RU2789456C2 - Compound containing oxadiazole and a pharmaceutical composition containing it - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to the field of heteroaromatic compounds. A compound represented by the chemical formula 1, or its optical isomer, stereoisomer, or pharmaceutically acceptable salt is proposed, where R1 is selected from a group consisting of the following formulas:

R2 is hydrogen, halogen, C₁-C₅ alkyl, halogen-C₁-C₅ alkyl, C₁-C₅ alkoxy-C₁-C₅ alkyl, C₁-C₅ alkoxy or C₁-C₅ alkylthio; R3 is hydrogen, C₁-C₅ alkyl, C₃-C₆ cycloalkyl, halogen-C₁-C₅ alkyl, carbamoyl, C₁-C₅ alkylcarbamoyl, di(C₁-C₅ alkyl)carbamoyl or carbonyl; R4 is hydrogen, halogen, C₁-C₅ alkyl, halogen- C₁-C₅ alkyl or C₁-C₅ alkoxy- C₁-C₅ alkyl; R5 is hydrogen, halogen, C₁-C₅ alkyl, halogen- C₁-C₅ alkyl or C₁-C₅ alkoxy- C₁-C₅ alkyl; each of R6, R7, R8 and R9 independently represents hydrogen, halogen, C₁-C₅ alkyl, halogen- C₁-C₅ alkyl, C₁-C₅ alkoxy- C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkylthio, halogen- C₁-C₅ alkoxy, amino, di(C₁-C₅ alkyl)amino, C₁-C₅ alkylcarbonylamino, halogen- C₁-C₅ alkylcarbonylamino or 5-8-membered heterocycloalkyl containing one or two nitrogen (N) atoms; each of X, Y and Z is independently selected from a group consisting of nitrogen (N) and oxygen (O), where one of X, Y or Z represents oxygen (O), the other two represent nitrogen (N); m represents 1-3; each of n, o, p is selected from 0-4, q represents 0-2. A pharmaceutical composition and a method for preventing or treating epilepsy are also proposed.

EFFECT: obtaining compounds containing oxadiazole, which are suitable for use as an antiepileptic drug.

Chemical formula I

15 cl, 2 tbl, 86 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to a novel oxadiazole-containing compound useful as an antiepileptic drug for the prevention or treatment of epilepsy, a method for its preparation, a pharmaceutical composition containing the same, and its use as a medicine.

BACKGROUND OF THE INVENTION

Epilepsy is a disease in which epileptic seizures recur and continue for no particular reason, and also cause brain damage and physical/mental disorders when they become chronic. As a result, epilepsy is a fatal disease that imposes a heavy social and economic burden, as well as impairs the quality of life. Epilepsy varies depending on its cause or the area of the brain where the changes occur, and exhibits a variety of symptoms from simple repetitive body movements that at first appear meaningless to generalized seizures and loss of consciousness. In most cases, it is impossible to predict the onset of symptoms because the symptoms appear suddenly. The mechanism of occurrence of epilepsy is known to be caused by an abnormality and excitation of the cerebral cortex, and it has been reported that a disease that causes lesions in the brain can also cause seizures. However, idiopathic epilepsy, the true cause of which is not exactly known, is 60 to 70%, and congenital diseases, infections, tumors, stroke, degenerative diseases, head injury, and the like are known as other causes. The prevalence of patients with epilepsy is 0.5% of the population (1 in every 200 people), and the World Health Organization (WHO) estimates that there are more than 50 million patients with epilepsy worldwide.

In principle, it is preferable to treat epilepsy using a drug, and surgical treatment can be used in case of refractory epilepsy not responding to a drug. The therapeutic agent for epilepsy is a drug that acts directly on the brain, and the drug is chosen differently depending on the type of seizures. There are about 10 drugs most commonly used, such as carbamazepine, phenytoin, valproic acid, phenobarbital, topiramate, levetiracetam and the like, and various new drugs have been developed since 1990. However, although appropriate drugs and doses have been selected, the ratio of refractory patients whose symptoms persist several times a week reaches 30 to 40% of the total number of patients with epilepsy, and since levetiracetam UCB, which is currently used as gold standard, reaches only 40-58% of the treatment rate of refractory patients, a significant improvement in terms of efficiency is required.

In this regard, European Patent No. 0162036 B1 describes the compound (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide, which is well known under the general name levetiracetam. In addition, International Publication No. WO 2003/006467 describes a sulfamate derivative useful in the treatment of epilepsy, and an exemplary compound is well known under the general name topiramate. EP 0021121 B1 describes a 1,2,4-triazine derivative useful in the treatment of epilepsy and an exemplary compound is well known under the generic name lamotrigine. Most of the existing therapeutic agents for epilepsy have been developed based on efficacy in an animal model of epilepsy rather than drug discovery based on drug targets.

[Prior Art Documents]

[Patent Documents]

(Patent Document 1) European Patent No. 0162036 B1

(Patent Document 2) International Publication No. W02003/006467

(Patent Document 3) European Patent No. 0021121 B1

DESCRIPTION OF THE PRESENT INVENTION

TECHNICAL PROBLEM

The purpose of the present invention is to provide a new compound represented by the chemical formula 1, or its optical isomer, stereoisomer or pharmaceutically acceptable salt.

Another object of the present invention is to provide a method for preparing a novel compound represented by the chemical formula 1, or an optical isomer, stereoisomer, or pharmaceutically acceptable salt thereof.

Still another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of epilepsy, containing the compound above, its optical isomer, stereoisomer, or pharmaceutically acceptable salt, and a process for its preparation.

Yet another object of the present invention is to provide a method for treating epilepsy in a subject using the compound above, or an optical isomer, stereoisomer, or pharmaceutically acceptable salt thereof.

SOLUTION

In order to achieve the above object, the present invention provides a compound represented by the following chemical formula 1, or an optical isomer, a stereoisomer, or a pharmaceutically acceptable salt thereof:

[Chemical formula 1]

Where

R1 is selected from the group consisting of the following formulas:

R2 is hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carbamoyloxy, alkoxy, alkylthio, haloalkoxy, or hydroxyalkoxy;

R3 is hydrogen, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, carbonyl or alkylcarbonyl;

R4 is hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;

R5 is hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;

each R6, R7, R8 and R9 is independently hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carbamoyloxyalkyl, alkyl-C(O)O-alkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, carbamoyloxyalkoxy, alkyl-C (O)O-alkoxy, amino, dialkylamino, carbonylamino, alkylcarbonylamino, haloalkylcarbonylamino or heterocycloalkyl containing 1-3 nitrogen atoms (N);

each X, Y and Z is independently selected from the group consisting of nitrogen (N) and oxygen (O), where at least one of X, Y and Z is oxygen (O);

m is an integer 0-3;

each n, o and p is independently an integer 0-5; And

q is an integer 0-2.

The compound of formula 1 according to the present invention may form a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include acid addition salts or their stereochemical isomeric forms. The salt may include, but is not limited to, any salt that retains the activity of the parent compound in the subject to which it is administered and does not cause any undesirable effects. Salts include inorganic salts and organic salts, and may be acid addition salts, for example, acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, ethanesulfonic acid, lactic acid, bicarboxylic acid, bisulfuric acid, ditaric acid, oxalic acid, butylic acid, calcium edetate, camsylic acid, carbonic acid, chlorobenzoic acid, citric acid, ethylenediaminetetraacetic acid, toluenesulfonic acid, edicilic acid, aecilic acid, fumaric acid, gluceptic acid, pamoic acid, gluconic acid, glycollarsanilic acid, methyl nitrate, polygalacturonic acid, hexyllysorcinonic acid, little New acid, hydrabamic acid, hydrochloric acid, hydroiodic acid, hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelic acid, estolinic acid, mucic acid, naphthenic acid, muconic acid, p-nitromethanesulfonic acid, hexamic acid, pantothenic acid, monohydrophosphoric acid, dihydrophosphoric acid, salicylic acid, sulfamic acid, sulfanilic acid, methanesulfonic acid or theoclic acid. In addition, examples of basic salts include alkali and alkaline earth metal salts such as ammonium salts, lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts, salts containing organic bases such as benzathine salts, N-methyl-D- glucamine and hydrabamine, and salts containing amino acids such as arginine and lysine. In addition, the salt form can be converted to the free form by treatment with a suitable base or acid. As used in the present invention, the term "additional salt" may include solvates derived from any compound represented by the chemical formula 1, and its salts. Examples of these solvates are hydrates or alcoholates. The compound of chemical formula 1 according to the present invention can be converted into its salt in a conventional manner.

Meanwhile, since the compounds of the present invention may contain an asymmetric carbon center and an asymmetric axis or an asymmetric plane, they may exist as essentially pure enantiomers such as the R and S enantiomers, as well as all optical and stereoisomeric forms, including the racemic mixture, and all of them. isomers and mixtures are within the scope of the present invention. Regarding the pure enantiomer, the enantiomeric excess of this enantiomer and its pharmaceutically acceptable salt represented by the chemical formula 1 containing oxadiazole may preferably be 60% ee or more, more preferably 95% ee or more, and most preferably 98% ee or more.

The term "ee" refers to enantiomeric excess. For example, one enantiomer in a particular compound is present as a mixture of enantiomers in the compound in greater amounts than the other enantiomers. Enantiomerically enriched forms may include enantiomeric compounds of a particular compound wherein the concentration of one enantiomer in an enantiomeric mixture of a particular compound is at least 50%, more typically at least 60%, 70%, 80%, or 90%, or more (eg, >95%, >97%, >98%, >99%, >99.5%) relative to the other enantiomers of the compound.

In the present invention, unless otherwise indicated, the compound represented by the chemical formula 1 is used as a designation including all of the compounds represented by the chemical formula 1, their optical isomer, stereoisomer, and pharmaceutically acceptable salt.

When defining the compound of chemical formula 1 in the present description, the following concepts apply in relation to substituents.

As used in the present invention, the term “halogen”, either alone or in combination with other terms (eg haloalkyl), refers to a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) radical.

As used in the present invention, the term "alkyl", either alone or in combination with other terms (e.g., haloalkyl), refers to the radical of a saturated or unsaturated aliphatic hydrocarbon group containing 1-10, preferably 1-5 straight or branched chain carbon atoms. , and may contain a single bond, a double bond, or a triple bond. For example, alkyl may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, 1-methylbutyl, 2-methylbutyl, 1 -ethylpropyl, and 1,2-dimethylpropyl, but not limited to.

As used in the present invention, the term "cycloalkyl" is a partially or fully saturated single or fused cyclic hydrocarbon, which may be C ₃ -C ₁₂ -cycloalkyl, and C ₃ -C ₆ -cycloalkyl is preferred, including, but not limited to eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohecanyl and the like.

As used in the present invention, the term "alkoxy" refers to alkyloxy containing 1-10, preferably 1-5 carbon atoms, unless otherwise indicated.

As used in the present invention, the term "heterocycloalkyl" refers to a partially or fully saturated hydrocarbon containing 1-3 nitrogen (N) atoms as ring atoms, and a 3-8 membered or 5-8 membered heterocycle is preferred. For example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, imidazolinyl, piperazinil, and the like are included, but are not limited to.

Alkyl, cycloalkyl, alkoxy and heterocycle and the like may optionally be substituted, for example, with one or more substituents selected from the following groups: hydroxy, halogen, alkyl, alkoxy, haloalkyl and haloalkoxy.

As used in the present invention, the term "epilepsy" refers to a group of diseases in which epileptic seizures occur repeatedly and become chronic, even if there is no causative factor capable of causing epileptic seizures. Epilepsy can be divided into seizures with focal onset, seizures with generalized onset, and seizures with unknown onset. In addition, epilepsy may be a specifically focal seizure with or without a secondary generalized seizure.

The hydrogen atoms of the chemical formula 1 of the present invention can be selected from hydrogen, deuterium and tritium.

According to another embodiment, in chemical formula 1,

R1 is selected from the group consisting of the following formulas:

R2 is hydrogen, halogen, hydroxy, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, hydroxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, carbamoyloxy, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, halo-C ₁ -C ₅ alkoxy, or hydroxy-C ₁ -C ₅ alkoxy;

R3 is hydrogen, C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, halo-C ₁ -C ₅ alkyl, hydroxy-C 1 -C ₅ alkyl, C _{1 -C 5} alkoxy-C ₁ -C ₅ alkyl , carbamoyl, C ₁ -C ₅ alkylcarbamoyl, di(C ₁ -C ₅ alkyl)carbamoyl, carbonyl, or C ₁ -C ₅ alkylcarbonyl;

R4 is hydrogen, halogen, hydroxy, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, hydroxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, carbamoyl, C ₁ -C ₅ alkylcarbamoyl or di(C ₁ -C ₅ alkyl)carbamoyl;

R5 is hydrogen, halogen, hydroxy, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, hydroxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, carbamoyl, C ₁ -C ₅ alkylcarbamoyl or di(C ₁ -C ₅ alkyl)-carbamoyl;

each R6, R7, R8 and R9 is independently hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, hydroxy-C 1 -C ₅ alkyl, C _{1 -C 5} alkoxy-C ₁ - C ₅ alkyl, carbamoyloxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkyl-C (O) OC ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, halogen-C ₁ - C ₅ alkoxy, hydroxy-C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkoxy, carbamoyloxy-C ₁ -C ₅ -alkoxy, C ₁ -C ₅ alkyl-C (O) OC ₁ -C ₅ alkoxy, amino, di(C ₁ -C ₅ alkyl)amino, carbonylamino, C ₁ -C ₅ alkylcarbonylamino, halogen -C ₁ -C ₅ alkylcarbonylamino or a 3-8 membered heterocycloalkyl containing 1-3 nitrogen atoms (N);

each X, Y, Z is independently selected from the group consisting of nitrogen (N) and oxygen (O), where at least one of X, Y or Z is oxygen (O);

m is an integer 0-3;

each n, o and p is independently an integer 0-5; And

q is an integer 0-2.

According to yet another embodiment, in chemical formula 1,

R1 is selected from the group consisting of the following formulas:

R2 is hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, alkylthio, haloalkoxy or hydroxyalkoxy;

R3 is hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxyalkyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, carbonyl, or alkylcarbonyl;

R4 is hydrogen, halogen, alkyl, haloalkyl, alkoxyalkyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;

R5 is hydrogen, halogen, alkyl, haloalkyl, alkoxyalkyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;

Each R6, R7, R8 and R9 is independently hydrogen, halogen, alkyl, haloalkyl, alkoxyalkyl, carbamoyloxyalkyl, alkyl-C(O)O-alkyl, alkoxy, alkylthio, haloalkoxy, alkoxyalkoxy, carbamoyloxy-alkoxy, alkyl-C(O )O-alkoxy, amino, dialkylamino, carbonylamino, alkylcarbonylamino, haloalkylcarbonylamino or heterocycloalkyl containing 1 or 2 nitrogen atoms (N);

each X, Y and Z is independently selected from the group consisting of nitrogen (N) and oxygen (O), where one of X, Y or Z is oxygen (O) and the other two are nitrogen (N);

m is an integer 0-3;

each n, o and p is independently an integer 0-4; And

q is an integer 0-2.

According to yet another embodiment, in chemical formula 1,

R1 is selected from the group consisting of the following formulas:

R2 is hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, hydroxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, halo-C ₁ -C ₅ alkoxy or hydroxy-C ₁ -C ₅ alkoxy;

R3 is hydrogen, C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, carbamoyl, C ₁ -C ₅ alkylcarbamoyl , di(C ₁ -C ₅ alkyl)carbamoyl, carbonyl or C ₁ -C ₅ alkylcarbonyl;

R4 is hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, carbamoyl, C ₁ -C ₅ alkylcarbamoyl, or di(C ₁ -C ₅ alkyl)carbamoyl;

R5 is hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, carbamoyl, C ₁ -C ₅ alkylcarbamoyl, or di(C ₁ -C ₅ alkyl)carbamoyl;

each R6, R7, R8 and R9 is independently hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, carbamoyloxy-C ₁ - C ₅ alkyl, C ₁ -C ₅ alkyl-C(O)OC ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, halogen-C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkoxy, carbamoyloxy-C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkyl-C (O) OC ₁ -C ₅ alkoxy, amino, di (C ₁ -C ₅ alkyl) amino, carbonylamino , C ₁ -C ₅ alkylcarbonylamino, halo-C ₁ -C ₅ alkylcarbonylamino, or 5-8 membered heterocycloalkyl containing one or two nitrogen atoms (N);

each X, Y, Z is independently selected from the group consisting of nitrogen (N) and oxygen (O), where one of X, Y or Z is oxygen (O) and the other two are nitrogen (N);

m is an integer 0-3;

each n, o and p is independently an integer 0-4; And

q is an integer 0-2.

According to yet another embodiment, in chemical formula 1,

R1 is selected from the group consisting of the following formulas:

R2 is hydrogen, halogen, alkyl, haloalkyl, alkoxyalkyl, alkoxy or alkylthio;

R3 is hydrogen, alkyl, cycloalkyl, haloalkyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or carbonyl;

R4 is hydrogen, halogen, alkyl, haloalkyl or alkoxyalkyl;

R5 is hydrogen, halogen, alkyl, haloalkyl or alkoxyalkyl;

each R6, R7, R8, and R9 is independently hydrogen, halogen, alkyl, haloalkyl, alkoxyalkyl, alkoxy, alkylthio, haloalkoxy, amino, dialkylamino, alkylcarbonylamino, haloalkylcarbonylamino, or heterocycloalkyl containing one or two nitrogen (N) atoms;

Each X, Y, Z is independently selected from the group consisting of nitrogen (N) and oxygen (O), where one of X, Y or Z is oxygen (O) and the other two are nitrogen (N);

m is an integer 1-3;

each n, o and p is independently an integer 0-4; And

q is an integer 0-2.

According to yet another embodiment of the present invention, in chemical formula 1,

R1 is selected from the group consisting of the following formulas;

R2 is hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, or C ₁ -C ₅ alkylthio;

R3 is hydrogen, C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, halo-C ₁ -C ₅ alkyl, carbamoyl, C ₁ -C ₅ alkylcarbamoyl, di(C ₁ -C ₅ alkyl)carbamoyl or carbonyl;

R4 is hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl;

R5 is hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl;

each R6, R7, R8 and R9 is independently hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, halo-C ₁ -C ₅ alkoxy, amino, di(C ₁ -C ₅ alkyl)amino, C ₁ -C ₅ alkylcarbonylamino, halo-C ₁ -C ₅ alkylcarbonylamino or 5-8 -membered heterocycloalkyl containing one or two nitrogen atoms (N);

each X, Y and Z is independently selected from the group consisting of nitrogen (N) and oxygen (O), where one of X, Y or Z is oxygen (O) and the other two are nitrogen (N);

m is an integer 1-3;

each n, o and p is independently an integer 0-4; And

q is an integer 0-2.

According to yet another embodiment, in chemical formula 1, R1 is selected from the group consisting of the following formulas:

According to yet another embodiment, in chemical formula 1, R1 is represented by the following formula:

According to yet another embodiment of the present invention, in chemical formula 1, each R6, R7, R8 and R9 is independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, dialkylamino, or heterocycloalkyl containing 1-3 nitrogen (N) atoms.

According to yet another embodiment of the present invention, in chemical formula 1, each R6, R7, R8 and R9 is independently hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, halogen -C ₁ -C ₅ alkoxy, di(C ₁ -C ₅ alkyl)amino or 3-8 membered heterocycloalkyl containing 1-3 nitrogen atoms (N).

According to yet another embodiment of the present invention, in chemical formula 1, each R6, R7 and R8 is independently halo, alkyl, haloalkyl, alkoxy, or haloalkoxy.

According to yet another embodiment of the present invention, in chemical formula 1, each R6, R7 and R8 is independently halo, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, or halo-C ₁ - C ₅ alkoxy.

According to yet another embodiment of the present invention, in chemical formula 1, R6 is halogen, haloalkyl, alkoxy, or haloalkoxy.

According to yet another embodiment of the present invention, in chemical formula 1, R6 is halo, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, or halo-C ₁ -C ₅ alkoxy.

According to yet another embodiment of the present invention, in the chemical formula 1

R2 is hydrogen, halogen, alkyl or alkoxy;

R3 is hydrogen, alkyl or carbamoyl;

R4 is hydrogen, halo or alkyl; And

R5 is hydrogen or alkyl.

According to yet another embodiment of the present invention, in chemical formula 1,

R2 is hydrogen, halogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy;

R3 is hydrogen, C ₁ -C ₅ alkyl or carbamoyl;

R4 is hydrogen, halogen or C ₁ -C ₅ alkyl; And

R5 is hydrogen or C ₁ -C ₅ alkyl.

According to yet another embodiment of the present invention, in chemical formula 1, X is oxygen (O) and each of Y and Z is nitrogen (N).

According to yet another embodiment of the present invention, in chemical formula 1,

m is an integer 1 or 2;

each n, o and p is independently an integer 1-4; And

q is an integer 0 or 1.

Representative examples of the compound of chemical formula 1 according to the present invention may include, but are not limited to, the compounds shown in Table 1.

[Table 1]

no. Connection name 1 1-[5-(4-chlorophenyl)-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 2 1-[2-fluoro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 3 [1-[2-fluoro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 4 [1-[5-(4-chlorophenyl)-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 5 1-[2-fluoro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol 6 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol 7 [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate 8 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(2,2,3,3-tetrafluoropropoxy)phenyl]ethanol 9 [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(2,2,3,3-tetrafluoropropoxy)phenyl]ethyl]carbamate 10 1-[2-fluoro-5-(3,3,3-trifluoropropyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol eleven [1-[2-fluoro-5-(3,3,3-trifluoropropyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 12 1-[2-fluoro-5-(3,3,3-trifluoropropyl)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol 13 (1R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol 14 (1S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol 15 1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 16 [1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 17 1-[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 18 [1-[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 19 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethanol 20 [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethyl]carbamate 21 1-(5-butoxy-2-fluorophenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 22 [1-(5-Butoxy-2-fluorophenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 23 1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol 24 [1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethyl]carbamate 25 1-(2-fluoro-5-propylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 26 1-(2-fluoro-5-pentylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 27 [1-(2-fluoro-5-propylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 28 [1-(2-fluoro-5-pentylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 29 1-[2-fluoro-5-(4,4,4-trifluorobutyl)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol thirty 1-[2-fluoro-5-(5,5,5-trifluoropentyl)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol 31 1-[2-fluoro-5-(4,4,4-trifluorobutyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 32 1-[2-fluoro-5-(5,5,5-trifluoropentyl)-phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 33 [1-[2-fluoro-5-(4,4,4-trifluorobutyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 34 [1-[2-fluoro-5-(5,5,5-trifluoropentyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 35 1-[2-fluoro-5-[3-(1-piperidyl)propoxy]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 36 1-[5-[3-(dimethylamino)propoxy]-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 37 4-fluoro-3-[1-hydroxy-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-N-(3,3,3-trifluoropropyl)benzamide 38 [1-[2-fluoro-5-(3,3,3-trifluoropropylcarbamoyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 39 1-[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 40 [1-[5-[3-(dimethylamino)propoxy]-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 41 [1-[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 42 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[2-methyl-5-[4-(trifluoromethyl)phenyl]phenyl]ethanol 43 1-[2-methoxy-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 44 [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[2-methyl-5-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate 45 [1-[2-methoxy-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 46 1-[2-methyl-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol 47 1-[2-methoxy-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol 48 1-[2-chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 49 1-[2-chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol 50 [1-[2-chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 51 [1-[2-chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethyl]carbamate 52 2-(1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol 53 2-(5-ethyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol 54 2-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol 55 [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]acetate 56 2-[2-methoxy-2-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]-5-methyl-1,3,4-oxadiazole 57 1-[3-(4-fluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 58 1-[3-(3,4-difluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 59 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethoxy)phenyl]phenyl]ethanol 60 1-[3-(2-methoxy-4-(trifluoromethoxy)phenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 61 1-[3-(4-chloro-2-(trifluoromethyl)phenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 62 1-[3-(4-chloro-2-methoxyphenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 63 1-[3-(2-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 64 1-[3-(3-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 65 1-[3-(4-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 66 2-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethanol 67 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]propan-1-ol 68 [1-[3-[2-Methoxy-4-(trifluoromethoxy)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 69 [1-[3-[4-Chloro-2-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 70 [1-[3-(4-Chloro-2-methoxyphenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 71 [1-[3-(3,4-difluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 72 [1-[3-(4-fluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 73 [1-[3-(2-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 74 [1-[3-(3-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 75 [1-[3-(4-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 76 1-[3-[2,4-bis(trifluoromethyl)phenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 77 [1-[3-[2,4-bis(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 78 [1-[3-[4-(trifluoromethoxy)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate 79 [2-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethyl]carbamate 80 [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]propyl]carbamate 81 2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol 82 [2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate 83 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol 84 [2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate 85 (1R)-1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 86 (1S)-1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

Terms and abbreviations used in the present description have their original meanings, unless otherwise indicated.

The present invention also relates to a method for producing a compound of chemical formula 1. In the present invention, hereinafter, a method for producing a compound of chemical formula 1 will be described based on an exemplary reaction scheme for a better understanding of the present invention. However, it should be understood that a person skilled in the art can prepare a compound of chemical formula 1 in various ways using known compounds based on the structure of chemical formula 1, or compounds that can be easily obtained from them, and it should be understood that all methods can be included within the scope of the present invention. That is, the compound of chemical formula 1 can be obtained by arbitrarily combining several synthetic methods described in the present description or described in the prior art, and thus the following description relating to the method of compounding chemical formula 1 is merely illustrative, and if necessary, the order of unit operations can be selectively changed, and the scope of the production method of the present invention is not limited to this.

In the present invention further, M refers to molar concentration, and N refers to normal concentration. Description of the terms and abbreviations used in the reaction schemes, preparation examples and examples of the present description is as follows:

LDA: lithium diisopropylamide

TBDMS: tert-butyldimethylsilyl

PPh3: triphenylphosphine

[Reaction Scheme 1]

The general preparation method is to prepare intermediate 4 into which R2 is introduced from the starting compound 2a or 2b by Suzuki coupling with intermediate 3 into which an ester is introduced. The oxadiazole can be introduced into intermediate 6 by a cyclization reaction using the hydrazide intermediate 5 from the compound, and the final compound 1 can be obtained by a hydroxy group nucleophilic substitution reaction in the final step.

[Reaction Scheme 2]

As another preparation method, compound 8 substituted with an ester group is obtained from starting material 7 by the Mitsunobu reaction, and intermediate compound 9, in which an ester is added, is obtained from the obtained compound in the same way as the preparation of intermediate compound 4 according to Reaction Scheme 1. Then the final compound 1 can be obtained in the same way as in the reaction scheme 1.

[Reaction Scheme 3]

As another preparation method, intermediate 11 having an amide group introduced therein can be obtained from starting compound 10, and final compound 13 can be obtained by substitution reaction using LDA through intermediate 12

[Reaction Scheme 4]

As another preparation method, intermediate 14, which is protected by a hydroxy group, using intermediate 4 from Reaction Scheme 1 as a starting compound, and then carboxyl intermediate 15 is obtained by a hydrolysis reaction. Intermediate 16, into which oxadiazole is introduced, is obtained from this compound by a cyclization reaction, and the final compound 18 can be obtained by nucleophilic substitution of the hydroxy group in the last step after the deprotection reaction.

[Reaction Scheme 5]

As another preparation method, intermediate 19 to which oxadiazole is introduced can be obtained by a cyclization reaction using intermediate 15 of Reaction Scheme 4 as a starting compound, and final compound 21 can be obtained by a hydroxy group nucleophilic substitution reaction in the last step after the removal reaction protective group.

[Reaction Scheme 6]

As another production method, intermediate 23 containing a nitrile group introduced by nucleophilic substitution reaction is prepared using compound 22 as a starting compound, and then intermediate 24 containing a hydroxy group introduced by reduction reaction is obtained. Intermediate 25 to which a protecting group is introduced at the hydroxy group, intermediate 28 to which oxadiazole is introduced is obtained by a two-step cyclization reaction, and the final compound 30 can be obtained by a nucleophilic substitution reaction of the hydroxy group in the last step after the removal reaction protective group.

Compounds that are not specifically described in the production method of the present specification are known compounds or compounds that can be easily obtained from known compounds by known production methods or the like.

The compound represented by the chemical formula 1 obtained by the above method can be isolated or purified by various known methods such as recrystallization, iontophoresis, silica gel column chromatography or ion exchange resin chromatography from the reaction product.

As described above, the compounds of the present invention, starting compounds or intermediates for their preparation, and the like, can be obtained by various methods, and these methods should be considered included in the scope of the present invention with respect to the preparation of the compound of chemical formula 1.

The compound represented by the chemical formula 1 according to the present invention has the effect of preventing or treating epilepsy. Accordingly, the present invention includes a medicament containing a therapeutically effective amount of a compound of chemical formula 1 as an active ingredient, and a pharmaceutical composition for the prevention or treatment of epilepsy containing a therapeutically effective amount of a compound of chemical formula 1 as an active ingredient, together with a pharmaceutically acceptable carrier. In addition, prodrugs having various forms that are converted to a compound of chemical formula 1, if necessary in vivo , are also included within the scope of the present invention.

As used in the present invention, the term “treatment” refers to interrupting, delaying or alleviating the progression of a disease when applied to a subject having a symptom.

As used in the present invention, the term "prevention" refers to reducing the likelihood of a disease occurring or eliminating the likelihood of a disease occurring.

As used in the present invention, the term "pharmaceutical composition" may include other chemical components such as carriers, diluents, excipients and the like, in addition to the active compounds of the present invention. Accordingly, the pharmaceutical composition may contain a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof, if necessary. The pharmaceutical composition facilitates the introduction of the active compound into the body. Various methods of administering pharmaceutical compositions containing a compound are known, which include, but are not limited to, oral, injection, aerosol, parenteral, and topical administration. In addition, the pharmaceutical composition may be sterilized, may further contain an adjuvant such as a preservative, stabilizer, hydrating or emulsifying accelerator, osmotic salt and/or buffer, may further contain other therapeutically useful substances, and may be formulated according to conventional mixing, granulating or coating methods.

As used in the present invention, the term "carrier" refers to a compound that facilitates the injection of the compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is a common carrier for easily introducing large amounts of organic compounds into the cells or tissues of the body.

As used in the present invention, the term "diluent" refers to a compound that stabilizes the biologically active form of the compound of interest, and diluted with water, which dissolves the compound. The salt dissolved in the buffer is used as a diluent in the art. A commonly used buffer is phosphate buffered saline, which mimics the saline form of a human body solution. Since the buffer salt is able to adjust the pH of the solution at low concentrations, the buffer diluent rarely changes the biological activity of the compound.

As used in the present invention, the term "pharmaceutically acceptable" refers to a property that does not interfere with the biological activity and physical properties of the compound.

The compound of the present invention can be formulated into various dosage forms, if necessary. When preparing a pharmaceutical composition according to the present invention, the active ingredient, in particular the compound of formula 1, its pharmaceutically acceptable salt or isomer, is mixed with various pharmaceutically acceptable carriers, which can be selected depending on the composition to be obtained. For example, the pharmaceutical composition of the present invention may be formulated as an injection preparation, an oral administration preparation, and the like, as needed.

For example, the pharmaceutical composition may be formulated into any oral dosage form such as tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, or elixirs. The composition for oral administration may contain, for example, a pharmaceutically acceptable carrier such as a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, or a lubricant such as silicon dioxide, talc, stearic acid, its a magnesium or calcium salt and/or polyethylene glycol, in addition to the active ingredient, depending on the typical configuration of each formulation.

In addition, when the composition for oral administration is a tablet, the composition may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and may optionally contain a disintegrant such as starch, agar, alginic acid or its sodium salt, boiling mixture, and/or absorbent, color, flavor or sweetener.

When the pharmaceutical composition is formulated into a parenteral dosage form, the pharmaceutical composition may be administered by a parenteral route such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. The pharmaceutical composition can be obtained in the form of a solution or suspension by mixing the active ingredient, i. compounds of the chemical composition of formula 1 or its pharmaceutically acceptable salt, with a stabilizer or buffer in water, and a solution or suspension can be obtained in the form of a unit dosage form of an ampoule or vial.

The compound of the present invention may be formulated in a known manner using a known pharmaceutical carrier and excipient and may be contained in the form of a unit container or in a multi-dose container. The formulation may be a solution, suspension or emulsion in an oily or aqueous medium and may contain a conventional dispersing agent, suspending agent or stabilizer. Also, for example, the dry powder can be dissolved in water from which the sterile or exothermic material has been removed and used. If necessary, the compound according to the present invention or a pharmaceutical composition containing it can be administered in combination with another therapeutic agent.

The dosage of the compound of the chemical formula 1 of the present invention can be determined in accordance with the prescription of a physician, depending on factors such as the specific properties of the patient: weight, age, disease and severity. For example, a compound of Formula 1 of the present invention can be included in a pharmaceutical composition in an effective amount of 0.1 to 500 mg/kg (body weight), preferably 0.5 to 100 mg/kg (body weight) per day, in relation to mammals, including humans, and the pharmaceutical composition can be divided into taking once or twice a day and administered orally or parenterally.

BENEFICIAL EFFECTS OF THE PRESENT INVENTION

The compound of chemical formula 1 according to the present invention has the effect of treating diseases of the nervous system, and in particular, acts as an anticonvulsant and antiepileptic drug. The compound may provide a superior anticonvulsant effect compared to levetiracetam, topiramate, and lamotrigine in a 6 Hz model, which is an animal model of a refractory focal seizure.

THE METHOD OF THE PRESENT INVENTION

In the present invention further, the present invention is explained in more detail by the following examples. However, it should be understood that the protected scope of the present invention is not limited to these examples.

Example 1 Preparation of 1-[5-(4-chlorophenyl)-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

Example 1-1 Preparation of ethyl 3-(5-bromo-2-fluorophenyl)-3-hydroxypropanoate

Diethylzinc (1.0 M n-hexane solution, 24.3 ml, 24.3 mmol) was slowly added to 100 ml of diethyl ether solution in which 5-bromo-2-fluorobenzaldehyde (1.9 ml, 16.2 mmol) was dissolved ) and ethyliodoacetate (2.9 ml, 24.3 mmol) in an ice bath while maintaining the temperature at 0°C. The reaction mixture was stirred at the same temperature for 1 hour, and then 100 ml of ethyl acetate was added, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution once each, and dried over anhydrous magnesium sulfate. A light brown oil obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a light yellow oil.

Example 1-2 Preparation of ethyl 3-[5-(4-chlorophenyl)-2-fluorophenyl)-3-hydroxypropanoate

4-Chlorophenylboronic acid (0.8 g, 5.1 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.2 g, 0.3 mmol) and 3.4 ml of 2M aqueous potassium carbonate solution were added successively to 20 ml 1,4-dioxane solution in which ethyl 3-(5-bromo-2-fluorophenyl)-3-hydroxypropanoate (1.0 g, 3.4 mmol) obtained in Example 1-1 was dissolved and the mixture was stirred at 90°C for 1 hour. The temperature was lowered to room temperature, 50 ml of ethyl acetate was added to the reaction mixture, and then the mixture was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution once each, and the organic layer was dried over anhydrous magnesium sulfate. A dark brown oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a yellow solid.

Example 1-3 Preparation of 3-[5-(4-chlorophenyl)-2-fluorophenyl)-3-hydroxypropanehydrazide

Hydrazine monohydrate (0.3 g, 6.2 mmol) was added to 20 ml of ethanol, with ethyl 3-[5-(4-chlorophenyl)-2-fluorophenyl)-3-hydroxypropanoate (1 g, 3, 1 mmol) obtained in example 1-2, and heated and boiled under reflux for 18 hours. The reaction mixture was cooled to room temperature and left for approximately 1 hour, washing the resulting white precipitate with isopropyl ether and filtering it to give the title compound.

Example 1-4 Preparation of 1-[5-(4-chlorophenyl)-2-fluorophenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

N,N'-dimethylacetamide dimethyl acetal (0.6 g, 4.8 mmol) was added to 20 ml of toluene containing 3-[5-(4-chlorophenyl)-2-fluorophenyl)-3-hydroxypropanehydrazide (1 g, 3.2 mmol) obtained in Example 1-3 and heated and refluxed for about 1 hour at 110°C, and para-toluenesulfonic acid (57 mg, 0.3 mmol) was added thereto, and further heated and refluxed with reflux for approximately 18 hours. The temperature was lowered to room temperature, 100 ml of ethyl acetate was added to the reaction mixture, and the mixture was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution once each, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and isopropyl ether was added to the reaction mixture and left at room temperature for 1 hour, washing the resulting white solid with isopropyl ether and filtering it to give the title compound. The NMR data of the resulting title compound are as follows.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.77 (d, J=8.5 Hz, 1H), 7.50-7.40 (m, 5H), 7.12 (t, J= 11.5 Hz, 1H), 5.60-5.58 (m, 1H), 3.56 (d, J=4.5 Hz, 1H), 3.29-3.22 (m, 2H), 2.53 (s, 3H).

Example 2 Preparation of 1-[2-fluoro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 4-trifluoromethylboronic acid was used instead of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.84 (d, J=8.5 Hz, 1H), 7.71-7.66 (m, 4H), 7.52-7.45 ( m, 1H), 7.16 (t, J=12 Hz, 1H), 5.20-5.59 (m, 1H), 3.67 (d, J=5.0 Hz, 1H) 3.31 -3.23 (m, 2H), 2.53 (s, 3H).

Example 3 Preparation of [1-[2-fluoro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1,1'-Carbonyldiimidazole (0.6 g, 4.0 mmol) was added to 20 ml of a tetrahydrofuran solution containing 1-[2-fluoro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5- methyl-1,3,4-oxadiazol-2-yl)ethanol (1 g, 2.7 mmol) obtained in Example 2, and the mixture was stirred at room temperature for 6 hours. 2 ml of ammonia water was added to the reaction mixture and stirred at the same temperature for 30 minutes, and then 100 ml of ethyl acetate was added, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution once each, and dried over anhydrous magnesium sulfate. A light yellow oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.70-7.52 (m, 6H), 7.17 (t, J=11.5 Hz, 1H), 6.37 (br s, 1H ), 5.01(br s, 2H) 3.53-3.37(m, 3H), 2.53(s, 3H).

Example 4 Preparation of [1-[5-(4-chlorophenyl)-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[5-(4-Chlorophenyl)-2-fluorophenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol, which was the final compound of Example 1, was used as the starting compound by in the same way as in example 3, obtaining the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.53 (d, J=8.0 Hz, 1H), 7.45-7.38 (m, 4H), 7.13 (m, 1H) , 6.34 (br s, 1H), 5.11 (br s, 2H, NH2), 3.51-3.35 (m, 2H), 2.47 (s, 3H).

Example 5 Preparation of 1-[2-fluoro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 4-trifluoromethylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1-2, and N,N'-dimethylformamide dimethyl acetal was used in place of N,N'- dimethylacetal dimethylacetamide in Example 1-4.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.40 (s, 1H) 7.83 (d, J=8.5 Hz, 1H), 7.70-7.65 (m, 4H), 7.52 (br s, 1H) 7.16 (m, 1H), 5.64 (m, 1H), 3.70 (br s, 1H), 3.39-3.34 (m, 2H).

Example 6 Preparation of 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol

The title compound was prepared in the same manner as in Example 1, except that 3-bromobenzaldehyde was used as the starting compound and 4-trifluoromethylboronic acid was used instead of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.70-7.68 (m, 4H), 7.57-7.55 (m, 1H), 7.51-7.45 (m, 3H ), 5.37-5.33 (m, 1H), 3.34-3.24 (m, 3H), 2.53 (s, 3H).

Example 7 Preparation of [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate

2-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol which was the final compound of Example 6 was used as the starting compound in the same way as in example 3, obtaining the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.67 (dd, J=10.0, 17.5 Hz, 4H), 7.58-7.39 (m, 4H), 6.13 ( s, 1H), 4.95 (br s, 2H, NH2), 3.52-3.29 (m, 2H), 2.49 (s, 3H).

Example 8 Preparation of 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(2,2,3,3-tetrafluoropropoxy)phenyl]ethanol

Example 8-1 Preparation of 3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde

2,2,3,3-Tetrafluoropropanol (1.6 g, 12.3 mmol) was added to 20 ml of tetrahydrofuran in which 3-hydroxybenzaldehyde (1.0 g, 8.2 mmol) and triphenylphosphine (3.2 g , 12.3 mmol), cooled to 0° C. in an ice bath, and diisopropyl azodicarboxylate (1.9 g, 9.84 mmol) was slowly added dropwise thereto while maintaining the temperature. The reaction mixture was stirred at room temperature for 18 hours, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution once each, and dried over anhydrous magnesium sulfate. A light yellow oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a light yellow liquid.

Example 8-2 Preparation of ethyl 3-hydroxy-[3-(2,2,3,3-tetrafluoropropoxy)phenyl]propanoate

Diethylzinc (1.0 M n-hexane solution, 6.4 ml, 6.4 mmol) was slowly added to 20 ml of diethyl ether in which 3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde (1.0 g, 4.2 mmol) and ethyl iodoacetate (1.4 g, 6.4 mmol) obtained in Example 8-1 in an ice bath while maintaining the temperature at 0°C. The reaction mixture was stirred at the same temperature for 1 hour, and then 100 ml of ethyl acetate was added, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution once each, and dried over anhydrous magnesium sulfate. A light brown oil obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a light yellow oil.

Example 8-3 Preparation of 3-hydroxy-3-[3-(2,2,3,3-tetrafluoropropoxy)phenyl]propanehydrazide

Hydrazine monohydrate (0.3 g, 6.2 mmol) was added to 20 ml of ethanol in which ethyl 3-hydroxy-[3-(2,2,3,3-tetrafluoropropoxy)phenyl]propanoate (1.0 g , 3.1 mmol) obtained in Example 8-2 and heated and refluxed for 18 hours. The reaction mixture was cooled to room temperature and left for approximately 1 hour, washing the resulting white solid with isopropyl ether and filtering it to give the title compound.

Example 8-4 Preparation of 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(2,2,3,3-tetrafluoropropoxy)phenyl]ethanol

N,N'-dimethylacetamide dimethylacetal (0.6 g, 4.8 mmol) was added to 20 ml of toluene containing 3-hydroxy-3-[3-(2,2,3,3-tetrafluoropropoxy)phenyl]propanehydrazide (1 0 g, 3.2 mmol) obtained in Example 8-3 was heated and refluxed at 110° C. for about 1 hour, and para-toluenesulfonic acid (57 mg, 0.3 mmol) was added thereto, and heated and refluxed for approximately 18 hours. The temperature was lowered to room temperature, 100 ml of ethyl acetate was added to the reaction mixture, and then the mixture was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution once each, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and isopropyl ether was added to the reaction mixture and left at room temperature for 1 hour, washing the resulting white solid with isopropyl ether and filtering it to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.30-6.85 (m, 4H), 6.21-5.94 (t, J=66.5 Hz, 1H), 5.22- 5.20 (m, 1H), 4.37 (t, J=14.5 Hz, 2H), 4.15 (s, 1H), 3.18-3.16 (m, 2H), 2.48 (s, 3H).

Example 9 Preparation of [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(2,2,3,3-tetrafluoropropoxy)phenyl]ethyl]carbamate

2-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-[3-(2,2,3,3-tetrafluoropropoxy)phenyl]ethanol, which is the final compound of Example 8, as the parent compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.29 (dd, J=9.0, 18.0 Hz, 1H), 7.29 (dd, J1=9.0, 10.5 Hz, 2H), 6.96 (s, 1H), 6.20-5.94 (m, 2H), 4.98 (br s, 2H, NH2), 4.37 (t, J=14.5 Hz, 2H) 4.35 (t, J=14.5 Hz, 2H), 3.43-3.41 (m, 1H), 3.24 (d, J=18.5 Hz, 1H), 2.49 (s, 3H).

Example 10 Preparation of 1-[2-fluoro-5-(3,3,3-trifluoropropyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 3,3,3-trifluoropropylboronic acid was used instead of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.43-7.41 (m, 1H), 7.13-7.11 (m, 1H), 6.99 (t, J=12.0 Hz, 1H), 5.54-5.52 (m, 1H), 3.55 (s, 1H), 3.27 (d, J=20.0 Hz, 2H), 3.17 (dd, J1 =11.5, 20.0 Hz, 1H), 2.87 (t, J=9.5 Hz, 2H), 2.53 (s, 3H), 2.39 (dd, J1=12.5, 22 Hz, 1H).

Example 11 Preparation of [1-[2-fluoro-5-(3,3,3-trifluoropropyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[2-Fluoro-5-(3,3,3-trifluoropropyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 10, as a starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.19 (d, J=8.0 Hz, 1H), 7.14-7.12 (m, 1H), 7.02 (t, J= 11.5 Hz, 1H), 6.28 (br s, 1H), 4.77 (br s, 2H, NH2), 3.45-3.35 (m, 2H), 2.85 (t, J =9.5 Hz, 2H), 2.50 (s, 3H), 2.36 (dd, J1=12.5, 22 Hz, 1H).

Example 12 Preparation of 1-[2-fluoro-5-(3,3,3-trifluoropropyl)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 3,3,3-trifluoropropylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1-2 and N,N'-dimethylacetamide dimethylacetal was used in place of N ,N'-dimethylacetamide dimethylacetal in example 1-4.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.39 (s, 1H), 7.41 (d, J=6.5 Hz, 1H), 7.13-7.11 (m, 1H) , 7.00 (t, J=12.5 Hz, 1H), 5.57-5.55 (m, 1H), 3.37-3.28 (m, 2H), 2.88-2.84 (m, 3H), 2.41-2.34 (m, 2H).

Example 13 Preparation of (1R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol

2-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol, which is the final compound of Example 6, was used as the starting compound to separate the optical isomeric compound using a preparative HPLC device on a chiralpak AD column (2×20 cm), n-hexane:ethyl acetate=90:10 at a flow rate of 20 ml/min.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.70-7.68 (m, 4H), 7.57-7.55 (m, 1H), 7.51-7.45 (m, 3H ), 5.37-5.33 (m, 1H), 3.34-3.24 (m, 3H), 2.53 (s, 3H).

Example 14 Preparation of (1S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol

2-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol, which is the final compound of Example 6, was used as the starting compound to separate the optical isomeric compound using a preparative HPLC device on a chiralpak AD column (2×20 cm), n-hexane:ethyl acetate=90:10 at a flow rate of 20 ml/min.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.70-7.68 (m, 4H), 7.57-7.55 (m, 1H), 7.51-7.45 (m, 3H ), 5.37-5.33 (m, 1H), 3.34-3.24 (m, 3H), 2.53 (s, 3H).

Example 15 Preparation of 1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 8, except that 2-fluoro-5-hydroxybenzaldehyde was used as the starting compound in Example 8-1 and 4,4,4-trifluorobutanol was used instead of 2,2, 3,3-tetrafluoropropanol.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.11-7.09 (m, 1H), 6.99 (d, J=9.6 Hz, 1H), 6.79-6.76 ( m, 1H), 5.51-5.48 (m, 1H), 4.01-3.98 (m, 2H), 3.52 (d, J=4.0 Hz, 1H), 3.28 -3.12(m, 2H), 2.52(s, 3H), 2.34-2.27(m, 2H), 2.07-2.02(m, 2H).

Example 16 Preparation of [1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[2-Fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 15, as a starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=6.98 (t, J=11.5 Hz, 1H), 6.88 (dd, J1=4.0, 7.0 Hz, 1H), 6 .25 (dd, J=6.0, 10.5 Hz, 1H), 5.05 (br s, 2H, NH2), 3.96 (t, J=7.5 Hz, 2H) 3.43 ( dd, J=10.5, 19.0 Hz, 1H), 3.31 (dd, J=6.0, 19.0 Hz, 1H), 2.49 (s, 3H), 2.31-2 .29 (m, 2H), 2.03-2.01 (m, 2H).

Example 17 Preparation of 1-[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 8 except that 2-fluoro-5-hydroxybenzaldehyde was used as the starting compound in Example 8-1 and 2,2,2-trifluoroethanol was used instead of 2,2 ,3,3-Tetrafluoropropanol.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.21-7.19 (m, 1H), 7.01 (t, J=11.5 Hz, 1H), 6.89-6.85 ( m, 1H), 5.53-5.49 (m, 1H), 4.35 (q, J=10 Hz, 2H), 3.65 (d, J=5.5 Hz, 1H), 3, 27 (dd, J=4.0, 20.5 Hz, 1H), 3.13 (dd, J=11.5, 20.5 Hz, 1H), 2.53 (s, 3H).

Example 18 Preparation of [1-[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[2-Fluoro-5-(2,2,2-trifluoroethoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 17, as a starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.03 (t, J=11.5 Hz, 1H), 6.97-6.95 (m, 1H), 6.88-6.84 ( m, 1H), 6.29-6.26 (m, 1H), 4.74 (br s, 2H, NH2), 4.31 (q, J=10 Hz, 2H), 3.43 (dd, J=10.5, 19.5 Hz, 1H), 3.34 (dd, J=6.0, 19.5 Hz, 1H), 2.50 (s, 3H).

Example 19 Preparation of 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethanol

The title compound was prepared in the same manner as in Example 8, except that 4,4,4-trifluorobutanol was used instead of 2,2,3,3-tetrafluoropropanol in Example 8-1.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.29 (d, J=10.0 Hz, 1H), 6.99-6.97 (m, 2H), 6.84-6.82 ( m, 1H), 5.23-5.21 (m, 1H), 4.02 (t, J=7.5 Hz, 2H), 3.32 (d, J=4.5 Hz, 1H) 3 .19-3.17(m, 1H), 2.51(s, 3H), 2.33-2.31(m, 2H), 2.05(m, 2H).

Example 20 Preparation of [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethyl]carbamate

2-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethanol, which is the final compound of Example 19, as starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.29 (d, J=10.0 Hz, 1H), 6.95 (d, J=10.0 Hz, 1H) 6.90-6, 83 (m, 2H), 6.02 (m, 1H), 4.71 (br s, 2H, NH2), 4.01 (t, J=7.5 Hz, 2H), 3.43 (dd, J=11.0, 19.0 Hz, 1H), 3.26 (dd, J=6.0, 19.0 Hz, 1H), 2.50 (s, 3H), 2.33-2.31 (m, 2H), 2.06-2.04 (m, 2H).

Example 21 Preparation of 1-(5-butoxy-2-fluorophenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 8, except that n-butanol was used instead of 2,2,3,3-tetrafluoropropanol in Example 8-1.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.11 (s, 1H), 6.94-6.92 (m, 1H), 6.78-6.76 (m, 1H), 5, 49-5.47 (m, 1H), 4.04 (s, 1H, OH), 3.95-3.93 (m, 2H), 3.23-3.21 (m, 2H), 2, 56 (s, 3H), 1.78-1.76 (m, 2H), 1.53-1.51 (m, 2H), 0.96-0.94 (m, 3H).

Example 22 Preparation of [1-(5-butoxy-2-fluorophenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-(5-Butoxy-2-fluorophenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol, which is the final compound of Example 21, was used as the starting compound in the same manner, as in example 3, getting the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=6.97-6.95 (m, 1H), 6.87-6.85 (m, 1H), 6.77-6.75 (m, 1H ), 6.25-6.23 (m, 1H), 4.78 (s, 2H, NH2), 3.95-3.93 (m, 2H), 3.48-3.46 (m, 2H ), 2.56 (s, 3H), 1.78-1.76 (m, 2H), 1.53-1.51 (m, 2H), 0.94-0.92 (m, 3H).

Example 23 Preparation of 1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 8, except that 2-fluoro-5-hydroxybenzaldehyde was used as the starting compound in Example 8-1, 4,4,4-trifluorobutanol was used instead of 2,2, 3,3-tetrafluoropropanol, and N,N'-dimethylformamide dimethylacetal was used in place of N,N'-dimethylacetamide dimethylacetal in Example 8-4.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.38 (s, 1H), 7.29 (dd, J=4.0, 7.5 Hz, 1H), 6.97 (t, J= 11.0 Hz, 1H), 6.80-6.77 (m, 1H), 5.54-5.52 (m, 1H), 4.00-3.98 (m, 2H), 3.56 (d, J=5.0 Hz, 1H), 3.34 (dd, J=4.5, 20.0 Hz, 1H), 3.26 (dd, J=11.0, 20.0 Hz, 1H), 2.33-2.31 (m, 2H), 2.05-2.03 (m, 2H).

Example 24 Preparation of [1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[2-Fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol, which is the final compound of Example 23, as starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.36 (s, 1H), 6.90 (t, J=12.0 Hz, 1H), 6.87-6.77 (m, 2H) , 6.30 (dd, J=6.0, 10.5 Hz, 1H) 4.89 (br s, 2H, NH2), 3.96 (t, J=7.5 Hz, 2H), 3, 53 (dd, J=10.5, 19.0 Hz, 1H), 3.42 (dd, J=6.0, 19.0 Hz, 1H), 2.32-2.30 (m, 2H) , 2.05-2.03 (m, 2H).

Example 25 Preparation of 1-(2-fluoro-5-propylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that n-propylboronic acid was used instead of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.36-7.33 (m, 1H), 7.10-7.06 (m, 1H), 6.97-6.92 (m, 1H ), 5.52-5.48 (m, 1H), 3.29-3.16 (m, 2H), 2.58 (t, J=7.6, 2H), 2.51 (s, 3H ), 1.66-1.57 (m, 2H), 0.94-0.90 (t, J=7.2, 3H).

Example 26 Preparation of 1-(2-fluoro-5-pentylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that N-chlorophenylboronic acid was used instead of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.36-7.34 (m, 1H), 7.08-7.06 (m, 1H), 6.97-6.92 (m, 1H ), 5.51-5.48 (m, 1H), 3.25 (br s, 1H), 3.24-3.20 (m, 2H), 2.58 (t, J=8.0, 2H), 2.51 (s, 3H), 1.60-1.55 (m, 2H*2), 1.34-1.30 (m, 2H) 0.90-0.87 (t, J =6.8, 3H).

Example 27 Preparation of [1-(2-fluoro-5-propylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-(2-Fluoro-5-propylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol, which is the final compound of Example 25, was used as the starting compound in the same manner, as in example 3, getting the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.15-7.12 (m, 1H), 7.09-7.08 (m, 1H), 6.99-6.94 (m, 1H ), 6.30-6.26 (m, 1H), 4.13 (br s, 2H), 4.13 (dd, J=15.2, J=8.4, 1H), 3.36 ( dd, J=15.2, J=4.8, 1H), 2.57 (t, J=7.6, 2H), 2.49 (s, 3H), 1.66-1.54 (m , 2H), 0.93-0.89 (t, J=7.2, 3H).

Example 28 Preparation of [1-(2-fluoro-5-pentylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-(2-Fluoro-5-pentylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol, which is the final compound of Example 26, was used as the starting compound in the same manner, as in example 3, getting the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.15-7.13 (m, 1H), 7.09-7.08 (m, 1H), 6.98-6.94 (m, 1H ), 6.29-6.26 (m, 1H), 4.63 (br s, 2H), 3.49 (dd, J=15.2, J=8.8, 1H), 3.35 ( dd, J=15.2, J=4.4, 1H), 2.56 (t, J=7.6, 2H), 2.49 (s, 3H), 1.58-1.54 (m , 2H), 1.34-1.25 (m, 2H*2), 0.91-0.89 (t, J=7.2, 3H).

Example 29 Preparation of 1-[2-fluoro-5-(4,4,4-trifluorobutyl)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 4,4,4-trifluorobutyric acid was used instead of 4-chlorophenylboronic acid in Example 1-2, and N,N'-dimethylacetamide dimethyl acetal was used in place of N , N'-dimethylacetamide dimethyl acetal in example 1-4.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.38 (s, 1H), 7.39-7.36 (m, 1H), 7.11-7.10 (m, 1H), 7, 02-6.98 (m, 1H), 5.58-5.55 (m, 1H), 3.40-3.26 (m, 3H), 2.71-2.67 (m, 2H), 2.10-2.05 (m, 2H), 2.18-2.05 (m, 2H), 1.90-1.86 (m, 2H).

Example 30 Preparation of 1-[2-fluoro-5-(5,5,5-trifluoropentyl)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 5,5,5-trifluoropentylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1-2, and N,N'-dimethylacetamide dimethyl acetal was used in place of N ,N'-dimethylacetamide dimethylacetal in example 1-4.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.37 (s, 1H), 7.36 (dd, J=2.1, 7.0 Hz, 1H), 7.12-7.05 ( m, 1H), 6.98 (dd, J=8.4, 10.2 Hz, 1H), 5.55 (dd, J=3.7, 8.3 Hz, 1H), 3.37-3 .28 (m, 2H), 2.63 (t, J=7.5 Hz, 2H), 2.1-2.02 (m, 2H), 1.73-1.64 (m, 2H), 1.59 (d, J=7.2 Hz, 2H).

Example 31 Preparation of 1-[2-fluoro-5-(4,4,4-trifluorobutyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 4,4,4-trifluorobutyric acid was used instead of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.40-7.38 (m, 1H), 7.12-7.09 (m, 1H), 7.02-6.97 (m, 1H ), 5.55-5.51 (m, 1H), 3.48-3.46 (m, 1H), 3.28-3.19 (m, 2H), 2.70-2.67 (m , 2H), 2.50 (s, 3H), 2.18-2.05 (m, 2H), 1.92-1.86 (m, 2H).

Example 32 Preparation of 1-[2-fluoro-5-(5,5,5-trifluoropentyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 5,5,5-trifluoropentylboronic acid was used instead of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.38 (dd, J=2.1, 7.0 Hz, 1H), 7.08 (dd, J=2.3, 5.3, 8 .1 Hz, 1H), 6.97 (dd, J=8.4, 10.3 Hz, 1H), 5.56-5.48 (m, 1H), 3.47 (d, J=4, 4 Hz, 1H), 3.33-3.15 (m, 2H), 2.69-2.59 (m, 2H), 2.53 (s, 3H), 2.21-2.03 (m , 2H), 1.74-1.61 (m, 4H).

Example 33 Preparation of [1-[2-fluoro-5-(4,4,4-trifluorobutyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[2-Fluoro-5-(4,4,4-trifluorobutyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 31 , was used as a starting compound in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.18-7.12 (m, 2H), 7.03-7.01 (m, 1H), 6.34-6.28 (m, 1H ), 4.77-4.64 (m, 2H), 3.50-3.44 (m, 1H), 3.38-3.34 (m, 1H), 2.69-2.65 (m , 2H), 2.50 (s, 3H), 2.11-2.05 (m, 2H), 1.90-1.84 (m, 2H).

Example 34 Preparation of [1-[2-fluoro-5-(5,5,5-trifluoropentyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[2-Fluoro-5-(5,5,5-trifluoropentyl)-phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 32 , was used as a starting compound in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.16 (d, J=5.8 Hz, 1H), 7.09 (d, J=5.0 Hz, 1H), 7.04-6 .95 (m, 1H), 6.29 (dd, J=4.6, 8.3 Hz, 1H), 4.73 (s, 2H), 3.55-3.28 (m, 2H), 2.61 (t, J=7.3 Hz, 2H), 2.50 (s, 3H), 2.18-2.03 (m, 2H), 1.64 (dd, J=7.8, 15.9 Hz, 4H).

Example 35 Preparation of 1-[2-fluoro-5-[3-(1-piperidyl)propoxy]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 8 except that 2-fluoro-5-hydroxybenzaldehyde was used as starting compound in Example 8-1 and 3-(1-piperidyl)propan-1-ol was used instead of 2,2,3,3-tetrafluoropropanol.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.12 (dd, J=5.8, 3.1 Hz, 1H), 6.95 (t, J=9.3 Hz, 1H), 6 .76 (dt, J=8.8, 3.6 Hz, 1H), 5.49 (dd, J=8.8, 3.6 Hz, 1H), 4.08-4.00 (m, 2H ), 3.29-3.15 (m, 2H), 2.94-2.77 (m, 6H), 2.52 (s, 3H), 2.29-2.20 (m, 2H), 1.95-1.83 (m, 4H), 1.63-1.54 (m, 2H).

Example 36 Preparation of 1-[5-[3-(dimethylamino)propoxy]-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 8 except that 2-fluoro-5-hydroxybenzaldehyde was used as the starting compound in Example 8-1 and 3-(dimethylamino)propan-1-ol was used in place of 2,2,3,3-tetrafluoropropanol.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.13 (dd, J=5.8, 3.2 Hz, 1H), 6.96 (t, J=9.3 Hz, 1H), 6 .77 (dt, J=8.8, 3.6 Hz, 1H), 5.49 (dd, J=8.8, 3.2 Hz, 1H), 4.09-4.04 (m, 2H ), 3.29-3.14 (m, 2H), 3.00 (t, J=3.6 Hz, 2H), 2.67 (s, 6H), 2.52 (s, 3H), 2 .28-2.21 (m, 2H).

Example 37 Preparation of 4-fluoro-3-[1-hydroxy-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-N-(3,3,3-trifluoropropyl)benzamide

Example 37-1 Preparation of 4-fluoro-3-formyl-N-(3,3,3-trifluoropropyl)benzamide

N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (2.3 g, 7.1 mmol) was added to 20 ml of methylene chloride, in which 4-fluoro-3- formylbenzoic acid (1.0 g, 5.9 mmol), N,N-diisopropylethylamine (3.1 ml, 17.8 mmol) and 3,3,3-trifluoropropylamine (0.8 g, 7.1 mmol), and stirred at room temperature for 1 hour. The reaction mixture was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution once each, and dried over anhydrous magnesium sulfate. The light yellow oil obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound in light yellow form.

Example 37-2 Preparation of 4-fluoro-3-[1-hydroxy-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-N-(3,3,3-trifluoropropyl) benzamide

To 10 ml of dry tetrahydrofuran, in which 2,5-dimethyl-1,3,4-oxadiazole (0.4 g, 3.8 mmol) was dissolved, the temperature was lowered to -78°C, lithium diisopropylamide (1.0 M n-hexane solution, 4.5 ml, 4.5 mmol) and stirred for 30 minutes, followed by the slow dropwise addition of 20 ml of dry tetrahydrofuran in which 4-fluoro-3-formyl-N-(3.3 ,3-trifluoropropyl)benzamide (1.0 g, 3.8 mmol) obtained in Example 37-1 while maintaining the temperature. The reaction mixture was slowly warmed to room temperature, stirred for 10 hours, washed with saturated ammonium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution one at a time, and dried over anhydrous magnesium sulfate. A light yellow oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.06 (d, J=2.5 Hz, 1H), 8.05-7.84 (m, 1H), 7.14 (t, J= 12.0 Hz, 1H), 7.00 (br s, 1H, NH), 5.54 (m, 1H), 4.44 (d, J=8.0 Hz, 1H), 3.75-3 .70(m, 2H), 3.30(dd, J1=20.0Hz, J2=4.0Hz, 1H), 3.20(dd, J1=20.0Hz, J2=11.5Hz , 1H), 2.55 (s, 3H), 2.50 (m, 2H).

Example 38 Preparation of [1-[2-fluoro-5-(3,3,3-trifluoropropylcarbamoyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

4-Fluoro-3-[1-hydroxy-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-N-(3,3,3-trifluoropropyl)benzamide, which is the final the compound of Example 37 as a starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.86 (d, J=3.0 Hz, 1H), 7.86-7.71 (m, 1H), 7.12 (t, J= 10.5 Hz, 1H), 6.74 (br s, 1H, NH), 6.31 (dd, J1=10.0 Hz, J2=6.5 Hz, 1H) 5.0 (br s, 2H , NH2), 3.68 (dd, J1=16.0 Hz, J2=8.0 Hz, 2H), 3.45 (dd, J1=19.0 Hz, J2=10.0 Hz, 1H), 3.33 (dd, J1=19.0 Hz, J2=6.5 Hz, 1H), 2.50-2.44 (m, 5H).

Example 39 Preparation of 1-[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 8, except that 2-chloro-5-hydroxybenzaldehyde was used as the starting compound in Example 8-1 and 4,4,4-trifluorobutanol was used instead of 2,2, 3,3-tetrafluoropropanol.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.25 (d, J=8.8 Hz, 1H), 7.22 (d, J=3.0 Hz, 1H), 6.79 (dd , J=8.8, 3.0 Hz, 1H), 5.55 (dt, J=9.4, 3.2 Hz, 1H), 4.05-3.99 (m, 2H), 3, 58 (d, J=3.6 Hz, 1H), 3.35-3.29 (m, 1H), 3.08-3.01 (m, 1H), 2.53 (s, 3H), 2 .35-2.28 (m, 2H), 2.09-2.02 (m, 2H).

Example 40 Preparation of [1-[5-[3-(dimethylamino)propoxy]-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[5-[3-(Dimethylamino)propoxy]-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol, which is the final compound of Example 36, as the parent compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=6.97 (t, J=9.6 Hz, 1H), 6.89 (dd, J=5.6, 3.2 Hz, 1H), 6 .80 (dt, J=8.8, 3.6 Hz, 1H), 6.27 (dd, J=8.4, 4.8 Hz, 1H), 4.74 (br s, 2H, NH2) , 3.97 (t, J=6.6 Hz, 2H), 3.47-3.29 (m, 2H), 2.53-2.47 (m, 2H), 2.50 (s, 3H ), 2.29 (s, 6H), 1.98-1.94 (m, 2H).

Example 41 Preparation of [1-[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[2-Chloro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 39, as a starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.28 (d, J=8.8 Hz, 1H), 6.94 (d, J=3.0 Hz, 1H), 6.78 (dd , J=8.8, 3.0 Hz, 1H), 6.34 (dd, J=7.4, 5.3 Hz, 1H), 4.77 (br s, 2H, NH2), 3.98 (t, J=5.8 Hz, 2H), 3.36-3.33 (m, 2H), 2.51 (s, 3H), 2.37-2.25 (m, 2H), 2, 09-2.01 (m, 2H).

Example 42 Preparation of 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[2-methyl-5-[4-(trifluoromethyl)phenyl]phenyl]ethanol

The title compound was prepared in the same manner as in Example 1, except that 5-bromo-2-methylbenzaldehyde was used as the starting compound in Example 1-1 and 4-trifluoromethylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1 -2.

¹ H-NMR (DMSO, 400 MHz) δ=7.88 (d, J=8.0 Hz, 2H), 7.85-7.84 (m, 1H), 7.82 (d, J=8 .0 Hz, 2H), 7.56 (dd, J=1.6, 8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 5.66 (d, J =4.8 Hz, 1H), 5.26-5.22 (m, 1H), 3.18-3.14 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H).

Example 43 Preparation of 1-[2-methoxy-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 5-bromo-2-methoxybenzaldehyde was used as the starting compound in Example 1-1 and 4-trifluoromethylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1 -2.

¹ H-NMR (DMSO, 400 MHz) δ=7.86-7.79 (m, 5H), 7.67 (dd, J=2.4, 8.4 Hz, 1H), 7.12 (d , J=8.4 Hz, 1H), 5.63 (d, J=5.2 Hz, 1H), 5.33-5.29 (m, 1H), 3.84 (s, 3H), 3 .18-3.14 (m, 2H), 2.47 (s, 3H).

Example 44 Preparation of [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[2-methyl-5-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate

2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[2-methyl-5-[4-(trifluoromethyl)phenyl]phenyl]ethanol which is the final compound of Example 42, in as the starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.70-7.63 (m, 4H), 7.59 (d, J=1.6 Hz, 1H), 7.45 (dd, J= 2.0, 8.0 Hz, 1H), 7.28-7.26 (m, 1H), 6.32-6.29 (m, 1H), 4.72 (br s, 2H, NH2), 3.48-3.24 (m, 2H), 2.50 (s, 3H), 2.49 (s, 3H).

Example 45 Preparation of [1-[2-methoxy-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[2-Methoxy-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 43, in as the starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.50-7.67 (m, 6H), 6.98 (d, J=8.4 Hz, 1H), 6.42 (dd, J= 5.2, 7.6 Hz, 1H), 4.84 (br s, 2H, NH2), 3.92 (s, 3H), 3.38-3.37 (m, 2H), 2.51 ( s, 3H).

Example 46 Preparation of 1-[2-methyl-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 5-bromo-2-methylbenzaldehyde was used as the starting compound in Example 1-1, 4-trifluoromethylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1 -2, and N,N'-dimethylformamide dimethylacetal was used in place of N,N'-dimethylacetamide dimethylacetal in Example 1-4.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.37 (s, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.70-7.65 (m, 4H) , 7.46 (dd, J=2.0, 8.0 Hz, 1H), 7.26 (d, J=7.2 Hz, 1H), 5.56-5.54 (m, 1H), 3.47-3.21 (m, 3H), 2.14 (s, 3H).

Example 47 Preparation of 1-[2-methoxy-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 5-bromo-2-methoxybenzaldehyde was used as the starting compound in Example 1-1, 4-trifluoromethylboronic acid was used instead of 4-chlorophenylboronic acid in Example 1 -2, and N,N'-dimethylformamide dimethylacetal was used in place of N,N'-dimethylacetamide dimethylacetal in Example 1-4.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.37 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.68-7.63 (m, 4H) , 7.53 (dd, J=2.4, 8.4 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 5.53-5.52 (m, 1H), 3.92 (s, 3H), 3.54-3.29 (m, 3H).

Example 48 Preparation of 1-[2-chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1 except that 5-bromo-2-chlorobenzaldehyde was used as the starting compound in Example 1-1 and 4-trifluoromethylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.94 (d, J=2.0 Hz, 1H), 7.70 (s, 4H), 7.51-7.45 (m, 2H) , 5.67 (dt, J=9.2, 3.2 Hz, 1H), 3.75 (d, J=3.9 Hz, 1H), 3.41-3.36 (m, 1H), 3.15-3.08 (m, 1H), 2.54 (s, 3H).

Example 49 Preparation of 1-[2-chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 5-bromo-2-chlorobenzaldehyde was used as the starting compound in Example 1-1, 4-trifluoromethylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1 -2, and N,N'-dimethylformamide dimethylacetal was used in place of N,N'-dimethylacetamide dimethylacetal in Example 1-4.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.41 (s, 1H), 7.93 (s, 1H), 7.70 (d, J=2.0 Hz, 4H), 7.50 -7.46 (m, 2H), 5.71 (dt, J=9.5, 2.9 Hz, 1H), 3.52 (d, J=3.9 Hz, 1H), 3.50- 3.45 (m, 1H), 3.26-3.19 (m, 1H).

Example 50 Preparation of [1-[2-chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[2-Chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 48, in as the starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.72-7.70 (m, 2H), 7.64-7.61 (m, 3H), 7.49 (s, 2H), 6, 45 (dd, J=7.4, 5.4 Hz, 1H), 4.80 (br s, 2H, NH2), 3.43-3.41 (m, 2H), 2.51 (s, 3H ).

Example 51 Preparation of [1-[2-chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[2-Chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol, which is the final compound of Example 49, was used as the starting compound in the same way as in example 3, obtaining the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.38 (s, 1H), 7.72-7.70 (m, 2H), 7.63-7.60 (m, 3H), 7, 50-7.49 (m, 2H), 6.49 (dd, J=6.9, 5.4 Hz, 1H), 4.78 (br s, 2H, NH2), 3.53-3.51 (m, 2H).

Example 52 Preparation of 2-(1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol

The title compound was prepared in the same manner as in Example 1, except that 3-bromobenzaldehyde was used as the starting compound in Example 1-1, 4-trifluoromethylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1-2, and N,N'-dimethylformamide dimethyl acetal was used instead of N,N'-dimethylacetamide dimethyl acetal in Example 1-4.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.39 (s, 1H), 7.7 (d, J=19.6 Hz, 4H), 7.53 (d, J=15.6 Hz , 1H), 7.48 (s, 1H), 7.46 (d, J=7.6 Hz, 2H), 5.39 (dd, J1=4, 8.4 Hz, 1H), 3.25 -3.37 (m, 3H).

Example 53 Preparation of 2-(5-ethyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol

Example 53-1 Preparation of ethyl 3-[tert-butyl(dimethyl)silyl]oxy-3-[3-[4-(trifluoromethyl)phenyl]phenyl]propanoate

Imidazole (0.5 g, 7.7 mmol) and tert-butyldimethylsilyl chloride (1.1 g, 7.7 mmol) were added successively to 20 ml of methylene chloride containing ethyl 3-hydroxy-3-[3-[4- (trifluoromethyl)phenyl]phenyl]propanoate (1.3 g, 3.8 mmol) prepared in Example 1-2 using 4-trifluoromethylboronic acid instead of 4-chlorophenylboronic acid, and the mixture was stirred at room temperature for one day. 100 ml of ethyl acetate was added to the reaction mixture, and the reaction mixture was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and then the organic layer was dried over anhydrous magnesium sulfate. A yellow oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a light yellow liquid.

Example 53-2 Preparation of 3-[tert-butyl(dimethyl)silyl]oxy-3-[3-[4-(trifluoromethyl)phenyl]phenyl]propionic acid

2N aqueous sodium hydroxide solution (1.1 ml, 5.7 mmol) was added to 20 ml of ethanol, with ethyl 3-[tert-butyl(dimethyl)silyl]oxy-3-[3-[4-(trifluoromethyl) )phenyl]phenyl]propanoate (1.3 g, 2.9 mmol) obtained in Example 53-1, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was adjusted to pH 2 with 1N aqueous hydrochloric acid, extracted with 100 ml of ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to give the title compound as a white solid.

Example 53-3 Preparation of tert-butyl-[2-(5-ethyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethoxy]dimethylsilane

1,1'-carbonyldiimidazole (0.1 g, 1.0 mmol) was added to 20 ml of methylene chloride solution containing 3-[tert-butyl(dimethyl)silyl]oxy-3-[3-[4-(trifluoromethyl) phenyl]phenyl]propionic acid (0.4 g, 1.0 mmol) obtained in Example 53-2, and the mixture was stirred at room temperature for 30 minutes. Propionic acid hydrazide (88 mg, 1.0 mmol) was added to the reaction mixture and stirred for 1 hour at the same temperature, and carbon tetrabromide (663 mg, 2.0 mmol) and triphenylphosphine (525 mg, 2 mmol), followed by stirring for 2 hours. 100 ml of ethyl acetate was added to the reaction mixture, and the reaction mixture was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and then the organic layer was dried over anhydrous magnesium sulfate. The yellow liquid obtained by removing the solvent by evaporation in vacuo was purified by flash chromatography to give the title compound as a pale yellow.

Example 53-4 Preparation of 2-(5-ethyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol

Tetra-N-butylammonium fluoride (0.1 ml, 0.3 mmol) was slowly added to 10 ml of tetrahydrofuran containing tert-butyl-[2-(5-ethyl-1,3,4-oxadiazol-2-yl)- 1-[3-[4-(trifluoromethyl)phenyl]ethoxy]dimethylsilane (70 mg, 0.2 mmol) prepared in Example 53-3 while maintaining the temperature at 0° C. in an ice bath. The reaction mixture was stirred at the same temperature for 1 hour, 20 ml of ethyl acetate was added thereto, washed with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. A light brown oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.7 (d, J=19.6 Hz, 4H), 7.56 (d, J=7.2 Hz, 2H), 7.44-7 .51 (m, 2H), 5.39 (dd, J=4.8, 8 Hz, 1H), 3.39 (s, 1H), 3.28-3.26 (m, 2H), 2, 86 (kv, J=7.6 Hz, 2H), 1.36 (t, J=7.6 Hz, 3H).

Example 54 Preparation of 2-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol

The title compound was prepared in the same manner as in Example 53, except that 2,2-dimethylpropanehydrazide was used instead of propionic acid hydrazide in Example 53-3.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.7 (d, J=19.6 Hz, 4H), 7.54 (d, J=7.6 Hz, 2H), 7. 44-7 . 50(m, 2H), 5.35(dd, J1=8.8Hz J2=4.8Hz, 1H), 3.44(s, 1H), 3.22-3.33(m, 2H) .

Example 55 Preparation of [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]acetate

As starting compound, acetyl chloride (0.3 g, 4.35 mmol) was added to 20 ml of methylene chloride with 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[ 3-[4-(trifluoromethyl)phenyl]phenyl]ethanol (1.0 g, 2.9 mmol), which is the final compound of Example 6, and triethylamine (1.1 ml, 8.6 mmol), and obtained in As a result, the solution was stirred at room temperature for about 6 hours. The reaction mixture was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution once each, and dried over anhydrous magnesium sulfate. A light yellow oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.72-7.65 (m, 4H), 7.55-7.46 (m, 3H), 7.42-7.40 (m, 1H ), 6.26-6.23 (m, 1H), 3.53 (dd, J=15.6, J=8.8, 1H), 3.35 (dd, J=15.6, J= 5.2, 1H), 2.50 (s, 3H), 2.08 (s, 3H).

Example 56 Preparation of 2-[2-methoxy-2-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]-5-methyl-1,3,4-oxadiazole

2-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol (1.0 g, 2.9 mmol), which is is the final compound of Example 6, and iodomethane (0.8 g, 5.8 mmol) was successively added to 20 ml of tetrahydrofuran containing sodium hydride (60% dispersion in mineral oil, 0.2 g, 5.8 mmol) as starting compounds, and heated and refluxed for approximately 1 hour. The temperature was lowered to room temperature, and the reaction mixture was dissolved in 100 ml of ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution once each, and the organic layer was dried over anhydrous magnesium sulfate. A light yellow oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.72-7.67 (m, 4H), 7.55-7.47 (m, 3H), 7.39-7.37 (m, 1H ), 4.75-4.72 (m, 1H), 3.36 (dd, J=15.6, J=8.8, 1H), 3.27 (s, 3H), 3.18 (dd , J=15.6, J=4.8, 1H), 2.50 (s, 3H).

Example 57 Preparation of 1-[3-(4-fluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1 except that 3-bromobenzaldehyde was used as the starting compound and 4-fluorophenylboronic acid was used instead of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.60 (s, 1H), 7.53-7.57 (m, 2H), 7.38-7.51 (m, 3H), 5, 33 (dd, J1=8.4 Hz J2=4 Hz, 1H), 3.23-3.27 (m, 3H), 2.50 (s, 3H).

Example 58 Preparation of 1-[3-(3,4-difluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 3-bromobenzaldehyde was used as the starting compound and 3,4-difluorophenylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.60 (s, 1H), 7.39-7.47 (m, 4H), 7.22-7.39 (m, 1H), 5, 33 (dd, J1=8.4Hz J2=4.4Hz, 1H), 3.32 (d, J=4Hz, 1H), 3.25 (d, J=7.6Hz, 2H), 2.50 (s, 3H).

Example 59 Preparation of 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethoxy)phenyl]phenyl]ethanol

The title compound was prepared in the same manner as in Example 1, except that 3-bromobenzaldehyde was used as the starting compound and 4-trifluoromethoxyphenylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.59-7.63 (m, 3H), 7.43-7.51 (m, 3H), 7.3 (d, J=8.4 Hz, 2H), 5.33 (dd, J1=8.4 Hz J2=4 Hz, 1H), 3.26 (m, 3H), 2.50 (s, 3H).

Example 60 Preparation of 1-[3-(2-methoxy-4-(trifluoromethoxy)phenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 3-bromobenzaldehyde was used as the starting compound and 2-methoxy-4-trifluoromethoxyphenylboronic acid was used instead of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.53-7.29 (m, 5H), 6.90 (d, J=8.4 Hz, 1H), 6.82 (s, 1H) , 5.31-5.27(m, 1H), 3.81(s, 3H), 3.30-3.18(m, 3H), 2.51(s, 3H).

Example 61 Preparation of 1-[3-(4-chloro-2-(trifluoromethyl)phenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 3-bromobenzaldehyde was used as the starting compound and 4-chloro-2-trifluoromethylphenylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.73 (s, 1H), 7.55-7.23 (m, 6H), 5.30-5.28 (m, 1H), 3, 49 (d, J=3.2 Hz, 1H), 3.28-3.17 (m, 2H), 2.49 (s, 3H).

Example 62 Preparation of 1-[3-(4-chloro-2-methoxyphenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 3-bromobenzaldehyde was used as the starting compound and 4-chloro-2-methoxyphenylboronic acid was used instead of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.59-6.96 (m, 7H), 5.29-5.25 (m, 1H), 3.79 (s, 3H), 3, 47 (d, J=3.6 Hz, 1H), 3.29-3.16 (m, 2H), 2.49 (s, 3H).

Example 63 Preparation of 1-[3-(2-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 3-bromobenzaldehyde was used as the starting compound and 2-chlorophenylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.50-7.45 (m, 4H), 7.42-7.41 (m, 1H), 7.34-7.29 (m, 3H ), 5.34-5. 30 (m, 1H), 3.27 (d, J=10.5 Hz, 1H), 3.25 (d, J=5.5 Hz, 1H), 3.18 (d, J=4.5 Hz, 1H), 2.52 (s, 3H).

Example 64 Preparation of 1-[3-(3-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1 except that 3-bromobenzaldehyde was used as the starting compound and 3-chlorophenylboronic acid was used instead of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.67-7.63 (m, 1H), 7.58-7.52 (m, 2H), 7.48-7.44 (m, 3H ), 7.42-7.33 (m, 2H), 5.36-5.32 (m, 1H), 3.27-3.24 (m, 3H), 2.53 (s, 3H).

Example 65 Preparation of 1-[3-(4-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

3-Bromobenzaldehyde as a starting compound was used in the same manner as in Example 1 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.70-7.62 (m, 2H), 7.53-7.51 (m, 3H), 7.48-7.41 (m, 3H ), 5.34-5.32 (m, 1H), 3.27-3.23 (m, 3H), 2.53 (s, 3H).

Example 66 Preparation of 2-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethanol

The title compound was prepared in the same manner as in Example 8, except that 4,4,4-trifluorobutanol was used in place of 2,2,3,3-tetrafluoropropanol in Example 8-1, and ethyl-2-bromo- 2-fluoroacetate was used instead of ethyliodoacetate in Example 8-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.33-7.22 (m, 1H), 7.03-6.83 (m, 3H), 5.71-5.51 (m, 1H ), 5.34-5.27 (m, 1H), 4.04-3.98 (m, 2H), 3.10-3.09 (m, 1H), 2.59-2.55 (m , 3H), 2.36-2.26 (m, 2H), 2.09-2.02 (m, 2H).

Example 67 Preparation of 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]propan-1-ol

The title compound was prepared in the same manner as in Example 8, except that 4,4,4-trifluorobutanol was used in place of 2,2,3,3-tetrafluoropropanol in Example 8-1, and ethyl-2-bromo- 2-methyl acetate was used instead of ethyliodoacetate in Example 8-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.28 (t, J=7.7 Hz, 1H), 6.96-6.92 (m, 2H), 6.85 (d, J= 7.9 Hz, 1H), 4.86 (dd, J=8.3, 4.0 Hz, 1H), 4.03 (t, J=5.8 Hz, 2H), 3.39-3, 32 (m, 1H), 3.28 (d, J=4.0 Hz, 1H), 2.53 (s, 3H), 2.36-2.28 (m, 2H), 2.09-2 .02 (m, 2H), 1.18 (d, J=7.2 Hz, 3H).

Example 68 Preparation of [1-[3-[2-methoxy-4-(trifluoromethoxy)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[3-(2-Methoxy-4-(trifluoromethoxy)phenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol, which is the final compound of Example 60, in as the starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.48-7.26 (m, 5H), 6.90 (d, J=8.4 Hz, 1H), 6.82 (s, 1H) , 6.12 (dd, J=4.8, 9.2 Hz, 1H), 4.71 (br s, 2H, NH2), 3.81 (s, 3H), 3.48 (dd, J= 9.2, 15.2 Hz, 1H), 3.29 (dd, J=4.8, 15.2 Hz, 1H), 2.50 (s, 3H).

Example 69 Preparation of [1-[3-[4-chloro-2-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[3-(4-Chloro-2-(trifluoromethyl)phenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 61, in as the starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.7 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.41-7.26 (m, 5H) , 6.08 (dd, J=4.8, 8.4 Hz, 1H), 4.86 (br s, 2H, NH2), 3.47 (dd, J=8.4, 15.2 Hz, 1H), 3.29 (dd, J=4.8, 15.2 Hz, 1H), 2.49 (s, 3H).

Example 70 Preparation of [1-[3-(4-chloro-2-methoxyphenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[3-(4-Chloro-2-methoxyphenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol, which is the final compound of Example 62, as starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.52-7.19 (m, 5H), 7.00 (d, J=8.0 Hz, 1H), 6.96 (s, 1H) , 6.09 (dd, J=4.4, 9.2 Hz, 1H), 4.86 (br s, 2H, NH2), 3.80 (s, 3H), 3.47 (dd, J= 9.2, 15.2 Hz, 1H), 3.29 (dd, J=4.4, 15.2 Hz, 1H), 2.48 (s, 3H).

Example 71 Preparation of [1-[3-(3,4-difluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[3-(3,4-Difluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol, which is the final compound of Example 58, was used as the starting compound in the same way as in example 3, obtaining the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.37-7.51 (m, 6H), 7.22-7.34 (m, 1H), 6.13 (dd, J=4.8 , 8 Hz, 1H), 4.66 (br s, 1H), 3.29-3.53 (m, 2H), 2.50 (s, 3H).

Example 72 Preparation of [1-[3-(4-fluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[3-(4-Fluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 57 as starting compound was used in the same manner , as in example 3, getting the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.35-7.58 (m, 6H), 7.12-7.16 (m, 2H), 6.13 (dd, J=5.2 , 9.6 Hz, 1H), 4.66 (br s, 1H), 3.29-3.53 (m, 2H), 2.50 (s, 3H).

Example 73 Preparation of [1-[3-(2-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[3-(2-Chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 63 was used as the starting compound in the same manner , as in example 3, getting the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.52-7.38 (m, 6H), 7.32-7.30 (m, 2H), 6.15-6.11 (m, 1H ), 4.64 (br s, 2H, NH2), 3.50 (dd, J=11, 19.5, 1H), 3.32 (dd, J=6, 19.5 Hz, 1H), 2 .50 (s, 3H).

Example 74 Preparation of [1-[3-(3-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[3-(3-Chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 64 as starting compound was used in the same manner , as in example 3, getting the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.54-7.47 (m, 4H), 7.45-7.36 (m, 4H), 6.15-6.11 (m, 1H ), 4.67 (br s, 2H, NH2), 3.50 (dd, J=11.5, 19 Hz, 1H), 3.32 (dd, J=6, 19 Hz, 1H), 2, 50 (s, 3H).

Example 75 Preparation of [1-[3-(4-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[3-(4-Chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol, which is the final compound of Example 65, was used as the starting compound in the same way , as in example 3, getting the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.55-7.52 (m, 3H), 7.47-7.40 (m, 2H), 7.40-7.26 (m, 3H ), 6.15-6.12 (m, 1H), 4.67 (br s, 2H, NH2), 3.50 (dd, J=11, 20 Hz, 1H), 3.32 (dd, J =6, 19 Hz, 1H), 2.51 (s, 3H).

Example 76 Preparation of 1-[3-[2,4-bis(trifluoromethyl)phenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

The title compound was prepared in the same manner as in Example 1, except that 3-bromobenzaldehyde was used as the starting compound and 2,4-bistrifluoromethylphenylboronic acid was used in place of 4-chlorophenylboronic acid in Example 1-2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.01 (s, 1H), 7.84 (d, J=9.5 Hz, 1H), 7.50-7.43 (m, 3H) , 7.38 (s, 1H), 7.29-7.28 (m, 1H), 5.33-5.30 (m, 1H), 3.29-3.22 (m, 3H), 2 .51 (s, 3H).

Example 77 Preparation of [1-[3-[2,4-bis(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

1-[3-[2,4-Bis(trifluoromethyl)phenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol, which is the final compound of Example 76, as the parent compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.01 (s, 1H), 7.84 (d, J=9.5 Hz, 1H), 7.50-7.44 (m, 3H) , 7.32 (s, 1H), 7.29-7.27 (m, 1H), 6.13-6.10 (m, 1H), 4.65 (br s, 2H, NH2), 3. 48 (dd, J=10.5, 19Hz, 1H), 3.31 (dd, J=6, 19Hz, 1H), 2.48 (s, 3H).

Example 78 Preparation of [1-[3-[4-(trifluoromethoxy)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate

2-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethoxy)phenyl]phenyl]ethanol, which is the final compound of Example 59, was used as the starting compound in the same way as in example 3, obtaining the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.51-7.59 (m, 4H), 7.46 (t, J=7.2 Hz, 1H), 7.38 (d, J= 7.2 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 6.13 (dd, J=4.4, 8.8 Hz, 1H), 4.66 (br s , 1H), 3.29-3.53 (m, 2H), 2.50 (s, 3H).

Example 79 Preparation of [2-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethyl]carbamate

2-Fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethanol which is the final compound of Example 66, as a starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.33-7.22 (m, 1H), 7.02-6.82 (m, 3H), 6.24-6.10 (m, 1H ), 5.90-5.74 (m, 1H), 4.72 (br s, 2H, NH2), 4.03-3.93 (m, 2H), 2.58-2.53 (m, 3H), 2.36-2.24 (m, 2H), 2.09-2.00 (m, 2H).

Example 80 Preparation of [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]propyl]carbamate

2-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]propan-1-ol which is the final compound of Example 67, as a starting compound was used in the same manner as in Example 3 to give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.29 (t, J=7.9 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 6.88-6 .84 (m, 2H), 5.74 (d, J=9.4 Hz, 1H), 4.59 (br s, 2H, NH2), 4.01 (t, J=5.9 Hz, 2H ), 3.63-3.55 (m, 1H), 2.53 (s, 3H), 2.38-2.28 (m, 2H), 2.09-2.04 (m, 2H), 1.19 (d, J=7.2 Hz, 3H).

Example 81 Preparation of 2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol

Example 81-1 Preparation of tert-butyl-dimethyl-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethoxy] silane

N-hydroxyacetamidine (74 mg, 1.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (186 mg, 1.2 mmol) and triethylamine (0.4 ml, 3.0 mmol) were added successively to 20 ml of methylene chloride containing 3-[tert-butyl(dimethyl)silyl]oxy-3-[3-[4-(trifluoromethyl)phenyl]phenyl]propionic acid (0.4 g, 1.0 mmol) obtained in the example 53-2 and the mixture was stirred at room temperature for 2 hours. 100 ml of ethyl acetate was added to the reaction mixture, and the reaction mixture was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and then the organic layer was dried over anhydrous magnesium sulfate. The yellow liquid obtained by removing the solvent by evaporation in vacuo was purified by flash chromatography to give the title compound as a pale yellow.

Example 81-2 Preparation of 2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol

Tetra-N-butylammonium fluoride (16.7 ml, 5.0 mmol) was slowly added to 10 ml of tetrahydrofuran containing tert-butyl-dimethyl-[2-(3-methyl-1,2,4-oxadiazol-5-yl )-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethoxy]silane (1.0 g, 2.48 mmol) obtained in Example 81-1 while maintaining the temperature at 0°C in an ice bath. The reaction mixture was stirred at the same temperature for 1 hour, 20 ml of ethyl acetate was added thereto, washed with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. A light brown oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.70-7.68 (m, 4H), 7.57-7.55 (m, 1H), 7.51-7.45 (m, 3H ), 5.37-5.33 (m, 1H), 3.44-3.34 (m, 3H), 2.43 (s, 3H).

Example 82 Preparation of [2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate

2-(3-Methyl-1,2,4-oxadiazol-5-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol which was the final compound of Example 81 was used as the starting compound in the same way as in example 3, obtaining the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.67 (dd, J=10.0, 17.5 Hz, 4H), 7.58-7.39 (m, 4H), 6.13 ( s, 1H), 4.95 (br s, 2H, NH2), 3.42-3.39 (m, 2H), 2.39 (s, 3H).

Example 83 Preparation of 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol

Example 83-1 Preparation of 2-bromo-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanone

4-Chlorophenylboronic acid (0.8 g, 5.1 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.2 g, 0.3 mmol) and 3.6 ml of 2M aqueous potassium carbonate solution were added successively to 20 ml 1,4-dioxane containing 2-bromo-1-(3-bromophenyl)ethanone (1.0 g, 3.6 mmol) dissolved therein, and the mixture was stirred at 90° C. for 1 hour. The temperature was lowered to room temperature, 50 ml of ethyl acetate was added to the reaction mixture, and then the mixture was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution once each, and the organic layer was dried over anhydrous magnesium sulfate. A dark brown oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a yellow solid.

Example 83-2 Preparation of 1-[3-[4-(trifluoromethyl)phenyl]phenyl]propan-1-one

Sodium cyanate (0.2 g, 5.8 mmol) was added to 10 ml of acetonitrile containing 2-bromo-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanone (1.0 g, 2.9 mmol ) obtained in Example 83-1 and heated and refluxed at 90° C. for about 10 hours. 20 ml of ethyl acetate was added to the reaction mixture, and the mixture was washed with an aqueous saturated ammonium chloride solution, an aqueous saturated sodium bicarbonate solution, and an aqueous saturated sodium chloride solution once each, and dried over anhydrous magnesium sulfate. A light brown oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a white solid.

Example 83-3 Preparation of 1-[3-[4-(trifluoromethyl)phenyl]phenyl]propan-1-ol

Sodium borohydride (0.2 g, 7.0 mmol) was slowly added to 20 ml of methanol with 1-[3-[4-(trifluoromethyl)phenyl]phenyl]propan-1-one (1.3 g, 4 .7 mmol) obtained in Example 83-2 while maintaining the temperature at 0° C. in an ice bath. The reaction mixture was stirred at the same temperature for 1 hour, 20 ml of ethyl acetate was added thereto, washed with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. A light brown oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a white solid.

Example 83-4 Preparation of tert-butyl-dimethyl-[1-[2-methyl-5-[4-(trifluoromethyl)phenyl]phenyl]propoxy]silane

Imidazole (0.5 g, 7.7 mmol) and tert-butyldimethylsilyl chloride (1.1 g, 7.7 mmol) were successively added to 20 ml of methylene chloride with 1-[3-[4-(trifluoromethyl)phenyl dissolved in it ]phenyl]propan-1-ol (1.3 g, 4.6 mmol) obtained in Example 83-3, and the mixture was stirred at room temperature for one day. 100 ml of ethyl acetate was added to the reaction mixture, and the reaction mixture was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and then the organic layer was dried over anhydrous magnesium sulfate. A yellow oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a light yellow liquid.

Example 83-5 Preparation of 3-[tert-butyl(dimethyl)silyl]oxy-N′-hydroxy-3-[3-[4-(trifluoromethyl)phenyl]phenyl]propanamidine

Hydroxylamine (66 mg, 2.0 mmol) and potassium carbonate (0.4 g, 3.0 mmol) were added to 20 ml of methanol containing t-butyl-dimethyl-[1-[2-methyl-5-[4- (trifluoromethyl)phenyl]phenyl]propoxy]silane (0.4 g, 1.0 mmol) obtained in Example 83-4 and heated and refluxed at 70°C for about 10 hours. 100 ml of ethyl acetate was added to the reaction mixture, and the reaction mixture was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and then the organic layer was dried over anhydrous magnesium sulfate. The yellow liquid obtained by removing the solvent by evaporation in vacuo was purified by flash chromatography to give the title compound as a pale yellow.

Example 83-6 Preparation of N-[(Z)-[2-[t-butyl(dimethyl)silyl]oxy-2-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]-N-hydroxycarbonimidoyl]acetamide

Acetyl chloride (0.1 g, 1.9 mmol) and triethylamine (0.7 ml, 4.8 mmol) were slowly added to 10 ml of toluene containing 3-[tert-butyl(dimethyl)silyl]oxy-N′-hydroxy -3-[3-[4-(trifluoromethyl)phenyl]phenyl]propanamidine (700 mg, 1.6 mmol) prepared in Example 83-5 while maintaining the temperature at 0° C. in an ice bath. The reaction mixture was stirred at the same temperature for 1 hour, 20 ml of ethyl acetate was added thereto, washed with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. A light brown oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a white solid.

Example 83-7 Preparation of tert-butyldimethyl-[2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethoxy]silane

20 ml of toluene containing N-[(Z)-[2-[tert-butyl(dimethyl)silyl]oxy-2-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]-N-hydroxycarbonimidoyl]acetamide ( 1.3 g, 2.7 mmol) obtained in Example 83-6 was heated and refluxed at 110° C. for about 1 hour. 100 ml of ethyl acetate was added to the reaction mixture, and the reaction mixture was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and then the organic layer was dried over anhydrous magnesium sulfate. A yellow oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a light yellow liquid.

Example 83-8 Preparation of 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol

Tetra-N-butylammonium chloride (16.7 ml, 5.0 mmol) was slowly added to 10 ml of tetrahydrofuran containing tert-butyl-dimethyl-[2-(5-methyl-1,2,4-oxadiazol-3-yl )-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethoxy]silane (1.0 g, 2.48 mmol) prepared in Example 83-7 while maintaining the temperature at 0° C. in an ice bath. The reaction mixture was stirred at the same temperature for 1 hour, 20 ml of ethyl acetate was added thereto, washed with a saturated ammonium chloride aqueous solution, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. A light brown oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to give the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.70-7.68 (m, 4H), 7.57-7.55 (m, 1H), 7.51-7.45 (m, 3H ), 5.37-5.33 (m, 1H), 3.34-3.24 (m, 3H), 2.63 (s, 3H).

Example 84 Preparation of [2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate

2-(5-Methyl-1,2,4-oxadiazol-3-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol, which is the final compound of Example 83, was used as the starting compound in the same way as in example 3, obtaining the connection declared in the header.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.67 (dd, J=10.0, 17.5 Hz, 4H), 7.58-7.39 (m, 4H), 6.13 ( s, 1H), 4.95 (br s, 2H, NH2), 3.32-3.29 (m, 2H), 2.59 (s, 3H).

Example 85 Preparation of (1R)-1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

1-[2-Fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 15, as the starting compound was used to separate the optical isomeric compound using a preparative HPLC device on a ChiralPak OD column (2×20 cm), normal hexane:ethyl acetate=70:30 at a flow rate of 25 ml/min.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.11-7.09 (m, 1H), 6.99 (d, J=9.6 Hz, 1H), 6.79-6.76 ( m, 1H), 5.51-5.48 (m, 1H), 4.01-3.98 (m, 2H), 3.52 (d, J=4.0 Hz, 1H), 3.28 -3.12(m, 2H), 2.52(s, 3H), 2.34-2.27(m, 2H), 2.07-2.02(m, 2H).

Example 86 Preparation of (1S)-1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol

1-[2-Fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol which is the final compound of Example 15, as the starting compound was used to separate the optical isomeric compound using a preparative HPLC device on a ChiralPak OD column (2×20 cm), normal hexane:ethyl acetate at a flow rate of 25 ml/min.

¹ H-NMR (CDCl ₃ , 400 MHz) δ=7.11-7.09 (m, 1H), 6.99 (d, J=9.6 Hz, 1H), 6.79-6.76 ( m, 1H), 5.51-5.48 (m, 1H), 4.01-3.98 (m, 2H), 3.52 (d, J=4.0 Hz, 1H), 3.28 -3.12(m, 2H), 2.52(s, 3H), 2.34-2.27(m, 2H), 2.07-2.02(m, 2H).

Experimental example

The usefulness of the compounds of the present invention as an anticonvulsant agent was investigated by the 6 Hz method, which is well established as pharmacological screening methods for anticonvulsants in focal seizures. The 6 Hz method for screening anticonvulsants was as follows:

1) Obtaining experimental animals

Male ICR mice are purchased from Orient Bio, Inc., Korea, and housed and maintained in accordance with the Institutional Animal Care and Use Committee (IACUC) laboratory animal standards by placing them in a wire mesh cage in an environment where ambient temperature was between 19 and 25°C, relative humidity between 40 and 60% and a 12-hour light/dark period were controlled automatically, and there was free access to water. After stabilization for a week, mice weighing from 18 to 23 g were used in the experiment.

2) Evaluation of the anticonvulsant effect of the compound

5% tetracaine (Sigma) was added to both eyes to provide a local anesthetic effect 5-10 minutes prior to the electrical stimulation period in ICR mice. Compounds to be tested were dissolved in distilled water, in which 30% polyethylene glycol 300+5% dimethylsulfoxide+5% cremophor was dissolved and administered intraperitoneally (ip) to the animal in a dosage volume of 10 ml/kg. Electrical stimulation of 44 mA, 6 Hz, 3 s was then applied to the eye to induce seizures.

After electrical stimulation, the presence of drug-induced convulsions was confirmed, and the ratio of animals that did not have convulsions was expressed as the degree of protection (number of animals without convulsions/number of animals used in experiments=degree of protection). It was assumed that the degree of protection is "0" when all objects showed convulsions, and the degree of protection is "1" when all objects did not show convulsions, the degree of protection from 0 to 0.2 is evaluated as "-", from 0, 2 to 0.6 is rated "+", 0.6 to 0.8 is rated "++", and 0.8 to 0.8 is rated "+++". The results are shown in Table 2. It was determined that a compound having a high degree of protection exhibits a stronger anticonvulsant effect.

[Table 2]

Compound 6 Hz, 44 mm degree of protection levitiracetam - topiramate - lamotrigine - Example 1 ++ Example 2 ++ Example 3 ++ Example 4 ++ Example 5 + Example 6 +++ Example 7 ++ Example 10 + Example 11 + Example 13 +++ Example 14 +++ Example 15 +++ Example 16 ++ Example 17 + Example 18 + Example 19 + Example 20 + Example 22 + Example 23 + Example 24 ++ Example 28 ++ Example 32 + Example 33 + Example 34 ++ Example 37 + Example 39 + Example 41 +++ Example 42 ++ Example 43 + Example 48 ++ Example 49 +++ Example 50 ++ Example 51 + Example 52 + Example 53 + Example 55 + Example 56 ++ Example 59 ++ Example 65 ++ Example 72 + Example 75 + Example 78 ++ Example 85 +++ Example 86 +++

Claims (124)

1. The compound represented by the following chemical formula 1, or its optical isomer, stereoisomer or pharmaceutically acceptable salt: [Chemical formula 1]

Where R1 is selected from the group consisting of the following formulas:

R2 is hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C 1 -C ₅ alkyl, C _{1 -C 5} alkoxy, or C ₁ -C ₅ alkylthio ; R3 is hydrogen, C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, halo-C ₁ -C ₅ alkyl, carbamoyl, C ₁ -C ₅ alkylcarbamoyl, di(C ₁ -C ₅ alkyl)carbamoyl or carbonyl; R4 is hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl; R5 is hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl; each R6, R7, R8 and R9 is independently hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, halo-C ₁ -C ₅ alkoxy, amino, di(C ₁ -C ₅ alkyl)amino, C ₁ -C ₅ alkylcarbonylamino, halo-C ₁ -C ₅ alkylcarbonylamino or 5-8 -membered heterocycloalkyl containing one or two nitrogen atoms (N); each X, Y and Z is independently selected from the group consisting of nitrogen (N) and oxygen (O), where one of X, Y or Z is oxygen (O), the other two are nitrogen (N); m is an integer 1-3; each n, o and p is independently an integer 0-4; And q is an integer 0-2. 2. The compound or its optical isomer, stereoisomer or pharmaceutically acceptable salt according to claim 1, where R1 is selected from the group consisting of the following formulas:

3. The compound or its optical isomer, stereoisomer or pharmaceutically acceptable salt according to claim 1, where R1 is represented by the following formula:

4. The compound or its optical isomer, stereoisomer or pharmaceutically acceptable salt according to claim 1, where each R6, R7, R8 and R9 independently represents hydrogen, halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, halo-C ₁ -C ₅ alkoxy, di(C ₁ -C ₅ alkyl)amino or 5-8 membered heterocycloalkyl containing 1 or 2 nitrogen atoms (N). 5. The compound or optical isomer, stereoisomer or pharmaceutically acceptable salt thereof according to claim 2, wherein each R6, R7 and R8 is independently halogen, C ₁ -C ₅ alkyl, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy or halo-C ₁ -C ₅ alkoxy. 6. The compound or optical isomer, stereoisomer or pharmaceutically acceptable salt thereof according to claim 3, wherein R6 is halo, halo-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, or halo-C ₁ -C ₅ alkoxy. 7. The compound or its optical isomer, stereoisomer or pharmaceutically acceptable salt according to claim 1, where R2 is hydrogen, halogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy; R3 is hydrogen, C ₁ -C ₅ alkyl or carbamoyl; R4 is hydrogen, halogen or C ₁ -C ₅ alkyl; And R5 is hydrogen or C ₁ -C ₅ alkyl. 8. The compound or optical isomer, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein X is oxygen (O) and each of Y and Z is nitrogen (N). 9. The compound or its optical isomer, stereoisomer or pharmaceutically acceptable salt according to claim 6, where m is an integer 1 or 2; each n, o, and p is independently an integer 1-4, and q is an integer 0 or 1. 10. The compound or its optical isomer, stereoisomer or pharmaceutically acceptable salt according to claim 1, where the compound is selected from the group consisting of: 1-[5-(4-chlorophenyl)-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 1-[2-fluoro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; [1-[2-fluoro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; [1-[5-(4-chlorophenyl)-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; 1-[2-fluoro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol; 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol; [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate; (1R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol; (1S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol; 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[2-methyl-5-[4-(trifluoromethyl)phenyl]phenyl]ethanol; 1-[2-methoxy-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[2-methyl-5-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate; [1-[2-methoxy-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; 1-[2-methyl-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol; 1-[2-methoxy-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol; 1-[2-chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 1-[2-chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol; [1-[2-chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; [1-[2-chloro-5-[4-(trifluoromethyl)phenyl]phenyl]-2-(1,3,4-oxadiazol-2-yl)ethyl]carbamate; 2-(1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol; 2-(5-ethyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol; 2-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol; [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]acetate; 2-[2-methoxy-2-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]-5-methyl-1,3,4-oxadiazole; 1-[3-(4-fluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 1-[3-(3,4-difluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethoxy)phenyl]phenyl]ethanol; 1-[3-(2-methoxy-4-(trifluoromethoxy)phenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 1-[3-(4-chloro-2-(trifluoromethyl)phenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 1-[3-(4-chloro-2-methoxyphenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 1-[3-(2-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 1-[3-(3-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 1-[3-(4-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; [1-[3-[2-methoxy-4-(trifluoromethoxy)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; [1-[3-[4-chloro-2-(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; [1-[3-(4-chloro-2-methoxyphenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; [1-[3-(3,4-difluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; [1-[3-(4-fluorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; [1-[3-(2-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; [1-[3-(3-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; [1-[3-(4-chlorophenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; 1-[3-[2,4-bis(trifluoromethyl)phenyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; [1-[3-[2,4-bis(trifluoromethyl)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; [1-[3-[4-(trifluoromethoxy)phenyl]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; 2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol; [2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate; 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethanol; And [2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate. 11. The compound or its optical isomer, stereoisomer or pharmaceutically acceptable salt according to claim 1, where the compound is selected from the group consisting of: 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(2,2,3,3-tetrafluoropropoxy)phenyl]ethanol; [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(2,2,3,3-tetrafluoropropoxy)phenyl]ethyl]carbamate; 1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; [1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; 1-[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; [1-[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethylcarbamate; 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethanol; [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethyl]carbamate; 1-(5-butoxy-2-fluorophenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; [1-(5-butoxy-2-fluorophenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; 1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol; [1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethyl]carbamate; 1-[2-fluoro-5-[3-(1-piperidyl)propoxy]phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 1-[5-[3-(dimethylamino)propoxy]-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 1-[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; [1-[5-[3-(dimethylamino)propoxy]-2-fluorophenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; [1-[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; 2-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethanol; 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]propan-1-ol; [2-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]ethyl]carbamate; [2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-(4,4,4-trifluorobutoxy)phenyl]propyl]carbamate; (1R)-1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; And (1S)-1-[2-fluoro-5-(4,4,4-trifluorobutoxy)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol. 12. The compound or its optical isomer, stereoisomer or pharmaceutically acceptable salt according to claim 1, where the compound is selected from the group consisting of: 1-[2-fluoro-5-(3,3,3-trifluoropropyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; [1-[2-fluoro-5-(3,3,3-trifluoropropyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; 1-[2-fluoro-5-(3,3,3-trifluoropropyl)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol; 1-(2-fluoro-5-propylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 1-(2-fluoro-5-pentylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; [1-(2-fluoro-5-propylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; [1-(2-fluoro-5-pentylphenyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; 1-[2-fluoro-5-(4,4,4-trifluorobutyl)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol; 1-[2-fluoro-5-(5,5,5-trifluoropentyl)phenyl]-2-(1,3,4-oxadiazol-2-yl)ethanol; 1-[2-fluoro-5-(4,4,4-trifluorobutyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; 1-[2-fluoro-5-(5,5,5-trifluoropentyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol; [1-[2-fluoro-5-(4,4,4-trifluorobutyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate; And [1-[2-fluoro-5-(5,5,5-trifluoropentyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate. 13. The compound or its optical isomer, stereoisomer or pharmaceutically acceptable salt according to claim 1, where the compound is selected from the group consisting of: 4-fluoro-3-[1-hydroxy-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-N-(3,3,3-trifluoropropyl)benzamide; And [1-[2-fluoro-5-(3,3,3-trifluoropropylcarbamoyl)phenyl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]carbamate. 14. Pharmaceutical composition for the prevention or treatment of epilepsy, containing a therapeutically effective amount of a compound or its optical isomer, stereoisomer or pharmaceutically acceptable salt, as defined in any of paragraphs. 1-13 as an active ingredient, together with a pharmaceutically acceptable carrier. 15. A method for preventing or treating epilepsy, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or its optical isomer, stereoisomer, or pharmaceutically acceptable salt, as defined in any one of paragraphs. 1-13.