KR20090007675A - Triazole derivatives having antifungal activity, method for the preparation thereof and pharmaceutical composition containing same - Google Patents

Abstract

A pharmaceutical composition comprising the triazole derivative having antifungal activity is provided to inhibit growth of various pathogenic bacteria, and reduce the toxicity compared to the conventional antifungal agent, thereby treating infection of fungus. The triazole derivative represented by the chemical formula(1) or pharmaceutically acceptable salts thereof have excellent antifungal activity, wherein n is 1 or 2; A indicates direct bonding or C=O; D is CH or N; Z is O or S; R2 is hydrogen, halogen, hydroxy, cyano, nitro, amino, hydroxy carbonyl, C1-6 alkyl, C2-6 alkenyl, C2-6 akynyl, C1-6 acyl, C1-6 acyloxy, heteroaryl-C1-6 alkyl amino or N-C1-6 alkyl N- heteroaryl-C1-6 alkyl amino; and R3 is phenyl and monocyclic heteroaryl, and is replaced by one radical selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, amino, hydroxy carbonyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkoxy C1-6 alkyl, perfluoro C1-6 alkyl and perfluoro C1-6 alkoxy.

Description

A triazole derivative having antifungal activity, a method for preparing the same, and a pharmaceutical composition containing the same TECHNICAL FIELD OF THE INVENTION

1 is Aspergillus fumigatus after administration of an example compound of the present invention This is a graph showing the survival rate of mice systemically infected with (ATCC 16424).

The present invention relates to a triazole derivative having antifungal activity, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.

In today's humans, the chances of infection with fungi are steadily increasing due to changes in the immune system such as living tissue transplantation and HIV/AIDS. In immunodeficiency patients, fungal infection is an important cause of mental and physical disorders and death, as well as skin mucosal disease. In order to prevent fungal infection, amphotericin B, flucytosine and azole compounds have been used as antifungal agents for prophylaxis and treatment. However, treatment of fungi with these drugs did not yield satisfactory results for long-term use due to the efficacy, toxicity, antifungal spectrum and the appearance of drug-resistant fungi. Amphotericin B is limitedly used because it exhibits side effects such as nephrotoxicity, hypokalaemia, and anemia, and flucytosine cannot be used as a single drug because it has genetic factor modification or secondary drug resistance. In addition, azole antifungal agents contain an azole ring containing 2 or 3 nitrogen groups, so imidazole (ketokonaole, miconazole, clotrimazole) and 3 It is classified as a triazole having a nitrogen group in dogs (itraconazole, fluconazole, voriconazole). Excluding ketoconazole, imidazole is used as a superficial fungal treatment, and triazole-based compounds are widely used as superficial and deep fungal treatments. Ketoconazole is very effective, such as Aspergillus, Candida, Cryptococcus, etc., but is used very limitedly due to the toxicity of the compound and the pharmacokinetic problem of the compound.

Pfizer's fluconazole (British Patent No. 2,099818 and U.S. Patent No. 404,216) as useful antifungal agents, and Janssen's Itraconazole (U.S. Patent No. 4,267,179, European Patent Publication No. EP6711) And Pfizer's voriconazole (European Patent Publication No. EP 440,372 and US 5278175) are known.

Fluconazole is widely used as a therapeutic agent for Candida infections, but new mutant strains and resistant strains of fluconazole have emerged. In particular, it does not exhibit antifungal activity against Aspergillus species. Itraconazole has excellent efficacy against Aspergillus infectious diseases, but it is difficult to develop as an oral drug due to its low solubility in water, and it is known to bind well with proteins that can cause uterine cancer in animals. Voriconaole has a disadvantage in that the inhibitory activity of ergosterol P450 is 1.6 to 160 times stronger in Candida albicans and Aspergillus compared to fluconazole, but the activity spectrum is narrow. In addition, although oral absorption is high, there is a problem in that toxicity increases accordingly.

On the other hand, in order to increase fluconazole drug-resistant strains and to alleviate toxicity due to oral administration, studies on drugs capable of overcoming drug resistance of fluconazole have been conducted, for example, synthesis and fungal activity of compounds introducing methyl groups in the side chain. Is known (Chem. Pharm. Bull. (2000), 48, 1947-1953., Chem. Pharm. Bull., (2000), 48, 1935-1946., US 6153616, JP 2000169473, JP 2000063364) , WO 9833778 and WO 9631491). However, the synthesis process of the compounds described in the above document is very complicated, and has a disadvantage in that the effect on resistant strains or aspergillus is weak.

Accordingly, the inventors of the present invention continued research to develop an antifungal agent that has a stronger antifungal activity than fluconazole and exhibits low toxicity to the human body.As a result, the triazole compound of a specific structure according to the present invention is Candida albicans, It has antifungal activity against various pathogens such as Torulopsis, Cryptococcus, Aspergillus, Tricophyton and Fluconazole resistant strains, and reduces toxicity than conventional antifungal agents. The present invention was completed by confirming Sikim.

Accordingly, an object of the present invention is to provide a novel compound having antifungal activity against various pathogens and less toxic than conventional antifungal agents, or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof.

Another object of the present invention is to provide a method for preparing the compound.

Another object of the present invention is to provide a pharmaceutical composition for treating a fungal infection, comprising the compound, or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof, as an active ingredient.

In order to achieve the above object, the present invention provides a compound represented by the following Formula 1 or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof:

In the above formula,

n is 1 or 2,

A represents a direct bond, C=O, or CH ₂ ,

R is a 5 to 10 membered monocyclic or bicyclic heteroaryl group including 1 to 4 ring heteroatoms independently selected from N, O and S, and hydrogen, halogen, hydroxy, cyano, nitro, Amino, hydroxycarbonyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, perfluoro C _1-6 alkyl, perfluoro C _1-6 alkoxy, C _1-6 alkylamino, di-C _1-6 alkylamino, amino-C _1-6 alkyl, C _1-6 alkylamino C _{1 -6} alkyl, diC _1-6 alkylaminoC _1-6 alkyl, C _1-6 acyl, C _1-6 acyloxy, C _1-6 acyloxy C _1-6 alkyl, C _1-6 acylamino, C _1-6 alkylthio, C _1-6 alkylthiocarbonyl, C _1-6 alkylthioxo, C _1-6 alkoxycarbonyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, amino Sulfonyl, C _1-6 alkylaminosulfonyl, diC _1-6 alkylaminosulfonyl, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkoxy, 3- to 8-membered cycloalkyl-C _1-6 alkoxy, 3- to 8-membered cycloalkyl-C _1-6 alkylamino, NC _1-6 alkyl N-3- to 8-membered cycloalkyl-C _1-6 alkylamino, 4- to 8-membered Heterocycloalkyl, 4- to 8-membered heterocycloalkyl-C _1-6 alkoxy, 4- to 8-membered heterocycloalkyl-C _1-6 alkylamino, NC _1-6 alkyl N-4- to 8-membered Heterocycloalkyl-C _1-6 alkylamino, heteroaryl-C _1-6 alkyl, heteroaryl-C _1-6 alkoxy, heteroaryl-C _1-6 alkylamino, NC _1-6 alkyl N-heteroaryl-C _1-6 may be substituted with one or more substituents independently selected from the group consisting of alkylamino, phenyl and monocyclic heteroaryl.

Hereinafter, the present invention will be described in detail.

In Formula 1, R is preferably

또는

이다.

or

to be.

In the above formula,

Y is O, S, or NR ⁵ ,

D is CH or N,

Z is O or S,

R ¹ and R ² are each independently hydrogen, halogen, hydroxy, cyano, nitro, amino, hydroxycarbonyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, perfluoroC _1-6 alkyl, perfluoroC _1-6 alkoxy, C _1-6 alkylamino, di C _1-6 alkylamino, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, diC _1-6 alkylamino C _1-6 alkyl, C _1-6 acyl, C _1-6 acyl Oxy, C _1-6 acyloxy C _1-6 alkyl, C _1-6 acylamino, C _1-6 alkylthio, C _1-6 alkylthiocarbonyl, C _1-6 alkylthioxo, C _1-6 Alkoxycarbonyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, aminosulfonyl, C _1-6 alkylaminosulfonyl, diC _1-6 alkylaminosulfonyl, 3- to 8-membered Cycloalkyl, 3- to 8-membered cycloalkoxy, 3- to 8-membered cycloalkyl-C _1-6 alkoxy, 3- to 8-membered cycloalkyl-C _1-6 alkylamino, NC _1-6 alkyl N- 3- to 8-membered cycloalkyl-C _1-6 alkylamino, 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl-C _1-6 alkoxy, 4- to 8-membered heterocyclo Alkyl-C _1-6 alkylamino, NC _1-6 alkyl N-4- to 8-membered heterocycloalkyl-C _1-6 alkylamino, heteroaryl-C _1-6 alkyl, heteroaryl-C _1-6 alkoxy , Heteroaryl-C _1-6 alkylamino, NC _1-6 alkyl N-heteroaryl-C _1-6 alkylamino,

R ³ and R ⁴ are phenyl and monocyclic heteroaryl, each independently hydrogen, halogen, hydroxy, cyano, nitro, amino, hydroxycarbonyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, perfluoroC _1-6 alkyl and perfluoroC _1-6 alkoxy It may be substituted with one or more substituents independently selected from the group consisting of,

R ⁵ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxyC _1-6 alkyl, perfluoroC _1-6 alkyl.

In the present invention, the 5 to 10 membered monocyclic or bicyclic "heteroaryl" group is furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl , Tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1 ,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3- Triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridineyl, purinyl, 6,7-dihydro-5H-[1]pyridine Il, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimi Dazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxaline It refers to one, quinazolinyl, or benzoxazineyl.

"Cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane Or it refers to a cycloalkyl group containing 0 to 2 unsaturated groups such as nobonanyl.

"Heterocycloalkyl" refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromaenyl, isoxazoli Dinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyra Zolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, mo Polyinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl or chromanyl, and the like are referred to.

Specific compounds of the triazole derivative of Formula 1 according to the present invention include compounds of the following structures.

The pharmaceutically acceptable salt of the compound of Formula 1 according to the present invention may include an acid addition salt formed by a pharmaceutically acceptable free acid. Organic acids and inorganic acids can be used as the free acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc. can be used as inorganic acids, and citric acid, acetic acid, maleic acid, fumaric acid, glucolic acid, and metalsulfonic acid can be used as organic acids. , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, etc. can be used, and methanesulfonic acid and hydrochloric acid are preferred.

The addition salt according to the present invention is a conventional method, that is, after dissolving the compound of formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, adding an excessive amount of organic acid or adding an aqueous acid solution of an inorganic acid. It can be prepared by precipitation or crystallization. Subsequently, the solvent or excess acid is evaporated from the mixture and dried to obtain an addition salt, or the precipitated salt can be prepared by suction filtration. The triazole derivative represented by Formula 1 of the present invention includes not only a pharmaceutically acceptable salt thereof, but also a possible solvate and hydrate that can be prepared therefrom.

In addition, the triazole derivative of Formula 1 according to the present invention may exist as a stereoisomer. The compound of formula 1 has two asymmetric carbons, so that each carbon atom can take on the R- or S-isomer, preferably when all are R-isomers. These optical isomers can be separated by a conventional optical splitting method. The optical isomers provided in Formula 1 of the present invention can be provided by asymmetric synthesis, and these optical isomers can be separated by conventional techniques such as chromatography.

인 화학식 1a의 화합물은 예를 들면 하기 반응식 1에 나타낸 바와 같이 두 가지 경로로 제조 가능하다.In the compound of Formula 1 according to the present invention, A is a direct bond, and R is phosphorus

Phosphorus compounds of formula 1a can be prepared by two routes, for example, as shown in Scheme 1 below.

In the above formula,

n, Y and R ¹ are as previously defined,

P ¹ is a hydrogen or amine protecting group, which means a functional group commonly used in the art (refer to PGM Wuts and TW Greene, John Wiley & Sons, Protective groups in organic synthesis , 4th ed., p696-926). , Preferably, P ¹ represents hydrogen, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl,

P ² is a leaving group, preferably halogen, mercapto, methanesulfonyloxy or trifluoromethanesulfonyloxy,

In the present invention, P ¹ and P ² have the same meaning unless otherwise stated.

First, as a first method, the piperazine compound of Formula 2 is reacted with the heterocyclic compound of Formula 3 in the presence of a base to obtain the compound of Formula 4, and when P ¹ of the compound of Formula 4 is an amine protecting group, an acid or After removing the amine protecting group in the presence of a base, the compound of Formula 5 may be reacted with the oxirane compound of Formula 6 to obtain the compound of Formula 1a.

The compound of Formula 6, which is a reaction intermediate used as a reaction precursor in the present invention, is described in [Chem. Pharm. Bull., 39 , 2241-2246 (1991)]; [Chem. Pharm. Bull., 41 , 1035-1042 (1993)]; And [Chem. Pharm. Bull., 43, 441-449 (1993)] can be prepared and used according to the method. The compound of Formula 6 is a compound having a chiral center, and the final product may be different depending on the stereoselectivity of the epoxide. In the present invention, the reaction intermediate is (2R,3S) 2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4) using a method using R-lactate as a starting material. A triazole compound of Formula 1 containing a piperazine group having stereoselectivity using a compound having a -triazol-1-yl)methyloxiran structure was prepared according to a known method (see WO 1998/031675).

As another method, the oxirane compound of Formula 6 and the piperazine compound of Formula 2 are first reacted to obtain the chiral compound of Formula 7, and when P ¹ is an amine protecting group, the protecting group is removed in the same manner as above, The obtained compound of Formula 8 may be reacted with the heterocyclic compound 3 of Formula 3 to obtain a compound of Formula 1a.

^{In the case where P 1} is hydrogen in the above two processes, compounds 4 and 5 or 7 and 8 are the same compounds, and reaction is possible even in the absence of an amine protecting group.

In the above reaction, the reaction of the (2 R , 3 S ) oxirane compound of Formula 6 with Formula 2 or Formula 5 is preferably carried out in a solvent, and the reaction solvent dissolves the starting material to some extent and does not inhibit the reaction. It is not particularly limited, and examples thereof include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether or dioxane; Aromatic hydrocarbon solvents such as benzene, toluene or xylene; Amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; Organic solvents such as dimethyl sulfoxide, acetonitrile or propionitrile; And one or more single or mixed solvents selected from alcohol-based solvents such as methanol, ethanol, propanol, n-butanol, and t-butanol, and these solvents may be used by mixing with water. Preferably, dimethylformamide, acetonitrile, propionitrile, or a mixture thereof is used.

The reaction may be performed using a conventional oil bath or a microwave generating reactor for professional experiments, and the reaction temperature and reaction time are generally different depending on the starting material, the solvent, and other reagents and equipment used for the reaction. For example, in the case of using an oil bath, based on the internal temperature of the reaction vessel, preferably, in a temperature range of 60 to 200 °C, more preferably 80 to 120 °C, 1 to 48 hours, preferably It is preferably carried out for 6 to 12 hours. When using a microwave reactor, it is preferable to stir while generating microwaves at 60° C. to 200° C. for 1 minute to 1 hour, preferably 10 minutes to 30 minutes.

The reaction of the compound of Formula 2 or the compound of Formula 7 with Formula 3 may be reacted in the presence of the same base as above, if necessary.

In the present invention, a compound in which R ¹ is amino in particular among the compounds represented by Formula 1a may be prepared as shown in Scheme 2 below.

In the above scheme,

n, P ² and Y are as previously defined,

R ⁶ and R ⁷ are each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, perfluoroC _1-6 alkyl, perfluoroC _1-6 alkoxy, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, diC _1-6 alkylamino C _1-6 alkyl, C _1-6 acyl, C _1-6 acyloxy C _1-6 alkyl, C _1-6 alkylthiocarbonyl, C _1-6 alkylthioxo, C _1-6 alkoxycarbonyl, C _1-6 alkylsulfonyl, aminosulfonyl, C _1-6 alkylaminosulfonyl, diC _1-6 alkylaminosulfonyl, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkylC _{1- 6} alkyl, 3- to 8-membered cycloalkylC _1-6 alkoxy, 4- to 8-membered heterocycloalkylC _1-6 alkyl, 4- to 8-membered heterocycloalkylC _1-6 alkoxy, direct nitrogen And 4- to 8-membered heterocycloalkyl.

Specifically, as shown in Reaction Scheme 2, when the heterocyclic compound of Formula 9 is _{subjected to a conventional nitro substitution reaction using KNO 3} and sulfuric acid, nitro is optionally substituted at position 6 of the heterocycle of the compound of Formula 9 The compound of formula 10 in which the group is substituted is obtained. When the resulting compound of Formula 10 is reacted with a piperazine derivative of Formula 11, a leaving group is removed from the compound of Formula 11 and a compound of Formula 12 in which piperazine is substituted can be obtained. The resulting compound of compound 12 is subjected to a reduction reaction to quantitatively obtain an amine compound of Formula 13, and then reacted with an oxirane compound of Formula 6 to stereoselectively obtain a compound of Formula 14 with an open epoxide ring. In addition, the compound of compound 14 can be obtained by differently from the above method. That is, the compound of Formula 12 substituted with piperazine may be first reacted with the oxirane compound of Formula 6 to obtain the compound of Formula 15, and then the compound of Formula 14 may be obtained through a reduction reaction. Finally, by reacting the compound of Formula 14 with various compounds with a leaving group (P ² -R ⁶ R ⁷ ), a compound of Formula 1a substituted with various amine compounds can be obtained through a conventional substitution reaction.

인 화학식 1b의 화합물은 예를 들면 하기 반응식 3에 나타낸 바와 같이 수행하여 얻을 수 있다.In the compound of Formula 1 according to the present invention, A is a direct bond or CH ₂ , and R is

Phosphorus compound of formula 1b can be obtained, for example, as shown in Scheme 3 below.

In the above formula, n, D, P ¹ , P ² and R ² are as previously defined.

The compound of Formula 1b of the present invention can be obtained by performing a method similar to Scheme 1. Specifically, as shown in Scheme 3, ^{a heteroaryl compound of Formula 16 having a leaving group P 2} is reacted with a piperazinyl compound of Formula 2 to obtain a heteroaryl compound in which piperazinyl of Formula 17 is substituted. At this time, when the leaving group is bonded to carbon adjacent to the nitrogen atom, the reaction may be performed directly at a temperature range of 100 to 180°C. Alternatively, the compound of formula 17 can be obtained through an amination reaction using a palladium catalyst of a known method (Buchwald, SL et al., J. Org. Chem. 60 (2000), 1158); and [Heo, J.-N. et al., Tetrahedron Letters 46 (2005), 4621). In the compound of Chemical Formula 17, the compound of Chemical Formula 18 may be obtained through a conventional amine protecting group removal process, except when ^{P 1, which is an amine protecting group, is hydrogen.} Then, the target compound of Formula 1b may be obtained by performing the same reaction as in Scheme 1 with the oxirane compound of Formula 6 with the compound of Formula 18. In addition, in Scheme 3, the compound of Formula 1b can be directly obtained by reacting with the compound of Formula 15 from the compound of Formula 8 in the same manner as in Scheme 1.

인 화학식 1c-1 (Z=O)및 1c-2 (Z=S)의 화합물은 각각 하기 반응식 5 및 6에 나타낸 바와 같이 수행하여 얻을 수 있다.In the compound of Formula 1 according to the present invention, A is C=O, and R is

Phosphorus compounds of formulas 1c-1 (Z=O) and 1c-2 (Z=S) can be obtained by carrying out as shown in Schemes 5 and 6, respectively.

In the above formula,

R ⁸ is hydrogen, halogen, hydroxy, C _1-6 alkoxy cyano, nitro, amino, hydroxycarbonyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, perfluoroC _1-6 alkyl, perfluoroC _1-6 alkoxy, C _1-6 alkylamino, diC _1-6 alkylamino, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, diC _1-6 alkylaminoC _1-6 alkyl, C _1-6 acyl, C _1-6 acyloxy , C _1-6 acyloxy-C _1-6 alkyl, C _1-6 acylamino, C _1-6 alkylthio, C _1-6 alkylthio Oka carbonyl, oxo-C _1-6 alkylthio, C _1-6 alkoxy Carbonyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, aminosulfonyl, C _1-6 alkylaminosulfonyl, diC _1-6 alkylaminosulfonyl, 3- to 8-membered cyclo Is independently selected from the group consisting of alkyl, 4- to 8-membered heterocycloalkyl,

n is as defined in Chemical Formula 1.

As shown in Scheme 4, known methods, for example in Goncalves, H and Secches, A of Bull. Soc. Chim. Fr. (1970), 7, 2589] and [J. Heterocyclic Chem. (1972) 9, 137 of Berndt, E. W et al.], the compound of Formula 19 was used as a base (eg, potassium carbonate, Sodium carbonate or sodium hydrogencarbonate) in the presence of hydroxyamine to obtain a hydroxybenzimide amide derivative of formula 20, and then react with ethyl chlorooxoacetate to obtain 5-aryl-1,2,4- The oxadiazole-3-carboxylate derivative is obtained. The compound of Formula 1c-1 can be obtained by heating the compound of Formula 21 with the compound of Formula 8 using a microreactor for a short period of time.

In the above formula, n and R ⁸ are as defined above.

As shown in Scheme 5 above, a known method, for example J. Org. Chem. (1974), 39(7), 962-4], by reacting a benzamide compound of formula 22 with chlorocarbonylsulphenyl chloride to obtain 1,2,4-oxathiazole-5 of formula 23 After obtaining the -one compound, it is reacted with ethyl cyanoformate to obtain a 1,2,4-thiadiazole derivative of formula (24). Then, the compound of Formula 24 may be reacted with the compound of Formula 8 using a microreactor to obtain the compound of Formula 1c-2.

인 화학식 1d의 화합물은 하기 반응식 6에 나타낸 바와 같이 수행하여 얻을 수 있다.In the compound of Formula 1 according to the present invention, A is C=O, and R is

Phosphorus compound of formula 1d can be obtained by carrying out as shown in Scheme 6 below.

In the above formula, n and R ⁸ are as defined above.

As shown in Scheme 6 above, the compound of Formula 28 was prepared by a known method, for example in J. Org. Chem. (2003), 68(12), 4912-4917], followed by hydrolysis in the presence of a base (eg sodium hydroxide) to obtain a carboxylic acid compound of formula 29. The resulting compound of Formula 29 can be reacted with a piperazinyl compound of Formula 8 using a conventional peptite coupling reagent to obtain a compound of Formula 1d.

A pharmaceutically acceptable salt, hydrate, solvate, or isomer of the compound of Formula 1 may be prepared and used from the compound of Formula 1 using conventional methods.

Thus prepared, the triazole-based compound of Formula 1 of the present invention and a pharmaceutically acceptable salt or isomer thereof have excellent activity against fungi. Examples of fungi include Candida species, Cryptococcus species, Aspergillus species, Mucor species, Histoplasma species, Blastomyces species, and Kosi. Coccidioides species, Paracoccidioides species, Trichophyton species, Epidermophyton species, Microsporum species, Malassezia species, Pseudallescheria species, Sporothrix species, Phinosporidium species, Alternaria species, Aureobasidium species, Chaetomium species, or Curvularia species and the like are included.

In addition, the present invention provides a pharmaceutical composition for the treatment of fungal infections comprising a triazole derivative represented by Formula 1 and a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient.

The pharmaceutical composition of the present invention can be formulated in various oral or parenteral dosage forms. In the case of formulation, commonly used excipients, binders, lubricants, disintegrants, emulsifiers, suspending agents, solvents, stabilizers, absorption enhancers and ointments may be mixed and used. Formulations for oral administration include, for example, tablets, coated tablets, powders, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, and granules. These formulations include diluents (e.g.: Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and magnesium or calcium salts thereof and/or polyethylene glycol). In addition, when formulated into tablets, it may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, in which case Accordingly, it may further contain a disintegrant or boiling mixture and/or an absorbent, a colorant, a flavoring agent, and a sweetening agent such as starch, agar, alginic acid or sodium salt thereof.

In addition, when the pharmaceutical composition of the present invention is formulated for parenteral administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories are included. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. may be used as the non-aqueous solvent and suspension. As a base for suppositories, witepsol, macrogol, Tween 61, cacao butter, laurin paper, glycerol, gelatin, and the like may be used. It can also be administered topically or transdermally, for example using ointments, creams, gels or solutions, and parenterally, for example using solutions for injection.

The pharmaceutical composition of the present invention may be sterilized and/or further contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances, and conventional mixing , It can be formulated according to the granulation or coating method.

In addition, the dosage of the compound of the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition, and degree of disease. The appropriate dosage level for oral administration is generally 1 to 2000 mg/day, preferably 5 to 1000 mg/day, based on an adult patient weighing 70 kg, and the dosage level for intravenous administration is Based on an adult patient, it is 0.1 to 600 mg/day, preferably 0.5 to 500 mg/day.

Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited thereto.

Example

Example 1: (2R,3R)-3-(4-(benzooxazol-2-yl)piperazin-1-yl)-2-(2,4-difluorophene

Preparation of neyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

In a dried round flask passed through nitrogen gas, 0.90 g (10.4 mmol) of piperazine was dissolved in 50 mL of dichloromethane, and 0.80 g (5.2 mmol) of 2-chlorobenzoxazole and 0.9 mL (52.1 mmol) of triethylamine were dissolved at 0 °C. ) And reacted at 0° C. for 30 minutes. After the reaction was terminated by adding water, the reaction product was extracted with ethyl acetate, the organic layer was dried with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by column chromatography using silica gel (dichloromethane:methanol=9:1) to obtain 0.58 g (yield 55%) of 2-(piperazin-1-yl)benzoxazole.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.37 (d, 1H, J = 7.5 Hz), 7.26 (d, 1H, J = 7.5 Hz), 7.17 (t, 1H, J = 7.7 Hz), 7.03 (t , 1H, J = 7.7 Hz), 3.72 (t, 4H, J = 4.8 Hz), 3.03 (t, 4H, J = 4.9 Hz), 2.69 (s, 1H).

Step 2

After dissolving 0.60 g (2.4 mmol) of an oxirane compound in acetonitrile in a dried round flask passed through nitrogen gas, 0.50 g (2.4) of 2-(piperazin-1-yl)benzoxazole obtained in step 1 was dissolved therein. mmol) and lithium perchlorate 0.39 g (3.7 mmol) were added and stirred under reflux for 24 hours. When the reaction was completed, distilled water and ethyl acetate were added to the reaction solution for separation, and the aqueous layer was further extracted with an organic solvent (more than 3 times), and the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. After distilling the solvent under reduced pressure, the obtained residue was purified by column chromatography using silica gel (dichloromethane:methanol=49:1) to give 0.54 g (yield 50%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.79 (s, 1H), 7.62-7.25 (m, 4H), 7.07 (dt, 1H, J = 1.1, 7.5 Hz), 6.81- 6.67 (m, 2H), 5.06 (br s, 1H), 5.01-4.85 (m, 2H), 3.66 (br s, 4H), 3.14-3.05 (m, 3H), 2.65-2.54 (m, 2H), 0.92 (d, 3H, J = 7.0 Hz).

Example 2: (2R,3R)-3-(4-(benzothiazol-2-yl)piperazin-1-yl)-2-(2,4-difluorophenyl)-1-(1H- Preparation of 1,2,4-triazol-1-yl)butan-2-ol

Step 1

In a dried round flask passed through nitrogen gas, 0.50 g (5.90 mmol) of piperazine was dissolved in 10 mL of 80% methanol/water, and 1.0 g (11.9 mmol) of sodium hydrogen carbonate and 0.50 g of 2-chlorobenzothiazole (3.0 mmol, 1eq) was slowly added, and the mixture was heated and stirred under reflux for 12 hours. Water was added to the reaction product to terminate the reaction, extracted with ethyl acetate, and then the organic layer was dried with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by column chromatography using silica gel (dichloromethane:methanol=9:1) to give 0.61 g (yield 94%) of 2-(piperazin-1-yl)benzothiazole.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.62-7.54 (m, 2H), 7.30 (t, 1H, J = 7.7 Hz), 7.08 (t, 1H, J = 7.6 Hz), 3.65 (t, 4H, J = 5.1 Hz), 3.04 (t, 4H, J = 5.1 Hz), 2.55 (br s, 1H); MS (EI) m/z C ₁₁ H ₁₃ N ₃ S calc. 219, found 219 (M ⁺ , 13), 135 (32), 42 (100).

Step 2

In the same manner as in Step 2 of Example 1, except that 2-(piperazin-1-yl)benzothiazole obtained in Step 1 was used instead of 2-(piperazin-1-yl)benzooxazole, 0.30 g (27% yield) of the compound was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.79 (s, 1H), 7.62-7.25 (m, 4H), 7.07 (dt, 1H, J = 1.1, 7.5 Hz), 6.81- 6.67 (m, 2H), 5.06 (br s, 1H), 5.01-4.85 (m, 2H), 3.66 (br s, 4H), 3.14-3.05 (m, 3H), 2.65-2.54 (m, 2H), 0.92 (d, 3H, J = 7.0 Hz); MS (EI) m/z C ₂₃ H ₂₄ F ₂ N ₆ OS calc. 470, found 469 (M ⁺ -1, 1), 388 (1), 246 (100).

Example 3: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(1-methyl-1H-benzoimidazol-2-yl)piperazin-1-yl)- Preparation of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

In a dried round flask passed through nitrogen gas, 1.5 g (9.8 mmol, 1 eq) of 2-chlorobenzoimidazole was dissolved in 10 mL of DMF, and 0.47 g (11.8 mmol, 1.2 eq) of sodium hydride was added little by little at 0°C. gave. After the reaction was allowed to react at room temperature for 1 hour, 1.7 g (11.8 mmol, 1.2 eq) of iodomethane was added and reacted at room temperature for 1 hour. When a precipitate was formed by adding cold water, this was filtered, washed with ethyl acetate and dried to give 1.3 g of 2-chloro-1-methylbenzoimidazole (79% yield).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.77-7.66 (m, 1H), 7.30-7.27 (m, 3H), 3.78 (s, 3H); MS (EI) m/z C ₈ H ₇ ClN ₂ calc. 166, found 166 (M ⁺ , 4), 43 (100).

Step 2

Piperazine 0.43 g (5.0 mmol) and 0.24 g (1.0 mmol) of 2-chloro-1-methylbenzoimidazole obtained in step 1 were added to a dried round flask through which nitrogen gas was passed, and reacted at 150° C. for 30 minutes. When the reaction was completed, the temperature was lowered to room temperature, treated with 1N-hydrochloric acid solution to make the solution acidic, and washed with dichloromethane. The water layer was made basic by treatment with 1N-sodium hydroxide solution, and then extracted with dichloromethane. The extracted organic layer was dried with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by column chromatography using silica gel (dichloromethane:methanol=9:1) to obtain 0.15 g of 1-methyl-2-(piperazin-1-yl)-benzoimidazole (yield 69%). Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.62-7.59 (m, 1H), 7.20-7.16 (m, 3H), 3.61 (s, 3H), 3.30-3.27 (m, 4H), 3.10-3.06 (m , 4H), 2.03 (br s, 1H); MS (EI) m/z C ₁₂ H ₁₆ N ₄ calc. 216, found 216 (M ⁺ , 7), 160 (100), 131 (20).

Step 3

Step 2 of Example 1, except that 1-methyl-2-(piperazin-1-yl)-benzoimidazole obtained in step 2 was used instead of 2-(piperazin-1-yl)benzooxazole. In the same manner, the target compound (yield 43%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.79 (s, 1H), 7.63-7.41 (m, 2H), 7.20-7.16 (m, 3H), 6.81-6.70 (m, 2H) ), 5.05 (s, 1H), 4.96 (d, 1H, J = 14.4 Hz), 4.86 (d, 1H, J = 14.6 Hz), 3.61 (s, 3H), 3.42-3.33 (m, 4H), 3.09 -2.98 (m, 3H), 2.70-2.62 (m, 2H), 1.01 (d, 3H, J = 6.8 Hz); MS (EI) m/z C ₂₄ H ₂₇ F ₂ N ₇ O calc. 467, found 468 (M ⁺ +1, 1), 385 (2), 243 (100).

Example 4: (2R,3R)-3-(4-(6-chlorobenzothiazol-2-yl)piperazin-1-yl)-2-(2,4-difluorophenyl)-1- Preparation of (1H-1,2,4-triazol-1-yl) butan-2-ol

Step 1

In the same manner as in Step 1 of Example 2, except that 2,6-dichlorobenzothiazole was used instead of 2-chlorobenzothiazole as a starting material and the reaction was carried out for 18 hours, 6-chloro-2-( Piperazin-1-yl)benzothiazole (yield 89%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.56 (d, 1H, J = 2.1 Hz), 7.44 (d, 1H, J = 8.7 Hz), 7.24 (dd, 1H, J = 2.1, 8.4 Hz), 3.62 -3.58 (m, 4H), 3.02-2.99 (m, 4H); MS (ESI) m/z C ₁₁ H ₁₂ ClN ₃ S calc. 253, found 253.39.

Step 2

Instead of 2-(piperazin-1-yl)benzoxazole, 6-chloro-2-(piperazin-1-yl)benzothiazole obtained in step 1 was used, and the reaction solvent was propionitrile instead of acetonitrile. Except for using, the target compound (yield 65%) was obtained in the same manner as in Step 2 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.79 (s, 1H), 7.57 (d, 1H, J = 2.1 Hz), 7.48-7.40 (m, 2H), 7.26-7.23 ( m, 1H), 6.80-6.69 (m, 2H), 5.02 (s, 1H), 4.97 (d, 1H, J = 14.4 Hz) 4.91 (d, 1H, J = 15.3 Hz), 3.65 (br s, 4H ), 3.11-3.04 (m, 3H), 2.64-2.57 (m, 2H), 0.92 (d, 3H, J = 6.6 Hz); MS (ESI) m/z C ₂₃ H ₂₃ ClF ₂ N ₆ OS calc. 504.13, found 504.28.

Example 5: (2R,3R)-3-(4-(5-chlorobenzooxazol-2-yl)piperazin-1-yl)-2-(2,4-difluorophenyl)-1- Preparation of (1H-1,2,4-triazol-1-yl) butan-2-ol

Step 1

In a dried round flask passed through nitrogen gas, 1.0 g (7 mmol) of 2-amino-4-chlorophenol and 1.34 g (8.4 mmol) of O -ethylxanthic acid potassium salt were dissolved in 20 mL of ethanol, and then heated to 16. It was stirred under reflux for an hour. After confirming the completion of the reaction, the solvent was removed under reduced pressure, dissolved in ethyl acetate, and washed with water. The organic layer was washed with sodium hydrogen carbonate solution and saturated sodium chloride solution, separated, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained residue was separated by column chromatography using silica gel (dichloromethane:methanol=49:1) to give 5-chloro-2-thiobenzoxazole (yield 57%).

¹ H NMR (300 MHz, CD ₃ OD) δ 7.27-7.13 (m, 3H); MS (ESI) m/z C ₇ H ₄ ClNOS calc. 184.97, found 185.98 (M ⁺ +1).

Step 2

To a 250 mL flask, add 2.97 g (15.9 mmol) of 5-chloro-2-thiobenzoxazole obtained in step 1 and 4.43 g (23.8 mmol) of 1-tert -butyloxycarbonylpiperazine and into p -xylene After melting, the mixture was heated and reacted at 138° C. for 15 hours. After confirming that the reaction was complete, the solvent was removed under reduced pressure, dissolved in ethyl acetate, and washed with water. The organic layer was washed with sodium hydrogen carbonate solution and saturated sodium chloride solution, separated, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The obtained residue was separated by column chromatography using silica gel (n-hexane:ethyl acetate = 9:1), and tert -butyl 4-(5-chlorobenzooxazol-2-yl)piperazine-1-carboxylate (Yield 63%) was obtained.

¹ H NMR (CDCl ₃ ) δ 7.32 (d, J = 2 Hz, 1H), 7.18-7.14 (d, J = 8.4 Hz, 1H), 7.02-6.97 (dd, J = 8.6, 2.0 Hz, 1H), 3.70-3.65 (m, 4H), 3.59-3.54 (m, 4H), 1.49 (s, 9H); MS (ESI) m/z C ₁₆ H ₂₀ ClN ₃ O ₃ calc. 337.12, found 338.17 (M ⁺ +1).

Step 3

To a dried round flask passed through nitrogen gas, 200 mg (0.6 mmol) of tert -butyl 4-(5-chlorobenzooxazol-2-yl) piperazine-1-carboxylate obtained in step 2 was added to 5 mL of dichloromethane. After dissolving in, 410 μL of trifluoroacetic acid was slowly added dropwise to the reaction solution. After reacting the reaction mixture at room temperature for 4 hours, the solvent was removed under reduced pressure, dissolved in ethyl acetate, and washed with water. The organic layer was washed with sodium hydrogen carbonate solution and saturated sodium chloride solution and separated. The product was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to quantitatively obtain 5-chloro-2-(piperazin-1-yl)benzoxazole.

Step 4

Instead of 2-(piperazin-1-yl)benzoxazole, 5-chloro-2-(piperazin-1-yl)benzoxazole obtained in step 3 was used, and propionitrile was used instead of acetonitrile as a reaction solvent. Except for using, it was carried out in the same manner as in Step 2 of Example 1 to obtain the target compound (yield 60%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.79 (s, 1H), 7.50-7.37 (m, 1H), 7.31-7.27 (m, 1H), 7.18-7.12 (m, 1H) ) 7.02-6.95 (m, 1H), 6.81-6.67 (m, 2H), 5.00-4.86 (m, 3H), 3.73 (s, 4H), 3.13-3.06 (m, 3H), 2.64-2.53 (m, 2H), 0.91 (d, J = 6.2 Hz, 3H); MS (ESI) m/z C ₂₃ H ₂₃ ClF ₂ N ₆ O ₂ cacl. 488.15, found 489.26 (M ⁺ +1).

Example 6: (2R,3R)-3-(4-(6-chlorobenzoxazol-2-yl)piperazin-1-yl)-2-(2,4-difluorophenyl)-1- Preparation of (1H-1,2,4-triazol-1-yl) butan-2-ol

Step 1

6-chloro-2-thiobenzoxazole (yield 78) was carried out in the same manner as in Step 1 of Example 5, except that 2-amino-5-chlorophenol was used instead of 2-amino-4-chlorophenol. %).

MS (ESI) m/z C ₇ H ₄ ClNOS cacl. 184.97, found 185.98 (M ⁺ +1).

Step 2

In the same manner as in Step 2 of Example 5, except that the 6-chloro-2-thiobenzoxazole obtained in Step 1 was used instead of 5-chloro-2-thiobenzooxazole, 4- (6- Chlorobenzoxazol-2-yl) piperazine-1-carboxylate (yield 50%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.26 (s, 1H), 7.22 (m, 1H), 7.17-7.16 (m, 1H), 3.69-3.63 (m, 4H), 3.58-3.53 (m, 4H) ), 1.49 (s, 9H); MS (ESI) m/z C ₁₆ H ₂₀ ClN ₃ O ₃ cacl. 337.12, found 338.15 (M ⁺ +1).

Step 3

Instead of 4-(5-chlorobenzooxazol-2-yl)piperazine-1-carboxylate, the 4-(6-chlorobenzooxazol-2-yl)piperazin-1-carboxylate obtained in step 2 was used. 6-chloro-2-(piperazin-1-yl)benzooxazole was quantitatively obtained by performing the same procedure as in Step 2 of Example 5 except that it was used.

Step 4

Same as Step 2 of Example 1, except that 6-chloro-2-(piperazin-1-yl)benzoxazole obtained in Step 3 was used instead of 2-(piperazin-1-yl)benzoxazole. To obtain the target compound (yield 58%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.79 (s, 1H), 7.42 (dd, 1H, J = 6.5, 8.8 Hz), 7.26-7.22 (m, 2H), 7.16- 7.12 (m, 1H), 6.80-6.69 (m, 2H), 5.00-4.88 (m, 3H), 3.72 (br s, 4H), 3.09-3.04 (m, 3H), 2.63-2.56 (m, 2H) , 0.91 (d, 3H, J = 6.9 Hz); MS (EI) m/z C ₂₃ H ₂₃ ClF ₂ N ₆ O ₂ calc. 488, found 488 (M ⁺ , 2), 406 (11), 264 (100).

Example 7: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-fluorobenzothiazol-2-yl)piperazin-1-yl)-1- Preparation of (1H-1,2,4-triazol-1-yl) butan-2-ol

Step 1

6-fluoro-2-(piperazin-1-yl)-benzo in the same manner as in Step 1 of Example 2, except that 2-chloro-6-fluorobenzothiazole was used instead of 2-chlorobenzothiazole. Thiazole (yield 85%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.49-7.44 (m, 1H), 7.31 (dd, 1H, J = 2.6, 8.2 Hz), 7.02 (dt, 1H, J = 2.6, 9.0 Hz), 3.61- 3.58 (m, 4H), 3.03-2.99 (m, 4H); MS (EI) m/z C ₁₁ H ₁₂ FN ₃ S, calc. 237.07, found 237.07 (100), 207.0 (9), 195.0 (81), 180.9 (34).

Step 2

Step 2 of Example 1, except that 6-fluoro-2-(piperazin-1-yl)-benzothiazole obtained in step 1 was used instead of 2-(piperazin-1-yl)benzooxazole. In the same manner, the target compound (yield 60%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.79 (s, 1H), 7.49-7.40 (m, 2H), 7.33-7.29 (m, 1H), 7.02 (dt, 1H, J = 2.6, 9.0 Hz), 6.80-6.69 (m, 2H), 5.02 (s, 1H), 4.99-4.87 (m, 2H), 3.63 (br s, 4H), 3.11-3.04 (m, 3H), 2.63 -2.56 (m, 2H), 0.92 (d, 3H, J = 6.7 Hz); MS (EI) m/z C ₂₃ H ₂₃ F ₃ N ₆ OS, cald. 488.16, found 489 (M ⁺ ,1), 264 (100).

Example 8: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-methylbenzothiazol-2-yl)piperazin-1-yl)-1- Preparation of (1H-1,2,4-triazol-1-yl) butan-2-ol

Step 1

6-methyl-2-(piperazin-1-yl)-benzo in the same manner as in Example 2 except that 2-chloro-6-methylbenzothiazole was used instead of 2-chlorobenzothiazole. Thiazole (yield 86%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.46-7.41 (m, 2H), 7.12-7.09 (m, 1H), 3.61-3.58 (m, 4H), 3.02-2.99 (m, 4H), 2.39 (s , 3H); MS (EI) m/z C ₁₂ H ₁₅ N ₃ S, calc. 233.1, found 233 (100), 191 (93), 177 (83), 165 (41), 150 (13).

Step 2

Step 2 of Example 1 except that 6-methyl-2-(piperazin-1-yl)-benzothiazole obtained in step 1 was used instead of 2-(piperazin-1-yl)-benzooxazole In the same manner as, the target compound (yield 86%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.79 (s, 1H), 7.49-7.41 (m, 3H), 7.10 (dd, 1H, J = 1.2, 8.2 Hz), 6.80- 6.69 (m, 2H), 5.04 (s, 1H), 4.97 (d, 1H, J = 14.8 Hz), 4.89 (d, 1H, J = 15.2 Hz), 3.63 (br s, 4H), 3.09-3.02 ( m, 3H), 2.62-2.55 (m, 2H), 2.05 (s, 3H), 0.93 (d, 3H, J = 6.9 Hz); MS (EI) m/z C ₂₄ H ₂₆ F ₂ N ₆ OS, calc. 484.19, found 484 (1), 260 (100), 191 (8).

Example 9: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-methoxybenzothiazol-2-yl)piperazin-1-yl)-1 Preparation of -(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

6-methoxy-2-(piperazin-1-yl) in the same manner as in Step 1 of Example 2, except that 2-chloro-6-methoxybenzothiazole was used instead of 2-chlorobenzothiazole. -Benzothiazole (yield 79%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.46 (d, 1H, J = 8.8 Hz), 7.15 (d, 1H, J = 2.6 Hz), 6.90 (dd, 1H, J = 2.6, 8.8 Hz), 3.81 (s, 3H), 3.59-3.56 (m, 4H), 3.02-2.99 (m, 4H); MS (EI) m/z C ₁₂ H ₁₅ N ₃ OS, calc. 249.09, found 249 (100), 207 (18), 193 (13), 180 (11), 166 (9).

Step 2

Step 2 of Example 1 except that 6-methoxy-2-(piperazin-1-yl)-benzothiazole obtained in step 1 was used instead of 2-(piperazin-1-yl)benzooxazole In the same manner as, the target compound (yield 95%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.79 (s, 1H), 7.48-7.41 (m, 2H), 7.15 (d, 1H, J = 2.6 Hz), 6.90 (dd, 1H, J = 2.6, 8.8 Hz), 6.80-6.69 (m, 2H), 5.05 (s, 1H), 4.96 (d, 1H, J = 14.7 Hz), 4.89 (d, 1H, J = 15.7 Hz), 3.82 (s, 3H), 3.61 (br s, 4H), 3.09-3.04 (m, 3H), 2.62-2.55 (m, 2H), 0.93 (d, 3H, J = 6.9 Hz); MS (EI) m/z C ₂₄ H ₂₆ F ₂ N ₆ O ₂ S, calc. 500.18, found 500 (1), 276 (100), 233 (11), 207 (17).

Example 10: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-(piperidin-1-yl)benzothiazol-2-yl)piperazine Preparation of -1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

In the same manner as in Step 1 of Example 2, except that 2,6-dichlorobenzothiazole was used instead of 2-chlorobenzothiazole, and the reaction was carried out for 18 hours, tert -butyl 4-(6-chlorobenzoic acid) Thiazol-2-yl) piperazine-1-carboxylate (yield 73%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.57 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.28-7.23 (m, 1H), 3.59 (s, 8H) , 1.49 (s, 9H); MS (ESI) m/z C ₁₆ H ₂₀ ClN ₃ O ₂ S calc. 353.10, found 353.31.

Step 2

In a 5 mL microwave reaction vessel, tert -butyl 4-(6-chlorobenzothiazol-2-yl) piperazine-1-carboxylate 100 mg (0.28 mmol) and piperidine 29 mg (0.34 mmol) obtained in step 1 ), tris (dibenzylideneacetone) dipalladium (0) 5 mg (0.0056 mmol), 2-dicyclohexylphosphino-2'- ( N,N -dimethylamino) biphenyl 3.3 mg (0.0085 mmol) and sodium 38 mg (0.40 mmol) of t -butoxide was added, and 3 mL of toluene was added. The mixture was reacted at 150° C. for 10 minutes in a microwave reactor and filtered through Celite. The resulting solution was distilled under reduced pressure and separated by column chromatography using silica gel (n-hexane:ethyl acetate = 9:1), and tert -butyl 4-(6-(piperidin-1-yl)benzothiazole-2 -Yl) piperazine-1-carboxylate (yield 73%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.78 (s, 1H), 7.46-7.40 (m, 2H), 7.26-7.16 (m, 3H), 6.98 (dd, J = 8.7 , 2.1 Hz, 1H) 6.79-6.70 (m, 2H), 4.98-4.86 (m, 3H), 3.60 (s, 4H), 3.11-3.01 (m, 7H), 2.57 (m, 2H), 2.35 (s , 1H), 1.77-1.69 (m, 4H), 1.59-1.26 (m, 2H), 0.93 (d, J = 6.9 Hz, 3H).

Step 3

Tert -butyl 4-(6-(piperidin-1-yl) obtained in step 2 above instead of tert -butyl 4-(5-chlorobenzooxazol-2-yl) piperazine-1-carboxylate as a starting material ) Benzothiazol-2-yl) piperazine-1-carboxylate was carried out in the same manner as in Step 3 of Example 5, and 2-(piperazin-1-yl)-6-(piperidine- 1-yl)benzothiazole was obtained quantitatively.

Step 4

2-(piperazin-1-yl)-6-(piperidin-1-yl)benzothiazole obtained in step 3 is used instead of 2-(piperazin-1-yl)benzooxazole as a starting material And the target compound (yield 52%) was obtained in the same manner as in Step 2 of Example 1, except that propionitrile was used instead of acetonitrile as the reaction solvent.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.78 (s, 1H), 7.46-7.40 (m, 2H), 7.26-7.16 (m, 1H), 6.98 (dd, J = 8.8 , 2.2 Hz, 1H), 6.79-6.69 (m, 2H), 5.05 (br s, 1H), 4.95 (d, J = 14.1 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H), 3.60 ( s, 4H), 3.11-3.01 (m, 7H), 2.61-2.54 (m, 2H), 1.77-1.69 (m, 4H), 1.59-1.54 (m, 2H), 0.93 (d, J = 6.6 Hz, 3H); MS (ESI) m/z C ₂₈ H ₃₃ F ₂ N ₇ OS, calc. 553.24, found 554.19 (M ⁺ +1).

Example 11: (2R,3R)-3-(4-(6-aminobenzothiazol-2-yl)piperazin-1-yl)-2-(2,4-difluorophenyl)-1- Preparation of (1H-1,2,4-triazol-1-yl) butan-2-ol

Step 1

In a 50 mL flask, 1.088 g (6.42 mmol) of 2-chlorobenzothiazole and 8.56 mL of sulfuric acid were added, and the mixture was reacted for 1 hour and 30 minutes while maintaining 10-17°C. If a white solution is observed, lower the temperature to 12 ℃ and then potassium nitrate 714 mg (7.062 mmol) was added and stirred for 1 hour. In the course of this reaction, the internal temperature was maintained so as not to exceed 18 ℃. After raising the reaction temperature to 25 °C, the mixture was stirred for an additional 1 hour and 30 minutes, and then the reaction temperature was slowly raised to 40 °C. After confirming the completion of the reaction by TLC, cooling it to room temperature and pouring it into ice water, a solid is formed. After filtering this, rinse it thoroughly with water (until the pH is about 7), and remove the water under reduced pressure in a vacuum to form 2-chloro- 6-nitrobenzothiazole (yield 87%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.75 (dd, 1H, J = 0.37, 2.3 Hz), 8.39 (dd, 1H, J = 2.3, 9.0 Hz), 8.08 (dd, 1H, J = 0.40, 9.0 Hz).

Step 2

In the same manner as in Step 1 of Example 2, except that 2-chloro-6-nitrobenzothiazole obtained in Step 1 was used instead of 2-chlorobenzothiazole as a starting material, 6-nitro-2- (pipe Razin-1-yl)benzothiazole (66% yield) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.51 (d, 1H, J = 2.3 Hz), 8.20 (dd, 1H, J = 2.4, 8.9 Hz), 7.50 (d, 1H, J = 8.9 Hz), 3.72 -3.68 (m, 4H), 3.05-3.01 (m, 4H); MS (EI) m/z C ₁₁ H ₁₂ N ₄ O ₂ S, cald. 264.07, found 264 (M ⁺ , 40), 222 (100), 209 (49), 196 (70), 176 (93), 162 (79).

Step 3

Dissolve 306 mg (1.20 mmol) of 6-nitro-2-(piperazin1-yl)benzothiazole obtained in step 2 in THF (5 mL) and Pd/C (31 mg, 10 wt%) and H ₂ And stirred at room temperature for 19 hours. After filtering through celite to remove palladium, the solvent was distilled under reduced pressure under low pressure. The obtained residue was purified by column chromatography using silica gel (dichloromethane:methanol=9:1) to obtain 6-amino-2-(piperazin-1-yl)benzothiazole (yield 60%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.36 (d, 1H, J = 8.5 Hz), 6.94 (d, 1H, J = 2.4 Hz), 6.68 (dd, 1H, J = 2.4, 8.5 Hz), 3.55 -3.51 (m, 5H), 3.00-2.96 (m, 6H).

Step 4

Same as Step 2 of Example 1 except that 6-amino-2-(piperazin-1-yl)benzothiazole obtained in Step 3 was used instead of 2-(piperazin-1-yl)benzooxazole. To obtain the target compound (yield 56%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.79 (t, 1H, J = 6.5 Hz), 7.44-7.35 (m, 2H), 6.96 (d, 1H, J = 2.0 Hz) , 6.79-6.67 (m, 3H), 5.05 (s, 1H), 4.98-4.86 (m, 2H), 3.52 (br s, 6H), 3.08-3.01 (m, 3H), 2.62-2.54 (m, 2H) ), 0.93 (d, 3H, J = 6.9 Hz).

Example 12: (2R,3R)-3-(4-(6-(2-morpholinoethylamino)benzothiazol-2-yl)piperazin-1-yl)-2-(2,4- Preparation of difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

115 mg (0.237 mol) of the compound obtained in step 4 of Example 11, 66.2 mg (0.356 mmol) of 4-(2-chloroethyl) morpholine, and 98.3 mg (0.711 mmol) of potassium carbonate were added to acetonitrile and 48 at 80°C. It was stirred under reflux for an hour. After confirming the completion of the reaction by TLC, the product was dissolved in ethyl acetate and washed with water after removing the solvent. The organic layer was washed with a saturated sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. After dissolving the obtained residue in ethyl acetate, n-hexane was added in small portions to obtain 92 mg (yield 65%) of the target compound by recrystallization.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.78 (s, 1H), 7.49-7.38 (m, 2H), 7.24-7.13 (m, 1H), 6.80 (d, 1H, J = 2.4 Hz), 6.76-6.65 (m, 2H), 5.05 (s, 1H), 4.94 (d, 1H, J = 15.0 Hz), 4.90 (d, 1H, J = 15.0 Hz), 4.24 (br s, 1H), 3.72 (t, 4H, J = 4.5 Hz), 3.58 (br s, 4H), 3.19-3.01 (m, 5H), 2.66-2.46 (m, 8H), 0.93 (d, 3H, J = 6.9 Hz); MS (EI) m/z C ₂₉ H ₃₆ F ₂ N ₃ O ₂ S, calc. 598.26, found 598 (4), 374 (100), 339 (34), 325 (16), 311 (64).

Example 13: (2R,3R)-3-(4-(6-(N-methyl-N-(2-morpholinoethyl)amino)benzothiazol-2-yl)piperazin-1-yl) Preparation of -2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

Tert -butyl 4-(6-(2-morpholinoethylamino)benzothione was carried out in the same manner as in Step 2 of Example 10, except that 2-morpholinoethanamine was used instead of piperidine as a starting material. Azol-2-yl) piperazine-1-carboxylate (72% yield) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.40 (d, 1H, J = 8.7 Hz), 6.89 (d, 1H, J =2.4 Hz), 6.68 (dd, 1H, J = 2.1, 8.7 Hz), 4.27 (br s, 1H), 3.74-3.71 (m, 4H), 3.55 (br s, 8H), 3.17 (t, 2H, J = 5.7 Hz), 2.65 (t, 2H, 4.2 Hz), 2.50-2.47 ( m, 4H), 1.49 (s, 9H).

Step 2

To a dried round flask passed through nitrogen gas, tert -butyl 4-(6-(2-morpholinoethylamino)benzothiazol-2-yl)piperazine-1-carboxylate 150 mg ( 0.34 mmol) and 10 mg (0.34 mmol) of formaldehyde were dissolved in dichloromethane, sodium triacetoxyborohydride (0.47 mmol) was added to the mixed solution, and reacted at room temperature for 16 hours. Water was added to the reaction product to terminate the reaction, and the product was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, separated, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained residue was separated by column chromatography using silica gel and tert -butyl 4-(6-(N-methyl-N-(2-morpholinoethyl)amino)benzothiazol-2-yl)piperazine-1 -Obtained carboxylate.

Step 3

Tert -butyl 4-(6-(N-methyl-N-(2) obtained in step 2 above instead of tert-butyl 4-(5-chlorobenzooxazol-2-yl) piperazine-1-carboxylate as a starting material) -Morpholinoethyl)amino)benzothiazol-2-yl)piperazine-1-carboxylate was carried out in the same manner as in Step 3 of Example 5, and N-methyl-N-(2-morpholino Ethyl)-2-(piperazin-1-yl)benzothiazol-6-amine was obtained quantitatively.

Step 4

N-methyl-N-(2-morpholinoethyl)-2-(piperazin-1-yl)benzo obtained in step 3 above instead of 2-(piperazin-1-yl)-benzooxazole as a starting material Thiazole-6-amine was used, and the target compound (yield 58%) was obtained in the same manner as in Step 2 of Example 1, except that propionitrile was used instead of acetonitrile as the reaction solvent.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.90 (s, 1H), 7.46-7.41 (m, 2H), 6.97 (d, J = 2.1 Hz, 1H), 6.80-6.69 ( m, 3H), 5.05 (br s, 1H), 4.96 (d, J = 14.4 Hz, 1H), 4.88 (d, J = 15.0 Hz, 1H), 3.71 (t, J = 4.5 Hz, 4H), 3.59 (s, 4H), 3.46 (t, J = 7.2 Hz, 2H), 3.08-3.01 (m, 3H), 2.94 (s, 3H), 2.61-2.48 (m, 8H), 0.93 (d, J = 6.6 Hz, 3H).

Example 14: (2R,3R)-3-(4-(6-nitro)benzothiazol-2-yl)piperazin-1-yl)-2-(2,4-difluorophenyl)- Preparation of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

In a 5 mL microwave reaction vessel dried by passing nitrogen gas, 1.0 g (3.98 mmol) of an oxirane compound and 0.86 g (10 mmol) of piperazine were dissolved in 3 mL of acetonitrile, and then 0.64 g (3.98 g) of lithium perchlorate in the reaction mixture solution. mmol) and reacted for 20 minutes at 150° C. in a microwave reactor. Distilled water was added to the reaction product and extracted three or more times with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (dichloromethane:methanol:triethylamine=9:1:0.5) and (2R,3R)-2-(2,4-difluorophenyl)-3- (Piperazin-1-yl)-1-(1H-1,2,4-triazol-1yl)butan-2-ol (yield 70%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.78 (s, 1H), 7.54-7.27 (m, 1H), 6.82-6.67 (m, 2H), 5.3 (br s, 1H) , 4.90 (d, 1H, J = 14.6 Hz), 4.79 (d, 1H, J = 15.0 Hz), 2.97-2.70 (m, 7H), 2.45-2.34 (m, 2H), 0.97 (d, 3H, J = 7.2 Hz).

Step 2

168 mg (0.5 mmol) of the compound obtained in step 1 and 107 mg (0.5 mmol) of 2-chloro-6-nitrobenzothiazole obtained in step 1 of Example 11 were dissolved in 10 mL of acetonitrile, and then in a mixed solution Potassium carbonate 207 mg (1.5 mmol) was added, heated, and stirred under reflux for 16 hours. After lowering the temperature of the reaction solution to room temperature, the solid material was removed by filtration, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride solution, and the organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and reduced pressure to remove the solvent. The residue was separated by column chromatography using silica gel (dichloromethane:methanol=19:1) to give 234 mg (yield 91%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.51 (d, 1H, J = 2.3 Hz), 8.20 (dd, 1H, J = 9.0, 2.3 Hz), 7.90 (s, 1H), 7.80 (s, 1H) , 7.51 (d, 1H, J = 8.9 Hz), 7.47-7.39 (m, 1H), 6.80-6.69 (m, 2H), 5.01-4.95 (m, 3H), 3.75 (br s, 4H), 3.20- 3.01 (m, 3H), 2.68-2.61 (m, 2H), 0.91 (d, 3H, J = 6.8 Hz); MS (EI) m/z C ₂₃ H ₂₃ F ₂ N ₇ O ₃ S, calc. 515.16, found 516.1 (M ⁺ +1, 1), 291.0 (100), 261.1 (16), 222.0 (15), 140.9 (19).

Example 15: (2R,3R)-3-(4-(benzoxazol-2-yl)-1,4-diazepan-1-yl)-2-(2,4-difluorophenyl)- Preparation of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

0.5 g (0.0025 mol) of tert -butyl 1,4-diazepan-1-carboxylate and 0.46 g (0.003 mol, 1.2 eq) of 2-benzoxazole were added to a round flask through which nitrogen gas was passed, and dissolved in 10 mL of chloroform. Then, the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate and then water was added to terminate the reaction. After the water layer was sufficiently extracted with ethyl acetate (more than 3 times), the collected organic layer was washed with saturated sodium chloride solution, separated, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated by column chromatography (ethyl acetate:n-hexane=9:1), and tert -butyl 4-(benzooxazol-2-yl)-1,4-diazepane-1-carboxylate (yield 50 %).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.34-7.38 (m, 1H), 7.12-7.33 (m, 2H), 6.96-7.05 (m, 1H), 3.60-3.83 (m, 6H), 3.36-3.46 (m, 2H), 1.98-2.09 (m, 2H), 1.44 (s, 9H).

Step 2

Tert -butyl 4-(benzooxazol-2-yl)- obtained in step 1 above instead of tert -butyl 4-(5-chlorobenzooxazol-2-yl)piperazine-1-carboxylate as a starting material 2-(1,4-diazepan-1-yl)benzooxazole was quantitatively obtained in the same manner as in Step 3 of Example 5, except that 1,4-diazepan-1-carboxylate was used.

Step 3

Instead of 2-(piperazin-1-yl)benzoxazole as a starting material, 2-(1,4-diazepan-1-yl)benzoxazole obtained in step 2 was used, and acetonitrile was used as a reaction solvent. In the same manner as in Step 2 of Example 1, except that propionitrile was used, the target compound (yield 42%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.72 (s, 1H), 7.68 (s, 1H), 7.43-7.11 (m, 4H), 7.00-6.97 (m, 1H), 6.73-6.68 (m, 2H) ), 5.03 (br s, 1H), 4.74-4.69 (m, 2H), 3.90-3.73 (m, 4H), 3.23-3.07 (m, 3H), 2.80 (br s, 1H), 2.58 (br s, 1H), 2.01-1.98 (m, 2H), 0.91 (d, 3H, J = 5.7 Hz); MS (EI) m/z C ₂₄ H ₂₆ F ₂ N ₆ O ₂ , calc. 468.21, found 466 (M ⁺ -2, 2), 386 (4), 244 (100), 141 (82).

Example 16: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(pyridin-2-yl)piperazin-1-yl)-1-(1H-1, Preparation of 2,4-triazol-1-yl)butan-2-ol

Step 1

In a 5 mL microwave reactor dried with nitrogen gas, 0.1 g (0.63 mmol) of 2-bromopyridine and 0.065 g (0.75 mmol) of piperazine were added and reacted at 150° C. for 20 minutes in a microwave reactor. The temperature of the reaction solution was lowered to room temperature, and a filter device filled with Celite was passed while washing with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was separated by column chromatography using silica gel (dichloromethane:methanol=4:1) to give 1-(pyridin-2-yl)piperazine (yield 54%). .

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.20-8.18 (m, 1H), 7.52-7.43 (m, 1H), 6.66-6.59 (m, 2H), 3.53-3.34 (m, 4H), 3.01-2.96 (m, 4H), 2.1 (br s, 1H); MS (EI) m/z C ₉ H ₁₃ N ₃ calc. 163.11, found 163 (M ⁺ , 29), 121 (63), 95 (100).

Step 2

In the same manner as in Step 2 of Example 1, except that 1-(pyridin-2-yl)piperazine obtained in Step 1 was used instead of 2-(piperazin-1-yl)benzooxazole as a starting material, The title compound (yield 34%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.18 (d, 1H, J = 5.8 Hz), 7.79 (s, 1H), 7.55 (s, 1H), 7.43-7.55 (m, 2H), 6.59-5.81 ( m, 4H), 5.21 (br s, 1H), 4.96 (d, 1H, J = 14.6 Hz), 4.85 (d, 1H, J = 14.6 Hz), 3.53 (br s, 4H), 2.88-3.01 (m , 3H), 2.48-2.59 (m, 2H), 0.96 (d, 3H, J = 7.0 Hz).

Example 17: 5-(4-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazole-1- Preparation of 1)butan-2-yl)piperazin-1-yl)picolinonitrile

Step 1

In a 5 mL microwave reactor dried with nitrogen gas, 0.10 g (0.55 mmol) of 5-bromopicolinonitrile and 0.060 g (0.66 mmol) of piperazine were added, dissolved in DMF, and 0.090 g (0.66 mmol) of potassium carbonate in the mixed solution. Was put, and the mixture was reacted at 200° C. for 30 minutes in a microwave reactor. The temperature of the reaction solution was lowered to room temperature, and a filter device filled with Celite was passed while washing with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was separated by column chromatography using silica gel (dichloromethane:methanol=4:1) to obtain 5-(piperazin-1-yl)picolinonitrile (yield 68%). Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.31 (d, 1H, J = 2.8 Hz), 7.51 (d, 1H, J = 9.0 Hz), 7.08 (dd, 1H, J = 2.9, 8.9 Hz), 3.37 -3.22 (m, 4H), 3.07-3.01 (m, 4H), 1.76 (brs, 1H); MS (EI) m/z C ₁₀ H ₁₂ N ₄ calc. 188.11, found 188 (M ⁺ , 23), 146 (63), 120 (100).

Step 2

In the same manner as in Step 2 of Example 1, except that 5-(piperazin-1-yl)picolinonitrile obtained in Step 1 was used instead of 2-(piperazin-1-yl)benzooxazole as a starting material. To obtain the target compound (yield 34%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.31 (d, 1H, J = 2.8 Hz), 7.90 (s, 1H), 7.79 (s, 1H), 7.54-7.38 (m, 2H), 7.12-7.06 ( m, 1H), 6.82-6.67 (m, 2H), 5.01 (br s, 1H), 4.94-4.85 (m, 2H), 3.43-3.30 (m, 4H), 3.19-3.04 (m, 3H), 2.67 -2.58 (m, 2H), 0.94 (d, 3H, J = 6.8 Hz); MS (EI) m/z C ₂₂ H ₂₃ F ₂ N ₇ O calc. 439.19, found 440 (M ⁺ +1, 1), 357 (87), 215 (100).

Example 18: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(pyrimidin-2-yl)piperazin-1-yl)-1-(1H-1 Preparation of ,2,4-triazol-1-yl)butan-2-ol

Step 1

2-(piperazin-1-yl)pyrimidine (2-(piperazin-1-yl)pyrimidine) was carried out in the same manner as in Step 1 of Example 2, except that 2-chloropyrimidine was used instead of 2-chlorobenzothiazole as a starting material, and reacted for 30 minutes. Yield 68%) was obtained.

¹ H NMR (300 MHz, MeOD-d4) δ 8.53 (dd, 2H, J = 1.5, 4.8 Hz), 6.80 (dt, 1H, J = 1.5, 4.8 Hz), 4.01-3.97 (m, 4H), 3.10 -3.06 (m, 4H); MS (EI) m/z C ₈ H ₁₂ N ₄ calc. 164.11, found 164 (M ⁺ , 22), 122 (100), 96 (66).

Step 2

In the same manner as in Step 2 of Example 1, except that 2-(piperazin-1-yl)pyrimidine obtained in Step 1 was used instead of 2-(piperazin-1-yl)benzooxazole as a starting material. Thus, the target compound (yield 41%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.30 (d, 2H, J = 4.4 Hz), 7.97 (s, 1H), 7.79 (s, 1H), 7.54-7.42 (m, 1H), 6.82-6.68 ( m, 2H), 6.51-6.46 (m, 1H), 5.21 (br s, 1H), 4.99 (d, 1H, J = 14.2 Hz), 4.88 (d, 1H, J = 14.6 Hz), 3.83 (br s , 4H), 3.07-2.85 (m, 3H), 2.54-2.43 (m, 2H), 0.94 (d, 3H, J = 7.0 Hz).

Example 19: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(quinolin-2-yl)piperazin-1-yl)-1-(1H-1, Preparation of 2,4-triazol-1-yl)butan-2-ol

Step 1

After dissolving piperazine 0.20 g (2.45 mmol) in 15 mL of isopropanol in a dried round flask passed through nitrogen gas, 0.20 g (1.2 mmol) of 2-chloroquinoline was added and stirred under reflux for 24 hours. Water was added to the reaction product to terminate the reaction, followed by extraction with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (dichloromethane:methanol=4:1) to give 2-(piperazin-1-yl)quinoline (yield 36%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87 (d, 1H, J = 9.0 Hz), 7.65 (d, 1H, J = 15.2 Hz), 7.55 (tt, 1H, J = 1.4, 7.1 Hz), 7.18 -7.26 (m, 1H), 6.95 (d, 1H, J = 9.2 Hz), 3.70 (t, 4H, J = 5.0 Hz), 3.00 (t, 4H, J = 5.4 Hz), 2.04 (br s, 1H ); MS (EI) m/z C ₁₃ H ₁₅ N ₃ calc. 213.13, found 213 (M ⁺ , 22), 171 (63), 145 (100).

Step 2

In the same manner as in Step 2 of Example 1, except that 2-(piperazin-1-yl)quinoline obtained in Step 1 was used instead of 2-(piperazin-1-yl)benzooxazole as a starting material, The title compound (yield 38%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.88 (d, 1H, J=9.4 Hz), 7.80 (s, 1H), 7.70 (d, 1H, J = 7.6 Hz), 7.43 -7.62 (m, 3H), 7.18-7.26 (m, 1H), 6.96 (d, 1H, J = 9.2 Hz), 6.70-6.82 (m, 2H), 5.15 (br s, 1H), 4.99 (q, 2H, J = 14.6, 20.8 Hz), 3.74 (br s, 4H), 2.91-2.97 (m, 3H), 2.51-2.59 (m, 2H), 0.97 (d, 3H, J = 6.8 Hz).

Example 20: (2R,3R)-3-(4-(6-(benzyloxy)pyridin-2-yl)piperazin-1-yl)-2-(2,4-difluorophenyl)-1 Preparation of -(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

0.30 g (12 mmol) of sodium hydride was added to a flask dried with nitrogen gas, and a suspension was made with anhydrous THF, and benzyl alcohol (12 mmol) was added, followed by stirring for 30 minutes. To the mixed solution, 2.4 g (10 mmol) of 2,6-dibromopyridine was added and reacted at room temperature for 18 hours. Water was added to the reaction product to terminate the reaction, followed by extraction with ethyl acetate three times or more. The collected organic layer was washed with a saturated sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (n-hexane:ethyl acetate = 19:1) to obtain 2-benzyloxy-6-bromopyridine (yield 90%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.30-7.48 (m, 6H), 7.07 (d, 1H, J = 7.5 Hz), 6.73 (d, 1H, J = 8.2 Hz), 5.36 (s, 2H) .

Step 2

After adding 0.50 g (1.9 mmol) of 2-benzyloxy-6-bromopyridine obtained in step 1 to a microwave reaction vessel dried with nitrogen gas, 0.53 g (2.9 mmol) of tert-butyl piperidine-1-carboxylate , Tris(dibenzylideneacetone)dipalladium 17 mg (1 mol%), BINAP [(±)-2,2'-bis(diphenylphosphino)-1,1'-binapthyl] 18 mg (1.5 mol%), sodium tert -butoxide 0.25 g (2.6 eq) and 4 mL of toluene were added and the reaction vessel was closed with a septum. It was reacted for 10 minutes at 120°C in a microwave reactor. The temperature of the reaction solution was lowered to room temperature, and a filter device filled with Celite was passed while washing with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was separated by column chromatography using silica gel (n-hexane:ethylacetate=19:1), and tert -butyl 4-(6-(benzyloxy)pyridin-2-yl ) Piperazine-1-carboxylate (71% yield) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.41-7.27 (m, 5H), 6.90 (br s, 3H), 5.02 (s, 2H), 3.60-3.55 (m, 4H), 3.01-2.99 (m, 4H), 1.49 (s, 9H).

Step 3

Tert -butyl 4-(6-(benzyloxy)pyridin-2-yl obtained in step 2 above instead of tert -butyl 4-(5-chlorobenzooxazol-2-yl)piperazine-1-carboxylate as a starting material ) 1-(6-(benzyloxy)pyridin-2-yl)piperazine was quantitatively obtained by performing the same procedure as in Step 3 of Example 5, except that piperazine-1-carboxylate was used.

Step 4

Instead of 2-(piperazin-1-yl)benzooxazole as a starting material, 1-(6-(benzyloxy)pyridin-2-yl)piperazine obtained in step 3 was used, and acetonitrile was used as a reaction solvent. Except that propionitrile was used for, the target compound (yield 35%) was obtained in the same manner as in Step 2 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.78 (s, 1H), 7.47-7.25 (m, 6H), 6.93-6.74 (m, 5H), 5.28 (br s, 1H) , 5.01 (s, 2H), 4.93 (d, J = 14.4 Hz, 1H), 4.83 (d, J = 14.4 Hz, 1H), 3.08-2.92 (m, 7H), 2.61-2.54 (m, 2H), 0.94 (d, 3H, J = 7.0 Hz); MS (EI) m/z C ₂₈ H ₃₀ F ₂ N ₆ O ₂ calc. 520.24, found 520 (M ⁺ , 1), 295 (100), 140 (15).

Example 21: (2R,3R)-3-(4-(6-(cyclopropylmethoxy)pyridin-2-yl)piperazin-1-yl)-2-(2,4-difluorophenyl) Preparation of -1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

2-bromo-6-(cyclopropylmethoxy)pyridine (yield 78%) was obtained in the same manner as in Step 1 of Example 20, except that cyclopropylmethanol was used instead of benzyl alcohol as a starting material.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.42 (t, 1H, J = 7.9 Hz), 7.05 (d, 1H, J = 7.4 Hz), 6.72 (d, 1H, J = 8.2 Hz), 4.14 (d , 2H, J = 7.0 Hz), 1.18-1.36 (m, 1H), 0.66-0.61 (m, 1H), 0.38-0.33 (m, 1H).

Step 2

In the same manner as in Step 2 of Example 20, except that 2-bromo-6-(cyclopropylmethoxy)pyridine obtained in Step 1 was used instead of 2-benzyloxy-6-bromopyridine as a starting material, tert -butyl 4-(6-(cyclopropylmethoxy)pyridin-2-yl)piperazine-1-carboxylate compound (yield 84%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.40 (t, 1H, J = 7.9 Hz), 6.16-6.10 (m, 2H), 4.05 (d, 2H, J = 7.0 Hz), 3.55-3.45 (m, 8H), 1.48 (s, 9H), 1.26 (t, 1H, J =7.1 Hz), 0.65-0.55 (m, 2H), 0.37-0.29 (m, 2H).

Step 3

Tert -butyl 4-(6-(cyclopropylmethoxy)pyridin-2 obtained in step 2 instead of tert -butyl-4-(5-chlorobenzooxazol-2-yl)piperazine-1-carboxylate as a starting material 1-(6-(cyclopropylmethoxy)pyridin-2-yl)piperazine was quantitatively obtained in the same manner as in Step 3 of Example 5, except that -yl)piperazine-1-carboxylate was used.

Step 4

Instead of 2-(piperazin-1-yl)benzooxazole as a starting material, 1-(6-(cyclopropylmethoxy)pyridin-2-yl)piperazine obtained in step 3 was used, and aceto was used as a reaction solvent. The target compound (yield 46%) was obtained in the same manner as in Step 2 of Example 1, except that propionitrile was used instead of nitrile.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.80 (s, 1H), 7.51-7.49 (m, 1H), 7.41 (t, 1H, J = 7.9 Hz), 6.81-6.77 ( m, 2H), 6.13 (t, 2H, J = 7.4 Hz), 5.25 (br s, 1H), 4.99-4.82 (m, 2H), 4.07 (d, 2H, J = 7.1 Hz), 3.51 (br s , 4H), 3.02-2.80 (m, 3H), 2.52 (br s, 2H), 1.30-1.27 (m, 1H), 0.99-0.98 (m, 3H), 0.62-0.59 (m, 2H), 0.37- 0.33 (m, 2H); MS (EI) m/z C ₂₅ H ₃₀ F ₂ N ₆ O ₂ calc. 484.24, found 484 (M ⁺ , 1), 260 (100), 224 (2), 206 (14).

Example 22: (2R,3R)-3-(4-(6-(cyclopentyloxy)pyridin-2-yl)piperazin-1-yl)-2-(2,4-difluorophenyl)- Preparation of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

2-bromo-6-(cyclopentyloxy)pyridine (yield 82%) was obtained in the same manner as in Step 1 of Example 20, except that cyclopentanol was used instead of benzyl alcohol as a starting material.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.38 (t, 1H, J = 7.8 Hz), 7.70 (d, 1H, J = 7.4 Hz), 6.61 (d, 1H, J = 8.2 Hz), 5.33-5.40 (m, 1H), 1.26-2.04 (m, 8H).

Step 2

In the same manner as in Step 2 of Example 20 except that 2-bromo-6-(cyclopentyloxy)pyridine obtained in Step 1 was used instead of 2-bromo-6-benzyloxypyridine as a starting material, tert -Butyl 4-(6-(cyclopentyloxy)pyridin-2-yl)piperazine-1-carboxylate (yield 68%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.42 (t, 1H, J = 8.1 Hz), 6.25 (d, 1H, J = 8.6 Hz), 6.11 (d, 1H, J = 7.6 Hz), 5.30-5.21 (m, 1H), 3.56-3.28 (m, 8H), 1.97-1.71 (m, 8H), 1.48 (s, 9H).

Step 3

The starting material, to tert-butyl 4- (5-Chloro-2-yl) piperazine-l-carboxylate obtained in Step 2 instead of tert-butyl 4- (6- (cyclopentyloxy) pyridin-2- Il) 1-(6-(cyclopentyloxy)pyridin-2-yl)piperazine was quantitatively obtained by performing the same procedure as in Step 3 of Example 5, except that piperazine-1-carboxylate was used.

Step 4

Instead of 2-(piperazin-1-yl)benzooxazole as a starting material, 1-(6-(cyclopentyloxy)pyridin-2-yl)piperazine obtained in step 3 was used, and acetonitrile as a reaction solvent. Instead, the target compound (yield 27%) was obtained in the same manner as in Step 2 of Example 1 except that propionitrile was used.

¹ H NMR (300 MHz, MeOD-d ₃ ) δ 8.28 (s, 1H), 7.73 (s, 1H), 7.43-7.36 (m, 2H), 6.90-6.81 (m, 2H), 6.22 (d, 1H) , J = 7.8 Hz), 5.99 (d, 1H, J = 7.8 Hz), 5.29-5.27 (m, 1H), 5.05-4.92 (m, 2H), 3.54 (br s, 4H), 3.27-3.24 (m) , 1H), 3.03-2.99 (m, 2H), 2.63-2.59 (m, 2H), 1.95-1.92 (m, 2H), 1.77-1.61 (m, 6H), 0.91 (d, 3H, J = 6.6 Hz ); MS (EI) m/z C ₂₆ H ₃₂ F ₂ N ₆ O ₂ calc. 498.26, found 498 (M ⁺ , 1), 274 (100), 224 (3), 163 (14).

Example 23: (2R,3R)-3-(4-(6-(butyloxy)pyridin-2-yl)piperazin-1-yl)-2-(2,4-difluorophenyl)-1 Preparation of -(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

2-bromo-6-(butyloxy)pyridine (yield 91%) was obtained in the same manner as in Step 1 of Example 20, except that n-butanol was used instead of benzyl alcohol as a starting material.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.40 (t, 1H, J = 7.8 Hz), 7.03 (d, 1H, J = 7.4 Hz), 6.66 (d, 1H, J = 7.8 Hz), 4.28 (t , 2H, J = 6.6 Hz), 1.81-1.67 (m, 2H), 1.56-1.37 (m, 2H), 0.97 (t, 3H, J = 7.2 Hz).

Step 2

In the same manner as in Step 2 of Example 20, except that 2-bromo-6-(butyloxy)pyridine obtained in Step 1 was used instead of 2-bromo-6-benzyloxypyridine as a starting material, tert − Butyl 4-(6-butoxypyridin-2-yl)piperazine-1-carboxylate (yield 78%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.42 (t, 1H, J = 7.9 Hz), 6.21-6.09 (m, 2H), 4.23 (t, 2H, J = 6.5 Hz), 3.51-3.53 (m, 8H), 1.56-1.81 (2H, m), 1.48 (s, 9H), 0.97 (t, 3H, J = 7.3 Hz).

Step 3

Tert -butyl 4-(6-butoxypyridin-2-yl) obtained in step 2 above instead of tert -butyl-4-(5-chlorobenzooxazol-2-yl)piperazine-1-carboxylate as a starting material 1-(6-(butyloxy)pyridin-2-yl)piperazine was quantitatively obtained by performing the same procedure as in Step 3 of Example 5, except that piperazine-1-carboxylate was used.

Step 4

Instead of 2-(piperazin-1-yl)benzooxazole as a starting material, 1-(6-(butyloxy)pyridin-2-yl)piperazine obtained in step 3 was used, and acetonitrile was used as a reaction solvent. Except that propionitrile was used for, the target compound (yield 39%) was obtained in the same manner as in Step 2 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.79 (s, 1H), 7.47 (dd, 1H, J = 6.6, 9.0 Hz), 7.39 (t, 1H, J = 7.9 Hz) , 6.82-6.71 (m, 2H), 6.14-6.05 (m, 2H), 5.24 (s, 1H), 4.95 (d, 1H, J = 14.7 Hz), 4.85 (d, 1H, J = 15.3 Hz), 4.22 (t, 2H, J = 6.6 Hz), 3.50 (br s, 4H), 3.01-2.89 (m, 3H), 2.54-2.50 (m, 2H), 1.76-1.69 (m, 2H), 1.50-1.42 (m, 2H), 0.99-0.94 (m, 6H); MS (EI) m/z C ₂₅ H ₃₂ F ₂ N ₆ O ₂ calc. 486.26, found 486 (M ⁺ , 1), 262 (100), 163 (12), 137 (6).

Example 24: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-(isopropyloxy)pyridin-2-yl)piperazin-1-yl)- Preparation of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

2-bromo-6-(isopropyloxy)pyridine (yield 79%) was obtained in the same manner as in Step 1 of Example 20, except that isopropanol was used instead of benzyl alcohol as a starting material.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.38 (t, 1H, J = 7.8 Hz), 7.00 (d, 1H, J = 7.8 Hz), 6.61 (d, 1H, J = 8.2 Hz), 5.35-5.22 (m, 1H), 1.33 (d, 6H, J = 6.0 Hz).

Step 2

In the same manner as in Step 2 of Example 20 except that 2-bromo-6-(isopropyloxy)pyridine obtained in Step 1 was used instead of 2-bromo-6-benzyloxypyridine as a starting material, tert -Butyl 4-(6-isopropyloxypyridin-2-yl)piperazine-1-carboxylate (yield 74%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.46 (t, 1H, J = 7.9 Hz), 6.33 (d, 1H, J = 8.2 Hz), 6.16 (d, 1H, J = 7.2 Hz), 5.25-5.19 (m, 1H), 3.60-3.50 (m, 8H), 1.51 (s, 9H), 1.36 (d, 6H, J = 6.2 Hz).

Step 3

As a starting material tert - butyl 4- (5-Chloro-2-yl) piperazine-l-carboxylate obtained in Step 2 instead of tert - butyl 4- (6-isopropyloxy-2-yl) 1-(6-(isopropyloxy)pyridin-2-yl)piperazine was quantitatively obtained by performing the same procedure as in Step 3 of Example 5, except that piperazine-1-carboxylate was used.

Step 4

Instead of 2-(piperazin-1-yl)benzooxazole as a starting material, 1-(6-(isopropyloxy)pyridin-2-yl)piperazine obtained in step 3 was used, and acetonitrile as a reaction solvent. Instead, the target compound (yield 27%) was obtained in the same manner as in Step 2 of Example 1 except that propionitrile was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.79 (s, 1H), 7.53-7.47 (m, 1H), 7.40-7.35 (m, 1H), 6.81-6.71 (m, 2H) ), 6.11 (d, 1H, J = 8.1 Hz), 6.03 (d, 1H, J = 7.8 Hz), 5.24-5.17 (m, 2H), 5.02-4.88 (m, 2H), 3.49 (br s, 4H) ), 3.01-2.90 (m, 3H), 2.54-2.50 (m, 2H), 1.33 (d, 6H, J = 6.3 Hz), 0.97 (d, 3H, J = 6.9 Hz); MS (EI) m/z C ₂₄ H ₃₀ F ₂ N ₆ O ₂ calc. 472.24, found 472 (M ⁺ , 1), 248 (100), 206 (8), 163 (25).

Example 25: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-(thiophen-2-ylmethoxy)pyridin-2-yl)piperazine-1 Preparation of -yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

2-((thiophen-2-yl)methoxy)-6-bromopyridine was carried out in the same manner as in Step 1 of Example 20, except that thiophen-2-ylmethanol was used instead of benzyl alcohol as a starting material. (Yield 88%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.43 (t, 1H, J = 7.7 Hz), 7.33 (dd, 1H, J = 1.0, 5.2 Hz), 7.19-7.17 (m, 1H), 7.09 (d, 1H, J = 7.6 Hz), 7.00 (dd, 1H, J = 3.4, 5.0 Hz), 6.72 (d, 1H, J = 8.0 Hz), 5.53 (s, 2H).

Step 2

Instead of 2-(benzyloxy)-6-bromopyridine as a starting material, 2-((thiophen-2-yl)methoxy)-6-bromopyridine obtained in step 1 was used, and tert -butyl piperazine 1-(6-((thiophen-2-yl)methoxy)pyridin-2-yl)piperazine was carried out in the same manner as in Step 2 of Example 20, except that piperazine was used instead of -1-carboxylate. (Yield 54%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.41 (t, 1H, J = 8.1 Hz), 7.27 (dd, 1H, J = 0.8, 5.6 Hz), 7.13-7.10 (m, 1H), 6.97 (dd, 1H, J = 3.5, 5.1 Hz), 6.17 (d, 1H, J = 8.0 Hz), 6.12 (d, 1H, J = 8.0 Hz), 5.50 (s, 2H), 3.58-3.53 (m, 4H), 3.04-2.99 (m, 4H), 2.43 (br s, 1H).

Step 3

Use 1-(6-((thiophen-2-yl)methoxy)pyridin-2-yl)piperazine obtained in step 2 in place of 2-(piperazin-1-yl)benzooxazole as a starting material. And, the target compound (yield 47%) was obtained in the same manner as in Step 2 of Example 1 except that propionitrile was used instead of acetonitrile as the reaction solvent.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.79 (s, 1H), 7.46 (dd, 1H, J = 2.4, 9.3 Hz), 7.39 (t, 1H, J = 8.1 Hz) , 7.26-7.28 (m, 1H), 7.10-7.11 (d, J = 3.3 Hz, 1H), 6.69-6.99 (m, 2H), 6.10 (dd, J = 7.8, 14.4 Hz, 2H), 5.49 (s , 2H), 5.21 (s, 1H), 4.94 (d, J = 14.5 Hz, 1H), 4.85 (d, J = 14.6 Hz, 1H), 3.55 (br s, 4H), 2.91-3.05 (m, 2H) ), 2.50-2.57 (m, 2H), 0.98 (d, J = 6.8 Hz, 3H); MS (EI) m/z C ₂₆ H ₂₈ F ₂ N ₆ O ₂ S calc. 526.20, found 526 (M ⁺ , 3), 149 (60), 96 (100).

Example 26: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-(2-morpholinoethoxy)pyridin-2-yl)piperazine-1 Preparation of -yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

2-bromo-6-(2-morpholinoethoxy)pyridine (yield 97%) was carried out in the same manner as in Step 1 of Example 20, except that 2-morpholinoethanol was used instead of benzyl alcohol as a starting material. ).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.41 (t, 1H, J = 7.9 Hz), 7.05 (d, 1H, J = 7.4 Hz), 6.70 (d, 1H, J = 8.0 Hz), 4.44 (t , 2H, J = 5.7 Hz), 3.70-3.76 (m, 4H), 2.77 (t, 2H, J = 5.8 Hz), 2.54-2.58 (m, 4H).

Step 2

Same as Step 2 of Example 20, except that 2-bromo-6-(2-morpholinoethoxy)pyridine obtained in Step 1 was used instead of 2-bromo-6-benzyloxypyridine as a starting material. To obtain tert -butyl 4-(6-(2-morpholinoethoxy)pyridin-2-yl)piperazine-1-carboxylate (yield 69%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.41 (t, 1H, J = 7.9 Hz), 6.13 (t, 2H, J = 7.9 Hz), 4.39 (t, 2H, J = 5.9 Hz), 3.76-3.71 (m, 4H), 3.51-3.50 (m, 8H), 2.77 (t, 2H, J = 6.1 Hz), 2.59-2.54 (m, 4H), 1.49 (s, 9H).

Step 3

As a starting material tert-butyl 4- (5-Chloro-2-yl) piperazine-l-carboxylate obtained in Step 2 instead of tert-butyl 4- (6- (2-morpholinophenyl) 1- (6- (2-morpholinoethoxy) pyridin-2-yl) pipe by performing the same procedure as in Step 3 of Example 5 except that pyridin-2-yl) piperazine-1-carboxylate was used. Razine was obtained quantitatively.

Step 4

Instead of 2-(piperazin-1-yl)benzooxazole as a starting material, 1-(6-(2-morpholinoethoxy)pyridin-2-yl)piperazine obtained in step 3 was used, and the reaction The target compound (yield 47%) was obtained in the same manner as in Step 2 of Example 1, except that propionitrile was used instead of acetonitrile as a solvent.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.78 (s, 1H), 7.76 (d, 1H, J = 2.7 Hz), 7.48-7.45 (m, 1H), 7.29-7.25 ( m, 1H), 6.80-6.68 (m, 3H), 5.15 (br s, 1H), 4.94 (d, 1H, J = 14.4 Hz), 4.84 (d, 1H, J = 14.4 Hz), 4.39 (t, 2H, 5.7 Hz), 3.73 (t, 4H, J = 4.8 Hz), 3.09-2.99 (m, 7H), 2.78 (t, 2H, J = 5.7 Hz), 2.64-2.55 (m, 6H), 0.98 ( d, 3H, J = 6.9 Hz); MS (EI) m/z C ₂₇ H ₃₅ F ₂ N ₇ O ₃ calc. 543.28, found 543 (M ⁺ , 1), 319 (100), 114 (29).

Example 27: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-(methyl(3-morpholinopropyl)amino)pyridin-2-yl)pipe Preparation of razin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

In a 5 mL microwave reactor dried with nitrogen gas, 95 mg (0.4 mmol) of 2,6-dibromopyridine and 86 mg (0.6 mmol) of 3-morpholinopropylamine were added and reacted at 150° C. for 20 minutes in a microwave reactor. . The temperature of the reaction solution was lowered to room temperature, and a filter device filled with Celite was passed while washing with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was separated by column chromatography using silica gel (n-hexane:ethyl acetate=19:1), and 2-bromo-6-(3-morpholinopropylamino)pyridine (Yield 90%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.20 (d, 1H, J = 7.6 Hz), 6.69 (d, 1H, J = 7.6 Hz), 6.27 (d, 1H, J = 8.4 Hz), 5.39 (br s, 1H), 3.73 (t, 4H, J = 4.6 Hz), 3.34 (q, 2H, J = 6.2 Hz), 2.50-2.43 (m, 6H), 1.77 (quint, 2H, J = 6.6 Hz).

Step 2

After adding 30 mg (1.2 mmol) of sodium hydride and DMF to a round flask through which nitrogen gas was passed, 2-bromo-6-(3-morpholinopropylamino)pyridine (1 mmol) obtained in step 1 was added. And stirred for about 30 minutes. 0.17 g (1.2 mmol) of iodomethane was added thereto and further reacted at room temperature for 4 hours. After adding water to the reaction product to terminate the reaction, the product was extracted three or more times with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (n-hexane:ethyl acetate = 19:1), and 6-bromo-N-methyl-N-(3-morpholinopropyl)pyridin-2-amine ( Yield 76)% was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.22 (t, 1H, J = 8.4 Hz), 6.64 (d, 1H, J = 7.2 Hz), 6.39 (d, 1H, J = 8.2 Hz), 3.76-3.70 (m, 4H), 3.55 (t, 2H, J = 7.2 Hz), 3.02 (s, 3H), 2.46-2.32 (m, 6H), 1.76 (quint, 2H, J = 7.2 Hz).

Step 3

Using 6-bromo-N-methyl-N-(3-morpholinopropyl)pyridin-2-amine obtained in step 2 in place of 2-bromo-6-benzyloxypyridine as a starting material and (±) Except for the use of 2-dicyclohexylphosphino-2'-(N, N'-dimethylamino)biphenyl instead of -2,2'-bis(diphenylphosphino)-1,1'-binaphthyl And carried out in the same manner as in Step 2 of Example 18 tert -butyl 4-(6-(N-methyl-N-(3-morpholinopropyl)amino)pyridin-2-yl)piperazine-1-carboxylate (Yield 74%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.30 (t, 1H, J = 8.2 Hz), 5.90 (d, 2H, J = 8.0 Hz), 3.74-3.69 (m, 4H), 3.56-3.45 (m 10H) ), 2.99 (s, 3H), 2.45-2.32 (m, 6H), 1.85-1.74 (m, 2H), 1.48 (s, 9H).

Step 4

The starting material in tert - butyl 4- (6- (N- methyl -N- (3 - butyl 4- (5-Chloro-2-yl) piperazine-l-carboxylate obtained in Step 3 instead of tert -Morpholinopropyl)amino)pyridin-2-yl)piperazin-1-carboxylate was carried out in the same manner as in Step 3 of Example 5, except that N-methyl-N-(3-morpholinopropyl )-6-(piperazin-1-yl)pyridin-2-amine was obtained quantitatively.

Step 5

N-methyl-N-(3-morpholinopropyl)-6-(piperazin-1-yl)pyridin-2 obtained in step 4 above instead of 2-(piperazin-1-yl)benzooxazole as a starting material -An amine was used, and the target compound (yield 35%) was obtained in the same manner as in Step 2 of Example 1, except that propionitrile was used instead of acetonitrile as the reaction solvent.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.79 (s, 1H), 7.50-7.47 (m, 1H), 7.31-7.26 (m, 1H), 6.82-6.71 (m, 2H) ), 5.88 (d, J = 8.1 Hz, 2H), 5.05 (br s, 1H), 4.94 (d, J = 14.5 Hz, 1H), 4.84 (d, J = 14.6 Hz, 1H), 3.71 (t, J = 4.6, 4H), 3.55-3.50 (m, 6H), 3.02-2.96 (m, 3H), 2.90-2.83 (m, 2H), 2.53-2.33 (m, 9H), 1.79-1.74 (m, 2H) ), 0.97 (d, J = 6.2 Hz, 3H); MS (EI) m/z C ₂₉ H ₄₀ F ₂ N ₈ O ₂ calc. 570.32, found 570 (M ⁺ , 2), 346 (75), 128 (37), 100 (100).

Example 28: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-(methyl(2-(thiophen-2-yl)ethyl)amino)pyridine- Preparation of 2-yl)piperazin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

2-(thiophen-2-yl)ethylamine was used instead of 3-morpholinopropylamine as a starting material, and 2-bromo-6-(2- (Thiophen-2-yl)ethylamino)pyridine (yield 84%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.28-7.15 (m, 2H), 6.97-6.92 (m, 1H), 6.86-6.84 (m, 1H), 6.73 (d, 1H, J = 8.2 Hz), 6.28 (d, 1H, J = 8.0 Hz), 4.75 (br s, 1H), 3.56 (q, 2H, J = 6.5 Hz), 3.12 (t, 2H, J = 6.7 Hz).

Step 2

Instead of 2-bromo-6-(3-morpholinopropylamino)pyridine as a starting material, 2-bromo-6-(2-(thiophen-2-yl)ethylamino)pyridine obtained in step 1 was used. 6-bromo-N-methyl-N-(2-(thiophen-2-yl)ethyl)pyridin-2-amine (yield 91%) was carried out in the same manner as in Step 2 of Example 27 except that it was used. Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.28-7.12 (m, 2H), 6.95-6.91 (m, 1H), 6.84-6.82 (m, 1H), 6.68 (d, 1H, J = 7.4 Hz), 6.34 (d, 1H, J = 8.4 Hz), 3.77 (t, 2H, J = 7.3 Hz), 3.11 (t, 2H, J = 7.3 Hz), 2.97 (s, 3H).

Step 3

Instead of 6-bromo-N-methyl-N-(3-morpholinopropyl)pyridin-2-amine as a starting material, 6-bromo-N-methyl-N-(2-(cy 2-yl) ethyl) pyridin-2-amine as tert used-in place of butyl 4-piperazine-l-carboxylate, except for using piperazine, and the same procedure of step 3 of example 27 and N- Methyl-N-(3-thiophen-2-yl)ethyl-6-(piperazin-1-yl)pyridin-2-amine (64% yield) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.33 (t, 1H, J = 7.8 Hz), 7.13 (dd, 1H, J = 1.4, 5.2 Hz), 6.93 (m, 1H), 6.80-6.82 (m, 1H), 5.91 (t, 2H, J = 8.6 Hz), 3.75-3.80 (m, 2H), 3.58-3.63 (m, 4H), 3.04-3.13 (m, 6H), 2.17 (br s, 3H).

Step 4

N-methyl-N-(3-thiophen-2-yl)ethyl-6-(piperazin-1-yl) obtained in step 3 above instead of 2-(piperazin-1-yl)benzooxazole as a starting material )Pyridine-2-amine was used, and propionitrile was used instead of acetonitrile as the reaction solvent, and the target compound (yield 62%) was obtained in the same manner as in Step 2 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.79 (s, 1H), 7.49-7.51 (m, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.14 (dd, 1H, J = 0.75, 4.9 Hz), 6.92-6.95 (m, 1H), 6.74-6.81 (m, 3H), 5.90 (q, J = 8.2 Hz, 2H), 5.30 (br s, 1H), 4.94 ( d, J = 14.6 Hz, 1H), 4.84 (d, J = 14.6 Hz, 1H), 3.73-3.78 (m, 2H), 3.52 (br s, 4H), 3.07-3.12 (m, 2H), 2.96- 2.97 (m, 4H), 2.84-2.88 (m, 2H), 2.48-2.52 (m, 2H), 0.98 (d, J = 6.9 Hz, 3H); MS (EI) m/z C ₂₈ H ₃₃ F ₂ N ₇ OS calc. 553.24, found 553 (M ⁺ , 2), 329 (100), 116 (9).

Example 29: (2R,3R)-3-(4-(6-(benzyloxy)pyridin-3-yl)piperazin-1-yl)-2-(2,4-difluorophenyl)-1 Preparation of -(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

2-benzyloxy-5-bromopyridine (yield 87) was carried out in the same manner as in Step 1 of Example 20, except that 2,5-dibromopyridine was used instead of 2,6-dibromopyridine as a starting material. %).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.21 (s, 1H), 7.66 (d, 1H, J = 8.8 Hz), 7.47-7.30 (m, 5H), 6.73 (d, 1H, J = 8.8 Hz) , 5.35 (s, 2H).

Step 2

Example 20, except that 2-benzyloxy-5-bromopyridine obtained in step 1 was used instead of 2-benzyloxy-6-bromopyridine as a starting material, and the reaction temperature was 180 °C instead of 120 °C. In the same manner as in Step 2 of, tert -butyl 4-(6-(benzyloxy)pyridin-3-yl)piperazine-1-carboxylate (yield 57%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.83 (d, 1H, J = 2.6 Hz), 7.48-7.30 (m, 6H), 6.76 (d, 1H, J = 9.0 Hz), 5.33 (s, 2H) , 3.62-3.57 (m, 4H), 3.05-3.00 (m, 4H), 1.48 (s, 9H).

Step 3

Tert -butyl 4-(6-(benzyloxy)pyridin-3- obtained in step 2 above instead of tert -butyl 4-(5-chlorobenzooxazol-2-yl)piperazine-1-carboxylate as a starting material Il) 1-(6-(benzyloxy)pyridin-3-yl)piperazine was quantitatively obtained by performing the same procedure as in Step 3 of Example 20, except that piperazine-1-carboxylate was used.

Step 4

Instead of 2-(piperazin-1-yl)benzooxazole as a starting material, 1-(6-(benzyloxy)pyridin-3-yl)piperazine obtained in step 3 was used, and acetonitrile was used as a reaction solvent. Except that propionitrile was used for, the target compound (yield 33%) was obtained in the same manner as in Step 2 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.80-7.78 (m, 2H), 7.46-7.28 (m, 7H), 6.77-6.73 (m, 3H), 5.32 (s, 2H) ), 5.17 (br s, 1H), 4.95 (d, 1H, J = 14.7 Hz), 4.85 (d, 1H, J = 14.4 Hz), 3.10-3.00 (m, 7H), 2.64-2.57 (m, 2H) ), 0.98 (d, 3H, J = 6.9 Hz); MS (EI) m/z C ₂₈ H ₃₀ F ₂ N ₆ O ₂ calc. 520, found 520 (M ⁺ , 1), 385 (3), 296 (100), 91 (20).

Example 30: (2R,3R)-3-(4-(6-(cyclopropylmethoxy)pyridin-3-yl)piperazin-1-yl)-2-(2,4-difluorophenyl) Preparation of -1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

As a starting material, 2,5-dibromopyridine was used instead of 2,6-dibromopyridine, and cyclopropylmethanol was used instead of benzyl alcohol, and 5-bromo- 2-cyclopropylmethoxypyridine (yield 78%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.15 (s, 1H), 7.67-7.60 (m, 1H), 6.70 (d, 1H, J = 8.8 Hz), 4.09 (d, 2H, J = 7.2 Hz) , 1.35-1.17 (m, 1H), 0.67-0.57 (m, 2H), 0.39-0.31 (m, 2H).

Step 2

Except that 5-bromo-2-cyclopropylmethoxypyridine obtained in step 1 was used instead of 2-benzyloxy-6-bromopyridine as a starting material, and the reaction temperature was 180 °C instead of 120 °C. In the same manner as in Step 2 of Example 20, tert -butyl 4-(6-(cyclopropylmethoxy)pyridin-3-yl)piperazine-1-carboxylate (yield 59%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.77 (d, 1H, J = 2.8 Hz), 7.34-7.30 (m, 1H), 6.73 (d, 1H, J = 9.0 Hz), 4.07 (d, 2H, J = 6.8 Hz), 3.58 (t, 4H, J = 5.2 Hz), 3.00 (t, 4H, J = 5.0 Hz), 1.48 (s, 9H), 1.30-1.20 (m, 1H), 0.65-0.56 ( m, 2H), 0.37-0.29 (m, 2H).

Step 3

As a starting material tert-butyl 4- (6- (cyclopropylmethoxy) pyridin-butyl-4 (5-Chloro-2-yl) piperazine-l-carboxylate instead of tert obtained in Step 2 - 3-yl) piperazine-1-carboxylate was carried out in the same manner as in Step 3 of Example 5, except that 1-(6-(cyclopropylmethoxy)pyridin-3-yl)piperazine was quantitatively obtained.

Step 4

Instead of 2-(piperazin-1-yl)benzooxazole as a starting material, 1-(6-(cyclopropylmethoxy)pyridin-3-yl)piperazine obtained in step 3 was used, and aceto was used as a reaction solvent. The target compound (yield 19%) was obtained in the same manner as in Step 2 of Example 1, except that propionitrile was used instead of nitrile.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.78 (s, 1H), 7.75 (d, 1H, J = 2.8 Hz), 7.48-7.43 (m, 1H), 7.29-7.25 ( m, 1H), 6.81-6.69 (m, 3H), 5.13 (s, 1H), 4.94 (d, 1H, J = 14.6 Hz), 4.84 (d, 1H, J = 15.2 Hz), 4.07 (d, 2H , J = 7.1 Hz), 3.08-2.99 (m, 7H), 2.63-2.58 (m, 2H), 1.26-1.25 (m, 1H), 0.98 (d, 3H, J = 6.9 Hz), 0.63-0.57 ( m, 2H), 0.36-0.32 (m, 2H); MS (EI) m/z C ₂₅ H ₃₀ F ₂ N ₆ O ₂ calc. 484, found 484 (M ⁺ , 1), 260 (100), 140 (5).

Example 31: (2R,3R)-3-(4-(6-(cyclopentyloxy)pyridin-3-yl)piperazin-1-yl)-2-(2,4-difluorophenyl)- Preparation of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

As a starting material, 2,5-dibromopyridine was used instead of 2,6-dibromopyridine, and cyclopentanol was used instead of benzyl alcohol, and 5-bromo- 2-cyclopentyloxypyridine (yield 78%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.18 (d, 1H, J = 2.4 Hz), 7.60 (dd, 1H, J = 2.6, 8.8 Hz), 6.58 (d, 1H, J = 9.0 Hz), 5.36 -5.28 (m, 1H), 2.03-1.57 (m, 8H).

Step 2

Example except that 5-bromo-2-cyclopentyloxypyridine obtained in step 1 was used instead of 2-benzyloxy-6-bromopyridine as a starting material, and the reaction temperature was 180 °C instead of 120 °C. In the same manner as in Step 2 of 20, tert -butyl 4-(6-(cyclopentyloxy)pyridin-3-yl)piperazine-1-carboxylate (yield 58%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.88 (d, 1H, J = 3.0 Hz), 7.40-7.35 (m, 1H), 6.72 (d, 1H, J = 9.4 Hz), 5.35-5.41 (m, 1H), 3.66 (t, 4H, J = 5.0 Hz), 3.08 (t, 4H, J = 5.0 Hz), 2.04-1.68 (m, 8H), 1.56 (s, 9H).

Step 3

Tert -butyl 4-(6-(cyclopentyloxy)pyridin-3 obtained in step 2 above instead of tert -butyl-4-(5-chlorobenzooxazol-2-yl)piperazine-1-carboxylate as a starting material -Yl) Piperazine-1-carboxylate was carried out in the same manner as in Step 3 of Example 5, except that 1-(6-(cyclopentyloxy)pyridin-3-yl)piperazine was quantitatively obtained.

Step 4

Instead of 2-(piperazin-1-yl)benzoxazole as a starting material, 1-(6-(cyclopentyloxy)pyridin-3-yl)piperazine obtained in step 3 was used, and acetonitrile as a reaction solvent. Instead, except that propionitrile was used, it was carried out in the same manner as in Step 2 of Example 1 to obtain the target compound (yield 21%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.79-7.78 (m, 2H), 7.48-7.45 (m, 1H), 7.27-7.23 (m, 1H), 6.80-6.70 (m , 2H), 6.62 (d, 1H, J = 9.0 Hz), 5.31-5.27 (m, 1H), 4.93 (d, 1H, J = 14.5 Hz), 4.84 (d, 1H, J = 14.7 Hz), 3.08 -2.98 (m, 7H), 2.63-2.58 (m, 2H), 1.95-1.94 (m, 2H), 1.81-1.75 (m, 4H), 1.64-1.63 (m, 2H), 0.98 (d, 3H, J = 6.9 Hz); MS (EI) m/z C ₂₆ H ₃₂ F ₂ N ₆ O ₂ calc. 498, found 498 (M ⁺ , 1), 274 (100), 149 (5).

Example 32: (2R,3R)-3-(4-(6-(butyloxy)pyridin-3-yl)piperazin-1-yl)-2-(2,4-difluorophenyl)-1 Preparation of -(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

As a starting material, 2,5-dibromopyridine was used instead of 2,6-dibromopyridine, and butanol was used instead of benzyl alcohol, and 5-bromo-2- Butyloxypyridine (yield 78%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.18 (d, 1H, J = 2.6 Hz), 7.62 (dd, 1H, J = 2.4, 8.4 Hz), 6.60 (d, 1H, J = 9.0 Hz), 4.26 (t, 2H, J = 6.6 Hz), 1.81-1.56 (m, 2H), 1.52-1.37 (m, 2H), 0.97 (t, 3H, J = 7.2 Hz).

Step 2

Example 20, except that 5-bromo-2-butyloxypyridine obtained in step 1 was used instead of 2-benzyloxy-6-bromopyridine as a starting material, and the reaction temperature was 180 °C instead of 120 °C. In the same manner as in Step 2 of, tert -butyl 4-(6-(butyloxy)pyridin-3-yl)piperazine-1-carboxylate (yield 57%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.81 (d, 1H, J = 2.2 Hz), 7.36-7.33 (m, 1H), 6.66 (d, 1H, J = 9.0 Hz), 4.24 (t, 2H, J = 6.8 Hz), 3.60 (t, 4H, J = 5.0 Hz), 3.02 (t, 4H, J = 4.6 Hz), 1.81-1.67 (m, 2H), 1.52-1.36 (m, 1H), 0.96 ( t, 3H, J = 7.2 Hz).

Step 3

Tert -butyl-4-(5-chlorobenzooxazol-2-yl)piperazine-1-carboxylate as a starting material, instead of tert -butyl 4-(6-(butyloxy)pyridin-3- Il) 1-(6-(butyloxy)pyridin-3-yl)piperazine was quantitatively obtained by performing the same procedure as in Step 3 of Example 5, except that piperazine-1-carboxylate was used.

Step 4

Instead of 2-(piperazin-1-yl)benzooxazole as a starting material, 1-(6-(butyloxy)pyridin-3-yl)piperazine obtained in step 3 was used, and acetonitrile was used as a reaction solvent. In the same manner as in Step 2 of Example 1, except that propionitrile was used, the target compound (yield 45%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 7.78-7.76 (m, 2H), 7.48-7.44 (m, 1H), 7.34-7.30 (m, 1H), 6.82-6.67 (m , 3H), 4.95-4.83 (m, 2H), 4.21 (t, 2H, J = 6.7 Hz), 3.39-2.98 (m, 7H), 2.62 (br s, 2H), 1.79-1.70 (m, 2H) , 1.54-1.44 (m, 2H), 1.01-0.94 (m, 6H); MS (EI) m/z C ₂₅ H ₃₂ F ₂ N ₆ O ₂ calc. 486, found 486 (M ⁺ , 1), 262 (100), 205 (3), 140 (4).

Example 33: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-(isopropyloxy)pyridin-3-yl)piperazin-1-yl)- Preparation of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

As a starting material, 2,5-dibromopyridine was used instead of 2,6-dibromopyridine, and isopropanol was used instead of benzyl alcohol, and 5-bromo-2- Isopropyloxypyridine (yield 76%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.17 (d, 1H, J = 2.6 Hz), 7.61 (dd, 1H, J = 2.7, 8.7 Hz), 6.59 (d, 1H, J = 8.6 Hz), 5.29 -5.17 (m, 1H, J = 6.1 Hz), 1.34 (d, 6H, J = 6.8 Hz).

Step 2

Example except that 5-bromo-2-isopropyloxypyridine obtained in step 1 was used instead of 2-benzyloxy-6-bromopyridine as a starting material, and the reaction temperature was 180 °C instead of 120 °C. In the same manner as in Step 2 of 20, tert -butyl 4-(6-(isopropyloxy)pyridin-3-yl)piperazine-1-carboxylate (yield 58%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.80 (d, 1H, J = 2.8 Hz), 7.33-7.28 (m, 1H), 6.64 (d, 1H, J = 9.0 Hz), 5.27-5.14 (m, 1H), 3.59 (t, 4H, J = 4.8 Hz), 3.01 (t, 4H, J = 5.2 Hz), 1,49 (s, 9H), 1.33 (d, 6H, J = 6.0 Hz).

Step 3

Tert -butyl 4-(6-(isopropyloxy)pyridin-3 obtained in step 2 above instead of tert -butyl-4-(5-chlorobenzooxazol-2-yl)piperazine-1-carboxylate as a starting material -Yl) Piperazine-1-carboxylate was carried out in the same manner as in Step 3 of Example 5, except that 1-(6-(isopropyloxy)pyridin-3-yl)piperazine was quantitatively obtained.

Step 4

Instead of 2-(piperazin-1-yl)benzoxazole as a starting material, 1-(6-(isopropyloxy)pyridin-3-yl)piperazine obtained in step 3 was used, and acetonitrile as a reaction solvent. Instead, the target compound (yield 32%) was obtained in the same manner as in Step 2 of Example 1 except that propionitrile was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.78-7.77 (m, 2H), 7.48-7.43 (m, 1H), 7.27-7.23 (m, 1H), 6.80-6.70 (m , 2H), 6.62 (d, 1H, J = 9.0 Hz), 5.21-5.13 (m, 2H), 4.94 (d, 1H, J = 14.4 Hz), 4.84 (d, 1H, J = 14.4 Hz), 3.08 -2.98 (m 7H), 2.63-2.57 (m, 2H), 1.32 (d, 6H, J = 6.3 Hz), 0.98 (d, 3H, J = 6.9 Hz); MS (EI) m/z C ₂₄ H ₃₀ F ₂ N ₆ O ₂ calc. 472, found 472 (M ⁺ , 1), 248 (100), 140 (23).

Example 34: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-(2-morpholinoethoxy)pyridin-3-yl)piperazine-1 Preparation of -yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

As a starting material, 2,5-dibromopyridine was used instead of 2,6-dibromopyridine, and 2-morpholinoethanol was used instead of benzyl alcohol, and the mixture was stirred under reflux rather than room temperature. In the same manner, 5-bromo-2-(2-morpholinoethoxy)pyridine (yield 97%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.17 (d, 1H, J = 2.6 Hz), 7.63 (dd, 1H, J = 2.6, 8.6 Hz), 6.70 (d, 1H, J = 8.8 Hz), 4.42 (t, 2H, J = 5.8 Hz), 3.77-3.70 (m, 4H), 2.77 (t, 2H, J = 6.0 Hz), 2.58-2.53 (m, 4H).

Step 2

As a starting material, 5-bromo-2-(2-morpholinoethoxy)pyridine obtained in step 1 was used instead of 2-benzyloxy-6-bromopyridine, and the reaction temperature was set to 180°C instead of 120°C. In the same manner as in Step 2 of Example 20 except that it was used, tert -butyl 4-(6-(2-morpholinoethoxy)pyridin-3-yl)piperazine-1-carboxylate (yield 66%) Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.76 (d, 1H, J = 3.0 Hz), 7.31-7.25 (m, 1H), 6.71 (d, 1H, J = 9.0 Hz), 4.39 (t, 2H, J = 5.6 Hz), 3.75-3.71 (m, 4H), 3.60-3.55 (m, 4H), 3.02-3.00 (m, 4H), 2.77 (t, 1H, J = 5.8 Hz), 2.59-2.54 (m , 4H), 1.48 (s, 9H).

Step 3

The starting material in tert-butyl-4- (5-Chloro-2-yl) piperazine-l-carboxylate obtained in Step 2 instead of tert-butyl 4- (6- (the morpholino ethoxy) pyridine 1-(6-(2-morpholinoethoxy)pyridin-3-yl)piperazine was carried out in the same manner as in Step 3 of Example 5 except that 3-yl)piperazin-1-carboxylate was used. Was obtained quantitatively.

Step 4

Instead of 2-(piperazin-1-yl)benzooxazole as a starting material, 1-(6-(2-morpholinoethoxy)pyridin-3-yl)piperazine obtained in step 3 was used, and the reaction The target compound (yield 43%) was obtained in the same manner as in Step 2 of Example 1, except that propionitrile was used instead of acetonitrile as a solvent.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.79 (s, 1H), 7.49-7.46 (m, 1H), 7.39 (t, 1H, J = 8.0 Hz), 6.81-6.71 ( m, 2H), 6.15-6.08 (m, 2H), 5.15 (br s, 1H), 4.95 (d, 1H, J = 14.7 Hz), 4.85 (d, 1H, J = 14.7 Hz), 4.39 (t, 2H, J = 6.0 Hz), 3.74 (t, 4H, J = 4.7 Hz), 3.50 (br s, 4H), 3.02-2.89 (m, 3H), 2.77 (t, 2H, J = 6.0 Hz), 2.58 -2.48 (m, 6H), 0.96 (d, 3H, J = 6.9 Hz); MS (EI) m/z C ₂₇ H ₃₅ F ₂ N ₇ O ₃ calc. 543, found 543 (M ⁺ , 1), 319 (100), 114 (29).

Example 35: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-(thiophen-2-ylmethoxy)pyridin-3-yl)piperazine-1 Preparation of -yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

Example 20, except that 2,5-dibromopyridine was used instead of 2,6-dibromopyridine as a starting material, and thiophen-2-yl-methanol was used instead of benzyl alcohol, and reflux agitation was performed other than room temperature. In the same manner as in Step 1 of, 2-((thiophen-2-yl)methoxy)-5-bromopyridine (yield 96%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.24 (d, 1H, J = 2.6 Hz), 7.63-6.69 (m, 1H), 7.31 (d, 1H, J = 5.2 Hz), 7.17-7.15 (m, 1H), 7.00 (dd, 1H, J = 3.6, 4.8 Hz), 6.69 (d, 1H, J = 9.0 Hz), 5.52 (s, 2H).

Step 2

Instead of 2-(benzyloxy)-6-bromopyridine as a starting material, 2-((thiophen-2-yl)methoxy)-5-bromopyridine obtained in step 1 above, tert -butyl peperazine- 1-(6-(thiophen-2-ylmethoxy)pyridin-3-yl)piperazine (yield 36%) by performing the same procedure as in Step 2 of Example 20 except that piperazine was used instead of 1-carboxylate. Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.81 (d, 1H, J = 2.8 Hz), 7.32-7.27 (m, 2H), 7.13-7.12 (m, 1H), 7.02-6.96 (m, 1H), 6.72 (dd, 1H, J = 2.0, 9.0 Hz), 5.49 (s, 2H), 3.05-3.04 (m, 8H).

Step 3

Instead of 2-(piperazin-1-yl)benzoxazole as a starting material, 1-(6-(thiophen-2-ylmethoxy)pyridin-3-yl)piperazine obtained in step 2 was used, and the reaction The target compound (yield 47%) was obtained in the same manner as in Step 2 of Example 1, except that propionitrile was used instead of acetonitrile as a solvent.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.79 (s, 1H), 7.50-7.47 (m, 1H), 7.40 (t, 1H, J = 8.0 Hz), 7.28-7.26 ( m, 1H), 7.11 (d, 1H, J = 3.3 Hz), 6.99-6.96 (m, 1H), 6.81-6.74 (m, 2H), 6.17-6.10 (m, 2H), 5.49 (s, 2H) , 5.21 (br s, 1H), 4.96 (d, 1H, J = 14.7 Hz), 4.86 (d, 1H, J = 14.7 Hz), 3.55 (br s, 4H), 3.05-2.91 (m, 3H), 2.57-2.50 (m, 2H), 0.97 (d, 3H, J = 6.9 Hz); MS (EI) m/z C ₂₆ H ₂₈ F ₂ N ₆ O ₂ S calc. 526, found 526 (M ⁺ , 3), 148 (60), 96 (100).

Example 36: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(5-(methyl(3-morpholinopropyl)amino)pyridin-2-yl)pipe Preparation of razin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

5-Bromo-N-(3-morpholino) was carried out in the same manner as in Step 1 of Example 27, except that 2,5-dibromopyridine was used instead of 2,6-dibromopyridine as a starting material. Propyl) pyridin-2-amine (yield 64%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.09 (d, 1H, J = 2.4 Hz), 7.44 (dd, 1H, J = 2.4, 8.8 Hz), 6.28 (d, 1H, J = 9.0 Hz), 5.40 (br s, 1H), 3.73 (t, 4H, J = 4.6 Hz), 3.34 (dd, 2H, J = 6.6, 12.0 Hz), 2.51-2.44 (m, 6H), 1.78 (t, 2H, J = 6.5 Hz).

Step 2

Instead of 6-bromo-N-(3-morpholinopropyl)pyridin-2-amine as a starting material, 5-bromo-N-(3-morpholinopropyl)pyridin-2- obtained in step 1 above. 5-bromo-N-methyl-N-(3-morpholinopropyl)pyridin-2-amine (yield 68%) was obtained in the same manner as in Step 2 of Example 27 except that an amine was used.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.13 (d, 1H, J = 2.4 Hz), 7.45 (dd, 1H, J = 2.2, 9.0 Hz), 6.42 (d, 1H, J = 9.0 Hz), 3.74 -3.69 (m, 4H), 3.54 (t, 2H, J = 7.2 Hz), 3.01 (s, 3H), 2.45-2.40 (m, 4H), 2.38 (t, 2H, J = 7.2 Hz), 1.80- 1.69 (m, 2H).

Step 3

Instead of 6-bromo-N-methyl-N-(3-morpholinopropyl)pyridin-2-amine as a starting material, 5-bromo-N-methyl-N-(3-morpholy) obtained in step 2 Tert -butyl 4-(6-(methyl(3-morpholinopropyl)amino)pyridin-3-yl) in the same manner as in Step 3 of Example 27 except that nopropyl)pyridin-2-amine was used. Piperazine-1-carboxylate (66% yield) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.87 (d, 1H, J = 2.8 Hz), 7.19 (dd, 1H, J = 3.2, 9.4 Hz), 6.51 (d, 1H, J = 9.2 Hz), 3.78 -3.66 (m, 4H), 3.59-3.48 (m, 6H), 3.04-2.91 (m, 5H), 2.46-2.33 (m, 6H), 1.84-1.69 (m, 4H), 1.48 (s, 9H) .

Step 4

The starting material in tert-butyl-4- (5-Chloro-2-yl) piperazine-l-carboxylate obtained in Step 3 instead of tert-butyl 4- (6- (methyl (3-morpholino N-methyl-N-(3-morpholinopropyl)-5- (Piperazin-1-yl) pyridin-2-amine was obtained quantitatively.

Step 5

N-methyl-N-(3-morpholinopropyl)-5-(piperazin-1-yl)pyridine- obtained in step 4 above instead of 2-(piperazin-1-yl)benzooxazole as a starting material 2-amine was used, and the target compound (yield 40%) was obtained in the same manner as in Step 2 of Example 1, except that propionitrile was used instead of acetonitrile as the reaction solvent.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.87 (d, J = 3.0 Hz, 1H), 7.78 (s, 1H), 7.49-7.46 (m, 1H), 7.18 (dd, J = 3.0, 9.0 Hz, 1H), 6.80-6.71 (m, 2H), 6.51 (d, J = 9.0 Hz, 1H), 5.20 (br s, 1H), 4.93 (d, J = 14.4 Hz, 1H) , 4.84 (d, J = 14.4 Hz, 1H), 3.73-3.70 (m, 4H), 3.54-3.48 (m, 2H), 3.04-2.95 (m, 10H), 2.62-2.59 (m, 2H), 2.45 -2.35 (m, 6H), 1.80-1.75 (m, 2H), 0.99 (d, J = 6.9 Hz, 3H); MS (EI) m/z C ₂₉ H ₄₀ F ₂ N ₈ O ₂ calc. 570, found 570 (M ⁺ , 39), 346 (100), 259 (97), 162 (23).

Example 37: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(6-(methyl(2-(thiophen-2-yl)ethyl)amino)pyridin-2 -Yl)piperazin-1-yl)-1-(1 H -1,2,4-triazol-1-yl) butan-2-ol

Step 1

2,5-dibromopyridine (0.505 g, 2.13 mmol) and 2-(thiophen-2-yl)ethanamine (0.542 g, 4.26 mmol) were heated at 150° C. for 4 hours, and then the temperature was lowered to room temperature. , The mixture was separated by column chromatography using silica gel (n-hexane:ethyl acetate = 9:1), and 5-bromo-N-(2-(thiophen-2-yl)ethyl)pyridin-2-amine (Yield 80%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.12 (d, 1H, J = 2.2 Hz), 7.46 (dd, 1H, J = 2.6, 8.8 Hz), 7.22 (dd, 1H, J = 1.2, 4.8 Hz) , 6.97-6.93 (m, 1H), 6.86-6.83 (m, 1H), 6.27 (d, 1H, J = 9.4 Hz), 4.62 (br s, 1H), 3.57 (q, 2H, J = 6.5 Hz) , 3.12 (t, 2H, J = 6.5 Hz).

Step 2

5-bromo-N-(2-thiophen-2-yl)ethyl)pyridin-2-amine obtained in step 1 above instead of 2-bromo-6-(3-morpholinopropylamino)pyridine as a starting material 5-Bromo-N-methyl-N-(2-(thiophen-2-yl)ethyl)pyridin-2-amine (yield 87%) was carried out in the same manner as in Step 2 of Example 27 except for using Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.17 (d, 1H, J = 2.4 Hz), 7.51-7.45 (m, 1H), 7.14 (dd, 1H, J = 1.0, 5.2 Hz), 6.93 (t, 1H, J = 3.4 Hz), 6.82-6.80 (m, 1H), 6.35 (d, 1H, J = 9.8 Hz), 3.78 (t, 2H, J = 7.0 Hz), 3.09 (t, 2H, J = 7.4 Hz), 2.96 (s, 3H).

Step 3

Instead of 6-bromo-N-methyl-N-(3-morpholinopropyl)pyridin-2-amine as a starting material, 5-bromo-N-methyl-N-(2-(cy Offen-2-yl)ethyl)pyridin-2-amine was carried out in the same manner as in Step 3 of Example 27, except that piperazine was used instead of tert-butyl peperazine-1-carboxylate, and N-methyl-N- (2-(thiophen-2-yl)ethyl)-5-(piperazin-1-yl)pyridin-2-amine (yield 59%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.93 (dd, 1H, J = 0.6, 2.8 Hz), 7.24-7.12 (m, 2H), 6.95-6.90 (m, 1H), 6.84-6.81 (m, 1H) ), 6.47 (dd, 1H, J = 0.6, 9.2 Hz), 3.80-3.73 (m, 2H), 3.31 (br s, 1H), 3.13-3.03 (m, 10H), 2.98 (s, 3H).

Step 4

N-methyl-N-(2-(thiophen-2-yl)ethyl)-5-(piperazin-1 obtained in step 3 above instead of 2-(piperazin-1-yl)benzooxazole as a starting material -Yl)pyridin-2-amine, and the reaction solvent was carried out in the same manner as in Step 2 of Example 1, except that propionitrile was used instead of acetonitrile to obtain the target compound (yield 50%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.91 (d, J = 3.0 Hz, 1H), 7.78 (s, 1H), 7.52-7.40 (m, 1H), 7.20 (dd, 1H, J = 3.0, 9.0 Hz), 7.13 (dd, 1H, J = 1.1, 5.3 Hz), 6.94-6.91 (m, 1H), 6.83-6.75 (m, 3H), 6.47 (d, J = 9.3 Hz) , 1H), 5.29 (br s, 1H), 4.93 (d, 1H, J = 14.4 Hz), 4.84 (d, 1H, J = 15.0 Hz), 3.79-3.74 (m, 2H), 3.12-2.94 (m) , 12H), 2.62-2.56 (m, 2H), 0.99 (d, J = 6.9 Hz, 3H); MS (EI) m/z C ₂₈ H ₃₃ F ₂ N ₇ OS calc. 553, found 553 (M ⁺ , 32), 456 (29), 329 (100), 84 (59).

Example 38: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(pyridin-2-yl)-1,4-diazepan-1-yl)-1- Preparation of (1H-1,2,4-triazol-1-yl) butan-2-ol

Step 1

In a 5 mL microwave reactor dried with nitrogen gas, 1.58 g (10 mmol) of 2-bromopyridine and 2.5 g (25 mmol, 2.5 eq) of homopiperazine were added and reacted at 120° C. for 20 minutes using a microwave reactor. Water was added to the reaction product to terminate the reaction, followed by extraction with ethyl acetate three times or more. The collected organic layer was washed with a saturated sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (dichloromethane:methanol=9:1) to give 1-(pyridin-2-yl)-1,4-diazepan (yield 62%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.17-8.13 (m, 1H), 7.53-7.45 (m, 1H), 6.63 (dd, 1H, J = 5.0, 7.4 Hz), 6.53 (d, 1H, J = 8.2 Hz), 4.12 (t, 2H, J = 4.7 Hz), 3.75 (t, 2H, J = 6.5 Hz), 3.38 (t, 2H, J = 4.9 Hz), 3.23 (t, 2H, J = 5.5 Hz), 2.39 (t, 2H, J = 5.7 Hz).

Step 2

Instead of 2-(piperazin-1-yl)benzooxazole as a starting material, 1-(pyridin-2-yl)-1,4-diazepane obtained in step 1 was used, and instead of acetonitrile as a reaction solvent The target compound (yield 36%) was obtained in the same manner as in Step 2 of Example 1 except that propionitrile was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.14-8.12 (m, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.48-7.38 (m, 2H), 6.79-6.67 (m, 2H) ), 6.52-6.47 (m, 2H), 5.30 (br s, 1H), 4.72-4.62 (m, 2H), 3.83-3.59 (m, 4H), 3.05-2.93 (m, 3H), 2.74-2.72 ( m, 1H), 2.47-2.45 (m, 1H), 1.99-1.93 (m, 2H), 0.93 (d, J = 6.9 Hz, 3H); MS (EI) m/z C ₂₂ H ₂₆ F ₂ N ₆ O calc. 428, found 429 (M ⁺ +1, 1), 306 (6), 205 (100), 147 (26).

Example 39: 6-(4-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazole-1- Preparation of i)butan-2-yl)-1,4-diazepan-1-yl)pyridin-3-carbonitrile

Step 1

5-(1,4-diazepan-1-yl)picolinonitrile was carried out in the same manner as in Step 1 of Example 17, except that homopiperazine was used instead of piperazine as a starting material, and was carried out at 180°C. (Yield 50%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.15 (d, 1H, J = 3.2 Hz), 7.47 (d, 1H, J = 9.0 Hz), 6.91 (dd, 1H, J = 2.8, 8.8 Hz), 3.69 -3.48 (m, 4H), 3.10-2.90 (m, 2H), 2.88-2.85 (m, 2H), 1.97-1.92 (m, 2H).

Step 2

As a starting material, 5-(1,4-diazepan-1-yl)picolinonitrile was used instead of 2-(piperazin-1-yl)benzooxazole, and propionitrile was used instead of acetonitrile as a reaction solvent. Except for using, it was carried out in the same manner as in Step 2 of Example 1 to obtain the target compound (yield 45%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.16 (d, J = 3.0 Hz, 1H), 7.85 (s, 1H), 7.77 (s, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.38 (dd, J = 6.6, 9.0 Hz, 1H), 6.92 (dd, J = 3.0, 8.7 Hz, 1H), 6.77-6.67 (m, 2H), 4.98 (br s, 1H), 4.80-4.69 (m, 2H), 3.71-3.58 (m, 4H), 3.28 (br s, 1H), 3.11 (q, J = 6.9 Hz, 2H), 2.78-2.75 (m, 1H), 2.52 (br s, 1H), 1.92 (br s, 2H), 0.89 (d, J = 6.6 Hz, 3H); MS (EI) m/z C ₂₃ H ₂₅ F ₂ N ₇ O calc. 453, found 454 (M ⁺ +1, 1), 229 (100), 141 (12).

Example 40: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(quinolin-2-yl)-1,4-diazepan-1-yl)-1- Preparation of (1H-1,2,4-triazol-1-yl) butan-2-ol

Step 1

2-(1,4-diazepan-1-yl)quinoline (yield 47) was carried out in the same manner as in Step 1 of Example 19, except that homopiperazine was used instead of piperazine as a starting material and reacted for 18 hours. %).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.85 (d, 1H, J = 9.4 Hz), 7.68-7.46 (m, 3H), 7.21 (t, 1H, J = 8.0 Hz), 6.86 (d, 1H, J = 9.0 Hz), 3.95-3.84 (m, 4H), 3.11 (t, 2H, J = 5.6 Hz), 2.87 (t, 2H, J = 5.8 Hz), 2.02-1.91 (m, 2H).

Step 2

Step 2 of Example 1 and step 2 of Example 1 except that 2-(1,4-diazepan-1-yl)quinoline obtained in step 1 was used instead of 2-(piperazin-1-yl)benzooxazole as a starting material. In the same manner, the target compound (yield 47%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.82 (d, J = 9.0 Hz, 1H), 7.67-7.65 (m, 2H), 7.54-7.38 (m, 4H), 7.20-7.17 (m, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.71-6.63 (m, 2H), 5.03 (br s, 1H), 4.47 (s, 2H), 3.95-3.85 (m, 4H), 3.14 (br s, 1H), 3.03 (q, 2H, J = 6.7 Hz), 2.84 (br s, 1H), 2.49 (br s, 1H), 1.99-1.88 (m, 2H), 0.89 (d, J = 7.0 Hz, 3H ); MS (EI) m/z 478 (M ⁺ , 1), 254 (100), 184 (19), 127 (20).

Example 41: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-((pyridin-2-yl)methyl)piperazin-1-yl)-1-(1H Preparation of -1,2,4-triazol-1-yl)butan-2-ol

Step 1

To a dried round flask passed through nitrogen gas, 1.00 g (6.09 mmol, 1 eq) of 2-(chloroethyl)pyridine hydrochloride and 1.05 g (12.19 mmol, 2 eq) of piperazine were added and dissolved in distilled water for 16 hours at room temperature. Stirred. When the reaction was completed, extraction was performed with ethyl acetate, and the aqueous layer was made basic with sodium hydroxide and extracted with dichloromethane. The collected organic layer was dried with anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (dichloromethane:methanol=4:1) to give 1-((pyridin-2-yl)methyl)piperazine (yield 70%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.56 (d, 1H, J = 2.8 Hz), 7.64 (dt, 1H, J = 1.7, 7.6 Hz), 7.40 (d, 1H, J = 7.8 Hz), 7.16 (t, 1H, J = 5.0 Hz), 3.67 (s, 2H), 2.53 (br s, 8H).

Step 2

Same as Step 2 of Example 1, except that 1-((pyridin-2-yl)methyl)piperazine obtained in Step 1 was used instead of 2-(piperazin-1-yl)benzooxazole as a starting material. To obtain the target compound (yield 28%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.56 (d, 1H, J = 4.8 Hz), 8.00 (s, 1H), 7.78 (s, 1H), 7.64 (t, 1H, J = 8.1 Hz), 7.49 -7.44 (m, 1H), 7.37 (d, 1H, J = 7.8 Hz), 7.18-7.14 (m, 1H), 6.80-6.69 (m, 2H), 4.88 (d, 1H, J = 14.4 Hz), 4.78 (d, 1H, J = 14.1 Hz), 3.65 (s, 2H), 2.88 (q, 1H, J = 6.9 Hz), 2.78-2.73 (m, 2H), 2.53-2.42 (m, 6H), 0.98 (d, 3H, J = 6.9 Hz); MS (EI) m/z C ₂₂ H ₂₆ F ₂ N ₆ O calc. 428, found 429 (M ⁺ +1, 1), 361 (17), 204 (63), 100 (100).

Example 42: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-((pyridin-4-yl)methyl)piperazin-1-yl)-1-(1H Preparation of -1,2,4-triazol-1-yl)butan-2-ol

Step 1

1-((pyridin-4-yl)methyl was carried out in the same manner as in Step 1 of Example 41, except that 4-(chloroethyl)pyridine hydrochloride was used instead of 2-(chloroethyl)pyridine hydrochloride as a starting material. ) Piperazine (71% yield) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.53 (dd, 2H, J = 1.7, 4.4 Hz), 7.27 (t, 2H, J = 2.4 Hz), 3.48 (s, 2H), 2.61-2.08 (m, 8H).

Step 2

As a starting material, 1-((pyridin-4-yl)methyl)piperazine obtained in step 1 was used instead of 2-(piperazin-1-yl)benzooxazole, and propio was used instead of acetonitrile as a reaction solvent. The target compound (yield 40%) was obtained in the same manner as in Step 2 of Example 1 except that nitrile was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.53 (d, J = 5.7 Hz, 2H), 7.97 (s, 1H), 7.77 (s, 1H), 7.45 (dd, J = 6.5, 8.9 Hz, 1H) , 7.27-7.24 (m, 2H), 6.79-6.68 (m, 2H), 5.15 (br s, 1H), 4.88 (d, J = 14.7 Hz, 1H), 4.79 (d, J = 14.7 Hz, 1H) , 3.49 (s, 2H), 2.92 (q, J = 6.9 Hz, 1H), 2.79 (t, J = 7.0 Hz, 2H), 2.46-2.43 (m, 6H), 0.97 (d, J = 6.9 Hz, 3H).

Example 43: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-((furan-2-yl)methyl)piperazin-1-yl)-1-(1H Preparation of -1,2,4-triazol-1-yl)butan-2-ol

Step 1

0.5 g (5.2 mmol) of 2-furaldehyde was added to a dried round flask passed through nitrogen gas, dissolved in acetic acid, 2.24 g (26 mmol) of piperazine was added thereto, and 0.4 g of sodium cyanoborohydride at 0°C. (6.36 mmol, 1.2 eq) was added slowly. After the reaction temperature was increased to room temperature, the reaction was further performed for 6 hours. When the reaction was completed, acetic acid was removed under reduced pressure, and the mixture was made basic with sodium hydroxide solution, followed by extraction with dichloromethane. The collected organic layer was dried with anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (dichloromethane:methanol=4:1) to give 1-((furan-2-yl)methyl)piperazine (yield 58%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.39-7.37 (1H, m), 6.32-6.30 (1H, m), 6.20 (1H, d, J = 3.0 Hz), 3.53 (2H, s), 2.94- 2.90 (5H, m), 2.48-2.44 (4H, m); C ₉ H ₁₄ N ₂ O m/z 166.11 MS (EI) m/z 166 (M ⁺ , 9), 81 (100), 56 (85).

Step 2

Same as in Step 2 of Example 1, except that 1-((furan-2-yl)methyl)piperazine obtained in Step 1 was used instead of 2-(piperazin-1-yl)benzooxazole as a starting material. To obtain the target compound (yield 28%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.78 (s, 1H), 7.48-7.45 (m, 1H), 7.38-7.37 (m, 1H), 6.79-6.69 (m, 2H) ), 6.31 (t, 1H, J = 2.3 Hz), 6.20 (d, 1H, J = 3.0 Hz), 4.86 (d, 1H, J = 14.7 Hz), 4.77 (d, 1H, J = 14.7), 3.53 (s, 2H), 2.89 (q, 1H, J = 7.2 Hz), 2.79-2.75 (m, 2H), 2.47-2.43 (m 6H), 0.96 (d, 3H, J = 7.1 Hz); MS (EI) m/z C ₂₁ H ₂₅ F ₂ N ₅ O ₂ calc. 417, found 418 (M ⁺ +1, 1), 224 (87), 215 (100).

Example 44: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-((thiophen-2-yl)methyl)piperazin-1-yl)-1-( Preparation of 1H-1,2,4-triazol-1-yl)butan-2-ol

Step 1

In the same manner as in Step 1 of Example 43, except that thiophene-2-carboxaldehyde was used instead of 2-furaldehyde as a starting material, 1-((thiophen-2-yl)methyl)piperazine ( Yield 49%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.24-7.21 (m, 1H), 6.96-6.91 (m, 2H), 3.7 (s, 2H), 2.95-2.90 (m, 2H), 2.50 (br s, 7H).

Step 2

Step 2 of Example 1 and step 2 of Example 1 except that 1-((thiophen-2-yl)methyl)piperazine obtained in Step 1 was used instead of 2-(piperazin-1-yl)benzooxazole as a starting material. In the same manner, the target compound (yield 28%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.77 (s, 1H), 7.45 (dd, 1H, J = 6.8, 9.3 Hz), 7.24-7.22 (m, 1H), 6.95- 6.90 (m, 2H), 6.79-6.69 (m, 2H), 4.86 (d, 1H, J = 14.4 Hz), 4.77 (d, 1H, J = 14.4 Hz), 3.72 (s, 2H), 2.89 (q , 1H, J = 7.0 Hz), 2.78-2.72 (m, 2H), 2.50-2.41 (m, 6H), 0.97 (d, 3H, J = 7.0 Hz).

Example 45: (4-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl) Preparation of butan-2-yl)piperazin-1-yl)(3-phenyl-1,2,4-oxadiazol-5-yl)methanone

Step 1

In a dried round flask passed through nitrogen gas, 2.0 g of benzonitrile (19.39 mmol, 1 eq), 4.0 g of hydroxyamine hydrochloride salt (58.18 mmol, 3 eq.), and 8.08 g of potassium carbonate (58.18 mmol, 3 eq.) were added. After dissolving in ethanol, the mixture was stirred under reflux for 5 hours. The reaction mixture was lowered to room temperature and concentrated under reduced pressure to remove the solvent. 20 mL of pyridine was added to the crude mixture thus obtained, and 1.89 mL (16.9 mmol, 1.5 eq.) of ethyl chlorooxoacetate was slowly added at 0° C., followed by heating and reacting at 40° C. for 2 hours. When the reaction was completed, pyridine was distilled under reduced pressure and concentrated, and then distilled water was added to the reaction product and extracted three or more times with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (n-hexane:ethyl acetate=9:1) to obtain ethyl 3-phenyl-1,2,4-oxadiazole-5-carboxylate (yield 30%). Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.18-8.13 (m, 2H), 7.56-7.46 (m, 3H), 4.58 (q, 2H, J = 7.1 Hz), 1.50 (t, 3H, J = 7.2 Hz).

Step 2

In a 5 mL microwave reaction vessel dried by passing nitrogen gas, 0.05 g (0.16 mmol) of the compound obtained in step 1 of Example 14 and ethyl 3-phenyl-1,2,4-oxadiazole-5 obtained in step 1 -Carboxylate 0.04 g (0.19 mmol) was added and reacted in a microwave reactor at 120° C. for 10 minutes. Distilled water was added to the reaction product and extracted three or more times with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (dichloromethane:methanol=19:1) to obtain the title compound (yield 65%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.12 (dd, 2H, J = 1.7, 7.7 Hz), 7.89 (s, 1H), 7.78 (s, 1H), 7.56-7.41 (m, 4H), 6.78- 6.69 (m, 2H), 4.94 (br s, 3H), 3.88-3.81 (m, 4H), 3.14-3.07 (m, 3H), 2.67-2.57 (m, 2H), 0.91 (d, 3H, J = 6.6 Hz).

Example 46: (3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)(4-((2R,3R)-3-(2,4-difluorophenyl )-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)piperazin-1-yl)methanone

Step 1

3-(4-bromophenyl)-1,2,4-oxadiazole-5 was carried out in the same manner as in Step 1 of Example 45, except that 4-bromobenzonitrile was used instead of benzonitrile as a starting material. -Carboxylate (yield 53%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.03 (d, 2H, J = 8.4 Hz), 7.66 (d, 2H, J = 8.6 Hz), 4.37 (q, 2H, J = 7.1 Hz), 1.42 (t , 3H, J = 7.2 Hz); MS (EI) m/z C ₁₁ H ₉ BrN ₂ O ₃ calc. 295, found 295 (M ⁺ , 57), 197 (94), 90 (82), 75 (100).

Step 2

Ethyl 3-(4-bromophenyl)-1,2,4-oxadiazole- obtained in step 1 above instead of ethyl 3-phenyl-1,2,4-oxadiazole-5-carboxylate as a starting material The target compound (yield 53%) was obtained in the same manner as in Step 2 of Example 45 except that 5-carboxylate was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.00-7.91 (m, 2H), 7.89 (s, 1H), 7.78 (s, 1H), 7.66 (dd, 2H, J = 2.0, 8.8 Hz), 7.43- 7.37 (m, 1H), 6.78-6.69 (m, 2H), 4.99-4.94 (m, 3H), 3.86-3.73 (m, 4H), 3.14-3.07 (m, 3H), 2.67-2.57 (m, 2H) ), 0.90 (d, 3H, J = 6.9 Hz)

Example 47: (4-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl) Preparation of butan-2-yl)piperazin-1-yl)(3-p-tolyl-1,2,4-oxadiazol-5-yl)methanone

Step 1

Ethyl 3-(4-methylphenyl)-1,2,4-oxadiazole-5-carboxyl was carried out in the same manner as in Example 45 except that 4-methylbenzonitrile was used instead of benzonitrile as a starting material. Rate (yield 30%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.03 (dd, 2H, J = 1.8, 6.6 Hz), 7.30 (d, 2H, J = 7.8 Hz), 4.58 (q, 2H, J = 7.2 Hz), 2.43 (s, 3H), 1.49 (t, 3H, J = 7.4 Hz).

Step 2

Ethyl 3-(4-methylphenyl)-1,2,4-oxadiazole-5- obtained in step 1 above instead of ethyl 3-phenyl-1,2,4-oxadiazole-5-carboxylate as a starting material The target compound (yield 64%) was obtained in the same manner as in Step 2 of Example 45 except that carboxylate was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.00 (d, 2H, J = 8.2 Hz), 7.89 (s, 1H), 7.78 (s, 1H), 7.43-7.38 (m, 1H), 7.32-7.27 ( m, 2H), 6.79-6.68 (m, 2H), 4.97-4.89 (m, 3H), 3.88-3.73 (m, 4H), 3.13-3.06 (m, 3H), 2.66-2.50 (m, 2H), 2.43 (s, 3H), 0.91 (d, 3H, J = 6.6 Hz).

Example 48: (3-(4-chlorophenyl-1,2,4-oxadiazol-5-yl)(4-((2R,3R)-3-(2,4-difluorophenyl)- Preparation of 3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)piperazin-1-yl)methanone

Step 1

Ethyl 3-(4-chlorophenyl)-1,2,4-oxadiazole-5- A carboxylate (59% yield) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.10 (d, 2H, J = 9.0 Hz), 7.49 (d, 2H, J = 8.8 Hz), 4.58 (q, 2H, J = 7.1 Hz), 1.53 (t , 3H, J = 7.2 Hz).

Step 2

Ethyl 3-(4-chlorophenyl)-1,2,4-oxadiazole-5 obtained in step 1 above instead of ethyl 3-phenyl-1,2,4-oxadiazole-5-carboxylate as a starting material -The target compound (yield 47%) was obtained in the same manner as in Step 2 of Example 45 except that carboxylate was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.06 (d, 2H, J = 8.7 Hz), 7.89 (s, 1H), 7.78 (s, 1H), 7.51-7.41 (m, 3H), 6.78-6.69 ( m, 2H), 4.99-4.89 (m, 3H), 3.87-3.80 (m, 4H), 3.14-3.07 (m, 3H), 2.67-2.57 (m, 2H), 0.91 (d, 3H, J = 6.6 Hz).

Example 49: (4-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl) Preparation of butan-2-yl)piperazin-1-yl)(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)methanone

Step 1

Ethyl 3-(4-methoxyphenyl)-1,2,4-oxadiazole- was carried out in the same manner as in Step 1 of Example 45, except that 4-methoxybenzonitrile was used instead of benzonitrile as a starting material. 5-carboxylate (yield 28%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.09 (d, 2H, J = 8.6 Hz), 7.59 (d, 2H, J = 8.8 Hz), 4.57 (q, 2H, J = 7.1 Hz), 3.87 (s , 3H), 1.46 (t, 3H, J = 7.0 Hz).

Step 2

Ethyl 3-(4-methoxyphenyl)-1,2,4-oxadiazole- obtained in step 1 above instead of ethyl 3-phenyl-1,2,4-oxadiazole-5-carboxylate as a starting material The target compound (yield 47%) was obtained in the same manner as in Step 2 of Example 45 except that 5-carboxylate was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.05 (dd, 2H, J = 2.0, 6.6 Hz), 7.89 (s, 1H), 7.79 (s, 1H), 7.43-7.38 (m, 1H), 7.01 ( dd, 2H, J = 1.8, 6.9 Hz), 6.79-6.69 (m, 2H), 4.90 (br s, 3H), 3.91-3.80 (m, 7H), 3.13-3.06 (m, 3H), 2.66-2.56 (m, 2H), 0.91 (d, 3H, J = 6.6 Hz).

Example 50: (4-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl) Preparation of butan-2-yl)piperazin-1-yl)(3-phenyl-1,2,4-thiadiazol-5-yl)methanone

Step 1

After dissolving 1.0 g (8.25 mmol, 1 eq) of benzamide in toluene in a 2-neck round flask through which nitrogen gas was passed, 0.83 mL (9.90 mmol, 1.2 eq.) of chlorocarbonyl sulphenyl chloride was added to the reaction solution, and 3 hours. It was stirred while refluxing. Distilled water was added to the reaction product and extracted three or more times with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (n-hexane:ethyl acetate = 19:1) and 3-phenyl-5 H -1,2,4-oxathiazol-5-one (yield 87%) Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.00-7.96 (2H, m), 7.62-7.29 (3H, m); MS (EI) m/z C ₈ H ₅ NO ₂ S calc. 179, found 179 (M ⁺ , 25), 105 (100).

Step 2

In a two-neck round flask through which nitrogen gas was passed, 0.3 g (1.7 mmol, 1 eq) of 3-phenyl-5 H -1,2,4-oxathiazol-5-one obtained in step 1 was added, and n-dode After dissolving in a compartment, 0.66 g (6.8 mmol, 4eq.) of ethyl cyanoformate was added thereto, followed by reaction at 130° C. for 24 hours. Distilled water was added to the reaction product and extracted three or more times with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n- hexane: ethyl acetate = 19: 1) and separated by ethyl 3-phenyl-oxazol -5 H -1,2,4- thiazole-5-carboxylate (yield: 85 %).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.39-8.35 (m, 2H), 7.54-7.48 (m, 3H), 4.55 (q, 2H, J = 7.2 Hz), 1.51 (t, 3H, J = 7.4 Hz); MS (EI) m/z C ₁₁ H ₁₀ N ₂ O ₂ S calc. 234, found 234 (M ⁺ , 34), 135 (100).

Step 3

Ethyl 3-phenyl-5 H -1,2,4-oxadiazole-5-carboxyl obtained in step 2 above instead of ethyl 3-phenyl-1,2,4-oxadiazole-5-carboxylate as a starting material Except for using a rate, it was carried out in the same manner as in Step 2 of Example 45 to obtain the target compound (yield 31%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.30-8.27 (m, 2H), 7.91 (s, 1H), 7.80 (s, 1H), 7.52-7.49 (m, 3H), 7.44 (dt, 1H, J = 6.6, 9.1 Hz), 6.79-6.71 (m, 2H), 5.00 (br s, 1H), 4.99 (d, 1H, J = 14.6 Hz), 4.94 (d, 1H, J = 15.5 Hz), 4.50 ( br s, 2H), 3.85 (br s, 2H), 3.20 (br s, 1H), 3.11 (q, 2H, J = 6.9 Hz), 2.64-2.63 (m, 2H), 0.92 (d, 3H, J = 6.8 Hz).

Example 51: (3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)(4-((2R,3R)-3-(2,4-difluorophenyl) Preparation of -3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)piperazin-1-yl)methanone

Step 1

3-(4-chlorophenyl)-5 H -1,2,4-oxathiazole-5 was carried out in the same manner as in Step 1 of Example 50, except that 4-chlorobenzamide was used instead of benzamide as a starting material. -On (yield 85%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.92 (2H, d, J = 7.6 Hz), 7.48 (2H, d, J = 7.6 Hz); MS (EI) m/z C ₈ H ₄ ClNO ₂ S calc. 213, found 213 (M ⁺ , 21), 139 (100).

Step 2

Instead of the starting material 3-phenyl -5 H -1,2,4- oxa-thiazol-5-one 3- (4-chlorophenyl) -5 H -1,2,4- oxa Sy obtained in the above Step 1 and except that the azole-5-one and the same way as in step 2 of example 50 ethyl 3- (4-chlorophenyl) -5 H -1,2,4- oxa-thiazole-5-carboxylate (yield: 70%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.31 (d, 2H, J = 8.0 Hz), 7.47 (d, 2H, J = 8.4 Hz), 4.54 (q, 2H, J = 7.4 Hz), 1.49 (t , 3H, J = 7.2 Hz).

Step 3

The starting material, ethyl 3-phenyl-1,2,4-oxadiazol-5-carboxylate instead of ethyl 3- (4-chlorophenyl) obtained in Step 2 -5 H-1, 2,4-oxa-thiazole The target compound (yield 30%) was obtained in the same manner as in Step 2 of Example 45 except that -5-carboxylate was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.22 (d, 2H, J = 7.6 Hz), 7.90 (s, 1H), 7.80 (s, 1H), 7.49-7.39 (m, 3H), 6.80-6.69 ( m, 2H), 5.02-4.91 (m, 3H), 4.55 (br s, 1H), 4.33 (br s, 1H), 3.83 (br s, 2H), 3.21 (br s, 1H), 3.11 (q, 2H, J = 6.8 Hz), 2.65-2.62 (m, 2H), 0.91 (d, 3H, J = 6.9 Hz).

Example 52: (3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)(4-((2R,3R)-3-(2,4-difluorophenyl) Preparation of -3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)piperazin-1-yl)methanone

Step 1

The starting material in place of the 4-fluoro benzamide, except for using the benzamide and Example 50 3- (4-fluorophenyl) in the same way as in Step 1 of -5 H -1,2,4- oxa-thiazol- Obtained 5-one (yield 85%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.03-7.96 (2H, m), 7.31-7.14 (2H, m); MS (EI) m/z 197 (M ⁺ +1, 19), 123 (100).

Step 2

Instead of the starting material 3-phenyl -5 H -1,2,4- oxa-thiazol-5-one 3- (4-fluorophenyl) -5 H -1,2,4- oxa-thiazole obtained in the above Step 2 and example 50 ethyl 3- (4-fluorophenyl) in the same way as in step 2 of -5 H -1,2,4- oxa thiazole, except for using 5-one-5-carboxylate (yield: 70 %).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.41-8.34 (m, 2H), 7.22-7.13 (m, 2H), 4.55 (q, 2H, J = 7.1 Hz), 1.48 (t, 3H, J = 7.1 Hz).

Step 3

Ethyl 3-(4-fluorophenyl)-5 H -1,2,4-oxathiazole obtained in step 2 above instead of ethyl 3-phenyl-1,2,4-oxadiazole-5-carboxylate as a starting material The target compound (yield 35%) was obtained in the same manner as in Step 2 of Example 45 except that -5-carboxylate was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.30-8.25 (m, 2H), 7.90 (s, 1H), 7.79 (s, 1H), 7.44 (q, 1H, J = 6.3 Hz), 7.18 (dt, 2H, J = 1.9, 7.7 Hz), 6.77-6.70 (m, 2H), 5.02-4.90 (m, 3H), 4.55 (br s, 1H), 4.31 (br s, 1H), 3.94 (br s, 1H ), 3.83 (br s, 1H), 3.21 (br s, 1H), 3.11 (q, 2H, J = 6.7 Hz), 2.65-2.62 (m, 2H), 0.91 (d, 3H, J = 6.3 Hz)

Example 53: (4-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl) Preparation of butan-2-yl)piperazin-1-yl)(3- p -tolyl-1,2,4-thiadiazol-5-yl)methanone

Step 1

3-(4-methylphenyl)-5 H -1,2,4-oxathiazole-5- On (yield 84%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.88 (d, 2H, J = 8.4 Hz), 7.29 (d, 2H, J = 8.0 Hz), 2.43 (s, 3H).

Step 2

Instead of the starting material 3-phenyl -5 H -1,2,4- oxa-thiazol-5-one 3- (4-methylphenyl) -5 H -1,2,4- oxa-thiazole obtained in the above Step 1 except for using 5-one and the same way as in step 2 of example 50 ethyl 3- (4-methylphenyl) -5 H -1,2,4- oxa-thiazole-5-carboxylate (yield: 91% ).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.25 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.6 Hz), 4.55 (q, 2H, J = 7.2 Hz), 2.43 (s , 3H), 1.48 (t, 3H, J = 6.8 Hz); MS (EI) m/z C ₁₂ H ₁₂ N ₂ O ₂ S calc. 248, found 248 (M ⁺ , 57), 149 (100).

Step 3

Ethyl 3- (4-methylphenyl) obtained in the above step 2 as the starting material in place of ethyl 3-phenyl-1,2,4-oxadiazol-5-carboxylate H -5-oxa-1,2,4-thiazole The target compound (yield 52%) was obtained in the same manner as in Step 2 of Example 45 except that -5-carboxylate was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.16 (d, 2H, J = 8.1 Hz), 7.91 (s, 1H), 7.79 (s, 1H), 7.48-7.40 (m, 1H), 7.30 (d, 2H, J = 8.1 Hz), 6.80-6.69 (m, 2H), 5.02- 4.90 (m, 3H), 4.53 (br s, 1H), 4.35 (br s, 1H), 3.91 (br s, 1H), 3.84 (br s, 1H), 3.19-3.07 (m, 3H), 2.64-2.62 (m, 2H), 2.43 (s, 3H), 0.91 (d, 3H, J = 6.9 Hz).

Example 54: (4-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl) Preparation of butan-2-yl)piperazin-1-yl)(3-(4-methoxyphenyl)-1,2,4-thiadiazol-5-yl)methanone

Step 1

As starting material instead of 4-methoxy-benzamide benzamide except that the ratio among used ahmayideueul the same way as in Step 1 of Example 50 3- (4-methoxyphenyl) -5 H -1,2,4- oxa-thiazole Obtained -5-one (yield 84%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.92 (d, 2H, J = 9.2 Hz), 6.97 (d, 2H, J = 9.0 Hz), 3.88 (s, 3H).

Step 2

3- (4-methoxyphenyl) obtained in Step 1 as starting material in place of 3-phenyl -5 H -1,2,4- oxa-thiazol-5-oxa -5 H -1,2,4- Ethyl 3-(4-methoxyphenyl)-5 H -1,2,4-oxathiazole-5-carboxylate was carried out in the same manner as in Step 2 of Example 50 except that thiazol-5-one was used. (Yield 92%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.30 (d, 2H, J = 8.8 Hz), 7.98 (d, 2H, J = 9.0 Hz), 4.55 (q, 2H, J = 7.4 Hz), 3.88 (s , 3H), 1.49 (t, 3H, J = 7.2 Hz); MS (EI) m/z C ₁₂ H ₁₂ N ₂ O ₃ S calc. 264, found 264 (M ⁺ , 100), 165 (88), 133 (95).

Step 3

As a starting material ethyl 3-phenyl-1,2,4-oxadiazol-5-carboxylate in place of ethyl obtained in Step 2 3- (4-methoxyphenyl) -5 H-1,2,4-oxazole The target compound (yield 47%) was obtained in the same manner as in Step 2 of Example 45, except that thiazole-5-carboxylate was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.22 (d, 2H, J = 7.1 Hz), 7.91 (s, 1H), 7.79 (s, 1H), 7.45-7.42 (m, 1H), 7.00 (d, 2H, J = 6.9 Hz), 6.80-6.70 (m, 2H), 5.02-4.90 (m, 3H), 4.54 (br s, 1H), 4.33 (br s, 1H), 3.96-3.82 (m, 5H) , 3.19-3.07 (m, 3H), 2.64-2.62 (m, 2H), 0.91 (d, 3H, J = 6.9 Hz).

Example 55: (4-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl) Preparation of butan-2-yl)piperazin-1-yl)(5-benzoyl-imidazo[2,1,-b]-thiazol-2-yl)methanone

Step 1

1.0 g (13.1 mmol) of thiourea was added to a round flask through which nitrogen gas was passed, dissolved in dichloromethane, and 5.25 ml (39.3 mmol) of DMF-DMA (N,N-dimethylformamidine dimethyl acetal) were added and 4 hours. It was stirred while refluxing. When the reaction was completed, distillation under reduced pressure to remove the solvent, and the yellow solid produced was recrystallized with diethyl ether and N',N''-thiocarbonylbis (N,N-dimethylformimidamide) 1.84 g (yield 74%) ).

¹ H NMR (200 MHz, DMSO-d ₆ ) δ 8.70 (s, 2H), 3.16 (s, 6H), 3.01 (s, 6H).

Step 2

1.84 g (9.87 mmol) of the compound obtained in step 1 was dissolved in dichloromethane in a round flask through which nitrogen gas was passed, and 1.09 mL (11.8 mmol, 1.2 eq) of methyl bromoacetate was slowly added dropwise to the mixed solution, and 15 Stir for a minute. After adding 2.8 mL (19.8 mmol, 2eq) of triethylamine to the reaction mixture, it was reacted at room temperature for 20 hours. Distilled water was added to the reaction product and extracted three or more times with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (ethyl acetate:dichloromethane=9:1), and 1.5 g of methyl 2-((dimethylamino)methyleneamino)thiazole-5-carboxylate (yield 73%) was obtained. Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 7.98 (s, 1H), 3.85 (s, 3H), 3.14 (s, 3H), 3.11 (s, 3H).

Step 3

After dissolving 1.5 g (7.2 mmol) of the compound obtained in step 2 in THF in a round flask through which nitrogen gas was passed, 2-bromo-1-phenylethanone (8.5 mmol) was added and stirred under reflux for 6 hours. After the reaction was cooled to room temperature, 2.0 mL (14.4 mmol) of triethylamine was added thereto, followed by reaction at room temperature for 20 hours. Distilled water was added to the reaction product and extracted three or more times with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (ethyl acetate:dichloromethane=9:1), and methyl 5-benzoylimidazo[2,1-b]thiazol-2-carboxylate (yield 65%) Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.09 (1H, s), 7.93 (1H, s), 7.85 (d, 2H, J = 7.1 Hz), 7.60-7.55 (m, 1H), 7.48 (t, 2H, J = 7.3 Hz), 3.92 (3H, s).

Step 4

5 mmol of methyl 5-benzoylimidazo[2,1-b]thiazol-2-carboxylate obtained in step 3 and 10 mL of 1N-sodium hydroxide were added to a round flask through which nitrogen gas was passed, and reacted at room temperature for 12 hours. Made it. Distilled water was added to the reaction product and extracted three or more times with ethyl acetate. The collected organic layer was washed with saturated sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to quantitatively obtain 5-benzoylimidazo[2,1-b]thiazole-2-carboxylic acid.

Step 5

After dissolving 0.06 g (0.18 mmol) of the compound obtained in step 1 of Example 14 in dichloromethane in a round flask through which nitrogen gas was passed, 5-benzoylimidazo obtained in step 4 [2,1-b] Thiazole-2-carboxylic acid 50 mg (0.18 mmol) was added, and 0.22 mmol of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride was added to the mixture, and then at room temperature for 4 hours. Reacted. Distilled water was added to the reaction product and extracted three or more times with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography using silica gel (dichloromethane:methanol=19:1) to obtain the title compound (yield 55%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.72 (s, 1H), 7.97 (s, 1H), 7.92-7.89 (m, 3H), 7.79 (s, 1H), 7.64-7.52 (m, 3H), 7.44-7.40 (m, 1H), 6.77-6.72 (m, 2H), 5.00-4.90 (m, 3H), 3.86 (br s, 4H), 3.13-3.07 (m, 3H), 2.61-2.57 (m, 2H), 0.92 (d, 3H, J = 6.9 Hz).

Example 56: (4-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl) Preparation of butan-2-yl)piperazin-1-yl)(5-(4-methylbenzoyl)-imidazo[2,1,-b]-thiazol-2-yl)methanone

Step 1

The starting material, 2-bromo-1-phenylethane in place of ethyl 2-bromo-1-on-p - methyl except for using tolyl ethanone and same way as in the step 3 of Example 55 from 5- (4- Methylbenzoyl)imidazo[2,1-b]thiazole-2-carboxylate (yield 70%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.07 (s, 1H), 7.92 (s, 1H), 7.75 (d, 2H, J = 8.1 Hz), 7.27 (d, 2H, J = 8.2 Hz), 3.91 (s, 3H), 2.40 (s, 3H).

Step 2

Instead of methyl 5-benzoylimidazo[2,1-b]thiazol-2-carboxylate as a starting material, methyl 5-(4-methylbenzoyl)imidazo[2,1-b]cylate obtained in step 1 above. 5-(4-methylbenzoyl)imidazo[2,1-b]thiazole-2-carboxylic acid was quantitatively prepared in the same manner as in Step 4 of Example 55 except that azole-2-carboxylate was used. Got it.

Step 3

5-(4-methylbenzoyl)imidazo[2,1-b]thiazole obtained in step 2 above instead of 5-benzoylimidazo[2,1-b]thiazole-2-carboxylic acid as a starting material Except for the use of -2-carboxylic acid, it was carried out in the same manner as in Step 5 of Example 55 to obtain the target compound (yield 57%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.83-7.79 (m, 3H), 7.47-7.33 (m, 3H), 6.78-6.69 (m, 2H), 4.99-4.90 (m, 3H), 3.86 (br s, 4H), 3.11-3.09 (m, 3H), 2.60-2.57 (m, 2H), 2.47 (s, 3H) , 0.92 (d, 3H, J = 6.7 Hz).

Example 57: (4-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl) Preparation of butan-2-yl)piperazin-1-yl)(5-(4-methylbenzoyl)-imidazo[2,1,-b]-thiazol-2-yl)methanone

Step 1

Methyl 5 was carried out in the same manner as in Example 55 except that ethyl 2-bromo-1-(4-methoxyphenyl)ethanone was used instead of 2-bromo-1-phenylethanone as a starting material -(4-methoxybenzoyl)imidazo[2,1-b]thiazole-2-carboxylate (yield 40%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.09 (1H, s), 7.94 (1H, s), 7.91-7.88 (2H, m), 7.01-6.97 (2H, m), 3.93 (3H, s), 3.86 (3H, s).

Step 2

Instead of methyl 5-benzoylimidazo[2,1-b]thiazol-2-carboxylate as starting material, methyl 5-(4-methoxybenzoyl)imidazo[2,1-b] obtained in step 1 above. 5-(4-methoxybenzoyl)imidazo[2,1-b]thiazole-2-carboxylic was quantitatively carried out in the same manner as in Step 4 of Example 55 except that thiazole-2-carboxylate was used. Got the acid.

Step 3

Instead of 5-benzoylimidazo[2,1-b]thiazol-2-carboxylic acid as a starting material, 5-(4-methoxybenzoyl)imidazo[2,1-b]cy The target compound (yield 50%) was obtained in the same manner as in Step 5 of Example 55, except that azole-2-carboxylic acid was used.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.69 (s, 1H), 7.97-7.94 (m, 2H), 7.91 (d, 2H, J = 3.3 Hz), 7.79 (s, 1H), 7.44-7.39 ( m, 1H), 7.03 (d, 2H, J = 8.7 Hz), 6.79-6.68 (m, 2H), 5.00-4.90 (m, 3H), 3.91-3.83 (m, 7H), 3.13-3.08 (m, 3H), 2.60-2.56 (m, 2H), 0.89 (d, 3H, J = 6.6 Hz).

Test example: in vitro ( in vitro ) Activity test

In order to compare the antifungal effect in fungi in the present invention, Candida albican ATCC 90873, 204276, 62342, 64124, 64550, 96901, MYA- 573, MYA- 574, MYA -575, MYA -576, MYA- 1003, Aspergillus fumigatus Antifungal efficacy test was performed using ATCC 16424. Both the test substance and the positive control substance were dissolved in DMSO and treated, and each strain was inoculated by diluting twice to a minimum of 0.125 μg/ml at the highest concentration at the concentration at which turbidity was not generated. The significance of the test was confirmed through _{the MIC 80} values of the positive controls amphotericin B, fluconazole, and itraconazole.

1) Test strain: Candida albican ATCC 90873, 204276, 62342, 64124, 64550, 96901, MYA- 573, MYA- 574, MYA -575, MYA -576, MYA- 1003, Aspergillus fumigatus Five to six strains such as ATCC 16424 were used in combination. The strains were commercially available from The American Type Culture Collection (ATCC), and all strains were subcultured in the pre-clinical research center of Chemon, Inc., and used in the test. (Sigma) was used, and fluconazole was prepared according to the method described in British Patent No. 2,099818, and itraconazole was prepared according to the method described in U.S. Patent No. 4,267,179).

2) Medium and culture: Candida was inoculated on sabouraud dextrose agar medium, YM agar, potato dextrose agar medium, etc., based on ATCC data. It was cultured at 25°C or the like. Aspergillus was inoculated on malt extract agar medium and potato dextrose agar medium and cultured at 24 to 27°C.

3) Preparation of test substance: An appropriate amount of test substance was dissolved in an excipient (usually DMSO), but 1 to 2 mL was prepared so that the concentration was 100 times the highest concentration in the measurement range (256 ㎍/ml).

4) Preparation of broth

A sterilized 12×75 mm disposable culture tube was prepared in advance, and then diluted with RPMI 1640 culture solution so that the concentration series was finally 0.25-256 mg/mL. At this time, the concentration of DMSO used as an excipient was finally adjusted to 2% (v/v).

5) Preparation and inoculation of bacterial solution

Candida strains used in this experiment were inoculated on savorrod dextrose agar medium, YM agar medium, and potato dextrose agar medium, and then sufficiently cultured at 35° C. for 2-3 days. Among the cultured strains, yeasts were sufficiently suspended in 5 mL of 0.85% sterile physiological saline prepared in advance by taking a single colony, corrected to have an absorbance of 0.108 at 530 nm, diluted 1:50 with RPMI 1640 culture solution, and diluted 1: The inoculum solution was prepared by diluting with 20 so that the strain was 1.0x10 ^{3 to 5.0x10 3 CFU/mL.} Aspergillus strain was inoculated on Malt Extract agar medium in advance, sufficiently cultured for 7-10 days under culture conditions, and obtained a spore suspension with 0.85% sterile physiological saline (0.2% Tween 20), and the transmittance at 530 nm was 80- After correcting with sterilized physiological saline to be 82%, the inoculum was prepared by diluting 1:50 with RPMI 1640 culture solution so that the number of bacteria was 0.4x10 ² ∼5x10 ⁴ CFU/mL. After preparing a sterilized 96-well microplate in advance, dispense 0.1 mL of the antifungal diluted solution series each, and dispense 0.1 mL of the inoculum solution of the corresponding bacteria, and then add 10 mL of alamarblue (Biosource, #DAL1100). Each treatment was performed, and the test was repeated twice for each test concentration group.

In the test using the strain in the present invention, each minimum inhibitory concentration (MIC ₈₀ ) for the synthetic material is shown in Table 2.

Control: A = amphotericin B, F = fluconazole, I = itraconazole

In Table 2, the following Aspergillus fumigatus strain expansion test was performed on the Aspergillus species of some of the representative test substances whose antifungal effect was observed. Minimum inhibitory concentrations were observed in ATCC 16424 and MYA-1163, Aspergillus terreus ATCC 28301, Aspergillus flavus ATCC MYA-1004, Aspergillus niger ATCC 9142 And the results are shown in Table 3 below.

Control: A = amphotericin B, F = fluconazole, I = itraconazole

<In vivo activity test>

In order to verify the antifungal effect of the compound obtained in the present invention in fungi in an animal infection model, a specific pathogen-free (SPF) ICR-type mouse was used.

1) Composition of test group: Healthy males were selected, weight was measured, and ranked, and 10 mice were randomly selected for each test substance. Individual identification of animals was carried out by the method of labeling the coloring of the hair using saturated picric acid and the method of labeling the individual identification card.

2) Administration of immune-lowering substances: CPA (200 mg/Kg) was administered intraperitoneally once 3 days before the fungal infection and administration of the test substance to reduce immunity.

3) Infection with strain: Aspergillosis fumigatus, a clinical strain isolated from the lungs of patients with aspergillosis (ATCC 16424) was sufficiently incubated in malt agar medium for 7-10 days, and then a spore suspension was ^{prepared with 0.85% sterile physiological saline (0.2% Tween 80) to a factor of 5x10 5} CFU/mL, and then 0.2 mL through the caudal vein of each mouse. It was administered as /head. Fungi were inoculated once on the start of administration of the test substance.

5) Test substance administration

The test substance was prepared by finely grinding a mortar and suspending it with PEG400. Amphotericin B, a positive control substance, was prepared with sterile physiological saline, and the test substance was prepared just before administration every day, and the test substance was stored at room temperature and used twice the day. Since the predicted route of clinical application of the test substance was oral, the test substance was forcibly administered orally on the basis of 50 mg/Kg by fixing the cervical skin and using a metal for oral administration. Amphotericin B was administered by a syringe intraperitoneally.

6) Frequency of administration and period of administration

Administration of the first test substance and positive control substance was carried out 2 hours after the fungal inoculation (day 0). The test substance administration for the survival rate observation was carried out for 5 days twice a day, 2 hours after infection once. Both positive reproducing substances were administered intraperitoneally once a day for 5 days.

7) Observation of general symptoms and mortality: General symptoms were observed for all animals during the experiment, and the survival for 14 days was expressed as a survival curve and survival rate (%). Aspergillus fumigatus The survival rate for evaluating the therapeutic efficacy in mice systemically infected with (ATCC 16424) is shown in FIG. 1.

As shown in Figure 1, it can be confirmed that the survival rate of the mouse is high when the compound-containing substance according to the present invention is administered.

As described above, the compound of Formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof according to the present invention is Candida albicans, Torulopsis, Cryptococcus ( Crytococcus), Aspergillus, Tricophyton and Fluconazole-resistant strains. Can be used.

Claims (6)

A compound of Formula 1, or a pharmaceutically acceptable salt or isomer thereof: Formula 1

 Where n is 1 or 2, A represents a direct bond or C = O, R is

ego, D is CH or N, Z is O or S, R ² is hydrogen, halogen, hydroxy, cyano, nitro, amino, hydroxycarbonyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy RoxyC _1-6 Alkyl, C _1-6 AlkoxyC _1-6 Alkyl, PerfluoroC _1-6 Alkyl, PerfluoroC _1-6 Alkoxy, C _1-6 Alkylamino, DiC _1-6 Alkylamino , AminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, diC _1-6 alkylaminoC _1-6 alkyl, C _1-6 acyl, C _1-6 acyloxy, C _1-6 acyloxy C _1-6 alkyl, C _1-6 acylamino, C _1-6 alkylthio, C _1-6 alkylthio Oka carbonyl, oxo-C _1-6 alkylthio, C _1-6 alkoxycarbonyl, C _{1 -6} alkylsulfonyl, C _1-6 alkylsulfonylamino, aminosulfonyl, C _1-6 alkylaminosulfonyl, diC _1-6 alkylaminosulfonyl, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkoxy, 3- to 8-membered cycloalkyl-C _1-6 alkoxy, 3- to 8-membered cycloalkyl-C _1-6 alkylamino, NC _1-6 alkyl N-3- to 8-membered Alkyl cycle -C _1-6 alkylamino, 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl -C _1-6 alkoxy, a 4- to 8-membered heterocycloalkyl -C _{1- 6} alkylamino, NC _1-6 alkyl N-4- to 8-membered heterocycloalkyl-C _1-6 alkylamino, heteroaryl-C _1-6 alkyl, heteroaryl-C _1-6 alkoxy, heteroaryl-C _1-6 alkylamino, or NC _1-6 alkyl N-heteroaryl-C _1-6 alkylamino, R ³ is phenyl and monocyclic heteroaryl, hydrogen, halogen, hydroxy, cyano, nitro, amino, hydroxycarbonyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, one selected from the group consisting of perfluoroC _1-6 alkyl and perfluoroC _1-6 alkoxy It may be substituted with the above substituents. The method of claim 1, A compound of formula (1), or a pharmaceutically acceptable salt or isomer thereof, characterized in that it is selected from the group consisting of the compounds of the structure:

1) reacting a compound of Formula 16 with a compound of Formula 2 and then optionally removing a protecting group to obtain a compound of Formula 18; And 2) preparing a compound of formula 1b comprising reacting a compound of formula 18 with a compound of formula 6 Formula 1b

Formula 16

Formula 2

Formula 18

Formula 6

Wherein n, D and R ² are as defined in claim 1, P ¹ is hydrogen, ethoxycarbonyl, t-butoxycarbonyl or benzyloxycarbonyl group, P ² is a halogen, mercapto, methanesulfonyloxy, or trifluoromethanesulfonyloxy group. 1) reacting a compound of formula 19 with hydroxyamine in the presence of a base to obtain a compound of formula 20; 2) reacting the compound of Formula 20 with ethyl chlorooxoacetate to obtain a compound of Formula 21; And 3) A process for preparing a compound of Formula 1c-1, comprising reacting a compound of Formula 21 with a compound of Formula 8: Formula 1c-1

Formula 19

Formula 20

Formula 21

Formula 8

Where n is as defined in claim 1, R ⁸ is hydrogen, halogen, hydroxy, C _1-6 alkoxy cyano, nitro, amino, hydroxycarbonyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, perfluoroC _1-6 alkyl, perfluoroC _1-6 alkoxy, C _1-6 alkylamino, di C _1-6 alkylamino, aminoC _1-6 alkyl, C _1-6 alkylaminoC _1-6 alkyl, diC _1-6 alkylaminoC _1-6 alkyl, C _1-6 acyl, C _1-6 acyloxy , C _1-6 acyloxy-C _1-6 alkyl, C _1-6 acylamino, C _1-6 alkylthio, C _1-6 alkylthio Oka carbonyl, oxo-C _1-6 alkylthio, C _1-6 alkoxy Carbonyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, aminosulfonyl, C _1-6 alkylaminosulfonyl, diC _1-6 alkylaminosulfonyl, 3- to 8-membered cyclo Independently selected from the group consisting of alkyl, 4- to 8-membered heterocycloalkyl. 1) reacting a compound of formula 22 with chlorocarbonylsulphenyl chloride to obtain a compound of formula 23; 2) reacting the compound of Formula 23 with ethyl cyanoformate to obtain a compound of Formula 24; And 3) A process for preparing a compound of Formula 1c-2 comprising reacting a compound of Formula 24 with a compound of Formula 8:  Formula 1c-2

Formula 22

Formula 23

 Formula 24

Formula 8

Wherein n and R ⁸ are as defined in claim 1 or 4 above. Claim 1 compound of formula 1, or a pharmaceutically acceptable salt or isomer thereof as an active ingredient, a pharmaceutical composition for treating fungal infections.

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