.42 (IH, s), 7.33 (2H, d, J=8.7Hz), 7.44 (2H, d, J=8.7Hz), 7.61 (IH, s) , 7.74 (IH, d, J=8.5Hz),

8.07 (IH, dd, J=1.8Hz and J-8.8Hz), 8.10 (IH, s), 8.20 (IH, d, J=8.8Hz), 8.51 (IH, d, J=8.5Hz), 8.67 (IH, d, J=1.8Hz) Mass : M+l = 404

Example 5-15)

2- (2, 4-Difluorophenyl) -3- (6-methylthioquinolin-2-yl) - 1- (lH-l,2,4-triazol-l-yl)propan-2-ol

IR (KBr) : 3217, 1591, 1497 cm^"1 NMR (CDCI3, δ) : 2.55 (3H, s) , 3.22 (IH, ABq, J=14.9Hz), 3.72 and 3.73 (total IH, two ABq, J=14.9Hz), 4.55 and 4.73 (2H, ABq, J=14.1Hz), 6.57-6.77 (2H, m) , 7.09 (IH, d, J=8.4Hz), 7.37- 7.50 (2H, m) , 7.55 (IH, dd, J=2.2Hz and 8.9Hz), 7.79 (IH, s), 7.81 (IH, d, J=8.9Hz), 7.82 (IH, s), 7.86 (IH, d, J=8.4Hz), 8.29 (IH, s) Mass : M+l = 413

Example 5-16) 2- (2, 4-Difluorophenyl) -3-methyl-l- (1H-1, 2, 4-triazol-l- yl) -3- (quinolin-2-yl)butan-2-ol mp : 110-114°C

IR (Nujol) : 3120.3, 1616.1, 1594.8 cm^"1 NMR (CDC1₃, δ) : 1.46 -(3H, s) , 1.63 (3H, d, J=3.4Hz), 4.15 (IH, dd, J=2.2, 14.0Hz), 5.26 (IH, dd,

J=1.8, 14.0Hz), 6.55-6.85 (2H, m) , 7.48-7.90 (6H, ) , 7.95-8.30 (4H, m) APCI-Mass : e/z = 395 (M+H) ⁺

Elemental Analysis Calculated for C20H21O9N3 : C 66.99%, H 5.11%, N 14.20%

Found : C 67.25%, H 5.15%, N 14.23%

Example 5-17)

2- (2, 4-Difluorophenyl) -3-methyl-3- (6- methylthioquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2- ol mp : 129-130°C

IR (Nujol) : 3116.4, 1589.1, 1498.4 cm^"1 NMR (CDCI3, δ) : 1.45 (3H, s) , 1.61 (3H, s), 2.61 (3H, s), 4.16 (IH, dd, J=2.1Hz and J=14.0Hz),

5.26 (IH, dd, J=2.1Hz, and 14.0Hz), 6.55-6.80 (2H, m) , 7.40-7.70 (5H, m) , 7.85-8.15 (4H, m) Elemental Analysis Calculated for C23H22F2N OS :

C 62.71%, H 5.03%, N 12.72% Found : C 62.71%, H 5.11%, N 12.55% APCI-Mass : e/z = 441 (M+H) ⁺

The following compounds were obtained in substantially the same manner as that of Example 4-1) .

Example 6-1)

Enantiomeric pair A of 2- (2, 4-difluorophenyl) -3- (5- hydroxyquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol from enantiomeric pair A of Example 5-4) mp : 127-139°C

IR (KBr) : 3120, 1595, 1500 crn^"1

NMR (DMSO-d₆, δ) : 1.06 (3H, d, J=7.0Hz), 3.87 (IH, q, J=7.0Hz), 4.09 and 4.78 (2H, ABq, J=14.3Hz), 6.92-7.00 (2H, ) ,- 7.23-7.29 (IH, m) , 7.25 (IH, s), 7.51-7.64 (2H, m) , 7.56 (IH, s) , 7.60 (IH, d,

J=8.6Hz), 8.18 (IH, s) , 8.56 (IH, d, J=8.6Hz), 10.57 (IH, s) Mass : M+l = 397

Example 6-2)

Enantiomeric pair B of 2- (2, 4-difluorophenyl) -3- (5- hydroxyquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol from enantiomeric pair B of Example 5-4) p : 78-95°C IR (KBr) : 3120, 1595, 1497 cm^"1

NMR (CDC1₃, δ) : 1.63 (3H, d, J=6.9Hz), 3.93 (IH, q, J=6.9Hz), 4.78 and 4.91 (2H, ABq, J=13.8Hz), 6.19-6.29 (IH, m) , 6.53-6.64 (IH, m) , 6.74 (IH, t, J=4.4Hz), 6.92-7.04 (IH, m) , 6.97 (IH, d, J=8.5Hz), 7.46 (2H, d, J=4.4Hz), 7.68 (IH, s) ,

8.10-8.80 (IH, br s), 8.20 (IH, s) , 8.36 (IH, d, J=8.5Hz) Mass : M+l = 397

The following compounds were obtained in substantially - 37 - the same manner as that of Example 7-6) .

Example 7-1)

Enantiomeric pair A of 2- (2, 4-difluorophenyl) -3- (6- methylsulfonylquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l- yl)butan-2-ol from enantiomeric pair A of Example 5-5) mp : 178-182°C

IR (KBr) : 3140, 1599, 1498, 1309, 1146 cm^"1 NMR (DMS0₆-δ) : 1.12 (3H, d, J=7.1Hz), 3.34 (3H, s) , 3.97 (IH, q, J=7.1Hz), 4.14 and 4.83 (2H, ABq,

J=14.3Hz), 6.69 (IH, s) , 6.93-6.97 (IH, m) , 7.18- 7.30 (IH, m) , 7.32-7.44 (IH, m) , 7.56 (IH, s) , 7.86 (IH, d, J=8.6Hz), 8.20 (IH, s) , 8.20-8.35 (2H, ) , 8.69-8.73 (2H, m) Mass : M+l = 459

Enantiomeric pair A of 2- (2, 4-difluorophenyl)-3- (6- methylsulfinylquinolin-2-yl) -1- (1H-1,2, 4-triazol-l- yl)butan-2-ol from enantiomeric pair A of Example 5-5) p : 160-165°C

IR (KBr) : 3140, 1599, 1500, 1140 cm^"1 NMR (DMSO-d₆, δ) : 1.11 (3H, d, J=7.0Hz), 2.86 (3H, s), 3.95 (IH, q, J=7.0Hz), 4.14 and 4.82 (2H, ABq, J=14.3Hz), 6.84 (IH, s), 6.91-7.01 (IH, m) , 7.17-7.29 (IH, m) , 7.33-7.46 (IH, m) , 7.56 (IH, s), 7.80 (IH, d, J=8.5Hz), 8-.03 (IH, dd, J=2.0Hz and J=8.8Hz), 8.20 (IH, s) , 8.27 (IH, d, J=8.8Hz), 8.39 (IH, d, J=2.0Hz), 8.61 (IH, d, J=8.5Hz) Mass : M+l = 443

Example 7-2)

Enantiomeric pair B of 2- (2, 4-difluorophenyl) -3- (6- methylsulfonylquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l- yl)butan-2-ol from enantiomeric pair B of Example 5-5) mp : 78-90°C

IR (KBr) : 3275, 1616, 1497, 1309, 1144 cm^"1

NMR (CDC1₃, δ) : 1.66 (3H, d, J=6.2Hz), 3.11 (3H, s) , 4.07 (IH, q, J=6.2Hz), 4.77 and 4.89 (2H, ABq, J=14.2Hz), 6.30-6.40 (IH, m) , 6.39-6.67 (IH, m) , 6.99-7.11 (IH, m) , 7.02-7.20 (IH, br s) , 7.26 (IH, d, J=8.4Hz), 7.66 (IH, s) , 8.08-8.14 (4H, m) , 8.40 (IH, s)

Mass : M+l = 459

Example 7-3)

Enantiomeric pair A of 2- (2, 4-dichlorophenyl) -3- (6- methylsulfinylquinolin-2-yl) -1- (1H-1,2, 4-triazol-l- yl)butan-2-ol from enantiomeric pair A of Example 5-10) mp : 155-167°C

IR (KBr) : 3132, 1595, 1506 cm^"1

NMR (DMSO-d₆, δ) : 1.05 (3H, d, J=7.1Hz), 2.86 (3H, s), 4.12 and 5.28 (2H, ABq, J=14.2Hz), 4.51 (IH, q, J=7.1Hz), 6.95 (IH, s) , 7.32 (IH, dd, J=2.2Hz and J=8.7Hz), 7.53 (IH, s) , 7.56 (IH, d,

J=8.7Hz) ,

7.60 (IH, d, J=2.2Hz), 7.82 (IH, d, J=8.5Hz), 8.04 (IH, dd, J=2.0Hz and J=8.8Hz), 8.18 (IH, s) , 8.28 (IH, d, J=8.8Hz), 8.39 (1, d, J=2.0Hz), 8.62 (IH, d, J=8.5Hz)

Mass : M⁺=475

Example 7-4)

Enantiomeric pair B of 2- (2, 4-dichlorophenyl) -3- (6- methylsulfinylquinolin-2-yl) -1- (1H-1,2, 4-triazol-l- yl)butan-2-ol from enantiomeric pair B of Example 5-10) mp : 80-90°C

IR (KBr) : 3366, 1593, 1495, 1138 cm^"1 NMR (DMSO-d₆, δ) : 1.58 (3H, d, J=6.9Hz), 2.80 (3H, s), 4.56 (IH, q, J=6.9Hz), 4.84 and 5.27 (2H, ABq, J=14.2Hz), 6.87 (IH, dd, J=2.2Hz and J=8.7Hz), 7.04 (IH, br s) , 7.22 (IH, d, J=8.7Hz), 7.34 (IH, d, J=2.2Hz), 7.41 (IH, d, J=8.5Hz), 7.63 (IH, s), 7.89-7.95 (IH, m) , 8.11 (IH, d, J=8.8Hz), 8.20 (IH, br s) , 8.33 (IH, d, J=8.5Hz), 8.33 (IH, s) Masss : M⁺ = 475

Example 7-5) Enantiomeric pair A of 2- (2, 4-dichlorophenyl) -3- (6- methylsulfonylquinolin-2-yl) -1- (1H-1,2, 4-triazol-l- yl)butan-2-ol from enantiomeric pair A of Example 7-3) mp : 147-148°C

IR (KBr) : 3216, 1618,. 1464 cm^"1 NMR (DMSO-d₆, δ) : 1.06 (3H, d, J=7.1Hz), 3.34 (3H, s), 4.13 and 5.29 (2H, ABq, J=14.4Hz), 4.54 (IH, q, J=7.1Hz), 6.80 (IH, br s) , 7.32 (IH, dd, J=2.2Hz and J=8.6Hz), 7.53 (IH, s) , 7.58 (IH, d, J=8.5Hz), 7.61 (IH, d, J=2.2Hz), 7.89 (IH, d, J=8.6Hz), 8.18 (IH, s) , 8.24 (IH, dd, J=2.0Hz and

J=8.9Hz), 8.35 (IH, d, J=8.9Hz), 8.70-8.74 (2H, m) Mass : M⁺ = 491, M+2 = 493

Example 7-6)

To a solution of enantiomeric pair B of 2-(2,4- dichlorophenyl) -3- (6-methylsulfinylquinolin-2-yl) -1- (1H- 1,2, 4-triazol-l-yl)butan-2-ol (1.56 g) in dichloromethane (16 ml) was added 80% 3-chloroperbenzoic acid (849 mg) . The additional stirring was continued for 2 hours, and then saturated aqueous sodium thiosulfate (20 ml) was added to the reaction mixture. After the stirring for 5 minutes, the mixture was extracted with ethyl acetate. The organic layer was separated, washed in turn with water and brine, dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel (250 g, n-hexane - ethyl acetate = 1:1 to 0:1, V/V) to give enantiomeric pair A of 2- (2, 4-dichlorophenyl) -3- (6- methylsulfonylquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l- yl)butan-2-ol (803 mg) . mp : 87-95°C

IR (KBr) : 3255, 1616, 1311, 1144 cm^"1 NMR (DMSO-d₆, δ) : 1.59 (3H, d, J=6.9Hz), 3.28 (3H, s), 4.58 (IH, q, J=6.9Hz), 4.85 and 5.29 (2H, ABq, J=14.4Hz), 6.86 (IH, s), 6.87 (IH, dd,

J=2.2Hz and J=8.7Hz), 7.21 (IH, d, J=8.7Hz), 7.34 (IH, d, J=2.2Hz), 7.49 (IH, d, J=8.5Hz), 7.64 (IH, s), 8.08-8.18 (2H, m) , 8.33 (IH, s), 8.44 (IH, d, J=8.5Hz), -8.52 (IH, br s) Mass : M⁺ = 491, M+2 = 493

Example 7-7)

Enantiomeric pair A of 2- (4-fluorophenyl) -3- (6- methylsulfinylquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l- yl)butan-2-ol from enantiomeric pair A of Example 5-12) mp : 130-135°C

IR (KBr) : 3277, 1599, 1510 cm^"1

NMR (DMSO-d₃, δ) : 1.08 (3H, d, J=7.0Hz), 2.86 (IH, s), 3.84 (IH, q, J=7.0Hz), 4.16 and 4.76 (2H, ABq, J=14.0Hz), 6.61 (IH, s) , 7.10 (2H, t,

J=8.9Hz), 7.46 (2H, dd, J=5.5Hz and J=8.8Hz), 7.61 (IH, s), 7.70 (IH, d, J=8.5Hz), 8.02 (IH, dd, J=2.0Hz and J=8.8Hz), 8.07 (IH, s), 8.24 (IH, d, J=8.8Hz), 8.36 (IH, d, J=2.0Hz), 8.57 (IH, d, J=8.5Hz)

Mass : M+l = 425

Example 7-8)

Enantiomeric pair A of 2- (4-fluorophenyl) -3- (6- methylsulfonylquinolin-2-yl) -1- (1H-1, 2, -triazol-l- yl)butan-2-ol from enantiomeric pair B of Example 5-13) mp : 133-146°C

IR (KBr) : 1603, 1508, 1313, 1144 cm^"1 NMR (DMSO-d₆, δ) : 1.10 (3H, d, J=7.0Hz), 3.33 (3H, s), 3.84 (IH, q, J=7.0Hz), 4.19 and 4.76 (2H,

ABq, J=14.1Hz), 6.46 (IH, s), 7.10 (2H, t, J=8.9Hz), 7.45 (2H, dd, J=5.6Hz and J=8.8Hz), 7.61 (IH, s), 7.74 (IH, d, J=8.5Hz), 8.08 (IH, s), 8.21 (IH, dd, J=1.9Hz and J=8.9Hz), 8.28 (IH, d, J=8.9Hz), 8.66 (IH, d, J=8.5Hz), 8.68 (IH, d,

J=1.9Hz) Mass : M+l = 441

Example 7-9) Enantiomeric pair B of 2- (4-fluorophenyl) -3- (6- methylsulfinylquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l- yl)butan-2-ol from enantiomeric pair B of Example 5-13) mp : 78-84°C

IR (KBr) : 3277, 1597, 1510 cm^"1 NMR (DMSO-d₆, δ) : 1.54 (3H, d, J=6.9Hz), 2.80 (3H, s), 3.96-4.05 (IH, m) , 4.66 and 4.80 (2H, ABq, J=14.1Hz), 6.66 (IH, s) , 6.82 (2H, t, J=8.9Hz), 7.22 (2H, dd, J=5.5Hz and J=8.8Hz), 7.41 (IH, d, J=8.5Hz), 7.77 (IH, s), 7.91 and 7.92 (total IH, two dd, J=2.3Hz and J=8.7Hz), 8.08 (IH, d,

J=8.7Hz), 8.08 (IH, s) , 8.20 (IH, d, J=2.3Hz), 8.31 (IH, d, J=8.5Hz) Mass : M+l = 425

Example 7-10)

Enantiomeric pair B of 2- (4-fluorophenyl) -3- (6- methylsulfonylquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l- yl)butan-2-ol from enantiomeric pair B of Example 7-9) mp : 85-91°C IR (KBr) : 3277, 1601, 1508 cm^"1 NMR (DMSO-d₆, δ) : 1.55 (3H, d, J=6.9Hz), 3.27 (3H, s), 4.03 (IH, q, J=6.9Hz), 4.67 and 4.82 (2H, ABq, J=14.2Hz), 6.51 (IH, s), 6.81 (2H, t, J=8.9Hz), 7.21 (2H, dd, J=5.5Hz and J=8.8Hz), 7.48 (IH, d, J=8.5Hz), 7.77 (IH, s) , 8.09 (IH, s), 8.12 (2H, s), 8.41 (IH, d, J=8.6Hz), 8.53 (IH, s)

Mass : M+l = 441

Example 7-11)

2- (2, 4-Difluorophenyl) -3- (6-methylsulfonylquinolin-2- yl)-l-(lH-l,2,4-triazol-l-yl)propan-2-ol mp : 65-70°C IR (KBr) : 3275, 1616, 1498, 1309, 1144 cm^"1

NMR (DMSO-d₆, δ) : 3.29 (3H, s) , 3.47 and 3.72 (2H, ABq, J=13.9Hz), 4.65 and 4.79 (2H, ABq, J=14.3Hz), 6.52 (IH, s) , 6.72-6.81 (IH, m) , 7.10- 7.22 (2H, m) , 7.50 (IH, d, J=8.5Hz), 7.79 (IH, s), 8.03-8.10 (2H, m) , 8.35 (IH, s) , 8.45 (IH, d,

J=8.5Hz) , 8.56 (IH, br s) Mass : M+l = 445

2- (2, 4-Difluorophenyl) -3- (6-methylsulfinylquinolin-2- yl) -1- (1H-1,2, 4-triazol-l-yl)propan-2-ol mp : 75-82°C

IR (KBr) : 3275, 1597, 1498, 1137 cm^"1 NMR (DMSO-d₆, δ) : 2.81 (3H, s) , 3.45 and 3.70 (2H, ABq, J=14.0Hz), 4.66 and 4.79 (2H, ABq, J=14.2Hz), 6.60-6.75 (IH, br s) , 6.72-6.81 (IH, m) , 7.10-7.26 (2H, ) , 7.46 (IH, d, J=8.5Hz), 7.78 (IH, s), 7.88-7.94 (IH, m) , 8.02 (IH, d, J=8.8Hz), 8.24 (IH, d, J=1.9Hz), 8.34 (IH, d, J=8.5Hz) , 8.38 (IH, s) Mass : M+l = 429 Example 7-12 )

2- (2, 4-Difluorophenyl) -3-methyl-3- (6- methylsulfinylquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l- yl)butan-2-ol from the product of Example 5-17) mp : 78-82°C

IR (Nujol) : 3403.7, 1733.7, 1614.1, 1594.8,

1496.5 cm^"1 NMR (CDC1₃, δ) : 1.51 (3H, s), 1.62 (3H, s), 2.83 (3H, s), 4.17 (IH, d, J=14.0Hz), 5.30 (IH, d, J=14.0Hz), 6.55-6.83 (2H, m) , 7.55-7.70 (3H, m) ,

7.72-7.95 (IH, m) , 8.05 (IH, s) , 8.10-8.30 (3H, m) APCI-Mass : e/z = 457 (M+H)⁺ Elemental Analysis Calculated for C23H22F₂N θ₂S-l/4 ethyl acetate :

C 60.24%, H 5.06%, N 11.71% Found : C 59.96%, H 4.92%, N 11.72%

Example 7-13) 2- (2, 4-Difluorophenyl) -3-methyl-3- (6- methylsulfonylquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l- yl)butan-2-ol from the product of Example 5-17) mp : 74-79°C

IR (Nujol) : 3390.2, 1733.7, 1616.1, 1457.9 cm^"1 NMR (CDCI3, δ) : 1.53 (3H, s) , 1.64 (3H, s) , 3.16

(3H, s), 4.18 (IH, dd, J=2.2Hz and J=14.2Hz), 5.33 (IH, dd, J=2.2Hz and J=14.2Hz), 6.50-6.83 (3H, m) , 7.50-7.80 (3H, m) , 8.02 (IH, s) , 8.10- 8.35 (3H, m) , 8.52 (IH, d, J=1.9Hz) APCI-Mass : e/z = 473 (M+H)⁺

Elemental Analysis Calculated for

^C23^H22^F2^N4°3^{S"1/10 eth λ} acetate :

C 58.39%, H 4.77%, N 11.64% Found : C 58.10%, H 4.78%, N 11.50% Example 8 A solution of enantiomeric pair A of 3- (6- cyanoquinolin-2-yl)-2- (2,4-dichlorophenyl)-1- (IH, 1,2, - triazol-l-yl)butan-2-ol (70.0 g) in cone, sulfuric acid (0.7 ml) and water (0.7 ml) was refluxed over 1.5 hours. The resulting mixture was allowed to warm to room temperature and neutralized with sodium hydrogen carbonate. The solution was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with ethyl acetate. The precipitate was collected by filtration to give enantiomeric pair A of 3- (6-carboxyquinolin-2-yl)-2- (2, 4-dichlorophenyl) 1- (1H-1,2,4- triazol-l-yl)butan-2-ol (27.1 mg) .

IR (KBr) : 3097, 1699,. 1286 cm^"1 NMR (DMSO-d₆, δ) : 1.05 (3H, d, J=7.1Hz), 4.14 and

5.28 (2H, ABq, J=14.3Hz), 4.51 (IH, q, J=7.1Hz), 7.00 (IH, br s) , 7.32 (IH, dd, J=2.2Hz and J=8.6Hz), 7.53-7.61 (3H, m) , 7.81 (IH, d, J=8.5Hz), 8.15-8.29 (3H, m) , 8.63-8.71 (2H, m) , 13.28 (IH, br s)

Mass : M=457, M+2 = 459

Example 9-1)

A solution of a mixture of enantiomeric pair B of 2- (4-fluorophenyl)-3- (6-methylthioquinolin-2-yl) -1- (1H-1,2, 4- triazol-l-yl)butan-2-ol (1.60 g) in ethyl acetate (75 ml) was triturated with 4N hydrogen chloride in ethyl acetate (1.96 ml) at 0°C. The solid was filtered, washed with ethyl acetate and dried in vacuo to give enantiomeric pair B of 2- (4-fluorophenyl)-3- (6-methylthioquinolin-2-yl)-1-

(1H-1,2, 4-triazol-l-yl)butan-2-ol dihydrochloride (1.89 g) . mp : 143-145°C

IR (KBr) : 3238, 1603, 1510 cm^"1

NMR (DMS0-d₆, δ) : 1.65 (3H, d, J=6.8Hz), 2.60 (3H, s), 4.38 (IH, q, J=6.8Hz), 4.85 and 4.96 (2H, ABq, J=14.5Hz), 5.70-6.20 (IH, br s), 6.84 (2H, t, J=8.8Hz), 7.29 (2H, dd, J=5.5Hz and J=8.6Hz), 7.76-7.90 (3H, ) , 8.00 (IH, s) , 8.26 (IH, d, J=9.6Hz), 8.54 (IH, s) , 8.67 (IH, d, J=8.7Hz) Mass : M+l = 409 (free)

The following compound was obtained by the similar manner to that of Example 9-1) .

Example 9-2)

3- (6-Bromoquinolin-2-yl)-2- (2,4-dichlorophenyl)-1- (1H- 1,2, 4-triazol-l-yl) utan-2-ol dihydrochloride mp : 131-135°C

IR (KBr : 3256, 1593, J470 cm^"1 NMR (DMSO-d₆, δ) : 1.60 (3H, d, J=6.9Hz), 4.58 (IH, q, J=6.9Hz), 4.92 and 5.32 (2H, ABq, J=14.3Hz), 6.10 (IH, br s) , 6.90 (IH, dd, J=2.2Hz and J=8.6Hz), 7.20 (IH, d, J=8.6Hz), 7.34 (IH, d, J=2.2Hz), 7.49 (IH, d, J=8.4Hz), 7.86 (IH, s) , 7.88 (IH, dd, J=2.0Hz and J=9.1Hz), 8.01 (IH, d,

J=9.1Hz), 8.21 (IH, d, J=2.0Hz), 8.28 (IH, d, J=8.4Hz), 8.71 (IH, s)

Example 10 Enantiomeric pair A of 2- (2, -difluorophenyl)-3- quinolin-2-yl)-1- (1H-1,2,4-triazol-l-yl)butan-2-ol was separated by high-performance liquid chromatography using a chiral column (Daicel, CHIRALCEL OD) and HITACHI L-6300 inteligent pump eluting with a solvent system comprised of hexane 2-propanol (80:20). The column was monitored by a UV detector set at 210 n . The former fraction and the latter one were respectively evaporated under reduced pressure to give enantiomeric pair Al (4.5 mg) and A2 (11.0 mg) of the same. enantiomeric pair Al

[α]§° = +31.1° (C=0.6%, CHC1₃)

enantiomeric pair A2 [α]² ₎ ⁰ = -33.2° (C=0.3%, CHCI3)

Example 11-1)

Enantiomeric pair A of 3- (6-cyanoquinolin-2-yl) -2- (4- fluorophenyl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol IR (KBr) : 3284, 2229, 1601, 1508 cm^"1 NMR (CDCI3, δ) : 1.17 ^"(3H, d, J=7.1Hz), 3.74 (IH, q, J=7.1Hz), 4.17 and 4.43 (2H, ABq, J=14.1Hz), 7.03

(2H, t, J=8.7Hz), 7.28-7.35 (2H, ) , 7.62 (IH, s), 7.65-7.69 (2H, m) , 7.91 (IH, dd, J=l.8Hz and J=8.7Hz), 8.15 (IH, d, J=8.7Hz), 8.26 (IH, s) , 8.26 (IH, d, J=8.7Hz) Mass : M+l = 388

Example 11-2)

3- (6-Cyanoquinolin-2-yl) -2- (2, 4-difluorophenyl) -1- (1H- 1,2, 4-triazol-l-yl)propan-2-ol IR (KBr) : 3149, 2229, 1618, 1595, 1502 cm^"1

NMR (CDCI3, δ) : 3.28 (IH, ABq, ^"J=15.0Hz), 3.84 and 3.85 (total IH, two ABq, J=15.0Hz), 4.54 (IH, ABq, J=14.1Hz), 4.75 (IH, ABq, J=14.1Hz), 6.59- 6.79 (2H, m) , 7.29 (IH, d, J=8.1Hz), 7.40-7.52 (IH, m) , 7.83 (IH, dd, J=l.8Hz and J=8.8Hz), 7.84

(IH, s), 8.02 (IH, d, J=8.8Hz), 8.05 (IH, d, J=8.1Hz), 8.14 (IH, d, J=1.8Hz), 8.28 (IH, s) Mass : M+l = 392

Example 11-3) Enantiomeric pair A of 3- (6-fluoroquinolin-2-yl)-2- (4- fluorophenyl)-1- (1H-1,2,4-triazol-l-yl)butan-2-ol

NMR (CDC1₃, δ) : 1.15 (3H, d, J=7.1Hz), 3.66 (IH, q, J=7.1Hz), 4.16 and 4.44 (2H, ABq, J=14.1Hz), 7.02 (2H, t, J=8.9Hz), 7.29-7.40 (3H, m) , 7.41-7.59

(3H, ) , 7.64 (IH, s) , 7.75 (IH, s), 8.06 (IH, dd, J=5.4Hz and J=9.1Hz), 8.18 (IH, d, J=8.4Hz) Mass : M+l = 381

enantiomeric pair B of the same

NMR (CDCI3, δ) : 1.69 (3H, d, J=7.1Hz), 4.12 (IH, q, J=7.1Hz), 4.49 and 4.69 (2H, ABq, J=13.9Hz), 6.70 (2H, t, J=8.8Hz), 6.75-7.12 (3H, m) , 7.29 (IH, dd, J=2.8Hz and J=9.2Hz), 7.43 (IH, dt, J=2.8Hz and J=9.2Hz), 7.48 (IH, s) , 7.74 (IH, s) , 7.81

(IH, s), 7.87-7.93 (2H, m) Mass : M+l = 381

The following compounds were obtained in substantially the same manner as that of Example 9-1) .

Example 12-1)

Enantiomeric pair A of 3- (6-cyanoquinolin-2-yl)-2- (4- fluorophenyl)-1- (1H-1,2, 4-triazol-l-yl)butan-2-ol dihydrochloride

IR (KBr) : 3400, 2235, 1645, 1603, 1510 cm^"1 NMR (DMSO-d₆, δ) : 1.16 (3H, d, J=7.1Hz), 4.15 (IH, q, J=7.1Hz), 4.39 and 4.96 (2H, ABq, J=14.2Hz), 7.16 (2H, t, J=8.8Hz), 7.51 (2H, dd, J=5.5Hz and J=8.8Hz), 7.87 (IH, d, J=8.7Hz), 8.06 (IH, s) ,

8.25 (IH, dd, J=1.7Hz and J=8.8Hz), 8.43 (IH, d, J=8.8Hz), 8.78 (IH, d, J=8.7Hz), 8.84 (IH, s) , 8.84 (IH, d, J=1.7Hz)

Example 12-2) - 48 -

3- (6-Cyanoquinolin-2-yl) -2- (4-fluorophenyl) -1- (1H- 1, 2, 4-triazol-l-yl)propan-2-ol dihydrochloride

IR (KBr) : 3381, 2235, 1647, 1616, 1500cm^"1

NMR (DMS0-d₆, δ) : 3.69 and 3.79 (2H, ABq, J=13.6Hz), 4.79 and 4.92 (2H, ABq, J=14.2Hz), 6.77-6.85 (IH, m) , 7.10-7.29 (2H, m) , 7.67 (IH, d, J=8.6Hz), 8.10 (IH, dd, J=1.5Hz and J=8.8Hz), 8.16 (IH, d, J=&.8Hz), 8.18 (IH, s), 8.53 (IH, d, J=8.6Hz), 8.68 (IH, d, J=1.5Hz), 8.96 (IH, s)

Example 12-3)

Enantiomeric pair A of 2- (4-fluorophenyl) -3- (6- fluoroquinolin-2-yl) -1- (1H-1,2, 4-triazol-l-yl)butan-2-ol dihydrochloride IR (KBr) : 3342, 1620, 1506 cm^"1

NMR (DMSO-d₆, δ) : 1.23 (3H, d, J=7.0Hz), 4.38 (IH, q, J=7.0Hz), 4.41 and 5.02 (2H, ABq, J=14.2Hz), 7.19 (2H, t, J=8.9Hz), 7.54 (2H, dd, J=8.9Hz and J=5.4Hz), 7.88 (IH, d, J=8.8Hz), 7.99(1H, s) , 8.07 (IH, dt, J=2.8Hz and J=8.8Hz), 8.18 (IH, dd,

J=2.8Hz and J=9.0Hz), 8.60 (IH, dd, J=5.0Hz and J=8.8Hz), 8.74 (IH, s) , 8.95 (IH, d, J=8.8Hz)

Example 12-4) Enantiomeric pair B of 2- (4-fluorophenyl) -3- (6- fluoroquinolin-2-yl) -1- (1H-1,2, 4-triazol-l-yl)butan-2-ol dihydrochloride

IR (KBr) : 3342, 1620, 1506 cm^"1

NMR (DMSO-d₆, δ) : 1.65 (3H, d, J=6.9Hz), 4.40 (IH, q, J=6.9Hz), 4.91 and 4.99 (2H, ABq, J=14.6Hz),

6.85 (2H, t, J=8.9Hz), 7.32 (2H, dd, J=5.5Hz and J=8.9Hz), 7.84 (IH, d, J=8.9Hz), 7.93 (IH, dt, J=2.7Hz and J=9.0Hz), 8.00 (IH, dd, J=2.7Hz and J=9.0Hz), 8.13 (IH, s) , 8.45 (IH, dd, J=5.0Hz and J=9.0Hz), 8.73 (IH, d, J=8.9Hz), 8.78 (IH, s) Example 13

Enantiomeric pair A of 3- (6-cyanoquinolin-2-yl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-l-yl) butan-2-ol was separated by using DAICEL chiralcel-OD (hexane: isopropanol = 71:29, flow rate 3.0 ml/min, UV wavelength 240 nm) in substantially the same manner as that of Example 10 to give enantiomeric pair Al and A' of the same.

enantiomeric pair Al retention time : 13.6 minutes

[α]§⁶ = -8.5° (C=0.25%, MeOH)

enantiomeric pair A2 retention time : 22.0 minutes

[α]§⁶ = +5.0° (C=0.25%, MeOH)

The folllowing compounds were obtained in substantially the same manner as that of Example 9-1) .

Example 14-1)

Enantiomeric pair Al of 3- (6-cyanoquinolin-2-yl) -2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-l-yl)butan-2-ol dihydrochloride IR (KBr) : 3246, 2235, 1647, 1618, 1502 cm^-1

Example 14-2)

Enantiomeric pair A2 of 3- (6-cyanoquinolin-2-yl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-l-yl)butan-2-ol dihydrochloride

IR (KBr) : 3284, 2235, 1649, 1618, 1504 cm^"1

Example 15-1)

Enantiomeric pair A of 2- (2, 4-difluorophenyl) -3- (6- methylsulfonylquinolin-2-yl)-l- (1H-1, 2, 4-triazol-l- yl)butan-2-ol dihydrochloride

IR (KBr) : 3381, 1645, 1616, 1500, 1309, 1149 cm^"1 NMR (DMS0-d₆, δ) : 1.16 (3H, d, J=7.2Hz), 3.36 (3H, s), 4.03 (IH, q, J=7.2Hz), 4.25 and 4.91 (2H, ABq, J=14.2Hz), 6.95-7.03 (IH, m) , 7.21-7.43 (2H, m) , 7.85 (IH, s) , 7.94 (IH, d, J=8.6Hz), 8.30 (IH, dd, J=2.0Hz and J=8.6Hz), 8.42 (IH, d, J=8.9Hz), 8.62 (IH, s), 8.78 (IH, d, J=2.0Hz), 8.82 (IH, d, J=8.6Hz)

Example 15-2)

Enantiomeric pair A of 2- (2, 4-dichlorophenyl) -3- (6- methylsulfonylquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l- yl)butan-2-ol dihydrochloride IR (KBr) : 3360, 1645, 1558, 1309, 1147cm^"1

NMR (DMSO-d₆, δ) : 1.08 (3H, d, J=7.1Hz), 3.35 (3H, s), 4.20 (IH, ABq, J=14.3Hz), 4.61 (IH, q, J=7.1Hz), 5.35 (IH, ABq, J=14.3Hz), 7.34 (IH, dd, J=2.2Hz and J=8.7Hz), 7.56 (IH, d, J=8.7Hz), 8.63 (IH, d, J=2.2Hz), 7.61 (IH, s) , 7.95 (IH, d,

J=8.6Hz), 8.28 (IH, dd, J=2.0Hz and J=8.9Hz), 8.42 (IH, d, J=8.9Hz), 8.50 (IH, s) , 8.76 (IH, d, J=2.0Hz), 8.81 (IH, d, J=8.6Hz)

Example 16

Enantiomeric pair A of 2- (2, 4-difluorophenyl) -3- (6- methylsulfonylquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l- yl)butan-2-ol was separated by using DAICEL chiralcel-OD (hexane:ethanol = 50:50, flow rate 3.0 ml/min, UV wavelength 240 nm) in substantially the same manner as that of Example 10 to give enantiomeric pair Al and A2 of the same.

enantiomeric pair Al retention time : 13.3 minutes [α]g° = +3.6° (C=0.25, EtOH)

enantiomeric pair A2 retention time : 27.0 minutes [α]§° = -4.0° (C=0.25, EtOH)

Claims

A compound of the formula:

in which R¹ and R² are each hydrogen or lower alkyl, R³ is optionally substituted quinolyi or oxide thereof, and X and Y are each hydrogen, halogen, cyano or lower alkyl, or a pharmaceutically acceptable salts thereof.

The compound of Claim 1 having the following formula:

in which R , R^, R , X and Y are each as defined in Claim 1.

The compound of Claim 2, wherein

3

R^J is quinolyi or its N-oxide, which is optionally substituted by the group consisting of hydroxy, protected hydroxy, halogen, lower alkoxy. halo(lower) alkyl, halo (lower) alkoxy, lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, amino, nitro, cyano and carboxy.

4. The compound of Claim 3, wherein

R is quinolyi or its N-oxide, which is optionally substituted by the group consisting of hydroxy, halogen, lower alkoxy, halo (lower) alkyl, halo(lower)alkoxy, lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano and carboxy.

The comopund of Claim 4, wherein

R^J is quinolyi, hydroxyqumolyl, haloquinolyl, lower alkoxyquinolyl, halo (lower)alkylquinolyl, halo(lower) alkoxyquinolyl, lower alkylquinolyl, lower alkylthioquinolyl, lower alkylsulfinylquinolyl, lower alkylsulfonylquinolyl, cyanoquinolyl, carboxyquinolyl, N-oxide of quinolyi or N-oxide of haloquinolyl.

The compound of Claim 5 having the following formula:

in which R , X and Y are each as defined in Claim 5, and

R¹ is lower alkyl. 7. A process for the preparation of a compound of the formula:

or a salt there, which comprises

(a) reacting a compound of the formula:

or a salt thereof, with a compound of the formula:

or a salt thereof, to give a compound of the formula:

or a salt thereof; or

(b) oxidizing the optionally substituted quinolyi of a compound of the formula :

or a salt thereof, to give a compound of the formula:

or a salt thereof; or

(c) hydrolyzing the lower alkoxy-substituent of optionally substituted quinolyi of a compound of the formula:

or a salt thereof, to give a compound of the formula:

or a salt thereof; or

(d) oxidizing the lower alkylthio- or lower alkylsulfinyl- substituent of optionally substituted quinolyi of a compound of the formula:

or a salt thereof, to give a compound of the formula:

or a salt thereof; or

(e) hydrolyzing the cyano-substituent of optionally substituted quinolyi of a compound of the formula:

or a salt thereof, to give a compound of the formula:

or a salt thereof; wherein R¹, R², R , X and Y are each as defined above, R³ is optionally substituted quinolyi, R_j3 is N-oxide of optionally substituted quinolyi. R³ is quinolyi substituted by lower alkoxy and optionally by suitable substituent(s) , R³ _} is quinolyi substituted by hydroxy and optionally by suitable substituent (s) , R³ is quinolyi substituted by lower alkylthio or lower alkyl sulfinyl, and optionally by suitable substituent(s) , R^ is quinolyi substituted by lower alkylsulfinyl or lower alkyl sulfonyl, and optionally by suitable substituent(s) ,

R³ is quinolyi substituted by cyano and optionally by suitable substituent(s) , and Rg is quinolyi substituted by carboxy and optionally by, suitable substituent(s) .

8. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier or excipient.

9. A method for treating or preventing infectious diseases which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.

10. A compound of claim 1 and a pharmaceutically acceptable salt thereof for use as a medicament.

11. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.