KR101250990B1

KR101250990B1 - Novel 1,2,4-oxadiazole derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for preventing or treating diseases associated with MCH containing the same as an active ingredient

Info

Publication number: KR101250990B1
Application number: KR1020100080755A
Authority: KR
Inventors: 이규양; 김낙정; 서지희; 임채조; 이병호; 오광석; 안미자
Original assignee: 한국화학연구원
Priority date: 2010-08-20
Filing date: 2010-08-20
Publication date: 2013-04-04
Also published as: KR20120017856A

Abstract

The present invention provides a novel 1,2,4-oxadiazole derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof, a preparation method thereof and the prevention of MCH (melanin concentration hormone) -related diseases containing the same as an active ingredient or The present invention relates to a therapeutic pharmaceutical composition, wherein the derivative according to the present invention acts as an antagonist to the MCH receptor to prevent MCH related diseases such as obesity, diabetes, metabolic disorders, anxiety and depression caused by MCH binding to the MCH receptor or It can be useful for treatment.
[Formula 1]

(In Chemical Formula 1, the R ¹ , R ² And R ³ is as defined herein.)

Description

Novel 1,2,4-oxadiazole derivatives or pharmaceutically acceptable salts thereof, preparation method thereof, and pharmaceutical composition for preventing or treating MHC-related diseases containing the same as an active ingredient {Novel 1,2,4-oxadiazole derivatives or pharmaceutically acceptable salts specifically, preparation method according to the formula and preventing or treating diseases associated with MCH containing the same as an active ingredient}

The present invention relates to a pharmaceutical composition for preventing or treating a novel MCH-related disease.

Over the last 10 years, obesity has surged due to lifestyle and nutritional changes, and this phenomenon is increasing in children and adolescents. Obesity and overweight are serious social problems because they cause type 2 diabetes, heart disease, cancer and high blood pressure. Therefore, studies for the treatment of obesity are actively progressed, among which MCH (melanin enrichment hormone) receptor-1 antagonist is being studied as a new obesity treatment.

MCH (Melanin Enriched Hormone) is the first cyclic peptide hormone / neural peptide isolated from fish (the pituitary gland of salmon) in 1983 ( Nature , 1983, 305 , 321-323). The fish are known to be involved in changes of body color causes aggregation of melanin granules in the black cell (International Review of Cytology , 1991, 126, 1; Trend in Endocrinology and Metabolism , 1994, 5 , 120-126). Human MCH is a cyclic 19-amino acid peptide identical to that of rats ( Mol . Endocrinol ., 1990, 4 , 632-637). MCH has been shown to regulate feeding behavior and energy balance in mammals ( Trends Endocrinol . Metab ., 2000, 11 , 299-303), also known to be involved in memory, anxiety, and depression ( Peptides , 1999, 20 , 1517; Physiol . Behav ., 1999, 67 , 813; Nat . Med . 2002, 8 , 825).

In mammals, the cell bodies of neurons containing MCH are present in the lateral hypothalamus and zona inserta, but nerve fibers are projected over a wide range within the brain ( J. Comp . Neurol., 1992) . , 319 , 218-245).

Of MCH receptor is a MCH receptor-1 and MCH receptor-2, these receptors are known to exhibit a sequence homology of 38% (Nature, 1999, 400 , 261;.. J. Biol chem, 2001, 276 , 201-225). Only MCH receptor-1 is expressed in rodents, while both MCH receptor-1 and MCH receptor-2 are expressed in humans, monkeys, dogs and higher mammals ( Genomics , 2002, 79 , 785-792). The role of MCH receptor-2 is not well known, but much research has been done on MCH receptor-1.

MCH in rodents were also found to act through the MCH receptor -1 (Nature, 1999, 400, 265-269) mice that overexpress MCH gene indicates overeating, obesity and insulin resistance (J. Clin. Invest., 2001 , 7 , 379-386) The cerebral ventricular injection of MCH into rats has been shown to stimulate feeding and chronic administration to Zyte ( Int . J. Obes . Relat . Metab . Disord . 2002, 26, 1289-1295; Am . J. Physiol . Endocrinol . Metab . , 2003, 284, E583-E588). On the other hand, MCH knock-out mice showed decreased appetite and decreased metabolism in rats, and MCH-R1 knock-out mice H showed rat reduction ( Nature , 1998, 396 , 670-). 674).

On the other hand, research is one of the MCH receptor-1 antagonists of the GPCR (G-protein coupled receptor) that mediates the effect of MCH would be useful not only to control food intake treat depression or anxiety (Nature Medicine , 2002, 8 (8) , 825-830) and studies showing that animals treated with MCH receptor-1 antagonists show significant weight loss and provide anxiety and antidepressant effects in addition to anorexia effects ( Nature Medicine , 2002, 8 (8), 825-30).

In addition, MCH receptor-1 antagonists have been shown to be effective in treating diabetes and metabolic disorders in addition to treating obesity, depression and anxiety ( J. Clin . Invest ., 2001, 107, 379-386).

Regarding MCH receptor-1 antagonists, drugs developed by Amsen and GlaxoSmithKline (GW3430) are currently known to be in clinical trials ( Med . Chem . Lett ., 2006, 16, 4237-). 4242).

In addition, with respect to obesity, Xenical ™ and Reductil ™, such as obesity treatments are commercially available, but the disadvantages of poor efficacy and side effects ( Science , 2003, 299, 849-852).

Therefore, the present inventors are studying to develop a compound that exhibits an excellent antagonistic effect on the MCH receptor. As a result, the novel 1,2,4-oxadiazole derivative compounds act as an antagonist to the MCH receptor and thus, The present invention has been found to be useful for preventing or treating MCH related diseases such as induced obesity, diabetes, metabolic disorders, anxiety and depression.

It is an object of the present invention to provide novel 1,2,4-oxadiazole derivatives or pharmaceutically acceptable salts thereof.

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

Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of MCH (melanin concentration hormone) -related diseases containing the novel derivative compound as an active ingredient.

In order to achieve the above object, the present invention provides a 1,2,4-oxadiazole derivative compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Chemical Formula 1, the R ¹ , R ² And R ³ is as defined herein).

The present invention also provides a method for preparing the 1,2,4-oxadiazole derivative compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating MCH (melanin enrichment hormone) -related diseases containing the 1,2,4-oxadiazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

1,2,4-oxadiazole derivatives of formula 1 according to the present invention act as an antagonist to the melanin enrichment hormone (MCH) receptor, obesity, diabetes, metabolic disorders, anxiety and depression caused by MCH binding to the MCH receptor It can be usefully used to prevent or treat MCH-related diseases such as.

The present invention provides 1,2,4-oxadiazole derivatives represented by the following formula (1) and pharmaceutically acceptable salts thereof.

In Formula 1,

R ¹ is AB;

At this time, A is - (CH) _m - or _{- (CH) m -O- (CH} ) n - and (m or n is an integer of 0 to 5, respectively);

B is C ₅ -C ₁₂ aryl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, CF ₃ , cyano, nitro, acetylamino, C ₁ -C ₄ alkoxy, phenoxy and phenyl ,

R ² is any one selected from the group consisting of amino, pyrrolidinyl, piperidinyl and morpholinyl, unsubstituted or substituted with C ₁ -C ₄ straight or branched alkyl,

R ³ is amino unsubstituted or substituted with any substituent selected from the group consisting of C ₁ -C ₄ straight or branched chain alkyl and acetyl; Nitro or C ₁ -C ₆ alkoxy.

Preferably, in the derivative compound of formula 1 according to the present invention,

R ¹ is AB;

At this time, A is - (CH) _m - or _{- (CH) m -O- (CH} ) n - and (m or n is an integer of 0 to 3);

B is C ₅ -C ₈ unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, chlorine, bromine, CF ₃ , cyano, nitro, acetylamino, methoxy, ethoxy, phenoxy and phenyl Is aryl,

R ³ is amino unsubstituted or substituted with any substituent selected from the group consisting of C ₁ -C ₃ straight or branched chain alkyl and acetyl; Nitro or C ₁ -C ₃ alkoxy.

More preferably, in the derivative compound of formula 1 according to the present invention,

R ¹ is 4-chloro-phenyl, 4-bromo-phenyl, 4-trifluoromethyl-phenyl, 4-phenoxy-phenyl, biphenyl-4-yl, 4-fluoro-biphenyl-4- 1, 4-fluoro-benzyl, 4-trifluoromethyl-benzyl, 4-chloro-phenoxymethyl, 3-acetylamino-phenoxymethyl, 4-fluoro-benzyloxymethyl, 3-chloro-benzyloxy Methyl, 4-chloro-benzyloxymethyl, 3,4-difluoro-benzyloxymethyl, 3,4-dichloro-benzyloxymethyl, 3-cyano-benzyloxymethyl, 4-cyano-benzyloxymethyl, 3-nitro-benzyloxymethyl, 4-nitro-benzyloxymethyl, 4-methyl-benzyloxymethyl, 4-methoxy-benzyloxymethyl, 3-acetylamino-benzyloxymethyl, 4-acetylaminobenzyloxymethyl, 2-4-fluoro-phenyl-ethyl or 2-4-chloro-phenoxy-ethyl,

R ² is dimethylamino, pyrrolidin-1-yl, piperidin-1-yl or morpholin-4-yl,

R ³ is amino, methylamino, acetylamino, nitro or methoxy.

Most preferably, the 1,2,4-oxadiazole derivatives represented by Formula 1 according to the present invention,

(1) 5- (4-chlorophenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole;

(2) 5- (4-bromophenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole;

(3) 5- [4- (trifluoromethyl) phenyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4- Oxadiazole;

(4) 5- (4-phenoxyphenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole;

(5) 5- (biphenyl-4-yl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole ;

(6) 5- (4'-fluorobiphenyl-4-yl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole;

(7) 5- (biphenyl-4-ylmethyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadia Sol;

(8) 5- [4- (trifluoromethyl) benzyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4- Oxadiazole;

(9) 5- (4-fluorobenzyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole;

(10) 5- [2- (4-fluorophenyl) ethyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole;

(11) 5-[(4-chlorophenoxy) methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxa Diazoles;

(12) 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole;

(13) 5-[[(3-chlorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole;

(14) 5- [2- (4-chlorophenoxy) ethyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole;

(15) 5-[[(4-fluorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole;

(16) 5-[[(3,4-dichlorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2 , 4-oxadiazole;

(17) 5-[[(3,4-difluorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1 , 2,4-oxadiazole;

(18) 5-[[(4-cyanobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole;

(19) 5-[[(3-cyanobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole;

(20) 5-[[(4-methylbenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole;

(21) 5-[[(4-methoxybenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole;

(22) 5-[[(3-acetylamino) phenoxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole;

(23) 5-[[(4-nitrobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole;

(24) 5-[[(4-acetylaminobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole;

(25) 5-[[(3-nitrobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole;

(26) 5-[[(3-acetylaminobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole;

(27) 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-nitro-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4- Oxadiazole;

(28) 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-amino-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4- Oxadiazole;

(29) 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-acetylamino-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole;

(30) 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-methylamino-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole;

(31) 5- (4-chlorophenyl) -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole;

(32) 5-[(4-trifluoromethyl) phenyl] -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -1,2,4- Oxadiazole;

(33) 5- (biphenyl-4-yl) -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole ;

(34) 5- (4-phenoxyphenyl) -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole;

(35) 5-[(4-chlorophenoxy) methyl] -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -1,2,4-oxa Diazoles;

(36) 5- (4-chlorophenyl) -3- [3-methoxy-4- (2-morpholin-4-yl-ethoxy) phenyl] -1,2,4-oxadiazole;

(37) 5-[(4-trifluoromethyl) phenyl] -3- [3-methoxy-4- (2-morpholin-4-yl-ethoxy) phenyl] -1,2,4-oxa Diazoles;

(38) 5- (4-phenoxyphenyl) -3- [3-methoxy-4- (2-morpholin-4-yl-ethoxy) phenyl] -1,2,4-oxadiazole;

(39) 5- (biphenyl-4-yl) -3- [3-methoxy-4-[(2-dimethylamino) ethoxy] phenyl] -1,2,4-oxadiazole; And

(40) group consisting of 5-[(4-chlorophenoxy) methyl] -3- [3-methoxy-4-[(2-dimethylamino) ethoxy] phenyl] -1,2,4-oxadiazole It is any one selected from.

Table 1 shows the preferred structure of the 1,2,4-oxadiazole derivatives represented by Formula 1 according to the present invention.

compound rescue

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 15

Example 16

Example 17

Example 18

Example 19

Example 20

Example 21

Example 22

Example 23

Example 24

Example 25

Example 26

Example 27

Example 28

Example 29

Example 30

Example 31

Example 32

Example 33

Example 34

Example 35

Example 36

Example 37

Example 38

Example 39

Example 40

The derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. From non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving a derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, , Or may be prepared by drying, or after the solvent and excess acid are distilled off under reduced pressure, followed by drying or crystallization in an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

In addition, the present invention includes not only 1,2,4-oxadiazole derivatives represented by Formula 1 and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, stereoisomers, and the like that can be prepared therefrom. do.

Furthermore, the present invention provides a method for preparing the 1,2,4-oxadiazole derivative represented by Chemical Formula 1.

Method 1:

As shown in Scheme 1, the derivative of formula 1 according to the present invention,

The hydroxyl group of the compound represented by the formula (2)

Preparing a compound represented by Chemical Formula 3 by introducing a substituent represented by Chemical Formula 3 (step 1);

Preparing a amide oxime compound of formula 4 by reacting the compound represented by formula 3 obtained in step 1 with hydroxylamine hydrochloride (step 2); And

It can be prepared by the preparation method comprising the step (step 3) of introducing a 1,2,4-oxadiazole ring to the compound represented by Formula 4 obtained in step 2:

[Reaction Scheme 1]

(In Scheme 1, R ¹ , R ² and R ³ are as defined in Formula 1, Formula 1a and 1b is a derivative of Formula 1).

Hereinafter, the preparation method 1 according to the present invention will be described in more detail step by step.

First, step 1 according to the present invention is a hydroxyl group of the compound represented by the formula (2)

It is a step of preparing a compound represented by the formula (3) by introducing a substituent represented by.

The reaction may be performed by adding a chloroethyl hydrochloride compound and a base substituted with R ² to the compound represented by Formula 2 and refluxing for 1 to 5 hours in a dimethoxyethane (DME) -water mixed solvent. As the compound of Formula 2, 4-hydroxy-3-methoxybenzonitrile or 4-hydroxy-3-nitrobenzonitrile may be used, and as a base, potassium carbonate, sodium carbonate, cesium carbonate, etc. may be used. It is preferable to use potassium carbonate among them. The ratio of dimethoxyethane and water in the dimethoxyethane (DME) -water mixed solvent is preferably 1: 1 to 10: 1, and more preferably 1: 1 to 7: 1.

After the reaction, extraction, drying, filtration and distillation under reduced pressure with an organic solvent may be further performed, and then column chromatography may be performed to obtain a compound represented by Chemical Formula 3.

Next, step 2 is a step of preparing the amide oxime compound of formula 4 by reacting the compound represented by formula 3 obtained in step 1 with hydroxylamine hydrochloride.

The reaction may be carried out by adding a compound hydroxylamine hydrochloride and a base represented by Formula 3 obtained in step 1 and reflux for 3 to 5 hours in an alcohol solvent. As the base, triethylamine, diisopropylentylamine, etc. may be used. Among these, it is preferable to use triethylamine. In addition, ethanol, Methanol, propanol, etc. can be used, It is preferable to use ethanol.

After the reaction, extraction, drying, filtration and distillation under reduced pressure with an organic solvent may be performed and additionally, column chromatography may be performed to obtain a compound represented by Chemical Formula 4.

Next, step 3 is a step of introducing 1,2,4-oxadiazole ring to the compound represented by Formula 4 obtained in step 2.

The reaction is carried out by the carboxylic acid, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (R) substituted with R ¹ in a solvent of dimethylformamide (DMF) EDC) and 4- (dimethylamino) pyridine (DMAP) may be reacted at room temperature for 10 to 20 hours to synthesize an amide compound, and then heated at 80 to 100 ° C. for 3 to 5 hours. After the reaction, the extraction, drying, filtration and distillation under reduced pressure with an organic solvent may be performed and additionally, column chromatography may be performed.

In addition, the reaction is a carboxylic acid, N- (3-dimethylaminopropyl) -N'-ethyl carbodiimide (EDC), in which the compound represented by Formula 4 obtained in step 2 is substituted with R ¹ in a DMF solvent, After reacting with 1-hydroxybenzotriazole (HOBt) and diisopropylethylamine (DIPEA) for 10 to 20 hours at room temperature to synthesize an amide compound, the process of extraction, drying, filtration and distillation under reduced pressure with an organic solvent This may be followed by refluxing with p-toluenesulfonic acid in a DMF solvent for 5 hours. After the reaction, the extraction, drying, filtration and distillation under reduced pressure with an organic solvent may be performed and additionally, column chromatography may be performed.

Further, the reaction was carried out by refluxing with carboxylic acid substituted with R ¹ and thionyl chloride in dichloroethane solvent for 2 to 5 hours, followed by distillation under reduced pressure, triethylamine in DMF solvent and step 2 After reacting with the compound represented by Formula 4 for 10 to 20 hours at room temperature to synthesize an amide compound, it can be carried out by heating at 80 to 100 ℃ for 3 to 5 hours. After the reaction, the extraction, drying, filtration and distillation under reduced pressure with an organic solvent may be performed and additionally, column chromatography may be performed.

Recipe 2:

The present invention also provides another method of preparing a derivative of formula (I).

Specifically, R ¹ of the compound represented by Formula 1a obtained after performing Step 3 of Preparation Method ¹ is

(Formula 1a '), the derivative of Formula 1 according to the present invention, as shown in Scheme 2 below,

R ¹ of the compound represented by Chemical Formula 1a obtained after Step 3 of Preparation Method ¹ is

Reducing the nitro group of the compound represented by Formula 1a '(step A); And

It may be prepared by the preparation method further comprises the step (step B) of introducing acetyl to the amine group of the compound represented by Formula 1c obtained in step A:

[Reaction Scheme 2]

(In Formula 2, Formulas 1a ', 1c, and 1d are derivatives of Formula 1).

Hereinafter, the preparation method 2 according to the present invention will be described in more detail.

First, Formula A is a compound of Formula 1a obtained after performing Step 3 of Formula 1, wherein R ¹ is

To reduce the nitro group of the compound represented by the formula (1a ') is a step of preparing a compound represented by the formula (1c).

The reduction reaction may be carried out by reacting the compound represented by Formula 1a 'obtained in step 3 of Preparation Method 1 with Pd / C in a methanol solvent for 2 to 5 hours at room temperature under hydrogen. After the reaction, the process of filtration, depressurization and concentration with celite may be performed, and column chromatography may be additionally performed.

In addition, the reduction reaction is refluxed for 1 to 2 hours iron and ammonium chloride in a mixed solvent of methanol and water, and then refluxed with a compound represented by the formula 1a 'obtained in step 3 of Preparation 1 for 2 to 5 hours Can be performed. After the reaction, the process of filtration, depressurization and concentration with celite may be performed, and column chromatography may be additionally performed.

Next, step B is a step of introducing acetyl to the amine group of the compound represented by Formula 1c obtained in step A.

The reaction may be carried out by reacting the compound represented by Formula 1c obtained in step A with triethylamine, 4- (dimethylamino) pyridine (DMAP) and acetic anhydride at room temperature for 5 to 10 hours in a dichloromethane solvent. have.

After the reaction, the extraction, drying, filtration and distillation under reduced pressure with an organic solvent may be performed and additionally, column chromatography may be performed.

Recipe 3:

Derivative of formula 1 according to the present invention is shown in Scheme 3 below,

It can be prepared by the preparation method further comprises the step of reducing the nitro group of the compound represented by Formula 1b obtained after performing step 3 of Preparation Method 1:

Scheme 3

(In Scheme 3, R ¹ and R ² are as defined in Formula 1, and Formula 1b and 1e are derivatives of Formula 1).

Hereinafter, the preparation method 3 according to the present invention will be described in more detail.

Preparation 3 is a step of preparing a compound represented by Chemical Formula 1e by reducing the nitro group of the compound represented by Chemical Formula 1b obtained after performing Step 3 of Preparation Method 1.

The reduction reaction may be carried out by refluxing iron and ammonium chloride in a mixed solvent of methanol and water for 1 to 2 hours, and then refluxing for 2 to 5 hours with the compound represented by the formula (1b) obtained in step 3 of Preparation 1 have.

After the reaction, the process of filtration, depressurization and concentration with celite may be performed, and column chromatography may be additionally performed.

Preparation 4:

The derivative of formula 1 according to the present invention, as shown in Scheme 4 below,

It can be prepared by the preparation method further comprises the step of introducing acetyl to the amine group of the compound represented by Formula 1e obtained after performing the above method 3.

[Reaction Scheme 4]

(In Scheme 4, R ¹ and R ² are as defined in Formula 1, and Formula 1e and 1f are derivatives of Formula 1).

Hereinafter, the preparation method 4 according to the present invention will be described in more detail.

Preparation 4 is a step of introducing acetyl to the amine group of the compound represented by Formula 1e obtained after performing Preparation 3.

The reaction was carried out by reacting the compound represented by the formula (1e) obtained after the above step 3 with triethylamine, 4- (dimethylamino) pyridine (DMAP) and acetic anhydride at room temperature for 5 to 10 hours in a dichloromethane solvent. Can be performed.

After the reaction, extraction, drying, filtration and distillation under reduced pressure with an organic solvent may be further performed, and then column chromatography may be performed to obtain a compound represented by Chemical Formula 1f.

Preparation 5:

As shown in Scheme 5, the derivative of Formula 1 according to the present invention,

It can be prepared by the preparation method further comprises the step of introducing alkyl to the amine group of the compound represented by Formula 1e obtained after performing the above Preparation 3.

Scheme 5

(In Scheme 5, R ¹ and R ² are as defined in Formula 1, and Formulas 1e and 1g are derivatives of Formula 1).

Hereinafter, the preparation method 5 according to the present invention will be described in more detail.

Preparation 5 is a step of introducing alkyl into the amine group of the compound represented by Formula 1e obtained after performing Preparation 3 above.

The reaction is carried out by adding the base of the compound represented by the formula (1e) after performing the above step 3 in a THF solvent and stirred for 20 to 40 minutes at room temperature, and reacted with methane iodide for 30 minutes to 2 hours at room temperature Can be. The base may be NaH, potassium carbonate and the like, it is preferable to use NaH.

After the reaction, extraction, drying, filtration and distillation under reduced pressure with an organic solvent may be further performed, and column chromatography may be performed to obtain the compound of Chemical Formula 1g.

The present invention also provides a pharmaceutical composition for the prevention or treatment of MCH-related diseases containing a derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The MCH-related diseases may include obesity, diabetes, metabolic disorders, anxiety and depression.

As a result of measuring the MCH receptor-1 binding inhibitory activity according to the present invention, the derivative of Formula 1 exhibited an excellent inhibitory effect on the MCH receptor by exhibiting an excellent IC ₅₀ value of 1 μM or less (Experimental Example and See Table 2).

Therefore, the derivative of formula 1 according to the present invention acts as an antagonist to the MCH receptor, thereby making it useful for preventing or treating MCH related diseases such as obesity, diabetes, metabolic disorders, anxiety and depression caused by MCH binding to the MCH receptor. Can be used.

When the composition of the present invention is used as a pharmaceutical, the pharmaceutical composition containing the derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be used in various oral or parenteral dosage forms as described below. It may be formulated and administered, but is not limited thereto.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain additives such as starch, agar, alginic acid or its sodium salt A disintegrating or boiling mixture and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.

Pharmaceutical compositions comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

In this case, in order to formulate into a formulation for parenteral administration, 1,2,4-oxadiazole derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a solution or suspension, It may be prepared in ampule or vial unit dosage forms. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

The dosage of the pharmaceutical composition containing the derivative of Formula 1 as an active ingredient to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and preferably 0.01 to 200 mg. / Kg / day may be administered by oral or parenteral route by dividing a predetermined time interval several times a day, preferably once to three times a day, depending on the judgment of the doctor or pharmacist.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.

However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Example 1 5- (4-Chlorophenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole Manufacture

Step 1 of Preparation 1: Synthesis of 3-methoxy-4- [2- (1-pyrrolidinyl) ethoxy] benzonitrile

To a mixed solution of 4-hydroxy-3-methoxybenzonitrile (7.46 g, 50.0 mmol) in DME-H ₂ O (5: 1, 300 mL) 1- (2-chloroethyl) pyrrolidine hydrochloride (10.20 g, 60.0 mmol) and potassium carbonate (20.73 g, 0.15 mol) were added and refluxed for 3 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and then the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to give 3-methoxy-4- [2- (1- Pyrrolidinyl) ethoxy] benzonitrile (11.21 g, 91%) was obtained.

Step 2 of Preparation Method 1: Synthesis of 3-methoxy-4- [2- (1-pyrrolidinyl) ethoxy] benzamide oxime

Hydroxylamine hydrochloride (204 mg) in an ethanol solution (10 ml) of 3-methoxy-4- [2- (1-pyrrolidinyl) ethoxy] benzonitrile (600 mg, 2.44 mmol) obtained in step 1 was obtained. , 2.93 mmol) and triethylamine (408 μl, 2.93 mmol) were added and refluxed for 5 hours. The reaction solution was distilled under reduced pressure, saturated sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain 3 -methoxy-4- [2- (1-pyrrolidinyl) ethoxy] benzamide oxime (572 mg, 84%) as a white solid.

Step 3 of Preparation Method 1: 5- (4-Chlorophenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadia Synthesis of Sol

4-chlorobenzoic acid (413 mg) in a DMF solution (10 mL) of 3-methoxy-4- [2- (1-pyrrolidinyl) ethoxy] benzamide oxime (700 mg, 2.51 mmol) obtained in step 2 was obtained. , 2.64 mmol), EDC (506 mg, 2.64 mmol), 4-di (methylamino) pyridine (61 mg, 0.50 mmol) were added thereto, stirred at room temperature for 15 hours, and then heated at 90 ° C. for 4 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give 5- (4-chlorophenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl) as a white solid. -Ethoxy) phenyl] -1,2,4-oxadiazole (500 mg, 50%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.16 (d. 2H, J = 8.8 Hz), 7.75 (dd, 1H, J = 8.4, 1.9 Hz), 7.64 (d, 1H, J = 1.9 Hz), 7.54 (d, 2H, J = 8.8 Hz), 6.99 (d, 1H, J = 8.4 Hz), 4.24 (t, 2H, J = 6.3 Hz), 3.97 (s, 3H), 3.01 (t, 2H, J = 6.3 Hz), 2.68 (m, 4H), 1.83 (m, 4H);

M ⁺ 399.

<Example 2> Preparation of 5- (4-bromophenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole

A white solid in the same manner as in steps 1, 2 and 3 of Example 1, except that 4-bromobenzoic acid (396 mg, 1.97 mmol) was used instead of 4-chlorobenzoic acid in Step 3 of Example 1 5- (4-bromophenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (337 mg , 40%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.08 (d, 2H, J = 8.6 Hz), 7.75 (dd, 1H, J = 8.4, 1.9 Hz), 7.70 (d, 2H, J = 8.6 Hz), 7.64 (d, 1H, J = 1.9 Hz), 6.99 (d, 1H, J = 8.4 Hz), 4.24 (t, 2H, J = 6.3 Hz), 3.97 (s, 3H), 3.01 (t, 2H, J = 6.3 Hz), 2.68 (m, 4H), 1.83 (m, 4H);

M ⁺ 444.

Example 3 5- [4- (trifluoromethyl) phenyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, Preparation of 4-oxadiazole

Except for using 4- (trifluoromethyl) benzoic acid (232 mg, 1.22 mmol) in place of 4-chlorobenzoic acid in step 3 of Example 1, the same procedure as in steps 1, 2 and 3 of Example 1 5- [4- (trifluoromethyl) phenyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole (290 mg, 58%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.35 (d, 2H, J = 8.1 Hz), 7.83 (d, 2H, J = 8.1 Hz), 7.77 (dd, 1H, J = 8.4, 1.9 Hz), 7.66 (d, 1H, J = 1.9 Hz), 7.01 (d, 1H, J = 8.4 Hz), 4.26 (t, 2H, J = 6.3 Hz), 3.98 (s, 3H), 3.03 (t, 2H, J = 6.3 Hz), 2.70 (m, 4H), 1.85 (m, 4H);

M ⁺ 433.

Example 4 5- (4-phenoxyphenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadia Preparation of the sol

A white solid in the same manner as in steps 1, 2 and 3 of Example 1, except that 4-phenoxybenzoic acid (163 mg, 0.76 mmol) was used instead of 4-chlorobenzoic acid in Step 3 of Example 1. 5- (4-phenoxyphenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (143 mg , 43%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.17 (d, 2H, J = 8.9 Hz), 7.76 (dd, 1H, J = 8.4, 1.8 Hz), 7.66 (d, 1H, J = 1.8 Hz), 7.42 (m, 2H), 7.22 (m, 1H), 7.11 (m, 4H), 6.99 (d, 1H, J = 8.4 Hz), 4.26 (t, 2H, J = 6.2 Hz), 3.97 (s, 3H) , 3.05 (t, 2H, J = 6.2 Hz), 2.73 (m, 4H), 1.85 (m, 4H);

M ⁺ 457.

Example 5 5- (biphenyl-4-yl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxa Preparation of Diazoles

Except for using biphenyl-4-carboxylic acid (151 mg, 0.76 mmol) in place of 4-chlorobenzoic acid in step 3 of Example 1 in the same manner as in steps 1, 2 and 3 of Example 1 5- (biphenyl-4-yl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole as a white solid (85 mg, 27%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.29 (d, 2H, J = 8.6 Hz), 7.78 (m, 3H), 7.67 (m, 3H), 7.52-7.42 (m, 3H), 7.01 (d, 1H, J = 8.4 Hz), 4.27 (t, 2H, J = 6.2 Hz), 3.98 (s, 3H). 3.06 (t, 2H, J = 6.2 Hz), 2.75 (m, 4H), 1.86 (m, 4H);

M ⁺ 441.

< Example 6> 5- (4'- Fluorobiphenyl -4-yl) -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Example 1 step 3, except that 4- (4-fluorophenyl) benzoic acid (164 mg, 0.76 mmol) in place of 4-chlorobenzoic acid in Example 3 and 5- (4'-fluorobiphenyl-4-yl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1 as a white solid in the same manner , 2,4-oxadiazole (156 mg, 47%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.28 (d, 2H, J = 8.5 Hz), 7.78 (dd, 1H, J = 8.4, 1.9 Hz), 7.73 (d, 2H, J = 8.5 Hz), 7.67 (d, 1H, J = 1.9 Hz), 7.63 (m, 2H), 7.18 (m, 2H), 7.01 (d, 1H, J = 8.4 Hz), 4.26 (t, 2H, J = 6.3 Hz), 3.98 (s, 3H), 3.04 (t, 2H, J = 6.3 Hz), 2.72 (m, 4H), 1.85 (m, 4H);

M ⁺ 459.

< Example 7> 5- ( Biphenyl -4- Yl methyl ) -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-oxadiazole

A white solid in the same manner as in steps 1, 2 and 3 of Example 1, except that 4-biphenylacetic acid (161 mg, 0.76 mmol) was used instead of 4-chlorobenzoic acid in Step 3 of Example 1. 5- (biphenyl-4-ylmethyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole ( 160 mg, 49%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.67 (dd, 1H, J = 2.0, 8.4 Hz), 7.60-7.54 (m, 5H), 7.46-7.41 (m, 4H), 7.37-7.32 (m, 1H ), 7.00 (d, 1H, J = 8.4 Hz), 4.32 (s, 2H), 4.23 (t, 2H, J = 6.2 Hz), 3.93 (s, 3H), 3.02 (t, 2H, J = 6.2 Hz ), 2.70 (m, 4 H), 1.84 (m, 4 H);

M ⁺ 455.

< Example 8> 5- [4- ( Trifluoromethyl ) Benzyl] -3- [3- Methoxy -4- (2- Pyrrolidine -1-yl-ethoxy) Phenyl ] -1,2,4- Oxadiazole Produce

Example 1 step 3, except that 4- (trifluoromethyl) phenylacetic acid (155 mg, 0.76 mmol) in place of 4-chlorobenzoic acid in Example 3 and 5- [4- (trifluoromethyl) benzyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2 as a white solid in the same manner , 4-oxadiazole (102 mg, 32%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.64 (m, 3H), 7.52 (m, 3H), 6.96 (d, 1H, J = 8.4 Hz), 4.34 (s, 2H), 4.24 (t, 2H, J = 6.2 Hz), 3.93 (s, 3H), 3.02 (t, 2H, J = 6.2 Hz), 2.71 (m, 4H), 1.84 (m, 4H);

M ⁺ 447.

< Example 9> 5- (4- Fluorobenzyl ) -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole Produce

Except for using 4-fluorophenylacetic acid (117 mg, 0.76 mmol) in place of 4-chlorobenzoic acid in step 3 of Example 1 White in the same manner as in steps 1, 2 and 3 of Example 1 Solid 5- (4-fluorobenzyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (140 Mg, 49%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.65 (dd, 1H, J = 8.4, 1.9 Hz), 7.55 (d, 1H, J = 1.9 Hz), 7.35 (m, 2H), 7.05 (m, 2H) , 6.96 (d, 1H, J = 8.4 Hz), 4.25 (s, 2H), 4.24 (t, 2H, J = 6.3 Hz), 3.93 (s, 3H), 3.03 (t, 2H, J = 6.3 Hz) , 2.72 (m, 4 H), 1.84 (m, 4 H);

M ⁺ 397.

< Example 10> 5- [2- (4- Fluorophenyl ) Ethyl] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Example 1 steps 3, 2 and 3 of Example 1, except that 3- (4-fluorophenyl) propionic acid (128 mg, 0.76 mmol) in place of 4-chlorobenzoic acid In the same manner as the white solid 5- [2- (4-fluorophenyl) ethyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1, 2,4-oxadiazole (130 mg, 44%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.66 (dd, 1H, J = 8.3, 1.9 Hz), 7.55 (d, 1H, J = 1.9 Hz), 7.20 (m, 2H). 6.99 (m, 3H), 4.24 (t, 2H, J = 6.4 Hz), 3.94 (s, 3H), 3.20 (m, 4H), 3.02 (t, 2H, J = 6.4 Hz), 2.70 (m, 4H ), 1.84 (m, 4 H);

M ⁺ 411.

< Example 11> 5-[(4- Chlorophenoxy ) methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole Produce

Except for using 4-chlorophenoxyacetic acid (244 mg, 1.31 mmol) in place of 4-chlorobenzoic acid in step 3 of Example 1, white was prepared in the same manner as in steps 1, 2 and 3 of Example 1 Solid 5-[(4-chlorophenoxy) methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadia A sol (356 mg, 66%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.68 (dd, 1H, J = 8.4, 1.8 Hz), 7.58 (d, 1H, J = 1.8 Hz), 7.29 (d, 2H, J = 9.0 Hz), 6.99 (d, 1H, J = 8.4 Hz), 6.96 (d, 2H, J = 9.0 Hz), 5.31 (s, 2H), 4.38 (t, 2H, J = 5.6 Hz), 3.93 (s, 3H), 3 , 22 (t, 2H, J = 5.6 Hz), 3.00 (m, 4H), 1.97 (m, 4H);

M ⁺ 429.

< Example 12> 5-[[(4- Chlorobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Example 1 step 3, except that 2- (4-chlorobenzyloxy) acetic acid (106 mg, 0.53 mmol) in place of 4-chlorobenzoic acid and In the same manner as the white solid 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1, 2,4-oxadiazole (78 mg, 35%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.69 (dd, 1H, J = 8.4, 1.8 Hz), 7.58 (d, 1H, J = 1.8 Hz), 7.35 (s, 4H), 6.98 (d, 1H, J = 8.4 Hz), 4.79 (s, 2H), 4.70 (s, 2H), 4.25 (t, 2H, J = 6.3 Hz), 3.94 (s, 3H), 3.03 (t, 2H, J = 6.3 Hz) , 2.71 (m, 4 H), 1.85 (m, 4 H);

M ⁺ 443.

< Example 13> 5-[[(3- Chlorobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Step 3 of Preparation Method 1: 5-[[(3- Chlorobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole synthesis

DMF solution of 3-methoxy-4- [2- (1-pyrrolidinyl) ethoxy] benzamide oxime (293 mg, 1.05 mmol) synthesized in the same manner as in steps 1 and 2 of Example 1 (10 2- (3-chlorobenzyloxy) acetic acid (201 mg, 1.00 mmol), EDC (201 mg, 1.05 mmol), HOBt (142 mg, 1.05 mmol) and DIPEA (183 μl, 1.05 mmol) were added to ㎖). Stir at 15 h. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. DMF (10 mL) and p -toluenesulfonic acid monohydrate (38 mg, 0.20 mmol) were added thereto, and the mixture was refluxed for 3 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to give 5-[[(3-chlorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pi) as a white solid. Ralidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (217 mg, 49%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.69 (d, 1H, J = 8.0 Hz), 7.59 (br s, 1H), 7.42 (s, 1H), 7.30 (m, 3H), 6.98 (d, 1H, J = 8.0 Hz,), 4.81 (s, 2H), 4.71 (s, 2H), 4.24 (t, 2H, J = 6.3 Hz), 3.94 (s, 3H), 3.01 (t, 2H, J = 6.3 Hz), 2.68 (m, 4H), 1.82 (m, 4H).

< Example 14> 5- [2- (4- Chlorophenoxy ) Ethyl] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Step 3 of Preparation Method 1: 5- [2- (4- Chlorophenoxy ) Ethyl] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole synthesis

Thionyl chloride (1 mL) was added to a dichloroethane solution (5 mL) of 3- (4-chlorophenoxy) propionic acid (159 mg, 0.79 mmol), and the mixture was refluxed for 3 hours. The reaction solution was distilled under reduced pressure, and then dissolved in DMF (5 mL), and triethylamine (201 μl, 1.44 mmol) was synthesized in the same manner as in Steps 1 and 2 of Example 1 to 3-methoxy-4. -[2- (1-pyrrolidinyl) ethoxy] benzamide oxime (200 mg, 0.72 mmol) was added thereto and stirred at room temperature for 15 hours. Then, the temperature was raised to 90 ° C and further reacted for 4 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give 5- [2- (4-chlorophenoxy) ethyl] -3- [3-methoxy-4- (2-pi) as a white solid. Ralidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (49 mg, 15%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.66 (dd, 1H, J = 8.4, 1.8 Hz), 7.56 (d, 1H, J = 1.8 Hz), 7.25 (d, 2H, J = 8.9 Hz), 6.98 (d, 1H, J = 8.4 Hz), 6.85 (d, 2H, J = 8.9 Hz), 4.44 (t, 2H, J = 6.5 Hz), 4.28 (t, 2H, J = 6.2 Hz), 3.93 (s , 3H), 3.42 (t, 2H, J = 6.5 Hz), 3.07 (t, 2H, J = 6.2 Hz), 2.78 (m, 4H), 1.87 (m, 4H);

M ⁺ 443.

< Example 15> 5-[[(4- Fluorobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole Produce

Example 1 steps 1, 2, and 3 of Example 1, except that 2- (4-fluorobenzyloxy) acetic acid (221 mg, 1.20 mmol) was used instead of 4-chlorobenzoic acid in Step 3 of Example 1 5-[[(4-fluorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl]-as a white solid in the same manner as 1,2,4-oxadiazole (291 mg, 68%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): 7.69 (dd, 1H, J = 8.4, 2.0 Hz), 7.58 (d, 1H, J = 2.0 Hz), 7.38 (m, 2H), 7.06 (m, 2H), 6.98 (d, 1H, J = 8.4 Hz), 4.78 (s, 2H), 4.69 (s, 2H), 4.29 (t, 2H, J = 6.3 Hz), 3.94 (s, 3H), 3.08 (t, 2H , J = 6.3 Hz), 2.79 (m, 4H), 1.88 (m, 4H);

M ⁺ 427.

< Example 16> 5-[[(3,4- Dichlorobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole Produce

Step 3 of Preparation Method 1: 5-[[(3,4- Dichlorobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole synthesis

To a dichloromethane solution (5 mL) of 2- (3,4-dichlorobenzyloxy) acetic acid (118 mg, 0.50 mmol) was added oxalyl chloride (131 μl, 1.50 mmol) and DMF (cat. Amount). Stir for hours. The reaction solution was distilled under reduced pressure, and then dissolved in DMF (5 mL), and triethylamine (209 μl, 1.50 mmol) was synthesized in the same manner as in Steps 1 and 2 of Example 1 to 3-methoxy-4. -[2- (1-pyrrolidinyl) ethoxy] benzamide oxime (140 mg, 0.50 mmol) was added thereto, followed by stirring at room temperature for MG. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. DMF (5 mL) and p -toluenesulfonic acid monohydrate (10 mg, 0.10 eq) were added thereto, and the mixture was refluxed for 3 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 5: 1) to give 5-[[(3,4-dichlorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2) as a white solid. -Pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (74 mg, 31%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): 7.69 (dd, 1H, J = 8.4, 1.9 Hz), 7.58 (d, 1H, J = 1.9 Hz), 7.52 (d, 1H, J = 2.0 Hz), 7.45 ( d, 1H, J = 8.2 Hz, 7.23 (dd, 1H, J = 8.2, 2.0 Hz), 6.99 (d, 1H, J = 8.4 Hz), 4.81 (s, 2H), 4.68 (s, 2H), 4.23 (t, 2H, J = 6.5 Hz), 3.94 (s, 3H), 2.99 (t, 2H, J = 6.5 Hz), 2.66 (m, 4H), 1.82 (m, 4H);

M ⁺ 478.

< Example 17> 5-[[(3,4- Difluorobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl] -1,2,4- Oxadiazole Produce

Except for using 2- (3,4-difluorobenzyloxy) acetic acid (202 mg, 1.0 mmol) instead of 2- (3,4-dichlorobenzyloxy) acetic acid in Step 3 of Example 16 above. In the same manner as in steps 1, 2 and 3 of Example 16, 5-[[(3,4-difluorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2- Pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (135 mg, 30%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): 7.69 (dd, 1H, J = 8.4, 2.0 Hz), 7.59 (d, 1H, J = 2.0 Hz), 7.29-7.10 (m, 3H), 6.99 (d, 1H , J = 8.4 Hz), 4.81 (s, 2H), 4.68 (s, 2H), 4.26 (t, 2H, J = 6.3 Hz), 3.94 (s, 3H), 3.04 (t, 2H, J = 6.3 Hz ), 2.73 (m, 4 H), 1.85 (m, 4 H);

M ⁺ 445.

< Example 18> 5-[[(4- Cyanobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Example 3, except that 2- (4-cyanobenzyloxy) acetic acid (191 mg, 1.0 mmol) was used instead of 2- (3,4-dichlorobenzyloxy) acetic acid in Step 3 of Example 16 5-[[(4-cyanobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidine-1- of a white solid in the same manner as in steps 1, 2 and 3 of 16 Mono-ethoxy) phenyl] -1,2,4-oxadiazole (145 mg, 33%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): 7.68 (m, 3H), 7.57 (d, 1H, J = 1.9 Hz), 7.52 (d, 2H, J = 8.2 Hz), 6.99 (d, 1H, J = 8.4 Hz), 4.85 (s, 2H), 4.79 (s, 2H), 4.26 (t, 2H, J = 6.4 Hz), 3.94 (s, 3H), 3.03 (t, 2H, J = 6.4 Hz), 2.72 ( m, 4H), 1.84 (m, 4H);

M ⁺ 434.

< Example 19> 5-[[(4- Cyanobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Example 3, except that 2- (3-cyanobenzyloxy) acetic acid (191 mg, 1.0 mmol) was used instead of 2- (3,4-dichlorobenzyloxy) acetic acid in Step 3 of Example 16 5-[[(4-cyanobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidine-1- of a white solid in the same manner as in steps 1, 2 and 3 of 16 Mono-ethoxy) phenyl] -1,2,4-oxadiazole (180 mg, 41%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): 7.72 (m 1 H), 7.69 (dd, 1H, J = 8.4, 1.9 Hz), 7.63 (m, 2H), 7.58 (d, 1H, J = 1.9 Hz), 7.49 (m, 1H), 6.99 (d, 1H, J = 8.4 Hz), 4.85 (s, 2H), 4.76 (s, 2H), 4.27 (t, 2H, J = 6.3 Hz), 3.94 (s, 3H) , 3.05 (t, 2H, J = 6.3 Hz), 2.75 (m, 4H), 1.86 (m, 4H);

M ⁺ 434.

< Example 20> 5-[[(4- Methylbenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Example 16 above, except that 2- (4-methylbenzyloxy) acetic acid (180 mg, 1.0 mmol) was used instead of 2- (3,4-dichlorobenzyloxy) acetic acid in Step 3 of Example 16. 5-[[(4-methylbenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl- as a white solid in the same manner as in steps 1, 2 and 3 of Ethoxy) phenyl] -1,2,4-oxadiazole (176 mg, 42%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): 7.69 (dd, 1H, J = 8.4, 1.8 Hz), 7.58 (d, 1H, J = 1.8 Hz), 7.29 (d, 2H, J = 7.9 Hz), 7.19 ( d, 2H, J = 7.9 Hz), 6.98 (d, 1H, J = 8.4 Hz), 4.76 (s, 2H), 4.69 (s, 2H), 4.25 (t, 2H, J = 6.3 Hz), 3.94 ( s, 3H), 3.02 (t, 2H, J = 6.3 Hz), 2.70 (m, 4H), 2.35 (s, 3H), 1.84 (m, 4H);

M ⁺ 423.

< Example 21> 5-[[(4-methoxybenzyl) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Example 3, except that 2- (4-methoxybenzyloxy) acetic acid (180 mg, 1.0 mmol) was used instead of 2- (3,4-dichlorobenzyloxy) acetic acid in Step 3 of Example 16 5-[[(4-methoxybenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidine-1- of a white solid in the same manner as in steps 1, 2 and 3 of 16 Mono-ethoxy) phenyl] -1,2,4-oxadiazole (132 mg, 30%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): 7.69 (dd, 1H, J = 8.4, 1.9 Hz), 7.58 (d, 1H, J = 1.9 Hz), 7.34 (d, 2H, J = 8.5 Hz), 6.99 ( d, 1H, J = 8.4 Hz), 6.91 (d, 2H, J = 8.5 Hz), 4.75 (s, 2H), 4.67 (s, 2H), 4.26 (t, 2H, J = 6.2 Hz), 3.93 ( s, 3H), 3.81 (s, 3H), 3.04 (t, 2H, J = 6.2 Hz), 2.72 (m, 4H), 1.85 (m, 4H);

M ⁺ 439.

< Example 22> 5-[[(3- Acetylamino ) Phenoxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole ;Produce

Example 1 steps 1, 2 and 2 except that 2- (3-acetamidophenoxy) acetic acid (360 mg, 1.72 mmol) was used instead of 4-chlorobenzoic acid in step 3 of Example 1. 5-[[(3-acetylamino) phenoxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] as a white solid, in the same manner as in 3 -1,2,4-oxadiazole; (295 mg, 40%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.68 (dd, 1H, J = 2.0, 8.4 Hz), 7.58 (d, 1H, J = 2.0 Hz), 7.43 (m, 2H), 7.23 (m, 1H) , 7.06 (d, 1H, J = 8.3 Hz), 6.97 (d, 1H, J = 8.4 Hz), 6.76 (dd, 1H, J = 8.3, 1.9 Hz), 5.31 (s, 2H), 4.23 (t, 2H, J = 6.4 Hz, 3.92 (s, 3H), 3.00 (t, 2H, J = 6.4 Hz), 2.66 (m, 4H), 2.16 (s, 3H), 1.82 (m, 4H); rf = 0.3 (MC: MeOH = 5: 1);

M ⁺ 452.

< Example 23> 5-[[(4- Nitrobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1-yl-on Toxic ) Phenyl ] -1,2,4- Oxadiazole Produce

Example 1 step 3, except that 2- (4-nitrobenzyloxy) acetic acid (422 mg, 2.0 mmol) in place of 4-chlorobenzoic acid in Example 3 and In the same manner as the white solid 5-[[(4-nitrobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1, 2,4-oxadiazole (450 mg, 50%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): 8.24 (d, 2H, J = 8.6 Hz), 7.69 (dd, 1H, J = 8.4, 1.9 Hz), 7.58 (d, 2H, J = 8.6 Hz), 7.57 ( d, 1H, J = 1.9 Hz), 6.99 (d, 1H, J = 8.4 Hz), 4.88 (s, 2H), 4.84 (s, 2H), 4.29 (t, 2H, J = 6.1 Hz), 3.94 ( s, 3H), 3.08 (t, 2H, J = 6.1 Hz), 2.79 (m, 4H), 1.89 (m, 4H);

M ⁺ 454.

< Example 24> 5-[[(4- Acetylaminobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl] -1,2,4- Oxadiazole Produce

Step A of Preparation 2: 5-[[(4- Aminobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole synthesis

5-[[(4-nitrobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1 obtained in Example 23; Pd / C (10 wt%, 100 mg) was added to a methanol solution of 2,4-oxadiazole (450 mg, 0.99 mmol) (20 mL) for 4 hours under the condition of H ₂ (40 psi). The reaction solution was filtered through celite and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give 5-[[(4-aminobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pi) as a white solid. Ralidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (45 mg) was obtained.

Step B of Preparation 2: 5-[[(4- Acetylaminobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole synthesis

5- (4-amino-benzyloxymethyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -1,2,4 obtained in step A above. Dissolve oxadiazole in dichloromethane (3 mL), add acetic anhydride (12 μL, 0.13 mmol), triethylamine (46 μL, 0.33 mmol), DMAP (2 mg, 0.02 mmol) and add 6 at room temperature. Stir for hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give 5-[[(4-aminobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pi) as a white solid. Ralidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (32 mg, 62%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.14 (s, 1H), 7.67 (dd, 1H, J = 8.4, 1.8 Hz), 7.57 (d, 1H, J = 1.8 Hz), 7.58 (d, 2H, J = 8.3 Hz), 7.32 (d, 2H, J = 8.3 Hz), 6.96 (d, 1H, J = 8.4 Hz), 4.75 (s, 2H), 4.66 (s, 2H), 4.34 (t, 2H, J = 5.6 Hz), 3.91 (s, 3H), 3.20 (t, 2H, J = 5.6 Hz), 2.98 (m, 4H), 2.17 (s, 3H), 1.94 (m, 4H).

< Example 25> 5-[[(3- Nitrobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Example 13 above, except that 2- (3-nitrobenzyloxy) acetic acid (5-tactic acid (5, 2.37 mmol)) was used instead of 2- (3-chlorobenzyloxy) acetic acid in Step 3 of Example 13. 5-[[(3-nitrobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl- as a white solid in the same manner as in steps 1, 2 and 3 of Ethoxy) phenyl] -1,2,4-oxadiazole (378 mg, 35%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.30 (m, 1H), 8.19 (m, 1H), 7.75 (m, 1H), 7.69 (dd, 1H, J = 8.4, 2.0 Hz), 7.59 (m, 2H), 6.98 (d, 1H, J = 8.4 Hz), 4.88 (s, 2H), 4.83 (s, 2H), 4.27 (t, 2H, J = 6.3 Hz), 3.94 (s, 3H), 3.07 ( t, 2H, J = 6.3 Hz), 2.77 (m, 4H), 1.86 (m, 4H).

< Example 26> 5-[[(3- Acetylaminobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl] -1,2,4- Oxadiazole Produce

Step A of Preparation 2: 5-[[(3- Aminobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole synthesis

Iron (123 mg, 2.20 mmol) and ammonium chloride (71 mg, 1.32 mmol) were added to a mixed solvent of methanol and water (2: 1, 5.0 mL) and refluxed for 1 hour. Then, 5- [ [(3-nitrobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (200 Mg, 0.44 mmol) was further refluxed for 3 hours. The reaction solution was filtered through celite, the solvent was concentrated under reduced pressure, saturated NaHCO ₃ solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give 5-[[(3-aminobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pi) as a white solid. Ralidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (93 mg) was obtained.

Step B of Preparation 2: 5-[[(3- Acetylaminobenzyl ) Oxy ] methyl ] -3- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole synthesis

5-[[(3-aminobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2 obtained in step A above , 4-oxadiazole was dissolved in dichloromethane solution (3 ml), and then acetic anhydride (25 µl, 0.26 mmol), triethylamine (92 µl, 0.66 mmol) and DMAP (3 mg, 0.02 mmol) were added thereto. Stir at room temperature for 6 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give 5-[[(3-acetylaminobenzyl) oxy] methyl] -3- [3-methoxy-4- (2- Pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (60 mg, 58%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.69 (dd, 1H, J = 8.4, 1.8 Hz), 7.58-7.49 (m, 3H), 7.30 (m, 2H), 7.13 (m, 1H), 6.97 ( d, 1H, J = 8.4 Hz), 4.78 (s, 2H), 4.70 (s, 2H), 4.25 (t, 2H, J = 6.0 Hz), 3.92 (s, 3H), 3.03 (t, 2H, J = 6.0 Hz), 2.72 (m, 4H), 2.16 (s, 3H), 1.83 (m, 4H).

< Example 27> 5-[[(4- Chlorobenzyl ) Oxy ] methyl ] -3- [3-nitro-4- (2- Pyrrolidine -1-yl-on Toxic ) Phenyl ] -1,2,4- Oxadiazole Produce

Step 1 of Preparation Method 1: 3-nitro-4- [2- (1- Pyrrolidinyl ) Ethoxy ] Benzonitrile synthesis

To a mixed solution of 4-hydroxy-3-nitrobenzonitrile (8.21 g, 50 mmol) in DME-H ₂ O (5: 1, 300 mL) 1- (2-chloroethyl) pyrrolidine hydrochloride (10.20 g , 60.0 mmol) and calcium carbonate (20.73 g, 0.15 mol) were added and refluxed for 3 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and the residue was then purified by column chromatography (dichloromethane: methanol = 20: 1) to give 3-nitro-4- [2- (1-pyrroli) as a yellow liquid. Diny) ethoxy] benzonitrile (11.62 g, 89%) was obtained.

Step 2 of Preparation Method 1: 3-nitro-4- [2- (1- Pyrrolidinyl ) Ethoxy ] Benzamide oxime synthesis

To an ethanol solution (10 mL) of -nitro-4- [2- (1-pyrrolidinyl) ethoxy] benzonitrile (627 mg, 2.4 mmol) obtained in step 1, hydroxylamine hydrochloride (204 mg, 2.93 mmol) and triethylamine (408 μl, 2.93 mmol) were added and refluxed for 5 hours. The reaction solution was distilled under reduced pressure, saturated sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain 3-nitro-4- [2- (1-pyrrolidinyl) ethoxy] benzamide oxime (367 mg, 52%) as a white solid.

Step 3 of Preparation Method 1: 5-[[(4- Chlorobenzyl ) Oxy ] methyl ] -3- [3-nitro-4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole synthesis

2- (4-chlorobenzyl) in DMF solution (20 mL) of 3-nitro-4- [2- (1-pyrrolidinyl) ethoxy] benzamide oxime (2.0 g, 6.80 mmol l) obtained in step 2 above. Oxy) acetic acid (1.30 g, 6.48 mmol), EDC (1.30 g, 6.80 mmol), 1-hydroxybenzotriazole (919 mg, 6.80 mmol) and DIPEA (1.18 mL, 6.80 mmol) were added for 15 hours at room temperature. After stirring, the mixture was reacted at 90 ° C. for 4 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to give 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-nitro-4- (2-pyrroli) as a white solid. Din-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (697 mg, 23%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.61 (d, 1H, J = 2.0 Hz), 8.26 (dd, 1H, J = 8.7, 2.0 Hz), 7.75 (d, 1H, J = 8.7 Hz), 7.35 (br s, 4H), 4.81 (s, 2H), 4.71 (s, 2H), 4.59 ((t, 2H, J = 5.7 Hz), 3.42 (t, 2H, J = 5.7 Hz), 3.21 (m, 4H), 2.03 (m, 4H).

< Example 28> 5-[[(4- Chlorobenzyl ) Oxy ] methyl ] -3- [3-amino-4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Preparation method 3: 5-[[(4- Chlorobenzyl ) Oxy ] methyl ] -3- [3-amino-4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Synthesis of azoles

Iron (56 mg, 1.0 mmol) and ammonium chloride (32 mg, 0.60 mmol) were added to a mixed solvent of methanol and water (2: 1, 5.0 mL) and refluxed for 1 hour, followed by step 3 of Example 27. 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-nitro-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (90 mg, 0.20 mmol) was added and further refluxed for 3 hours. The reaction solution was filtered through celite, the solvent was concentrated under reduced pressure, saturated NaHCO ₃ solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-amino-4- (2-pyrroli) as a white solid. Din-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (47 mg, 55%) was obtained.

] ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.44 (m, 2H), 7.33 (br s, 4H), 6.86 (d, 1H, J = 8.2 Hz), 4.76 (s, 2H), 4.67 (s, 2H), 4.20 (t, 2H, J = 5.3 Hz), 2.97 (t, 2H, J = 5.3 Hz), 2.68 (m, 4H), 1.83 (m, 4H).

< Example 29> 5-[[(4- Chlorobenzyl ) Oxy ] methyl ] -3- [3- Acetylamino -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole Produce

Production method 4: 5-[[(4- Chlorobenzyl ) Oxy ] methyl ] -3- [3- Acetylamino -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole synthesis

5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-amino-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2 obtained in Example 28 above In a dichloromethane solution (3 mL) of, 4-oxadiazole (80 mg, 0.19 mmol), acetic anhydride (22 μL, 0.23 mmol), triethylamine (79 μL, 0.57 mmol), DMAP (3 mg, 0.02 mmol) ) Was added and stirred at room temperature for 6 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give a white solid of 5-[[(4-chlorobenzyl) oxy] methyl] -3. -[3-acetylamino-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (78 mg, 87%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 9.04 (d, 1H, J = 1.8 Hz), 8.82 (s, 1H), 7.77 (dd, 1H, J = 8.2, 1.8 Hz), 7.34 (s, 4H) , 7.01 (d, 1H, J = 8.2 Hz), 4.78 (s, 2H), 4.68 (s, 2H), 4.23 (t, 2H, J = 5.4 Hz), 2.87 (t, 2H, J = 5.4 Hz) , 2.66 (m, 4H), 2.20 (s, 3H), 1.85 (m, 4H).

< Example 30> 5-[[(4- Chlorobenzyl ) Oxy ] methyl ] -3- [3- Methylamino -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole Produce

Preparation 5: 5-[[(4- Chlorobenzyl ) Oxy ] methyl ] -3- [3- Methylamino -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Synthesis of azoles

5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-amino-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2 obtained in Example 28 above NaH (3 mg, 60% in oil, 0.08 mmol) was added to a THF (1 mL mL) solution of, 4-oxadiazole (20 mg, 0.05 mmol) at 0 ° C., followed by stirring at room temperature for 30 minutes. Methane iodide (5 μl, 0.08 mmol) was added thereto, followed by further stirring for 1 hour. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and then the residue was purified by column chromatography (dichloromethane: methanol = 10: 1 + 0.5% NH ₄ OH) to give 5-[[(4-chloro as a white solid). Benzyl) oxy] methyl] -3- [3-methylamino-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazol (10 mg, 45%) Obtained.

< Example 31> 5- (4- Chlorophenyl ) -3- [3- Methoxy -4- (2-piperidin-1-yl- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole Produce

Step 1 of Preparation 1: 3- Methoxy -4- [2- (1- Piperidinyl ) Ethoxy ] Benzonitrile synthesis

To a mixed solution of 4-hydroxy-3-methoxybenzonitrile (447 mg, 3.0 mmol) in DME-H ₂ O (5: 1, 25 mL) 1- (2-chloroethyl) piperidine hydrochloride (828 Mg, 4.5 mmol) and calcium carbonate (1.24 g, 9.0 mol) were added and refluxed for 4 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and then the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to give 3-methoxy-4- [2- (1-pipe) as a white solid. Ridinyl) ethoxy] benzonitrile (728 mg, 93%) was obtained.

Step 2 of Preparation 1: 3- Methoxy -4- [2- (1- Piperidinyl ) Ethoxy ] Benzamide oxime synthesis

Hydroxylamine hydrochloride (113 mg) in an ethanol solution (10 mL) of 3-methoxy-4- [2- (1-piperidinyl) ethoxy] benzonitrile (400 mg, 1.54 mmol) obtained in step 1 was obtained. , 1.62 mmol) and triethylamine (226 μl, 1.62 mmol) were added and refluxed for 4 hours. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and the residue was then purified by column chromatography (dichloromethane: methanol = 10: 1 + 1% NH ₄ OH) to give 3-methoxy-4- [as a white solid. 2- (1-piperidinyl) ethoxy] benzamide oxime (324 g, 72%) was obtained.

Step 3 of Preparation Method 1: 5- (4- Chlorophenyl ) -3- [3- Methoxy -4- (2-piperidin-1-yl- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole synthesis

To 4-chlorobenzoic acid (153 mg) in a DMF solution (10 ml) of 3-methoxy-4- [2- (1-piperidinyl) ethoxy] benzamide oxime (257 mg, 0.88 mol) obtained in step 2 above. , 0.98 mmol), EDC (188 mg, 0.98 mmol), 4-di (methylamino) pyridine (23 mg, 0.19 mmol) were added thereto, stirred at room temperature for 15 hours, and heated at 90 ° C. for 4 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to give 5- (4-chlorophenyl) -3- [3-methoxy-4- (2-piperidin-1-yl) as a white solid. -Ethoxy) phenyl] -1,2,4-oxadiazole (170 mg, 47%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.16 (d, 2H, J = 8.4 Hz), 7.76 (d, 1H, J = 8.4 Hz), 7.64 (s, 1H), 7.53 (d, 2H, J = 8.4 Hz), 7.00 (d, 1H, J = 8.4 Hz), 4.25 (t, 2H, J = 6.2 Hz), 3.97 (s, 3H), 2.88 (t, 2H, J = 6.2 Hz), 2.57 (m , 4H), 1.64 (m, 4H), 1.48 (m, 2H).

< Example 32> 5-[(4- Trifluoromethyl ) Phenyl ] -3- [3- Methoxy -4- (2-piperidin-1-yl- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Example 3 except that 4-trifluoromethylbenzoic acid (165 mg, 0.87 mmol) was used instead of 4-chlorobenzoic acid in step 3, and the reaction solution was extracted with ethyl acetate instead of dichloromethane. 5-[(4-trifluoromethyl) phenyl] -3- [3-methoxy-4- (2-piperidin-1-yl] as a white solid in the same manner as in steps 1,2 and 3 of Example 31 -Ethoxy) phenyl] -1,2,4-oxadiazole (150 mg, 43%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.35 (d, 2H, J = 7.9 Hz), 7.83 (d, 2H, J = 7.9 Hz), 7.77 (dd, 1H, J = 8.4, 1.8 Hz), 7.66 (d, 1H, J = 1.8 Hz), 7.01 (d, 1H, J = 8.4 Hz), 4.24 (t, 2H, J = 6.5 Hz), 3.98 (s, 3H), 2.87 (t, 2H, J = 6.5 Hz), 2.55 (m, 4H), 1.63 (m, 4H), 1.46 (m, 2H).

< Example 33> 5- ( Biphenyl -4-yl) -3- [3- Methoxy -4- (2-piperidin-1-yl- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole Produce

Except for using biphenyl-4-carboxylic acid (202 mg, 1.02 mmol) in place of 4-chlorobenzoic acid in step 3 of Example 31 in the same manner as in steps 1,2 and 3 of Example 31 5- (biphenyl-4-yl) -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole as a white solid (100 mg, 24%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.29 (d, 2H, J = 8.2 Hz), 7.78 (m, 3H), 7.66 (m, 3H), 7.52-7.42 (m, 3H), 7.01 (d, 1H, J = 8.4 Hz), 4.24 (t, 2H, J = 6.4 Hz), 3.98 (s, 3H), 2.87 (t, 2H, J = 6.4 Hz), 2.55 (m, 4H), 1.62 (m, 4H), 1.47 (m, 2H).

< Example 34> 5- (4- Phenoxyphenyl ) -3- [3- Methoxy -4- (2-piperidin-1-yl- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole Produce

Example 31, except that 4-phenoxybenzoic acid (236 mg, 1.10 mmol) was used instead of 4-chlorobenzoic acid in Step 3 of Example 31, and the reaction solution was extracted with ethyl acetate instead of dichloromethane. 5- (4-phenoxyphenyl) -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] as a white solid in the same manner as in steps 1,2 and 3 of -1,2,4-oxadiazole (125 mg, 27%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.17 (d, 2H, J = 8.6 Hz), 7.75 (dd, 1H, J = 8.4, 1.8 Hz), 7.65 (d, 1H, J = 1.8 Hz), 7.42 (m, 2H), 7.24 (m, 2H), 7.09 (m, 3H), 7.00 (d, 1H, J = 8.4 Hz), 4.23 (t, 2H, J = 6.5 Hz), 3.97 (s, 3H) , 2.86 (t, 2H, J = 6.5 Hz), 2.53 (m, 4H), 1.61 (m, 4H), 1.46 (m, 2H).

< Example 35> 5-[(4- Chlorophenoxy ) methyl ] -3- [3- Methoxy -4- (2-piperidin-1-yl- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Except for using 4-chlorophenoxyacetic acid (162 mg, 0.87 mmol) in place of 4-chlorobenzoic acid in step 3 of Example 31, and the white in the same manner as steps 1,2 and 3 of Example 31 Solid 5-[(4-chlorophenoxy) methyl] -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -1,2,4-oxadia A sol (250 mg, 72%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.67 (dd, 1H, J = 8.4, 1.7 Hz), 7.57 (d, 1H, J = 1.7 Hz), 7.28 (d, 2H, J = 9.1 Hz), 6.98 (d, 1H, J = 8.4 Hz), 6.96 (d, 2H, J = 9.1 Hz), 5.31 (s, 2H), 4.23 (t, 2H, J = 6.2 Hz), 3.94 (s, 3H), 2.87 (t, 2H, J = 6.2 Hz), 2.56 (m, 4H), 1.64 (m, 4H), 1.46 (m, 2H).

< Example 36> 5- (4- Chlorophenyl ) -3- [3- Methoxy -4- (2- Morpholine Yl- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole Produce

Step 1 of Preparation 1: 3- Methoxy -4- [2- (4- Morpholinyl ) Ethoxy ] Benzonitrile synthesis

4- (2-chloroethyl) morpholine hydrochloride (837 mg) in a mixed solution of 4-hydroxy-3-methoxybenzonitrile (447 mg, 3.0 mmol) with DME-H ₂ O (5: 1, 25 mL) , 4.5 mmol) and calcium carbonate (1.24 g, 9.0 mmol) were added and refluxed for 5 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and then the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to give 3-methoxy-4- [2- (4-mol) as a white solid. Polyvinyl) ethoxy] benzonitrile (716 mg, 91%) was obtained.

Step 2 of Preparation 1: 3- Methoxy -4- [2- (4- Morpholinyl ) Ethoxy ] Benzamide oxime synthesis

Hydroxylamine hydrochloride (320 mg) in an ethanol solution (20 mL) of 3-methoxy-4- [2- (4-morpholinyl) ethoxy] benzonitrile (1.10 g, 4.19 mmol) obtained in step 1 above. , 4.61 mmol) and triethylamine (643 μl, 4.61 mmol) were added and refluxed for 9 hours. Saturated sodium hydrogen carbonate was added to the reaction solution to make it neutral, and the reaction solvent was distilled off under reduced pressure. The concentrated solution was dissolved in methanol to remove insoluble matters, and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give 3-methoxy-4- [2- (4-morpholinyl) ethoxy] benzamide oxime (1.03 g, 83%) as a white solid. ) Was obtained.

Step 3 of Preparation Method 1: 5- (4- Chlorophenyl ) -3- [3- Methoxy -4- (2- Morpholine Yl- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole synthesis

To a 4-chlorobenzoic acid (230 mg) in a DMF solution (10 mL) of 3-methoxy-4- [2- (4-morpholinyl) ethoxy] benzamide oxime (414 mg, 1.40 mmol) obtained in step 2 was obtained. , 1.47 mmol), EDC (282 mg, 1.47 mmol), 4-di (methylamino) pyridine (34 mg, 0.28 mmol) were added thereto, stirred at room temperature for 15 hours, and heated at 90 ° C. for 4 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (hexane: acetone = 2: 1) to give 5- (4-chlorophenyl) -3- [3-methoxy-4- (2-morpholin-4-yl-) as a white solid. Oxy) phenyl] -1,2,4-oxadiazole (353 mg, 61%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.15 (d, 2H, J = 8.5 Hz), 7.75 (dd, 1H, J = 8.4, 1.8 Hz), 7.65 (d, 1H, J = 1.8 Hz), 7.54 (d, 2H, J = 8.5 Hz), 6.99 (d, 1H, J = 8.4 Hz), 4.23 (t, 2H, J = 6.0 Hz), 3.97 (s, 3H), 3.75 (m, 4H), 2.89 (t, 2H, J = 6.0 Hz), 2.62 (m, 4H).

< Example 37> 5-[(4- Trifluoromethyl ) Phenyl ] -3- [3- Methoxy -4- (2- Morpholine Yl- Ethoxy ) Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Example 3, except that 4- (trifluoromethyl) benzoic acid (270 mg, 1.42 mmol) was used instead of 4-chlorobenzoic acid in Step 3 of Example 36. 5-[(4-trifluoromethyl) phenyl] -3- [3-methoxy-4- (2-morpholin-4-yl-ethoxy) phenyl] -1,2,4 -Oxadiazol (350 mg, 58%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.36 (d, 2H, J = 8.2 Hz), 7.83 (d, 2H, J = 8.2 Hz), 7.77 (dd, 1H, J = 8.4, 1.8 Hz), 7.66 (d, 1H, J = 1.8 Hz), 7.01 (d, 1H, J = 8.4 Hz), 4.24 (t, 2H, J = 6.0 Hz), 3.98 (s, 3H), 3.75 (m, 4H), 2.89 (t, 2H, J = 6.0 Hz), 2.62 (m, 4H).

< Example 38> 5- (4- Phenoxyphenyl ) -3- [3- Methoxy -4- (2- Morpholine Yl- Ethoxy ) Phenyl ] -1,2,4- Oxadiazole Produce

A white solid in the same manner as in steps 1, 2 and 3 of Example 36, except that 4-phenoxybenzoic acid (289 mg, 1.35 mmol) was used instead of 4-chlorobenzoic acid in Step 3 of Example 36. 5- (4-phenoxyphenyl) -3- [3-methoxy-4- (2-morpholin-4-yl-ethoxy) phenyl] -1,2,4-oxadiazole (310 mg, 51%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.18 (d, 2H, J = 8.8 Hz), 7.75 (dd, 1H, J = 8.4, 1.7 Hz), 7.66 (d, 1H, J = 1.7 Hz), 7.42 (m, 2H), 7.22 (m, 1H), 7.11 (m, 4H), 6.99 (d, 1H, J = 8.4 Hz), 4.23 (t, 2H, J = 6.0 Hz), 3.97 (s, 3H) , 3.75 (m, 4H), 2.89 (t, 2H, J = 6.0 Hz), 2.62 (m, 4H).

< Example 39> 5- ( Biphenyl -4-yl) -3- [3- Methoxy -4-[(2-dimethylamino) Ethoxy ] Phenyl ] -1,2,4- Oxadiazole Produce

Step 1 of Preparation Method 1: 4- [2- (dimethylamino) Ethoxy ] -3- Of methoxybenzonitrile synthesis

To a mixed solution of 4-hydroxy-3-methoxybenzonitrile (447 mg, 3.0 mmol) in DME-H ₂ O (5: 1, 25 mL), 2-chloro- N , N -dimethylethylamine hydrochloride (648 Mg, 4.5 mmol) and calcium carbonate (1.24 g, 9.0 mmol) were added and refluxed for 6 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and then the residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give a colorless liquid 4- [2- (dimethylamino) ethoxy] -3. -Methoxybenzonitrile (564 mg, 85%) was obtained.

Step 2 of Preparation Method 1: 4- [2- (dimethylamino) Ethoxy ] -3- Methoxybenzamide oxime synthesis

Hydroxylamine hydrochloride (308 mg, 4.43 mmol) in an ethanol solution (10 mL) of 4- [2- (dimethylamino) ethoxy] -3-methoxybenzonitrile (930 mg, 4.22 mmol) obtained in step 1 above. ) And triethylamine (617 μl, 4.43 mmol) were added and refluxed for 5 hours. Saturated sodium hydrogen carbonate was added to the reaction solution to make it neutral, and the reaction solvent was distilled off under reduced pressure. The concentrated solution was dissolved in methanol to remove insoluble matters, and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1 + 0.5% Et ₃ N) to give a white solid of 4- [2- (dimethylamino) ethoxy] -3-methoxybenzamide oxime (783 mg). , 69%) was obtained.

Step 3 of Preparation 1: 5- ( Biphenyl -4-yl) -3- [3- Methoxy -4-[(2-dimethylamino) Ethoxy ] Phenyl ] -1,2,4- Oxadiazole synthesis

Biphenyl-4-carboxylic acid (240 mg) in a DMF solution (10 mL) of 4- [2- (dimethylamino) ethoxy] -3-methoxybenzamide oxime (290 mg, 1.15 mmol) obtained in step 2 was obtained. , 1.21 mmol), EDC (232 mg, 1.21 mmol), 4-di (methylamino) pyridine (28 mg, 0.23 mmol) were added thereto, stirred at room temperature for 15 hours, and heated at 90 ° C. for 4 hours. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to 5- (biphenyl-4-yl) -3- [3-methoxy-4-[(2-dimethylamino) as a white solid. Oxy] phenyl] -1,2,4-oxadiazole (190 mg, 40%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.28 (d, 2H, J = 8.3 Hz), 7.77 (m, 3H), 7.67 (m, 3H), 7.52-7.42 (m, 3H), 7.01 (d, 1H, J = 8.4 Hz), 4.20 (t, 2H, J = 6.1 Hz), 3.98 (s, 3H), 2.83 (t, 2H, J = 6.1 Hz), 2.37 (s, 6H);

M ⁺ 415.

< Example 40> 5-[(4- Chlorophenoxy ) methyl ] -3- [3- Methoxy -4-[(2-dimethylamino) Ethoxy ] Phenyl ] -1,2,4-jade Sadai Preparation of azoles

Example 3, except that 4-chlorophenoxyacetic acid (157 mg, 0.84 mmol) was used instead of biphenyl-4-carboxylic acid in Step 3 of Example 39, except that Steps 1, 2, and 3 of Example 39 were used. 5-[(4-chlorophenoxy) methyl] -3- [3-methoxy-4-[(2-dimethylamino) ethoxy] phenyl] -1,2,4-oxadiazole as a white solid by the method (193 mg, 610%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.68 (dd, 1H, J = 8.4, 1.9 Hz), 7.57 (d, 1H, J = 1.9 Hz), 7.27 (m, 2H), 6.97 (m, 3H) , 5.31 (s, 2H), 4.17 (t, 2H, J = 6.0 Hz), 3.94 (s, 3H), 2.81 (t, 2H, J = 6.0 Hz), 2.36 (s, 6H);

M ⁺ 403.

< Experimental Example 1> MCH Determination of Receptor-1 Binding Inhibitory Activity

In order to determine the MCH receptor-1 binding inhibitory activity of the derivative according to the present invention was carried out the following experiment.

The buffer solution is prepared by two kinds of washing solution (25 mM HEPES pH 7.4, 5 mM MgCl ₂ , 1 mM CaCl ₂ ) and experimental solution (adding 0.5% BSA to the washing solution), and MCH receptor-1 (melanin). Enriched Hormone Receptor Subtype-1; Euroscreen, Gosselies, Belgium) and 1 μM Europium labeled melanin enriched hormone (Europium-labeled MCH, Eu-MCH), PerkinElmer, Turku, Finland) and 1 mM melanin enriched hormone (MCH) , # 070-47, Phoenix, Belmont CA, USA) was prepared at 4 ° C. 1 μM of europium-labeled melanin-enriched hormone (Eu-MCH) and 1 mM of melanin-enriched hormone were diluted to 8 nM (final reaction concentration: 2 nM) and 2 μM (final reaction concentration: 0.5 μM), respectively. The buffer solution used in all dilutions and preparations was the experimental solution, and the wash solution was used only to wash the plate at the end.

After diluting and homogenizing MCH receptor-1 (200 assays / vial) in 1 ml of experimental solution, the 8-channel pie was placed on a filter paper-attached microplate (Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA). The reaction was dispensed using a pet (multi 8-channel, Eppendorf, Hamburg, Germany) to 100 μl total volume per well. In this case, 25 μl of melanin-enriched hormone (Eu-MCH), 50 μl of receptor and 25 μl of melanin-enriched hormone were used as a non-specific binding control, and total binding control. 25 μl of 10% DMSO test solution, 25 μl of melanin enriched hormone (Eu-MCH) labeled with europium and 50 μl of receptor were used. As an experimental group, 25 μl of the compound represented by Formulas 1 to 40 prepared in Example, 25 μl of melanin enriched hormone (Eu-MCH) labeled with europium and 50 μl of a receptor were used. Each test compound, europium-labeled melanin enriched hormone (Eu-MCH) and melanin enriched hormone occupy 25% of the total volume during the reaction, so it was prepared at a concentration of 4 times immediately before addition. Then, shake gently for 15 seconds and reacted for 90 minutes 40 minutes at room temperature. At the end of the reaction, the plate was partially cleaned by applying pressure to a microplate washer (EMBLA, Molecular Devices). 300 μl / well of the washing solution was filtered three times to remove melanin-enriched hormone (Eu-MCH) labeled with europium that remained without reaction. Wipe off the water on the bottom and 150 μl per well was added to the dissociation solution (DELFIA Enhancement solution, PerkinElmer, Turku, Finland). After standing at room temperature for 2 to 4 hours, time-resolved fluorescence (TRF) values were measured using a multi-function fluorometer (multilabel counter, Victor2, PerkinElmer, Turku, Finland) (emission wavelength: 615 nm). , Excitation wavelength: 340 nm), and the differential fluorescence inhibition rate was calculated by the following equation.

After measuring the differential fluorescence inhibition rate, IC ₅₀ values were calculated for test substances inhibited by 50% or more, and the results are shown in Table 2 below.

division IC ₅₀ ([mu] M) Rat MCH 0.68 Example 4 8.70 Example 5 1.13 Example 6 1.50 Example 10 0.30 Example 11 0.24 Example 12 0.10 Example 14 0.62 Example 15 0.63 Example 16 0.74 Example 17 0.94 Example 20 0.10 Example 21 0.27 Example 23 1.08 Example 27 0.61 Example 28 0.09 Example 29 2.91 Example 30 1.44 Example 33 0.42 Example 35 1.20 Example 39 1.60 Example 40 0.68

As shown in Table 2, in Examples 10, 11, 12, 14, 15, 16, 17, 20, 21, 27, 28, 33 and 40, by showing excellent IC ₅₀ values of 1 μM or less It can be seen that the inhibitory activity on the MCH receptor is excellent, and particularly in Examples 12, 20, and 28, a very good IC ₅₀ value of 0.1 μM or less indicates that the inhibitory effect on the MCH receptor is very excellent. Through this, the compound according to the present invention is excellent in the inhibitory effect on the MCH receptor can be usefully used to prevent or treat MCH-related diseases by acting as an antagonist to the MCH receptor.

Therefore, the derivative according to the present invention can be usefully used to prevent or treat MCH related diseases such as obesity, diabetes, metabolic disorders, anxiety and depression caused by MCH binding to the MCH receptor by acting as an antagonist to the MCH receptor.

On the other hand, 1,2,4-oxadiazole derivatives represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

< Formulation example 1> Sanje Produce

2 g of 1,2,4-oxadiazole derivative of Formula 1

1 g lactose

The above components were mixed and packed in airtight bags to prepare powders.

< Formulation example 2> Preparation of tablets

100 mg of 1,2,4-oxadiazole derivative of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

< Formulation example 3> Preparation of capsules

100 mg of 1,2,4-oxadiazole derivative of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

< Formulation example 4> Preparation of injection

100 mg of 1,2,4-oxadiazole derivative of Formula 1

Mannitol 180 mg

Na ₂ HPO ₄ 2H ₂ O 26 mg

Distilled water 2974 mg

According to a conventional method for preparing an injection, an injection was prepared by containing the above components in the contents shown.

Claims

1,2,4-oxadiazole derivatives represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1,
R ¹ is AB;
At this time, A is - (CH ₂₎ _m - or _{- (CH 2) m -O- (} CH 2) n - (m or n is an integer of 0 to 5, respectively), and;
B is phenyl substituted with one or more substituents selected from the group consisting of halogen, CF ₃ , cyano, nitro, acetylamino, alkoxy, phenoxy and phenyl of C ₁ -C ₄ ,
R ² is any one selected from the group consisting of amino, pyrrolidinyl, piperidinyl and morpholinyl, unsubstituted or substituted with C ₁ -C ₄ straight or branched alkyl,
R ³ is amino unsubstituted or substituted with any substituent selected from the group consisting of C ₁ -C ₄ straight or branched chain alkyl and acetyl; Nitro or C ₁ -C ₆ alkoxy).

The method of claim 1,
R ¹ is AB;
At this time, A is - (CH ₂₎ _m - or _{- (CH 2) m -O- (} CH 2) n - (m or n is an integer of 0 to 3) and;
B is phenyl substituted with one or more substituents selected from the group consisting of fluoro, chlorine, bromine, CF ₃ , cyano, nitro, acetylamino, methoxy, phenoxy and phenyl,
R ² is any one selected from the group consisting of amino, pyrrolidinyl, piperidinyl and morpholinyl, unsubstituted or substituted with C ₁ -C ₄ straight or branched alkyl,
R ³ is amino unsubstituted or substituted with any substituent selected from the group consisting of C ₁ -C ₃ straight or branched chain alkyl and acetyl; 1,2,4-oxadiazole derivatives or pharmaceutically acceptable salts thereof, characterized in that they are nitro or C ₁ -C ₃ alkoxy.

The method of claim 1,
R ¹ is 4-chloro-phenyl, 4-bromo-phenyl, 4-trifluoromethyl-phenyl, 4-phenoxy-phenyl, biphenyl-4-yl, 4-fluoro-biphenyl-4- 1, 4-fluoro-benzyl, 4-trifluoromethyl-benzyl, 4-chloro-phenoxymethyl, 3-acetylamino-phenoxymethyl, 4-fluoro-benzyloxymethyl, 3-chloro-benzyloxy Methyl, 4-chloro-benzyloxymethyl, 3,4-difluoro-benzyloxymethyl, 3,4-dichloro-benzyloxymethyl, 3-cyano-benzyloxymethyl, 4-cyano-benzyloxymethyl, 3-nitro-benzyloxymethyl, 4-nitro-benzyloxymethyl, 4-methyl-benzyloxymethyl, 4-methoxy-benzyloxymethyl, 3-acetylamino-benzyloxymethyl, 4-acetylaminobenzyloxymethyl, 2-4-fluoro-phenyl-ethyl or 2-4-chloro-phenoxy-ethyl,
R ² is dimethylamino, pyrrolidin-1-yl, piperidin-1-yl or morpholin-4-yl,
R ³ is amino, methylamino, acetylamino, nitro or methoxy, 1,2,4-oxadiazole derivatives or pharmaceutically acceptable salts thereof.

The method of claim 1, wherein the derivative of Formula 1
(1) 5- (4-chlorophenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (implemented Example 1);
(2) 5- (4-bromophenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole ( Example 2);
(3) 5- [4- (trifluoromethyl) phenyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4- Oxadiazole (Example 3);
(4) 5- (4-phenoxyphenyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole ( Example 4);
(5) 5- (biphenyl-4-yl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (Example 5);
(6) 5- (4'-fluorobiphenyl-4-yl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole (Example 6);
(7) 5- (biphenyl-4-ylmethyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadia Sol (Example 7);
(8) 5- [4- (trifluoromethyl) benzyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4- Oxadiazole (Example 8);
(9) 5- (4-fluorobenzyl) -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole ( Example 9);
(10) 5- [2- (4-fluorophenyl) ethyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole (Example 10);
(11) 5-[(4-chlorophenoxy) methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4-oxa Diazoles (Example 11);
(12) 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole (Example 12);
(13) 5-[[(3-chlorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole (Example 13);
(14) 5- [2- (4-chlorophenoxy) ethyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole (Example 14);
(15) 5-[[(4-fluorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole (Example 15);
(16) 5-[[(3,4-dichlorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2 , 4-oxadiazole (Example 16);
(17) 5-[[(3,4-difluorobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1 , 2,4-oxadiazole (Example 17);
(18) 5-[[(4-cyanobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole (Example 18);
(19) 5-[[(3-cyanobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole (Example 19);
(20) 5-[[(4-methylbenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole (Example 20);
(21) 5-[[(4-methoxybenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole (Example 21);
(22) 5-[[(3-acetylamino) phenoxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole (Example 22);
(23) 5-[[(4-nitrobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole (Example 23);
(24) 5-[[(4-acetylaminobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole (Example 24);
(25) 5-[[(3-nitrobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole (Example 25);
(26) 5-[[(3-acetylaminobenzyl) oxy] methyl] -3- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2, 4-oxadiazole (Example 26);
(27) 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-nitro-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4- Oxadiazole (Example 27);
(28) 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-amino-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4- Oxadiazole (Example 28);
(29) 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-acetylamino-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole (Example 29);
(30) 5-[[(4-chlorobenzyl) oxy] methyl] -3- [3-methylamino-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -1,2,4 Oxadiazole (Example 30);
(31) 5- (4-chlorophenyl) -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (implemented Example 31);
(32) 5-[(4-trifluoromethyl) phenyl] -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -1,2,4- Oxadiazole (Example 32);
(33) 5- (biphenyl-4-yl) -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole (Example 33);
(34) 5- (4-phenoxyphenyl) -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -1,2,4-oxadiazole ( Example 34);
(35) 5-[(4-chlorophenoxy) methyl] -3- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -1,2,4-oxa Diazoles (Example 35);
(36) 5- (4-chlorophenyl) -3- [3-methoxy-4- (2-morpholin-4-yl-ethoxy) phenyl] -1,2,4-oxadiazole (Example 36);
(37) 5-[(4-trifluoromethyl) phenyl] -3- [3-methoxy-4- (2-morpholin-4-yl-ethoxy) phenyl] -1,2,4-oxa Diazoles (Example 37);
(38) 5- (4-phenoxyphenyl) -3- [3-methoxy-4- (2-morpholin-4-yl-ethoxy) phenyl] -1,2,4-oxadiazole (implemented Example 38);
(39) 5- (biphenyl-4-yl) -3- [3-methoxy-4-[(2-dimethylamino) ethoxy] phenyl] -1,2,4-oxadiazole (Example 39 ); And
(40) 5-[(4-chlorophenoxy) methyl] -3- [3-methoxy-4-[(2-dimethylamino) ethoxy] phenyl] -1,2,4-oxadiazole Example 40) 1,2,4-oxadiazole derivatives or a pharmaceutically acceptable salt thereof, characterized in that any one selected from the group consisting of.

As shown in Scheme 1 below,
The hydroxyl group of the compound represented by the formula (2)

Preparing a compound represented by Chemical Formula 3 by introducing a substituent represented by Chemical Formula 3 (step 1);
Reacting the compound represented by Formula 3 obtained in step 1 with hydroxylamine hydrochloride to prepare an aminedoxim compound of Formula 4 (step 2); And
Method for preparing 1,2,4-oxadiazole derivatives of claim 1 comprising introducing a 1,2,4-oxadiazole ring into the compound represented by Formula 4 obtained in step 2 (step 3) :
[Reaction Scheme 1]

(In Scheme 1, R ¹ , R ² and R ³ are as defined in formula 1 of claim 1, wherein formulas 1a and 1b are derivatives of formula 1 of claim 1).

As shown in Reaction Scheme 2 below,
Reducing the nitro group of the compound represented by Formula 1a '(step A); And
Method for preparing the 1,2,4-oxadiazole derivative of claim 1 further comprising the step (step B) of introducing acetyl to the amine group of the compound represented by Formula 1c obtained in step A:
[Reaction Scheme 2]

(In Formula 2, Formulas 1a ', 1c and 1d are derivatives of Formula 1 of claim 1).

As shown in Scheme 3 below,
A method for preparing the 1,2,4-oxadiazole derivative of claim 1 further comprising the step of reducing the nitro group of the compound represented by Formula 1b:
[Reaction Scheme 3]

(In Scheme 3, R ¹ and R ² are as defined in Formula 1 of claim 1, wherein Formula 1b and 1e are derivatives of Formula 1 of claim 1).

As shown in Scheme 4,
A method for preparing the 1,2,4-oxadiazole derivative of claim 1 further comprising introducing acetyl to an amine group of a compound represented by Formula 1e:
[Reaction Scheme 4]

(In Reaction Scheme 4, R ¹ and R ² are as defined in Formula 1 of claim 1, Formula 1e and 1f are derivatives of Formula 1 of claim 1).

As shown in Scheme 5,
A method for preparing the 1,2,4-oxadiazole derivative of claim 1 further comprising introducing an alkyl group into an amine group of the compound represented by Formula 1e:
Scheme 5

(In Scheme 5, R ¹ and R ² are as defined in formula 1 of claim 1, wherein formulas 1e and 1g are derivatives of formula 1 of claim 1).

MCH selected from the group consisting of obesity, diabetes mellitus, metabolic disorders, anxiety and depression containing 1,2,4-oxadiazole derivatives represented by the formula (1) of claim 1 and pharmaceutically acceptable salts thereof as an active ingredient Pharmaceutical compositions for the prevention or treatment of diseases.

The pharmaceutical composition for preventing or treating MCH-related diseases according to claim 10, wherein the 1,2,4-oxadiazole derivatives of Chemical Formula 1 exhibit antagonistic activity against MCH receptors.

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