KR100847448B1 - 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives, method for the preparation thereof, and composition for preventing or treating obesity containing the same - Google Patents

Abstract

3-Aryl-5-alkyl-1,2,4-oxadiazole derivatives are provided to reduce eating by competing with MCH R1(melanin-concentrating hormone receptor subtype-1) associated with obesity, so that the compounds are useful for preventing or treating obesity. The 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives represented by the formula(1) are useful as antagonist of MCH R1, wherein R1 is (C3-C5) branched alkyl, (C1-C3)dialkylamino(C1-C3)alkyl or (C1-C3) linear alkyl which is optionally substituted by pyridine, piperidine or (C5-C7) cycloalkyl; R2 is halogen-substituted phenyl, CF3-substituted phenyl, phenyl substituted by phenoxy which is optionally substituted by halogen or (benzo[1,3]dioxol-5-yl)phenyl; and X is -NHCO or -NHCONH-. A method for preparing the 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives represented by the formula(1a) comprises the steps of: (1) reacting 4-aminobenzonitrile represented by the formula(2) with organic acid(R2COOH) in the presence of solvent and binding reagent to prepare amide compounds represented by the formula(3); (2) reacting the amide compounds represented by the formula(3) with hydroxylamine hydrochloride in the presence of solvent to prepare amidoxime represented by the formula(4); and (3) reacting the amidoxime represented by the formula(4) with another organic acid(R1COOH) in the presence of solvent and binding reagent to prepare 1,2,4-oxadiazole ring.

Description

3-aryl-5-alkyl-1,2,4-oxadiazole derivatives, preparation method thereof, and composition for preventing or treating obesity comprising the same {3-ARYL-5-ALKYL-1,2,4-OXADIAZOLE DERIVATIVES, METHOD FOR THE PREPARATION THEREOF, AND COMPOSITION FOR PREVENTING OR TREATING OBESITY CONTAINING THE SAME}

The present invention relates to a novel 3-aryl-5-alkyl-1,2,4-oxadiazole derivative, a preparation method thereof and a composition for preventing or treating obesity comprising the same as an active ingredient.

Melanin-concentrating hormone (MCH) is a cyclic peptide consisting of 19 amino acids and is known to be involved in mammalian feeding behavior. Administration of MCH in rats stimulates feeding, and in MCH-deficient mice, weight loss results from reduced feeding and increased metabolic rate. The effect of MCH on body weight is known to be due to MCH's intracellular receptor, melanin-concentration hormone receptor subtype-1 (MCH R1), and administration of MCH to animals that do not express MCH R1 does not stimulate feeding or cause obesity. (Witty et al , Bioorg. Med. Chem, Lett. 2006, 16 , 4865-4871).

According to the above results, antagonists for MCH R1 can be used as antiobesity agents, and recently, effects on depression or anxiety have been announced. In this regard, drugs developed by Amgen and GlaxoSmithKline (GW3430) are known to be currently in clinical trials (Dyck et. al , Bioorg . Med . Chem , Lett . 2006, 16 , 4237-4242.

On the other hand, obesity and overweight are serious social problems because they cause type 2 diabetes, heart disease, cancer and hypertension (Hu et al , Bioorg. Med. Chem, Lett. 2006, 16 , 5445-5450). However, currently available Xenical ^™ and Reductil ^™ Obesity treatments, such as the poor drug efficacy and has the disadvantages of showing side effects (Trisha Gura, Science 2003, 299 , 849-852).

Therefore, studies for the treatment of obesity are still active, and in recent years, the treatment of obesity through the MCH R1 antagonist is of interest.

Therefore, the present inventors are trying to develop a compound having an antagonistic effect on the MCH receptor, while a novel 3-aryl-5-alkyl-1,2,4-oxadiazole derivative having a specific structure acts as an antagonist of the MCH receptor By doing so, it has been found that it can be used as a prophylactic and therapeutic agent for obesity and completed the present invention.

It is therefore an object of the present invention to provide novel 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives and methods for their preparation.

Another object of the present invention is to provide a composition for preventing and treating obesity, containing the 3-aryl-5-alkyl-1,2,4-oxadiazole derivative as an active ingredient.

In accordance with the above object, the present invention provides a 3-aryl-5-alkyl-1,2,4-oxadiazole derivative of the formula (1) or a pharmaceutically acceptable salt thereof.

Where

R ₁ is (C ₃ -C ₅ ) branched alkyl, (C ₁ -C ₃ ) dialkylamino (C ₁ -C ₃ ) alkyl or (C ₁ -C ₄ ) straight chain alkyl, wherein (C ₁ -C ₄ In the case of linear alkyl, it may be optionally substituted with C ₄ -C ₅ heterocycloalkyl or heterocycloaryl or (C ₅ -C ₇ ) cycloalkyl including N, O or S as a hetero atom,

R ₂ is halogen-substituted phenyl; (C ₁ -C ₃ ) alkyl unsubstituted or substituted with halogen, (C ₁ -C ₃ ) alkoxy unsubstituted or substituted with halogen or phenyl substituted with aryloxy unsubstituted or substituted with halogen; Alkyl substituted with aryloxy unsubstituted or substituted with halogen; Or (benzo {1,3] dioxol-5-yl) phenyl,

X is -NHCO- or -NHCONH-.

According to the above another object, the present invention provides a method for preparing the 3-aryl-5-alkyl-1,2,4-oxadiazole derivative and the 3-aryl-5-alkyl-1,2,4-oxadiazole It provides a composition for preventing and treating obesity containing a derivative as an active ingredient.

Hereinafter, the present invention will be described in more detail.

Specific examples of the 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives of the present invention include those in Formula 1, wherein R ₁ is (pyridin-3-yl) ethyl, (piperidin-1-yl) ) Ethyl, cyclopentyl ethyl, (dimethylamino) methyl or isopropyl; R ₂ is 4-chlorophenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-chlorophenoxymethyl or (benzo [1, 3] dioxol-5-yl) phenyl.

Pharmaceutically acceptable salts of the 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives of the invention illustrate acid addition salts formed by pharmaceutically acceptable free acids. Can be. Examples of the free acid include inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid, nitric acid, sulfuric acid, and sulfonic acid, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, acetic acid, tartaric acid, and fumaric acid. The same organic acid may be used, preferably hydrochloric acid or methanesulfonic acid may be used.

Acid addition salt according to the present invention is prepared by a conventional method, for example, by dissolving the compound of formula (1) in an organic solvent, that is, methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, and filtering and drying the precipitate produced by adding an organic or inorganic acid. Alternatively, the solvent and excess acid can be prepared by distillation under reduced pressure, followed by drying or crystallization in an organic solvent.

The present invention encompasses all of the 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives and their pharmaceutically acceptable salts as well as the possible solvates, hydrates and stereoisomers that can be prepared therefrom. Include within.

Examples of preferred 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives of the present invention are as follows, and the respective structural formulas thereof are shown in Table 1 below:

1) 3- [4- (4-chlorobenzamido) phenyl] -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole

2) 3- [4- (4-phenoxybenzamido) phenyl] -5- [2- (piperidin-1-yll) ethyl] -1,2,4-oxadiazole

3) 3- {4- [4- (trifluoromethyl) benzamido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole

4) 3- [4- (3,5-dichlorobenzamido) phenyl] -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole

5) 3- {4-[(4-chlorophenoxy) acetamido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole

6) 3- {4- [3- (4-chlorophenyl) ureido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2, 4-oxadiazole

7) 3- {4- [3- (4-chlorophenyl) ureido] phenyl} -5- (2-cyclopentylethyl) -1,2,4-oxadiazole

8) 3- {4- [3- (4-chlorophenyl) ureido] phenyl} -5-[(dimethylamino) methyl] -1,2,4-oxadiazole

9) 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2, 4-oxadiazole

10) 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5- (2-cyclopentylethyl) -1,2,4-oxadiazole

11) 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5-[(dimethylamino) methyl] -1,2,4-oxadiazole

12) 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5- (isopropyl) -1,2,4-oxadiazole

13) 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5- [2- (pyridin-3-yl) ethyl] -1,2,4-oxadiazole

14) 3- (4- {3- [4- (trifluoromethyl) phenyl] ureido} phenyl) -5- [2- (piperidin-1 -yl) ethyl] -1,2,4- Oxadiazole

15) 3- {4- [3- (benzo [1,3] dioxol-5-yl) ureido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2 , 4-oxadiazole and

16) 3- {4- [3- (3-chloro-4-fluorophenyl) ureido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2,4- Oxadiazole

When X is -NHCO- in the 3-aryl-5-alkyl-1,2,4-oxadiazole derivative of the present invention represented by Formula 1 (compound of Formula 1a), the exemplified in Scheme 1 below Specifically, 4-aminobenzonitrile of Formula 2 and an organic acid (R ₂ COOH) may be reacted for about 15 hours at room temperature in the presence of a coupling reagent and optionally a base in a solvent. A first step of synthesizing the amide compound of; A second step of synthesizing the amidoxime compound of Formula 4 by refluxing for about 6 hours by adding hydroxylamine hydrochloride and optionally a base to the amide compound of Formula 3 in the presence of a solvent; And reacting the amidoxime compound of Formula 4 with another organic acid (R ₁ COOH) in a solvent at room temperature for about 12 hours in the presence of a binding reagent and optionally a base, and then at about 90 ° C. for about 5 hours to react 1,2,4 It can be prepared through the third step of synthesizing the oxadiazole ring.

In which R ₁ And R ₂ is as defined in formula (1).

In the above scheme, solvents may be conventionally known ones. For example, DMF or DCM may be used in the first step of synthesizing Formula 3, EtOH or MeOH in the second step of synthesizing Formula 4, and In the third step of synthesizing 1a, DMF can be used.

In addition, as a binding reagent in the synthesis of Chemical Formula 3 and Chemical Formula 1a (Steps 1 and 3), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohex Silkcarbodiimide (DCC) and (diisopropylcarbodiimide (DIC) can be used, wherein 4-dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBt) is used as a base to improve reactivity. Bases mixed with Et ₃ N or diisopropylethylamine (DIPEA) can be used together.

In addition, Et ₃ N, NaOMe, K ₂ CO ₃ or NaHCO ₃ may be used as a base in the step of synthesizing Formula 4 (step 2).

In addition, each reactant and binding reagent in each reaction may be added or reacted in a stoichiometric molar ratio or in excess of 1.2 equivalents, and the base may be added in a conventional amount, for example, about 0.1 to 1 equivalent ratio. have.

In the 3-aryl-5-alkyl-1,2,4-oxadiazole derivative of the present invention, when X is -NHCONH- (compound of Formula 1b), it can be prepared as illustrated in Scheme 2 below. Specifically, 4-aminobenzonitrile of Formula 2 is reacted with an isocyanate compound (R ₂ NCO) at room temperature for about 5 hours in the presence of a solvent or an amine compound (R ₂ NH ₂ ) and carbonyldiimidazole (CDI). ) Is reacted at room temperature for about 15 hours, and then heated at about 50 ° C. for about 5 hours to synthesize a urea derivative of Formula 5; A second step of synthesizing the amidoxime compound represented by Chemical Formula 6 by refluxing for about 6 hours by adding hydroxylamine hydrochloride and optionally a base to the urea derivative in the presence of a solvent; And reacting the amidoxime compound of Formula 6 with an organic acid (R ₁ COOH) in a solvent at room temperature for about 12 hours in the presence of a binding reagent and optionally a base, and then reacting at about 90 ° C. for about 5 hours to produce 1,2,4-oxa. It can be prepared through the step of synthesizing the diazole ring.

In which R ₁ And R ₂ is as defined in formula (1).

In addition, in the above formula, a solvent may be conventionally known ones, for example, DMF or DCM in the first step to synthesize the formula (5), EtOH or MeOH in the second step to synthesize the formula (6), In the third step of synthesizing Formula 1b, DMF may be used.

In addition, Et ₃ N, NaOMe, K ₂ CO ₃ or NaHCO ₃ may be used as the base in the step of synthesizing Chemical Formula 6 (second step).

In addition, in the step of synthesizing Chemical Formula 1b (Step 3), the binding reagents include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), and ( Diisopropylcarbodiimide (DIC) may be used, in which 4-dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBt) may be replaced with Et ₃ N or diisopropylethylamine ( Base mixed with DIPEA) can be used together.

In addition, each reactant and binding reagent in each reaction may be added or reacted in a stoichiometric molar ratio or in excess of 1.2 equivalents, and the base may be added in a conventional amount, for example, about 0.1 to 1 equivalent ratio. have.

3-aryl-5-alkyl-1,2,4-oxadiazole derivatives according to the present invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same are orally administrable in clinical administration It may be used in the form of a formulation, and when formulated, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants that are generally used.

Solid preparations for oral administration include tablets, pills, granules, capsules or troches, and the like, at least one of which is one or more 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives according to the present invention. Excipients, for example, can be prepared by mixing starch, calcium carbonate, sucrose, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. can be used in addition to commonly used simple diluents such as water and liquid paraffin. have.

In addition, the dosage to the human body of a pharmaceutical composition comprising the 3-aryl-5-alkyl-1,2,4-oxadiazole derivative of the present invention is determined by the age, weight, sex, dosage form, health status and It may vary depending on the degree of disease, preferably 0.01 ~ 200 ㎎ / ㎏ / day, can be divided into several times a day, preferably once to three times a day at regular intervals according to the judgment of the doctor or pharmacist have.

Hereinafter, the present invention will be described in more detail with reference to Examples.

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

Example 1: 4-chloro- N Preparation of-(4-cyanophenyl) benzamide (compound of formula 3)

DMF (70 mL) was dissolved in 4-chlorobenzoic acid (5.0 g, 31.9 mmol), and then 4-aminobenzonitrile (3.77 g, 31.9 mmol), EDCI (6.12 g, 31.9 mmol), and DMAP (0.39) were added thereto. g, 3.2 mmol) and stirred at room temperature for 15 hours. The reaction solution was distilled under reduced pressure to remove DMF. The residue was poured into water, extracted with CH ₂ Cl ₂ , dried over MgSO ₄ , filtered, and distilled under reduced pressure. The residue was separated by column chromatography (hexane / acetone, 4: 1) to give a white solid (4.8 g, 59%) of the compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.68 (s, 1H), 7.98 (d, 4H, J = 8.6 Hz), 7.80 (d, 2H, J = 8.6 Hz), 7.60 (d, 2H, J = 8.4 Hz).

Example 2: N Preparation of-(4-cyanophenyl) -4-phenoxybenzamide (compound of formula 3)

DMF (20 mL) was dissolved in 4-phenoxybenzoic acid (1.81 g, 8.46 mmol), and then 4-aminobenzonitrile (1.0 g, 8.46 mmol), EDCI (1.62 g, 8.46 mmol) and DMAP ( 103.8 mg, 0.85 mmol) was added and stirred at room temperature for 15 hours. The reaction solution was distilled under reduced pressure to remove DMF. The residue was poured into water, extracted with CH ₂ Cl ₂ , dried over MgSO ₄ , filtered, and distilled under reduced pressure. The residue was separated by column chromatography (hexane / acetone, 4: 1) to give a white solid (1.1 g, 41%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.84 (d, 2H, J = 8.7 Hz), 7.78 (d, 2H, J = 8.7 Hz), 7.65 (d, 2H, J = 8.5 Hz), 7.41 (m, 2H), 7.22 (t, 1H, J = 7.4 Hz), 7.07-7.04 (m, 4H).

Example 3:  N Preparation of-(4-cyanophenyl) -4- (trifluoromethyl) benzamide (compound of formula 3)

DMF (20 mL) was dissolved in 4- (trifluoromethyl) benzoic acid (1.61 g, 8.46 mmol), followed by 4-aminobenzonitrile (1.0 g, 8.46 mmol), EDCI (1.62 g, 8.46 mmol). ) And DMAP (103.8 mg, 0.85 mmol) were added and stirred at room temperature for 15 hours. The reaction solution was distilled under reduced pressure to remove DMF. The residue was poured into water, extracted with CH ₂ Cl ₂ , dried over MgSO ₄ , filtered, and distilled under reduced pressure. The residue was separated by column chromatography (hexane / acetone, 2: 1) to give a white solid (1.33 g, 54%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.12 (br s, 1H), 7.98 (d, 2H, J = 8.3 Hz), 7.82 (d, 2H, J = 8.5 Hz), 7.77 (d, 2H, J = 8.5 Hz), 7.67 (d, 2H, J = 8.5 Hz).

Example 4: N Preparation of-(4-cyanophenyl) -3,5-dichlorobenzamide (compound of formula 3)

DMF (20 mL) was dissolved in 3,4-dichlorobenzoic acid (1.46 g, 7.62 mmol), followed by 4-aminobenzonitrile (900 mg, 7.62 mmol), EDCI (1.46 g, 7.62 mmol) and DMAP. (92.8 mg, 0.76 mmol) was added and stirred at room temperature for 15 hours. The reaction solution was distilled under reduced pressure to remove DMF, and water was added to the residue, followed by extraction with AcOEt. The mixture was dried over MgSO ₄ , filtered, and distilled under reduced pressure. The residue was separated by column chromatography (hexane / acetone, 2: 1) to give a white solid (1.55 g, 70%) of the compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.79 (s, 1H), 7.97-7.93 (m, 4H), 7.90 (t, 1H, J = 2.0 Hz), 7.83 (m, 2H).

Example 5: 2- (4-chlorophenoxy)- N Preparation of-(4-cyanophenyl) acetamide (compound of formula 3)

DMF (20 mL) was dissolved in 4-chlorophenoxyacetic acid (1.58 g, 8.46 mmol), and then 4-aminobenzonitrile (1.0 g, 8.46 mmol), EDCI (1.62 g, 8.46 mmol) and DMAP. (103.8 mg, 0.85 mmol) was added and stirred at room temperature for 15 hours. The reaction solution was distilled under reduced pressure to remove DMF. The residue was poured into water, extracted with CH ₂ Cl ₂ , dried over MgSO ₄ , filtered, and distilled under reduced pressure. The residue was separated by column chromatography (hexane / acetone, 3: 1) to give a white solid (1.45 g, 60%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.53 (s, 1H), 7.80 (m, 4H), 7.35 (d, 2H, J = 9.1 Hz), 7.01 (d, 2H, J = 9.0 Hz) , 4.76 (s, 2 H).

Example 6: Preparation of 1- (4-chlorophenyl) -3- (4-cyanophenyl) urea (compound of formula 5)

DMF (20 mL) was added to 4-aminobenzonitrile (2.0 g, 16.9 mmol) and 4-chlorophenyl isocyanate (3.12 g, 20.3 mmol), followed by stirring at room temperature for 15 hours. The resulting solid was filtered and washed with CH ₂ Cl ₂ to give a white solid (3.42 g, 74%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.22 (s, 1H), 8.99 (s, 1H), 7.72 (d, 2H, J = 8.4 Hz), 7.62 (d, 2H, J = 8.7 Hz) , 7.49 (d, 2H, J = 8.7 Hz), 7.34 (d, 2H, J = 8.4 Hz).

Example 7: Preparation of 1- (4-cyanophenyl) -3- (4-phenoxyphenyl) urea (compound of formula 5)

To 4-aminobenzonitrile (1.0 g, 8.46 mmol), 4-phenoxyaniline (1.57 g, 8.46 mmol) and 1,1'-carbonyldiimidazole (1.37 g, 8.46 mmol) was added DMF (10 mL). After stirring at room temperature for 15 hours, it was made to react at 50 degreeC for 5 hours. The reaction solution was distilled off under reduced pressure to remove DMF and the residue was separated by column chromatography (hexane / AcOEt, 2: 1) to give a white solid (1.49 g, 53%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.19 (s, 1H), 8.88 (s, 1H), 7.72 (d, 2H, J = 8.8 Hz), 7.63 (d, 2H, J = 9.0 Hz) , 7.48 (d, 2H, J = 9.1 Hz), 7.35 (m, 2H), 7.08 (m, 1H), 6.96 (m, 4H).

Example 8: Preparation of 1- (4-cyanophenyl) -3- [4- (trifluoromethyl) phenyl] urea (compound of formula 5)

DMF (5 mL) was added to 4-aminobenzonitrile (500 mg, 4.23 mmol) and 4- (trifluoromethyl) phenyl isocyanate (604.2 μL, 4.23 mmol), followed by stirring at room temperature for 3 hours. CH ₂ Cl ₂ was added to the reaction solution to give a solid, which was filtered and washed with CH ₂ Cl ₂ to obtain a white solid (850 mg, 66%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.33 (s, 1H), 9.29 (s, 1H), 7.75 (m, 2H), 7.65 (m, 6H).

Example 9: Preparation of 1- (benzo [1,3] dioxol-5-yl) -3- (4-cyanophenyl) urea (compound of formula 5)

CH ₂ Cl ₂ (30 mL) was added to 4-aminobenzonitrile (1.41 g, 11.89 mmol) and 4- (methylenedioxy) phenyl isocyanate (1.94 g, 11.89 mmol), followed by stirring at room temperature for 6 hours. The resulting solid was filtered and washed with CH ₂ Cl ₂ to give a white solid. The filtrate was distilled under reduced pressure and separated by column chromatography (hexane / acetone, 2: 1) to give a white solid (2.66 g, 80%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.12 (s, 1H), 8.73 (s, 1H), 7.71 (d, 2H, J = 8.9 Hz), 7.60 (d, 2H, J = 9.1 Hz) , 7.18 (d, 1H, J = 2.1 Hz), 6.79 (m, 2H), 5.97 (s, 2H).

Example 10 Preparation of 1- (3-chloro-4-fluorophenyl) -3- (4-cyanophenyl) urea (compound of Formula 5)

CH ₂ Cl ₂ (10 mL) was added to 3-chloro-4-fluorophenyl isocyanate (1.2 mL, 9.63 mmol) and 4-aminobenzo-nitrile (1.37 g, 11.56 mmol), followed by stirring at room temperature for 5 hours. The resulting solid was filtered and washed with CH ₂ Cl ₂ to afford the white solid (1.52 g, 55%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.30 (s, 1H), 9.06 (s, 1H), 7.78 (m, 1H), 7.72 (d, 2H, J = 8.9 Hz), 7.33 (d, 2H, J = 8.9 Hz), 7.35 (m, 2H).

Example 11: 4-chloro- N -[4-( N Preparation of '-hydroxycarbamimidoyl) phenyl] benzamide (compound of formula 4)

4-Chloro- N- (4-cyanophenyl) benzamide (3.80 g, 14.8 mmol), hydroxyamine hydrochloride (1.03 g, 14.8 mmol) and triethylamine (Et ₃ N) prepared in Example ₁ ( 2.06 ml, 14.8 mmol) was added EtOH (200 ml) and refluxed for 6 hours. After the reaction solution was cooled to room temperature, the resulting solid was filtered and washed with AcOEt. The filtrate was concentrated again, then filtered and washed in the same manner to give a total of 4.12 g (96%) of the white solid of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 9.59 (s, 1H), 7.99 (d, 2H, J = 8.6 Hz), 7.78 (d, 2H, J = 8.6 Hz) , 7.67 (d, 2H, J = 8.6 Hz), 7.60 (d, 2H, J = 8.4 Hz), 5.80 (s, 2H).

Example 12: N -[4-( N Preparation of '-hydroxycarbamimidoyl) phenyl] -4-phenoxybenzamide (compound of formula 4)

N- (4-cyanophenyl) -4-phenoxybenzamide (930 mg, 2.96 mmol), hydroxyamine hydrochloride (205.7 mg, 2.96 mmol) and Et ₃ N (412.6 μL, 2.96 prepared in Example ₂ mmol) was added EtOH (30 mL) and refluxed for 6 hours. After cooling the reaction solution to room temperature, the resulting solid was filtered and washed with AcOEt to give a white solid (518 mg, 50%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.28 (s, 1H), 9.56 (s, 1H), 7.99 (d, 2H, J = 9.0 Hz), 7.75 (d, 2H, J = 8.7 Hz) , 7.64 (d, 2H, J = 8.7 Hz), 7.45 (m, 2H), 7.22 (t, 1H, J = 7.4 Hz), 7.12-7.07 (m, 4H), 5.77 (s, 2H).

Example 13: N -[4-( N Preparation of '-hydroxycarbamimidoyl) phenyl] -4- (trifluoromethyl) benzamide (compound of formula 4)

N- (4-cyanophenyl) -4- (trifluoromethyl) benzamide (1.22 g, 4.20 mmol), hydroxyamine hydrochloride (291.9 mg, 4.20 mmol) and Et ₃ N (prepared in Example ₃ ) 585.4 μl, 4.20 mmol) was added EtOH (30 mL) and refluxed for 6 hours. After the reaction solution was cooled to room temperature, the resulting solid was filtered and washed with AcOEt. The filtrate was concentrated again and then filtered and washed in the same manner to give 1.31 g (96%) of the white solid of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.56 (s, 1H), 9.59 (s, 1H), 8.14 (d, 2H, J = 8.2 Hz), 7.92 (d, 2H, J = 8.2 Hz) , 7.78 (d, 2H, J = 8.7 Hz), 7.67 (d, 2H, J = 8.7 Hz), 5.80 (s, 2H).

Example 14: N -[4-( N Preparation of '-hydroxycarbamimidoyl) phenyl] -3,5-dichlorobenzamide (compound of formula 4)

N- (4-cyanophenyl) -3,5-dichlorobenzamide (1.20 g, 4.12 mmol), hydroxyamine hydrochloride (286.3 mg, 4.12 mmol) and Et ₃ N (574.3 μl, prepared in Example 4) 4.12 mmol) was added EtOH (30 mL) and refluxed for 6 hours. After the reaction solution was cooled to room temperature, the resulting solid was filtered and washed with AcOEt. The filtrate was concentrated again and then filtered and washed in the same manner to give a total of 1.23 g (92%) of the white solid of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.63 (s, 1H), 9.60 (s, 1H), 8.02 (d, 2H, J = 1.9 Hz), 7.87 (t, 1H, J = 1.8 Hz) , 7.77 (d, 2H, J = 8.7 Hz). 7.65 (d, 2H, J = 8.7 Hz), 5.81 (s, 2H).

Example 15: 2- (4-Chlorophenoxy)- N -[4-( N Preparation of '-hydroxycarbamimidoyl) phenyl] acetamide (compound of formula 4)

Example A 2- (4-chlorophenoxy) prepared from 5 - N - (4-cyanophenyl) acetamide (1.16 g, 4.05 mmol), hydroxyl amine hydrochloride (281.4 mg, 4.05 mmol) and Et ₃ N EtOH (30 mL) was added to (564.5 μl, 4.05 mmol) and refluxed for 6 hours. The reaction solution was distilled under reduced pressure and the residue was separated by column chromatography (hexane / acetone, 1: 1) to give a white solid (470 mg, 36%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.19 (s, 1H), 9.55 (s, 1H), 7.62 (s, 4H), 7.36 (d, 2H, J = 9.0 Hz), 7.02 (d, 2H, J = 9.0 Hz), 5.75 (s, 2H), 4.72 (s, 2H).

Example 16: 1- (4-chlorophenyl) -3- [4- ( N Preparation of '-hydroxycarbamimidoyl) phenyl] urea (compound of formula 6)

EtOH (30 mL) in 1- (4-chlorophenyl) -3- (4-cyanophenyl) urea (1.77 g, 6.51 mmol) and hydroxyamine hydrochloride (452.4 mg, 6.51 mmol) prepared in Example 6. Et ₃ N (907.4 μl, 6.51 mmol) was added thereto, and the mixture was refluxed for 4 hours. After the reaction solution was cooled to room temperature, the resulting solid was filtered and washed with acetone. The filtrate was concentrated again and then filtered and washed in the same manner to give 1.19 g (60%) of the white solid of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.48 (s, 1H), 8.83 (s, 1H), 8.80 (s, 1H), 7.58 (d, 2H, J = 8.7 Hz), 7.48 (d, 2H, J = 8.9 Hz, 7.43 (d, 2H, J = 8.7 Hz), 7.32 (d, 2H, J = 8.9 Hz), 5.72 (s, 2H).

Example 17: 1- [4- ( N Preparation of '-hydroxycarbamimidoyl) phenyl] -3- (4-phenoxyphenyl) urea (compound of formula 6)

EtOH (10 mL) in 1- (4-cyanophenyl) -3- (4-phenoxyphenyl) urea (540 mg, 1.64 mmol) and hydroxyamine hydrochloride (119.5 mg, 1.72 mmol) prepared in Example 7. ) Was added, Et ₃ N (239.7 μl, 1.72 mmol) was added thereto, and the mixture was refluxed for 4 hours. After the reaction solution was cooled to room temperature, the resulting solid was filtered and washed with acetone. The filtrate was concentrated again and then filtered and washed in the same manner to give a total of 326 mg (55%) of the white solid of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.49 (s, 1 H), 8.75 (s, 1 H), 8.71 (s, 1 H), 7.58 (d, 2H, J = 8.9 Hz), 7.47 (m, 4H), 7.35 (m, 2H), 7.07 (m, 1H), 6.96 (m, 4H), 5.72 (s, 2H).

Example 18: 1- [4- ( N Preparation of '-hydroxycarbamimidoyl) phenyl] -3- [4- (trifluoromethyl) phenyl] urea (compound of formula 6)

To 1- (4-cyanophenyl) -3- [4- (trifluoromethyl) phenyl] urea (810 mg, 2.65 mmol) and hydroxyamine hydrochloride (184.2 mg, 2.65 mmol) prepared in Example 8 EtOH (20 mL) was added, and Et ₃ N (387.5 μl, 2.78 mmol) was added thereto and refluxed for 6 hours. After cooling the reaction solution to room temperature, the resulting solid was filtered and washed with CH ₂ Cl ₂ . The filtrate was concentrated again and then filtered and washed in the same manner to give a total of 434 mg (48%) of the white solid of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.50 (s, 1H), 9.13 (s, 1H), 8.90 (s, 1H), 7.64 (m, 4H), 7.59 (d, 2H, J = 8.7 Hz), 7.45 (d, 2H, J = 8.7 Hz), 5.73 (s, 2H).

Example 19: 1- (benzo [1,3] dioxol-5-yl) -3- [4- ( N Preparation of '-hydroxycarbamimidoyl) phenyl] urea (compound of formula 6)

1- (benzo [1,3] dioxol-5-yl) -3- (4-cyanophenyl) urea (1.64 g, 5.83 mmol) and hydroxyamine hydrochloride (425.3 mg, 6.12 prepared in Example 9 EtOH (50 mL) was added, followed by Et ₃ N (853.0 μl, 6.12 mmol), followed by reflux for 5 hours. After the reaction solution was cooled to room temperature, the resulting solid was filtered and washed with acetone. The filtrate was concentrated again and then filtered and washed in the same manner to give 1.06 g (58%) of the white solid of the title compound.

¹ H NMR (200 MHz, DMSO- d ₆ ) δ 9.47 (s, 1H), 8.70 (s, 1H), 8.58 (s, 1H), 7.58 (d, 2H, J = 8.6 Hz), 7.42 (d, 2H, J = 8.6 Hz), 7.20 (br s, 1H), 6.79 (m, 2H), 5.97 (s, 2H), 5.71 (s, 2H).

Example 20: 1- (3-chloro-4-fluorophenyl) -3- [4- ( N Preparation of '-hydroxycarbamimidoyl) phenyl] urea (compound of formula 6)

To 1- (3-chloro-4-fluorophenyl) -3- (4-cyanophenyl) urea (815 mg, 2.81 mmol) and hydroxyamine hydrochloride (205.0 mg, 2.95 mmol) prepared in Example 10 EtOH (50 mL) was added, and Et ₃ N (411.2 μl, 2.95 mmol) was added thereto and refluxed for 8 hours. The reaction solution was distilled under reduced pressure and the residue was separated by column chromatography (CH ₂ Cl ₂ / MeOH, 20: 1) to give a white solid (600 mg, 66%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.49 (s, 1H), 8.91 (s, 1H), 8.86 (s, 1H), 7.80 (m, 1H), 7.59 (d, 2H, J = 8.9 Hz), 7.44 (d, 2H, J = 8.9 Hz), 7.32 (m, 2H), 5.73 (s, 2H).

Example 21: 3- [4- (4-chlorobenzamido) phenyl] -5- [2- (piperidin-1-yl) ethyl] -1,2, 4-oxadiazole of Formula 1a Compound; Preparation of Compound 1)

4-Chloro- N- [4- ( N' -hydroxycarbamimidoyl) phenyl] benzamide (300 mg, 1.04 mmol), 1-piperidine propionic acid (163.5 mg, 1.04 mmol) prepared in Example 11 , DMF (20 mL) was added to EDCI (199.4 mg, 1.04 mmol) and DMAP (12.2 mg, 0.10 mmol), followed by stirring at room temperature for 12 hours, followed by further reaction at 90 ° C for 5 hours. The reaction solution was distilled under reduced pressure to remove DMF. The residue was poured into water, extracted with CH ₂ Cl ₂ , dried over MgSO ₄ , filtered, and distilled under reduced pressure. The residue was separated by column chromatography (CH ₂ Cl ₂ / MeOH, 20: 1) to give a white solid (132 mg, 31%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.17 (s, 1H), 8.06 (d, 2H, J = 8.4 Hz), 7.81 (d, 2H, J = 8.4 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.1 Hz), 3.14 (t, 2H, J = 7.5 Hz), 2.89 (t, 2H, J = 7.6 Hz), 2.48 (m, 4H), 1.58 (m , 4H), 1.45 (m, 2H); MS (m / z): 410 (M ⁺ ).

Example 22: 3- [4- (4-phenoxybenzamido) phenyl] -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole (Formula 1a) Compounds; Preparation of Compound 2)

Embodiment manufactured by Example 12 N - [4- (N ' - hydroxy-carbamimidoyl) phenyl] -4-phenoxy benzamide (300 mg, 0.86 mmol) was dissolved into DMF (10 ㎖) Next, here To 1-piperidine propionic acid (135.2 mg, 0.86 mmol), EDCI (164.9 mg, 0.86 mmol) and DMAP (10.1 mg, 0.09 mmol) were added and stirred at room temperature for 12 hours, followed by further reaction at 90 ° C for 5 hours. . The reaction solution was distilled under reduced pressure to remove DMF. The residue was poured into water, extracted with CH ₂ Cl ₂ , dried over MgSO ₄ , filtered, and distilled under reduced pressure. The residue was separated by column chromatography (CH ₂ Cl ₂ / MeOH, 20: 1) to give a white solid (50 mg, 12%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 8.06 (d, 2H, J = 8.5 Hz), 7.86 (d, 2H, J = 8.5 Hz), 7.78 (d, 2H, J = 8.5 Hz), 7.39 (t, 2H, J = 7.8 Hz), 7.19 (t, 1H, J = 7.3), 7.06 (d, 2H, J = 8.3 Hz), 7.02 (d, 2H, J = 8.5 Hz) , 3.14 (t, 2H, J = 7.6 Hz), 2.89 (t, 2H, J = 7.5 Hz), 2.48 (m, 4H), 1.59 (m, 4H), 1.45 (m, 2H); MS (m / z): 468 (M ⁺ )

Example 23: 3- {4- [4- (trifluoromethyl) benzamido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole Preparation of Compound (1a; Compound 3)

Example 13 a N manufactured by - [4- (N '- hydroxy-carbamimidoyl) phenyl] dissolved into the DMF (20 ㎖) on -4- (trifluoromethyl) benzamide (1.20 g, 3.71 mmol) Then, 1-piperidine propionic acid (583.3 mg, 3.71 mmol), EDCI (711.2 mg, 3.71 mmol) and DMAP (45.2 mg, 0.37 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours, followed by 5 at 90 ° C. The reaction was further time. The reaction solution was distilled under reduced pressure to remove DMF. The residue was poured into water, extracted with CH ₂ Cl ₂ , dried over MgSO ₄ , filtered, and distilled under reduced pressure. The residue was separated by column chromatography (CH ₂ Cl ₂ / MeOH, 30: 1) to give a white solid (375 mg, 23%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09 (d, 2H, J = 8.5 Hz), 8.04 (s, 1H), 7.99 (d, 2H, J = 8.0 Hz), 7.77 (m, 4H), 3.15 (t, 2H, J = 7.6 Hz), 2.89 (t, 2H, J = 7.5 Hz), 2.48 (m, 4H), 1.59 (m, 4H), 1.45 (m, 2H); MS (m / z): 444 (M ⁺ ).

Example 24 3- [4- (3,5-dichlorobenzamido) phenyl] -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole Compound of 1a; Preparation of Compound 4)

One embodiment N prepared in Example 14-a was put - [4- (N 'hydroxy-carbamimidoyl) phenyl] -3,5-dichloro-benzamide DMF (20 ㎖) a (1.14 g, 3.52 mmol) was dissolved and then, 1-piperidine propionic acid (553.4 mg, 3.52 mmol), EDCI (674.8 mg, 3.52 mmol) and DMAP (42.8 mg, 0.35 mmol) were added thereto, the mixture was stirred at room temperature for 12 hours, and further reacted at 90 ° C for 5 hours. I was. The reaction solution was distilled under reduced pressure to remove DMF. The residue was poured into water, extracted with CH ₂ Cl ₂ , dried over MgSO ₄ , filtered, and distilled under reduced pressure. The residue was separated by column chromatography (CH ₂ Cl ₂ / MeOH, 30: 1) to give a white solid (120 mg, 8%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.12 (s, 1H), 8.07 (d, 2H, J = 8.7 Hz), 7.78-7.74 (m, 4H), 7.53 (t, 1H, J = 1.8 Hz) , 3.15 (t, 2H, J = 7.7 Hz), 2.90 (t, 2H, J = 7.6 Hz), 2.49 (m, 4H), 1.59 (m, 4H), 1.45 (m, 2H); MS (m / z): 445 (M ⁺ ).

Example 25 3- {4-[(4-chlorophenoxy) acetamido] phenyl} -5 [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole Preparation of Compound (1a; Compound 5)

Example A 2- (4-chlorophenoxy) prepared in 15 - N - [4- (N '- hydroxy-carbamimidoyl) phenyl] into the DMF (5 ㎖) in acetamide (319.7 mg, 1.0 mmol) After dissolving, 1-piperidine propionic acid (157.2 mg, 1.0 mmol), EDCI (191.7 mg, 1.0 mmol) and DMAP (12.2 mg, 0.1 mmol) were added thereto, stirred at room temperature for 12 hours, and then stirred at 90 ° C. The reaction was further performed for 5 hours. The reaction solution was distilled under reduced pressure to remove DMF. The residue was poured into water, extracted with CH ₂ Cl ₂ , dried over MgSO ₄ , filtered, and distilled under reduced pressure. The residue was separated by column chromatography (CH ₂ Cl ₂ / MeOH, 20: 1) to give a white solid (230 mg, 52%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 8.08 (d, 2H, J = 8.7 Hz), 7.73 (d, 2H, J = 8.7 Hz), 7.33 (d, 2H, J = 9.2 Hz), 6.95 (d, 2H, J = 9.0 Hz), 4.61 (s, 2H), 3.14 (m, 2H), 2.89 (m, 2H), 2.48 (m, 4H), 1.59 (m, 4H) , 1.44 (m, 2 H); MS (m / z): 440 (M ⁺ ).

Example 26: 3- {4- [3- (4-chlorophenyl) ureido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole Preparation of Compound 1b; Compound 6

DMF (5 mL) was dissolved in 1- (4-chlorophenyl) -3- [4- ( N' -hydroxycarbamidomiyl) phenyl] urea (304.7 mg, 1.0 mmol) prepared in Example 16. Next, 1-piperidine propionic acid (157.2 mg, 1.0 mmol), EDCI (191.7 mg, 1.0 mmol) and DMAP (12.2 mg, 0.1 mmol) were added thereto and stirred at room temperature for 12 hours, followed by 3 hours at 90 ° C. Reacted further. The reaction solution was distilled under reduced pressure and the residue was separated by column chromatography (CH ₂ Cl ₂ / MeOH, 20: 1) to give a white solid (119 mg, 28%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.07 (s, 1H), 8.93 (s, 1H), 7.90 (d, 2H, J = 8.6 Hz), 7.62 (d, 2H, J = 8.8 Hz) , 7.50 (d, 2H, J = 8.8 Hz), 7.33 (d, 2H, J = 8.8 Hz), 3.13 (t, 2H, J = 7.2 Hz), 2.74 (t, 2H, J = 7.2 Hz), 2.38 (m, 4H), 1.44 (m, 4H), 1.35 (m, 2H); MS (m / z): 425 (M ⁺ ).

Example 27: 3- {4- [3- (4-chlorophenyl) ureido] phenyl} -5- (2-cyclopentylethyl)-1,2,4-oxadiazole (compound of Formula 1b; compound 7) Manufacture

DMF (3 mL) was dissolved in 1- (4-chlorophenyl) -3- [4- ( N' -hydroxycarbamidomiyl) phenyl] urea (304.7 mg, 1.0 mmol) prepared in Example 16. Next, 3-cyclopentylpropionic acid (142.8 μl, 1.0 mmol), EDCI (191.7 mg, 1.0 mmol), DMAP (12.2 mg, 0.1 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours, followed by 3 hours at 90 ° C. Reacted. The reaction solution was distilled under reduced pressure to remove DMF, and a small amount of water was added to the residue, followed by extraction with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , filtered and distilled under reduced pressure. The residue was separated by column chromatography (hexane / acetone, 3: 1) to give a white solid (184 mg, 45%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.06 (s, 1H), 8.91 (s, 1H), 7.91 (d, 2H, J = 8.7 Hz), 7.62 (d, 2H, J = 8.7 Hz) , 7.50 (d, 2H, J = 8.7 Hz), 7.33 (d, 2H, J = 8.9 Hz), 2.97 (t, 2H, J = 7.2 Hz), 1.78 (m, 5H), 1.50 (m, 4H) , 1.12 (m, 2 H); MS (m / z): 410 (M ⁺ ).

Example 28: 3- {4- [3- (4-chlorophenyl) ureido] phenyl} -5-[(dimethylamino) methyl]-1,2,4-oxadiazole (compound of Formula 1b; compound 8) Manufacture

DMF (3 mL) was dissolved in 1- (4-chlorophenyl) -3- [4- ( N' -hydroxycarbamidomiyl) phenyl] urea (304.7 mg, 1.0 mmol) prepared in Example 16. Next, N, N -dimethylglycine (103.1 mg, 1.0 mmol), EDCI (191.7 mg, 1.0 mmol) and DMAP (12.2 mg, 0.1 mmol) were added thereto, and stirred at room temperature for 12 hours, followed by 3 hours at 90 ° C. Reacted further. The reaction solution was distilled under reduced pressure to remove DMF, and a small amount of water was added to the residue, followed by extraction with CH ₂ Cl _{2. The} organic layer was dried over MgSO ₄ , filtered, and distilled under reduced pressure. The residue was separated by column chromatography (hexane / acetone, 1: 1) to give a white solid (153 mg, 41%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.07 (s, 1H), 8.92 (s, 1H), 7.93 (d, 2H, J = 8.7 Hz), 7.63 (d, 2H, J = 8.7 Hz) , 7.49 (d, 2H, J = 9.0 Hz), 7.33 (d, 2H, J = 8.9 Hz), 3.87 (s, 2H), 2.28 (s, 6H); MS (m / z): 371 (M ⁺ ).

Example 29: 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiaza Preparation of Sol (Compound 1b; Compound 9)

DMF (5 ml) was dissolved in 1- [4- ( N' -hydroxycarbamidoyl) phenyl] -3- (4-phenoxyphenyl) urea (363 mg, 1.0 mmol) prepared in Example 17. Then, 1-piperidine propionic acid (157.2 mg, 1.0 mmol), EDCI (191.7 mg, 1.0 mmol) and DMAP (12.2 mg, 0.1 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours, and then, 3 at 90 ° C. The reaction was further time. The reaction solution was distilled under reduced pressure and the residue was separated by column chromatography (CH ₂ Cl ₂ / MeOH, 20: 1) to give a white solid (130 mg, 27%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.02 (s, 1H), 8.80 (s, 1H), 7.90 (d, 2H, J = 8.6 Hz), 7.63 (d, 2H, J = 8.6 Hz) , 7.48 (d, 2H, J = 8.8 Hz), 7.35 (t, 2H, J = 7.7 Hz), 7.08 (t, 1H, J = 7.4 Hz), 6.97 (m, 4H), 3.13 (t, 2H, J = 7.2 Hz), 2.75 (t, 2H, J = 7.2 Hz), 2.38 (m, 4H), 1.44 (m, 4H), 1.35 (m, 2H); LC / MS: 484 (M ⁺ +1).

Example 30: 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5- (2-cyclopentylethyl)-1,2,4-oxadiazole (Compound 1b; Preparation of Compound 10)

DMF (3 ml) was dissolved in 1- [4- ( N' -hydroxycarbamimidyl) phenyl] -3- (4-phenoxyphenyl) urea (363 mg, 1.0 mmol) prepared in Example 17. Then, 3-cyclopentylpropionic acid (142.8 μl, 1.0 mmol), EDCI (191.7 mg, 1.0 mmol) and DMAP (12.2 mg, 0.1 mmol) were added thereto, the mixture was stirred at room temperature for 12 hours, and then stirred at 90 ° C. for 3 hours. Reacted further. The reaction solution was distilled under reduced pressure to remove DMF, and a small amount of water was added to the residue, followed by extraction with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , filtered and distilled under reduced pressure. The residue was separated by column chromatography (hexane / acetone, 3: 1) to give a white solid (190 mg, 41%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.00 (s, 1H), 8.78 (s, 1H), 7.90 (d, 2H, J = 8.7 Hz), 7.62 (d, 2H, J = 8.7 Hz) , 7.49 (d, 2H, J = 8.9 Hz), 7.35 (m, 2H), 7.08 (t, 1H, J = 7.4 Hz), 6.94 (m, 4H), 2.96 (m, 2H), 1.78 (m, 5H), 1.52 (m, 4H), 1.12 (m, 2H); MS (m / z): 468 (M ⁺ ).

Example 31: 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5-[(dimethylamino) methyl] -1, 1,2,4-oxadiazole (Compound 1b; Preparation of Compound 11)

DMF (3 ml) was dissolved in 1- [4- ( N' -hydroxycarbamimidyl) phenyl] -3- (4-phenoxyphenyl) urea (256 mg, 0.71 mmol) prepared in Example 17. Then, N, N -dimethylglycine (73.2 mg, 0.71 mmol), EDCI (136.1 mg, 0.71 mmol) and DMAP (8.6 mg, 0.07 mmol) were added thereto, and stirred at room temperature for 12 hours, followed by 4 at 90 ° C. The reaction was further time. The reaction solution was distilled under reduced pressure to remove DMF, and the residue was separated by column chromatography (hexane / acetone, 3: 1) to give a white solid (75 mg, 25%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.04 (s, 1H), 8.81 (s, 1H), 7.92 (d, 2H, J = 8.5 Hz), 7.64 (d, 2H, J = 8.7 Hz) , 7.49 (d, 2H, J = 8.7 Hz), 7.35 (m, 2H), 7.08 (t, 1H, J = 7.3 Hz), 6.97 (m, 4H), 3.87 (s, 1H), 2.28 (s, 6H); MS (m / z): 429 (M ⁺ ).

Example 32: 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5- (isopropyl) -1,2,4-oxadiazole (Compound 1b; Compound 12) Manufacture

DMF (3 mL) was dissolved in 1- [4- ( N' -hydroxycarbamidoyl) phenyl] -3- (4-phenoxyphenyl) urea (300 mg, 0.83 mmol) prepared in Example 17. Then, isobutyric acid (77.0 μl, 0.83 mmol), EDCI (159.1 mg, 0.83 mmol) and DMAP (9.8 mg, 0.08 mmol) were added thereto, stirred at room temperature for 12 hours, and further reacted at 90 ° C. for 4 hours. . The reaction solution was distilled under reduced pressure to remove DMF, and a small amount of water was added to the residue, followed by extraction with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , filtered and distilled under reduced pressure. The residue was separated by column chromatography (hexane / acetone, 3: 1) to give a white solid (200 mg, 58%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.00 (s, 1H), 8.77 (s, 1H), 7.91 (d, 2H, J = 8.5 Hz), 7.63 (d, 2H, J = 8.5 Hz) , 7.49 (d, 2H, J = 8.9 Hz), 7.35 (m, 2H), 7.08 (t, 1H, J = 7.3 Hz), 6.97 (m, 4H), 3.33 (m, 1H), 1.37 (d, 6H, J = 7.1 Hz); MS (m / z): 414 (M ⁺ ).

Example 33: 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5- [2- (pyridin-3-yl) ethyl] -1,2,4-oxadiazole ( Compound of Formula 1b; Preparation of Compound 13)

DMF (3 ml) was dissolved in 1- [4- ( N' -hydroxycarbamidoyl) phenyl] -3- (4-phenoxyphenyl) urea (260 mg, 0.72 mmol) prepared in Example 17. Then, 3-pyridinepropionic acid (108.9 mg, 0.72 mmol), EDCI (138.0 mg, 0.72 mmol), and DMAP (8.6 mg, 0.07 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours, followed by 4 hours at 90 ° C. Reacted. The reaction solution was distilled under reduced pressure and the residue was separated by column chromatography (hexane / acetone, 1: 1) to give a white solid (100 mg, 29%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ + D ₂ O) δ 8.98 (s, 1H), 8.75 (s, 1H), 8.46 (br s, 1H), 8.37 (m, 1H), 7.87 (br d , 2H, J = 8.7 Hz), 7.70 (m, 1H), 7.59 (br d, 2H, J = 8.7 Hz), 7.44 (br d, 2H, J = 9.0 Hz), 7.31 (m, 3H), 7.07 (br t, 1H, J = 7.4 Hz), 6.94 (m, 4H), 3.31 (br t, 2H, J = 7.3 Hz), 3.12 (br t, 2H, J = 7.2 Hz); MS (m / z): 477 (M ⁺ ).

Example 34: 3- (4- {3- [4- (trifluoromethyl) phenyl] ureido} phenyl) -5- [2- (piperidin-1-yl) ethyl] -1,2, Preparation of 4-oxadiazole (compound of Formula 1b; Compound 14)

To 1- [4- ( N' -hydroxycarbamidoyl) phenyl-3- [4- (trifluoromethyl) phenyl] urea (700 mg, 2.07 mmol) prepared in Example 18, DMF (10 mL) 1-piperidine propionic acid (325.4 mg, 2.07 mmol), EDCI (396.8 mg, 2.07 mmol) and DMAP (252.9 mg, 2.07 mmol) were added thereto and stirred at room temperature for 12 hours. It was made to react at 4 degreeC further. The reaction solution was distilled under reduced pressure to remove DMF, and a small amount of water was added to the residue, followed by extraction with CH ₂ Cl ₂ , followed by drying with MgSO ₄ , filtration, and distillation under reduced pressure. The residue was separated by column chromatography (hexane / acetone, 1: 1) to give a white solid (320 mg, 34%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.21 (s, 1H), 9.17 (s, 1H), 7.92 (d, 2H, J = 8.9 Hz), 7.66 (m, 6H), 3.13 (t, 2H, J = 7.3 Hz, 2.75 (t, 2H, J = 7.3 Hz), 2.38 (m, 4H), 1.45 (m, 4H), 1.36 (m, 2H); MS (m / z): 460 (M ⁺ +1).

Example 35: 3- {4- [3- (benzo [1,3] dioxol-5-yl) ureido] phenyl} -5- [2- (piperidin-1 -yl) ethyl] -1 Preparation of 2,4-oxadiazole (compound of Formula 1b; Compound 15)

To 1- (benzo [1,3] dioxol-5-yl) -3- [4- ( N -hydroxycarbamimidoyl) phenyl] urea (890 mg, 2.83 mmol) prepared in Example 19 was added DMF ( 10 ml) was added to dissolve it, and then 1-piperidine propionic acid (444.9 mg, 2.83 mmol), EDCI (542.5 mg, 2.83 mmol) and DMAP (34.2 mg, 0.28 mmol) were added thereto and stirred at room temperature for 12 hours. After that, the mixture was further reacted at 90 ° C. for 5 hours. The reaction solution was distilled under reduced pressure and the residue was separated by column chromatography (CH ₂ Cl ₂ / MeOH, 20: 1) to give a white solid (550 mg, 45%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.95 (s, 1H), 8.65 (s, 1H), 7.90 (d, 2H, J = 8.9 Hz), 7.61 (d, 2H, J = 8.6 Hz) , 7.21 (d, 1H, J = 1.8 Hz), 6.85-6.75 (m, 2H), 5.97 (s, 2H), 3.12 (t, 2H, J = 7.3 Hz), 2.75 (t, 2H, J = 7.3 Hz), 2.38 (m, 4H), 1.45 (m, 4H), 1.36 (m, 2H); MS (m / z): 435 (M ⁺ ).

Example 36: 3- {4- [3- (3-chloro-4-fluorophenyl) ureido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2, Preparation of 4-oxadiazole (compound of Formula 1b; Compound 16)

To 1- (3-chloro-4-fluorophenyl) -3- [4- ( N -hydroxycarbamimidoyl) phenyl] urea (168 mg, 0.52 mmol) prepared in Example 20, DMF (3 mL) 1-piperidine propionic acid (81.7 mg, 0.52 mmol), EDCI (99.7 mg, 0.52 mmol) and DMAP (6.1 mg, 0.05 mmol) were added thereto, the mixture was stirred at room temperature for 12 hours, and then 90 It was made to react at 4 degreeC further. The reaction solution was distilled under reduced pressure and the residue was separated by column chromatography (CH ₂ Cl ₂ / MeOH, 15: 1) to give a white solid (110 mg, 48%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.16 (s, 1H), 9.02 (s, 1H), 7.90 (d, 2H, J = 8.6 Hz), 7.81 (m, 1H), 7.63 (d, 2H, J = 8.9 Hz, 7.33 (m, 2H), 3.13 (t, 2H, J = 7.2 Hz), 2.76 (t, 2H, J = 7.3 Hz), 2.39 (m, 4H), 1.46 (m, 4H), 1.36 (m, 2H); LC / MS: 444 (M ⁺ + H).

The following experiments were performed on the 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives of the present invention.

Experimental Example: Measurement of antagonism of 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives against MCH receptor

The buffer solution was prepared in two forms, a washing solution (25 mM HEPES pH7.4, 5 mM MgCl ₂ , 1 mM CaCl ₂ ) and an experimental solution (adding 0.5% BSA to the washing solution), and MCH R1 (Melanin Concentration). 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 Eu-MCH and 1 mM MCH 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 washing solution was used only to wash the plate at the end.

First, homogenize by diluting MCH R1 (200 assays / vial) in 1 ml of experimental solution, and then using an 8-channel pipette on a filter paper-attached microplate (Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA). (multi 8-channel, Eppendorf, Hamburg, Germany) was used to dispense the reaction to 100 μl total volume per well. At this time, 25 μl of Eu-MCH, 50 μl of receptor and 25 μl of MCH were used as a non-specific binding control, and 25 μl of 10% DMSO experimental solution and Eu-MCH 25 were used as the total binding control. Μl and 50 μl of receptor were used. As the experimental group, 25 µl of the compound prepared in Example, 25 µl of Eu-MCH and 50 µl of receptor were used. Each test compound, Eu-MCH and MCH, accounted for 25% of the total volume during the reaction, and was prepared at a concentration of 4 times immediately before addition. Then, shake gently for 15 seconds and reacted at room temperature for 90 minutes. After the reaction, the plate was washed by applying pressure to a partially prepared washer (microplate washer, EMBLA, Molecular Devices). 300 μl / well of the wash solution was filtered three times to remove Eu-MCH 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 ~ 4 hours, the time-resolved fluorescence (TRF) value was measured using a multi-function fluorimeter (multilabel counter, Victor2, PerkinElmer, Turku, Finland) (emission wavelength: 615 nm, Excitation wavelength: 340 nm), the differential fluorescence inhibition rate was calculated according to the following equation, and the results are shown in Table 2 below.

Differential Fluorescence Inhibition Ratio = [(Total Binding Average Value-Test Material's Differential Fluorescence Value) / (Total Binding Average Value-Nonspecific Binding Average Value)] * 100

As shown in Table 2, the compounds of the present invention exhibited an antagonistic action on the MCH receptor, of which compounds No. 2, 3, 6, 9, 14 showed IC ₅₀ of 4 μM or less. In particular, compound 14 yields an IC ₅₀ of 92 nM. It showed the best MCH receptor inhibitory effect. From these results, it was confirmed that the 3-aryl-5-alkyl-1,2,4-oxadiazole derivative of the present invention is effective as an antagonist to the MCH receptor and can be applied as a therapeutic drug for obesity and metabolic disorders. .

As described above, the 3-aryl-5-alkyl-1,2,4-oxadiazole derivative of the present invention is effectively used as an antagonist to the MCH (melanin enriched hormone) receptor, and for the treatment of obesity and metabolic disorders. Can be.

Claims (13)

3-aryl-5-alkyl-1,2,4-oxadiazole derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof: [Formula 1]

R ₁ is (C ₃ -C ₅ ) branched alkyl, (C ₁ -C ₃ ) dialkylamino (C ₁ -C ₃ ) alkyl or (C ₁ -C ₄ ) straight chain alkyl, wherein (C ₁ -C ₄ ) Can be optionally substituted with pyridine, piperidine or (C ₅ -C ₇ ) cycloalkyl, R ₂ is halogen-substituted phenyl; Phenyl substituted with CF ₃ ; Phenyl substituted with halogen or unsubstituted phenoxy; Or (benzo [1,3] dioxol-5-yl) phenyl, X is -NHCO- or -NHCONH-. The method of claim 1, R ₁ is (pyridin-3-yl) ethyl, (piperidin-1-yl) ethyl, cyclopentylethyl, (dimethylamino) methyl or isopropyl; R ₂ is 4-chlorophenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl or (benzo [1,3] dioxol-5- 1) phenyl, 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives or pharmaceutically acceptable salts thereof. The method of claim 1, 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives or pharmaceutically acceptable salts thereof, characterized in that they are selected from the group consisting of 1) 3- [4- (4-chlorobenzamido) phenyl] -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole 2) 3- [4- (4-phenoxybenzamido) phenyl] -5- [2- (piperidin-1-yll) ethyl] -1,2,4-oxadiazole 3) 3- {4- [4- (trifluoromethyl) benzamido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole 4) 3- [4- (3,5-dichlorobenzamido) phenyl] -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole 5) 3- {4-[(4-chlorophenoxy) acetamido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole 6) 3- {4- [3- (4-chlorophenyl) ureido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole 7) 3- {4- [3- (4-chlorophenyl) ureido] phenyl} -5- (2-cyclopentylethyl) -1,2,4-oxadiazole 8) 3- {4- [3- (4-chlorophenyl) ureido] phenyl} -5-[(dimethylamino) methyl] -1,2,4-oxadiazole 9) 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazole 10) 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5- (2-cyclopentylethyl) -1,2,4-oxadiazole 11) 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5-[(dimethylamino) methyl] -1,2,4-oxadiazole 12) 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5- (isopropyl) -1,2,4-oxadiazole 13) 3- {4- [3- (4-phenoxyphenyl) ureido] phenyl} -5- [2- (pyridin-3-yl) ethyl] -1,2,4-oxadiazole 14) 3- (4- {3- [4- (trifluoromethyl) phenyl] ureido} phenyl) -5- [2- (piperidin-1-yl) ethyl] -1,2,4- Oxadiazole 15) 3- {4- [3- (benzo [1,3] dioxol-5-yl) ureido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2 , 4-oxadiazole and 16) 3- {4- [3- (3-chloro-4-fluorophenyl) ureido] phenyl} -5- [2- (piperidin-1-yl) ethyl] -1,2,4- Oxadiazole. 1) reacting 4-aminobenzonitrile of Formula 2 with an organic acid (R ₂ COOH) in the presence of a solvent and a coupling reagent to synthesize an amide compound of Formula 3; 2) synthesizing the amidoxime compound of Formula 4 by refluxing by adding hydroxylamine hydrochloride in the presence of a solvent to the amide compound of Formula 3; And 3) reacting the amidoxime compound of Formula 4 with another organic acid (R ₁ COOH) in the presence of a solvent and a coupling reagent to synthesize 1,2,4-oxadiazole ring, wherein Process for the preparation of -aryl-5-alkyl-1,2,4-oxadiazole derivatives:

Wherein R ₁ and R ₂ are as defined in claim 1. The method of claim 4, wherein The binding reagents in the first and third steps are 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC). ), A process for producing 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives. The method of claim 4, wherein In the above steps 1) and 3) further using a base obtained by mixing 4-dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBt) with Et ₃ N or diisopropylethylamine (DIPEA) Method for producing a 3-aryl-5-alkyl-1,2,4-oxadiazole derivative, characterized in that. The method of claim 4, wherein Preparation of 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives, further comprising using Et ₃ N, NaOMe, K ₂ CO ₃ or NaHCO ₃ as the base in step 2). Way. 1) Reacting 4-aminobenzonitrile of Formula 2 with an isocyanate compound (R ₂ NCO) in the presence of a solvent or with an amine compound (R ₂ NH ₂ ) and carbonyldiimidazole (CDI) Synthesizing urea derivatives; 2) synthesizing the amidoxim compound of Formula 6 by refluxing by adding hydroxylamine hydrochloride in the presence of a solvent to the urea derivative of Formula 5; And 3) reacting the amidoxime compound of Formula 6 with an organic acid (R ₁ COOH) in the presence of a solvent and a coupling reagent to synthesize 1,2,4-oxadiazole ring, 3-aryl of Formula 1b Process for preparing -5-alkyl-1,2,4-oxadiazole derivatives: [Formula 2]

Wherein R ₁ and R ₂ are as defined in claim 1. The method of claim 8, The binding reagent used in step 3) is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC). Method for producing a 3-aryl-5-alkyl-1,2,4-oxadiazole derivative, characterized in that. The method of claim 8, In step 3), a mixed base of 4-dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBt) and Et ₃ N or diisopropylethylamine (DIPEA) is further used. , 3-aryl-5-alkyl-1,2,4-oxadiazole derivative. The method of claim 8, Preparation of 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives, further comprising using Et ₃ N, NaOMe, K ₂ CO ₃ or NaHCO ₃ as the base in step 2). Way. delete A composition for the prevention or treatment of obesity, comprising as an active ingredient a 3-aryl-5-alkyl-1,2,4-oxadiazole derivative of Formula 1 or a pharmaceutically acceptable salt thereof.