KR102176621B1 - A phenylpyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating Glucagon Receptor activity related diseases containing the same as an active ingredient - Google Patents

Abstract

It relates to a phenylpyrimidine derivative, a preparation method thereof, and a pharmaceutical composition for preventing or treating diseases related to glucagon receptor activity containing the same as an active ingredient, wherein the phenylpyrimidine derivative is excellent in inhibiting cAMP or glucagon production, thereby inhibiting GCGR activity. It has been confirmed not only in vitro but also in vivo as well as in vitro and has low cytotoxicity, and its safety has been verified, so it can be usefully used in the treatment of metabolic diseases, especially diabetes, which are diseases related to GCGR activity. .

Description

Phenylpyrimidine derivatives, preparation methods thereof, and pharmaceutical compositions for preventing or treating diseases related to glucagon receptor activity containing them as active ingredients {A phenylpyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating Glucagon Receptor activity related diseases containing the same as an active ingredient}

It relates to a phenylpyrimidine derivative, a preparation method thereof, and a pharmaceutical composition for preventing or treating diseases related to glucagon receptor activity containing the same as an active ingredient.

Glucagon is an endocrine hormone secreted by the alpha cells of the pancreatic islet of Langerhans. It increases glycogenolysis and glucose neosynthesis in the liver, thereby promoting the production of glucose (glucose) in the blood. It is well known to increase

Glucagon acts on target tissues through the glucagon receptor (GCGR), one of the seven-transmembrane G-protein coupled receptor superfamily. Glucagon, which binds to GCGR, activates adenylyl cyclase and increases intracellular cyclic adenosine monophosphate (cAMP), causing biological effects. Inhibition of GCGR by GCGR neutralizing antibodies, anti-sense oligonucleotides and/or peptides and small molecule GCGR antagonists has been shown to reduce hepatic glucose production and improve glucose tolerance in various diabetes models. appear.

In type 2 diabetes, hyperglucagonemia is associated with hyperglycemia, and elevated glucagon levels exacerbate the hyperglycemic condition by increasing hepatic glucose production. Therefore, reducing glucagon levels or inhibiting glucagon action may be a logical therapeutic strategy for the treatment of diabetes.

To date, Bayer's BAY 27-9955, Merck's MK-0893/MK-3577, Pfizer's PF-06291874, and Eli Lily's LY-2409021 have been developed, but development has been stopped due to various side effects in clinical trials.

Republic of Korea Patent Publication 1020150118203

One object of the present invention is to provide a phenylpyrimidine derivative.

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

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases containing a phenylpyrimidine derivative as an active ingredient.

Another object of the present invention is to provide a functional food composition for preventing or improving metabolic diseases containing a phenylpyrimidine derivative as an active ingredient.

To achieve the above object,

According to an aspect of the present invention, there is provided a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Formula 1,

R ¹ is independently hydrogen, halogen, straight-chain or branched C _1-10 alkyl unsubstituted or substituted with one or more halogens, straight-chain or branched C _1-10 alkoxy unsubstituted or substituted with one or more halogens, non-substituted Cyclic C _6-10 aryl or unsubstituted C _6-10 aryloxy;

R ² is unsubstituted straight or branched C _1-10 alkyl;

R ³ is independently hydrogen, halogen, straight-chain or branched C _1-10 alkyl unsubstituted or substituted with one or more halogens, or straight-chain or branched C _1-10 alkoxy unsubstituted or substituted with one or more halogens;

l is an integer from 1 to 5;

m is an integer from 1 to 4; And

n is an integer from 1 to 7).

According to another aspect of the present invention, as shown in Scheme 1 below,

Reacting a compound represented by Formula 3 with a compound represented by Formula 4 to obtain a compound represented by Formula 3 (Step 1); And

There is provided a method for preparing a compound represented by Formula 1, comprising the step of obtaining a compound represented by Formula 1 by hydrolyzing the compound represented by Formula 2 obtained in Step 1 (Step 2):

[Scheme 1]

(In the above Scheme 1,

R ¹ , R ² , R ³ , l, m and n are as defined in Formula 1;

R ⁴ is straight or branched C _1-5 alkyl;

X ¹ is halogen; And

또는

이다).L ¹ is

or

to be).

According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating metabolic diseases containing a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

According to another aspect of the present invention, there is provided a health functional food composition for preventing or improving metabolic diseases containing a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

According to another aspect of the present invention, there is a need for a pharmaceutical composition or a health functional food composition for preventing or treating metabolic diseases containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. A method of preventing or treating a metabolic disease comprising administering to a subject is provided.

According to another aspect of the present invention, in the prevention or treatment of metabolic diseases, for the prevention or treatment of metabolic diseases containing a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient The use of a pharmaceutical composition or a dietary food composition is provided.

The compound represented by Formula 1 of the present invention has excellent cAMP or glucagon production inhibitory effect, exhibits GCGR activity inhibitory effect, and has been confirmed not only in vitro but also in vivo, and has low cytotoxicity and safety. As proven, it can be usefully used in the treatment of metabolic diseases, especially diabetes, which are diseases related to GCGR activity.

1 shows the evaluation of the cell viability of the Example compound.
7a: Example 1, 7b: Example 2, 7c: Example 3, 7d: Example 4, 7e: Example 5, 7f: Example 6, 7g: Example 7, 7h: Example 8, 7i: Example 9, 7j: Example 10, GA: Comparative Example 2
Figure 2 shows the intracellular glucagon-induced cAMP production rate according to the treatment of the compound of the present invention.
7a: Example 1, 7b: Example 2, 7c: Example 3, 7d: Example 4, 7e: Example 5, 7f: Example 6, 7g: Example 7, 7h: Example 8, 7i: Example 9, 7j: Example 10, GA: Comparative Example 2
Figure 3 shows the intracellular glucagon-induced glucose production rate according to the treatment of the compound of the present invention.
7a: Example 1, 7b: Example 2, 7c: Example 3, 7d: Example 4, 7e: Example 5, 7f: Example 6, 7g: Example 7, 7h: Example 8, 7i: Example 9, 7j: Example 10, GA: Comparative Example 2
4 shows the results of evaluating the degree of inhibition of glucagon-induced cAMP production according to the treatment concentration of the compound of the present invention.
7a: Example 1, 7f: Example 6, 7g: Example 7, 7i: Example 9, 7j: Example 10
Figure 5 shows the glucagon-induced glucose production rate according to the treatment concentration of the compound of the present invention.
7a: Example 1, 7f: Example 6, 7g: Example 7
6 shows the results of measuring the inhibitory effect of glucagon-induced glucose production according to the enantiomeric compound treatment.
7a: Example 1, (S)-7a: Example 12, (R)-7a: Example 11, 7f: Example 6, (S)-7f: Example 16, (R)-7f: Example 15
7 shows the results of measuring the cell viability according to the treatment of the enantiomeric compound.
7a: Example 1, (S)-7a: Example 12, (R)-7a: Example 11, 7f: Example 6, (S)-7f: Example 16, (R)-7f: Example 15
8 shows the results of measuring the blood glucose concentration according to the compound treatment.
(S)-7a: Example 12, (R)-7a: Example 11, LY-2409021: Comparative Example 1
9 shows the change in blood glucagon-induced glucose concentration according to the compound treatment.
(S)-7a: Example 12, (R)-7a: Example 11, LY-2409021: Comparative Example 1
Figure 10 shows by evaluating the GCGR signaling inhibitory effect of the Example compound.
SD-366: Example 17, SD-367: Example 18, SD-368: Example 19, SD-369: Example 20, SD-370: Example 21, SD-371: Example 22, SD- 372: Example 23, SD-373: Example 24, SD-374: Example 25, SD-375: Example 26, SD-376: Example 27, SD-499: Example 28, SD-500: Example 29, SD-501: Example 30, SD-502: Example 31, SD-503: Example 32, SD-504: Example 33, SD-505: Example 34, SD-506: Example 35, 7a: Example 1, 7b: Example 2, 7c: Example 3, 7d: Example 4, 7e: Example 5, 7f: Example 6, 7g: Example 7, 7h: Example 8, 7i: Example 9, 7j: Example 10

Hereinafter, the present invention will be described in detail.

An aspect of the present invention provides a compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

R ¹ is independently hydrogen, halogen, straight-chain or branched C _1-10 alkyl unsubstituted or substituted with one or more halogens, straight-chain or branched C _1-10 alkoxy unsubstituted or substituted with one or more halogens, non-substituted Cyclic C _6-10 aryl or unsubstituted C _6-10 aryloxy;

R ² is unsubstituted straight or branched C _1-10 alkyl;

R ³ is independently hydrogen, halogen, straight-chain or branched C _1-10 alkyl unsubstituted or substituted with one or more halogens, or straight-chain or branched C _1-10 alkoxy unsubstituted or substituted with one or more halogens;

l is an integer from 1 to 5;

m is an integer from 1 to 4; And

n is an integer of 1 to 7.

In Formula 1,

R ¹ is independently hydrogen, halogen, straight or branched C _1-6 alkyl unsubstituted or substituted with one or more halogens, straight or branched C _1-6 alkoxy unsubstituted or substituted with one or more halogens, It may be unsubstituted phenyl or unsubstituted phenoxy.

In addition, the R ¹ is independently hydrogen, halogen, straight or branched C _1-4 alkyl unsubstituted or substituted with one or more halogens, straight or branched C _1-4 unsubstituted or substituted with one or more halogens It may be alkoxy, unsubstituted phenyl or unsubstituted phenoxy.

In addition, R ¹ may be independently hydrogen, Cl, Et, t-Bu, CF ₃ or phenoxy.

In Formula 1,

R ² may be an unsubstituted linear or branched C _1-6 alkyl.

In addition, R ² may be an unsubstituted linear or branched C _1-6 alkyl.

In addition, R ² may be an unsubstituted linear or branched C _1-4 alkyl.

In addition, R ² may be Me, i-Bu or n-Bu.

In Formula 1,

Wherein R ³ is independently hydrogen, halogen, C _1-6 alkoxy or unsubstituted C _1-6 alkyl or unsubstituted or straight or branched chain substituted with one or more halogens in a straight or branched chain substituted with one or more halogen days I can.

Further, the R ³ is independently C _1-3 of hydrogen, halogen, unsubstituted or with one or more C _1-3 alkyl or unsubstituted or substituted by one or more halogens in a straight or branched chain substituted with a halogen-substituted straight-chain or branched-chain It can be alkoxy.

In addition, R ³ may be hydrogen.

In Formula 1,

The l may be an integer of 1 to 3, may be 1 or 2.

The m may be 1 or 2, and may be 1.

The n may be an integer of 1 to 5, may be an integer of 1 to 3, and may be 2.

In Formula 1,

는 페닐에 결합된 알킬옥시와 파라 (para) 위치로 결합될 수 있다. 보다 상세히는, 상기

는 페닐에 결합된 알킬옥시와 파라위치로 결합하여 하기 화학식 1a로 표시되는 화합물을 형성할 수 있다.

May be bonded to the phenyl-linked alkyloxy and para-position. In more detail, the above

May be bonded to the alkyloxy bonded to phenyl in a para position to form a compound represented by the following formula (1a).

[Formula 1a]

Formula 1a is a derivative of Formula 1.

Examples of the compound represented by Formula 1 according to the present invention include the following compounds:

<1> 3-(4-(1-((5-phenylpyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<2> 3-(4-(1-((5-(2-chlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<3> 3-(4-(1-((5-(3-chlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<4> 3-(4-(1-((5-(4-chlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<5> 3-(4-(1-((5-(4-trifluoromethylphenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<6> 3-(4-(1-((5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<7> 3-(4-(1-((5-(3,5-dichlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<8> 3-(4-(1-((5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid ;

<9> 3-(4-(1-((5-(4-phenoxyphenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<10> 3-(4-(1-((5-(4-Ethylphenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<11> (R)-3-(4-(1-(5-phenylpyrimidin-2-yloxy)pentyl)benzamido)propanoic acid;

<12> (S)-3-(4-(1-(5-phenylpyrimidin-2-yloxy)pentyl)benzamido)propanoic acid;

<13> (R)-3-(4-(1-((5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<14> (S)-3-(4-(1-((5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<15> (R)-3-(4-(1-((5-(3,5-dichlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<16> (S)-3-(4-(1-((5-(3,5-dichlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;

<17> 3-(4-(1-(5-(4-bromophenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;

<18> 3-(4-(1-(5-phenylpyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;

<19> 3-(4-(1-(5-(4-chlorophenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;

<20> 3-(4-(1-(5-(4-(trifluoromethyl)phenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;

<21> 3-(4-(1-(5-(4-tert-butylphenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;

<22> 3-(4-(1-(5-(3,5-dichlorophenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;

<23> 3-(4-(1-(5-(3-methoxyphenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;

<24> 3-(4-(1-(5-(5-isopropyl-2-methoxyphenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;

<25> 3-(4-(1-(5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;

<26> 3-(4-(1-(5-(4-tert-butylphenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid;

<27> 3-(4-(3-methyl-1-(5-(4-(trifluoromethyl)phenyl)pyrimidin-2-yloxy)butyl)benzamido)propanoic acid;

<28> 3-(4-(3-methyl-1-(5-phenylpyrimidin-2-yloxy)butyl)benzamido)propanoic acid;

<29> 3-(4-(1-(5-(3,5-dichlorophenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid;

<30> 3-(4-(1-(5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propano Ripe acid;

<31> 3-(4-(1-(5-(2-chlorophenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid;

<32> 3-(4-(1-(5-(3-chlorophenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid;

<33> 3-(4-(1-(5-(4-chlorophenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid;

<34> 3-(4-(3-methyl-1-(5-(4-phenoxyphenyl)pyrimidin-2-yloxy)butyl)benzamido)propanoic acid;

<35> 3-(4-(1-(5-(4-ethylphenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid.

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and 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, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Get from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Rate, sebacate, fumarate, maleate, butine-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid It can be prepared by filtration and drying, or it can be prepared by distilling a solvent and an excess of acid under reduced pressure and then drying to crystallize under an organic solvent.

In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).

Further, the present invention includes not only the compound represented by Formula 1 and its pharmaceutically acceptable salts, but also solvates, optical isomers, hydrates, etc. that may be prepared therefrom.

Another aspect of the present invention, as shown in Scheme 1 below,

Reacting a compound represented by Formula 3 with a compound represented by Formula 4 to obtain a compound represented by Formula 3 (Step 1); And

It provides a method for preparing a compound represented by Formula 1, including the step of obtaining a compound represented by Formula 1 by hydrolyzing the compound represented by Formula 2 obtained in Step 1 (Step 2).

[Scheme 1]

In Scheme 1 above,

R ¹ , R ² , R ³ , l, m and n are as defined in Formula 1;

R ⁴ is straight or branched C _1-5 alkyl;

X ¹ is halogen; And

또는

이다.L ¹ is

or

to be.

Hereinafter, a method for preparing the compound represented by Chemical Formula 1 according to the present invention will be described in detail.

In the above preparation method, step 1 is a step of reacting a compound represented by Formula 3 with a compound represented by Formula 4 to obtain a compound represented by Formula 3, and specifically, a halogen of the compound represented by Formula 3 and Formula 4 This is a step of obtaining a compound represented by Chemical Formula 2 by performing a C-arylation reaction of a boronic acid compound represented by a metal ligand and a basic condition.

At this time, the boronic acid compound may be commercially available compounds, or may be prepared from a corresponding halide compound by a known method, and the halide compound may be iodide or bromide.

In addition, the metal ligand may be copper, palladium, nickel, tin, or the like, and in the present invention, Pd (dppf)Cl ₂ was used as the palladium ligand, but this is only an example and is not limited thereto.

In addition, the base is N,N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene Organic bases such as (DBU) or inorganic bases such as sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, NaH, etc. Can be used.

Further, the solvent usable in the reaction may include an ether solvent such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, and the like; Lower alcohols such as methanol, ethanol, propanol and butanol; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile, water, and the like may be used alone or in combination.

In the above manufacturing method, step 2 is a step of obtaining a compound represented by Formula 1 by hydrolyzing the compound represented by Formula 2 obtained in step 1, and specifically, the ester compound represented by Formula 2 is used as a base or an acid. This is a step of obtaining a carboxylic acid compound represented by Chemical Formula 1 by performing a hydrolysis reaction under conditions.

At this time, the base includes inorganic bases such as sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, NaH, etc., and can be used alone or in combination in an equivalent or excessive amount. As the acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, and the like may be used alone or in combination, and in an equivalent amount or in excess.

In addition, solvents that can be used in the reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, methanol, ethanol, and The same alcohol-based solvent, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, water, and the like, may be used alone or in combination.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases containing a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

At this time, the metabolic disease is any one selected from the group consisting of diabetes, obesity, hyperlipidemia, hypertension, hyperinsulinemia, fatty liver, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome (Syndrome X), and dyslipidemia. Can be

The compound can inhibit GCGR (Glucagon Receptor) activity.

The compound may exhibit a blood glucose lowering effect.

The compound can inhibit the production of cAMP induced by glucagon.

The compound can inhibit glucose production induced by glucagon.

The compound represented by Formula 1 of the present invention has excellent cAMP or glucagon production inhibitory effect, exhibits GCGR activity inhibitory effect, and it was confirmed not only in vitro but also in vivo, and has low cytotoxicity (Experimental Example Reference).

Accordingly, the compound represented by Formula 1 of the present invention can be usefully used in the treatment of metabolic diseases, particularly diabetes, which are diseases related to GCGR activity.

The compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations upon clinical administration. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose, or lactose ( lactose), gelatin, etc. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as humectants, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.

A pharmaceutical composition comprising the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration may be administered by subcutaneous injection, intravenous injection, intramuscular injection, or chest It depends on how I inject my injections.

At this time, in order to formulate a formulation for parenteral administration, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is mixed in water with a stabilizer or buffer to prepare a solution or suspension, and this is an ampoule or It can be prepared in vial unit dosage form. The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances, which are conventional methods of mixing, granulation. It can be formulated according to the method of painting or coating.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and troches.These formulations include diluents (e.g., lactose) in addition to the active ingredients. , Dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (such as silica, talc, stearic acid and magnesium or calcium salts thereof and/or polyethylene glycol). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, boron such as starch, agar, alginic acid or sodium salt thereof. It may contain release or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.

The pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual therapeutic agent or used in combination with other anticancer agents in use. I can.

Another aspect of the present invention provides a health functional food composition for preventing or improving metabolic diseases containing a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

At this time, the metabolic disease is any one selected from the group consisting of diabetes, obesity, hyperlipidemia, hypertension, hyperinsulinemia, fatty liver, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome (Syndrome X), and dyslipidemia. Can be

The compound represented by Formula 1 according to the present invention may be added to food as it is or may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement). In general, the amount of the compound in the health food may be added in 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

In addition, the health functional beverage composition of the present invention is not particularly limited to other ingredients other than containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates, etc. as additional ingredients, as in ordinary beverages. have. Examples of the aforementioned natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

Further, in addition to the above, the compound represented by Formula 1 according to the present invention is a variety of nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pect Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like. In addition, the compound represented by Chemical Formula 1 of the present invention may contain flesh for the manufacture of natural fruit juice and fruit juice beverages and vegetable beverages.

Another aspect of the present invention is a subject in need of a pharmaceutical composition for preventing or treating metabolic diseases or a health functional food composition containing a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient It provides a method of preventing or treating metabolic diseases comprising administering to a patient.

Another aspect of the present invention is a pharmaceutical for the prevention or treatment of metabolic diseases containing as an active ingredient a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of metabolic diseases It provides the use of a suitable composition or a health functional food composition.

Hereinafter, the present invention will be described in detail by examples and experimental examples.

However, the following examples and experimental examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following examples and experimental examples.

<Preparation Example 1> Preparation of ethyl 3-(4-(1-(5-bromopyrimidin-2-yloxy)pentyl)benzamido)propanoate

Step 1: Preparation of methyl 4-(1-hydroxypentyl)benzoate

Methyl 4-formylbenzoate (2.00 g, 12.2 mmol) was reacted at 0° C. for 1 hour using n- BuMgBr (12.0 ml, 24.4 mmol) and dry THF (tetrahydrofuran) (60 ml) as starting materials. The reaction product was checked by TLC to confirm that the starting material disappeared, and then acidified to pH 2 by adding 1N HCl, and extracted with ethyl ester (300 ml). It was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.20 g, yield: 60%) as a white solid by column chromatography.

Step 2: Preparation of methyl 4-(1-(5-bromopyrimidin-2-yl)oxy)pentyl)benzoate

Using the compound of Step 1 (188 mg, 0.846 mmol) as starting materials, 5-bromo-2-hydroxypyrimidine (178 mg, 1.02 mmo), DIAD (Diisopropyl azodicarboxylate) (0.25 ml, 1.27 mmol), PPh ₃ (Triphenylphosphine) (333 mg, 1.27 mmol) and THF (4.5 ml) were used to react at room temperature for 2 hours. Ethyl acetate (30 ml), water, and Brine were added, washed, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (509 mg, yield: 63%) as an oil by column chromatography.

Step 3: Preparation of 4-(1-(5-bromopyrimidin-2-yl)oxy)pentyl)benzoic acid

Using the compound of step 2 (984 mg, 2.59 mmol) as starting materials LiOH-H ₂ O (218 mg, 5.19 mmol) and THF: H ₂ O (v:v=1.5:1) (20 ml) It was reacted at room temperature for 12 hours. 1N HCl was added, acidified to pH 2, and extracted with ethyl ester (300 ml). It was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (786 mg, yield: 80%) as a white solid by column chromatography.

Step 4: Preparation of ethyl 3-(4-(1-(5-bromopyrimidin-2-yl)oxy)pentyl)benzamido)propanoate

Using the compound of step 3 (674 mg, 1.85 mmol) as a starting material, betaalanine ethyl ester hydrochloride (567 mg, 3.69 mmol), HOBt (565 mg, 3.69 mmol), EDCI (708 mg, 3.69 mmol), DIEA ( 0.90 ml, 5.54 mmol) and DMF (9 ml) were used to react at 50 ^o C for 1 hour. Extracted with ethyl ester (300 ml), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and column chromatography to obtain the title compound (774 mg, yield: 90%) as an oil.

<Preparation Example 2> Preparation of (S)-ethyl 3-(4-(1-(5-bromopyrimidin-2-yloxy)pentyl)benzamido)propanoate

Step 1: Preparation of methyl 4-pentanoylbenzoate

Using the compound (1.60 g, 7.22 mmol) obtained in step 1 of Preparation Example 1 as a starting material, PDC (Pyridinium Dichromate) (4.00 g, 10.8 mmol), 4ÅMS (molecular sieves) (500 mg) and DCM (Dichloromethane) (36 ml) was used and reacted at room temperature for 24 hours. After filtering with Celite, it was concentrated under reduced pressure to obtain the title compound (936 mg, yield: 59%) as a white solid by column chromatography.

Step 2: Preparation of (R)-methyl 4-(1-hydroxypentyl)benzoate

Using the compound obtained in step 1 (400 mg, 1.82 mmol) as a starting material, ( S) -Me-CBS catalyst (50.0 mg, 0.182 mmol), BH ₃ -THF complex (2.72 ml, 2.72 mmol) and dry THF (9 ml) was used and reacted at 0°C for 12 hours. Extracted with ethyl ester (300 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (295 mg, yield: 73%) as a white solid by column chromatography.

Step 3: Preparation of (S)-methyl 4-(1-(5-bromopyrimidin-2-yloxy)pentyl)benzoate

(S)-methyl 4-(1-(5-bromopyrimidin-2-yloxy) using a method similar to Step 2 of Preparation Example 1, except that the compound obtained in Step 2 was used as a starting material. ) Pentyl) benzoate was prepared.

Step 4: Preparation of (S)-4-(1-(5-bromopyrimidin-2-yloxy)pentyl)benzoic acid

(S)-4-(1-(5-bromopyrimidin-2-yloxy) using a method similar to Step 3 of Preparation Example 1, except that the compound obtained in Step 3 was used as a starting material. Pentyl)benzoic acid was prepared.

Step 5: Preparation of (S)-ethyl 3-(4-(1-(5-bromopyrimidin-2-yloxy)pentyl)benzamido)propanoate

(S)-ethyl 3-(4-(1-(5-bromopyrimidine-2) using a method similar to Step 4 of Preparation Example 1, except that the compound obtained in Step 4 was used as a starting material. -Iloxy)pentyl)benzamido)propanoate was prepared.

<Preparation Example 3> Preparation of (R)-ethyl 3-(4-(1-(5-bromopyrimidin-2-yloxy)pentyl)benzamido)propanoate

Step 1: Preparation of (S)-methyl 4-(1-hydroxypentyl)benzoate

Using the compound obtained in step 1 of Preparation Example 2 (400 mg, 1.82 mmol) as a starting material, ( R) -Me-CBS catalyst (50.0 mg, 0.182 mmol), BH ₃ -THF complex (2.72 ml, 2.72 mmol) and dry THF (9 ml) were used to react at 0° C. for 12 hours. Extracted with ethyl ester (300 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (316 mg, yield: 78%) as a white solid by column chromatography.

Step 2: Preparation of (R)-methyl 4-(1-(5-bromopyrimidin-2-yloxy)pentyl)benzoate

(R)-methyl 4-(1-(5-bromopyrimidin-2-yloxy) using a method similar to Step 2 of Preparation Example 1, except that the compound obtained in Step 1 was used as a starting material. ) Pentyl) benzoate was prepared.

Step 3: Preparation of (R)-4-(1-(5-bromopyrimidin-2-yloxy)pentyl)benzoic acid

(R)-4-(1-(5-bromopyrimidin-2-yloxy) using a method similar to Step 3 of Preparation Example 1, except that the compound obtained in Step 2 was used as a starting material. Pentyl)benzoic acid was prepared.

Step 4: Preparation of (R)-ethyl 3-(4-(1-(5-bromopyrimidin-2-yloxy)pentyl)benzamido)propanoate

(R)-ethyl 3-(4-(1-(5-bromopyrimidine-2) using a method similar to Step 4 of Preparation Example 1, except that the compound obtained in Step 3 was used as a starting material. -Iloxy)pentyl)benzamido)propanoate was prepared.

<Preparation Example 4> Preparation of ethyl 3-(4-(1-(5-bromopyrimidin-2-yloxy)ethyl)benzamido)propanoate

Ethyl 3-(4-(1-(5-bromopyrimidin-2-yloxy)ethyl)benzamido)pro using a method similar to that of Preparation Example 1, except that MeMgBr was used instead of n- BuMgBr. Panoate was prepared.

<Preparation Example 5> Preparation of ethyl 3-(4-(1-(5-bromopyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoate

Ethyl 3-(4-(1-(5-bromopyrimidin-2-yloxy)ethyl)benzamido using a method similar to Preparation Example 1, except that i- BuMgBr was used instead of n- BuMgBr. ) Propanoate was prepared.

<Example 1> Preparation of 3-(4-(1-((5-phenylpyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid

Step 1: Preparation of ethyl 3-(4-(1-((5-(2-phenylpyrimidin-2-yl)oxy)pentyl)benzamido)propanoate

Using the step 4 compound (70.0 mg, 0.152 mmol) obtained in Preparation Example 1 as a starting material, phenyl boronic acid (20.0 mg, 0.172 mmol), NaHCO ₃ (38.0 mg, 0.450 mmol), Pd (dppf) Cl ₂ ( 37.0 mg, 0.051 mmol) and DMF (dimethylformamide) (0.8 ml) were used to react at 90° C. for 12 hours. Extracted with ethyl ester (300 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (35.0 mg, yield: 50%) as an oil by column chromatography.

Step 2: Preparation of 3-(4-(1-((5-phenylpyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid

Using the compound obtained in step 1 (34 mg, 0.071 mmol) as a starting material, LiOH-H ₂ O (6.00 mg, 0.152 mmol), THF:H ₂ O (1.5:1=v:v) (0.60 ml) And reacted at room temperature for 12 hours. 1N HCl was added, acidified to pH 2, and extracted with ethyl ester (300 ml). It was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (11.0 mg, yield: 36%) as a white solid by column chromatography.

<Example 2> Preparation of 3-(4-(1-((5-(2-chlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid

A target compound was prepared using a method similar to that of Example 1, except that 2-chlorophenylboronic acid was used instead of phenylboronic acid (yield: 30%).

<Example 3> Preparation of 3-(4-(1-((5-(3-chlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid

The target compound was prepared using a method similar to Example 1, except that 3-chlorophenylboronic acid was used instead of phenylboronic acid (yield: 78%).

<Example 4> Preparation of 3-(4-(1-((5-(4-chlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid

A target compound was prepared using a method similar to Example 1, except that 4-chlorophenylboronic acid was used instead of phenylboronic acid (yield: 52%).

<Example 5> Preparation of 3-(4-(1-((5-(4-trifluoromethylphenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid

The target compound was prepared using a method similar to Example 1, except that 4-trifluoromethylphenylboronic acid was used instead of phenylboronic acid (yield: 80%).

<Example 6> Preparation of 3-(4-(1-((5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid

A target compound was prepared using a method similar to Example 1, except that 4-(tert-butyl)phenylboronic acid was used instead of phenylboronic acid (yield: 70%).

<Example 7> Preparation of 3-(4-(1-((5-(3,5-dichlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid

A target compound was prepared using a method similar to Example 1, except that 3,5-dichlorophenylboronic acid was used instead of phenylboronic acid (yield: 97%).

<Example 8> 3-(4-(1-((5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propano Preparation of ripe acid

The target compound was prepared using a method similar to Example 1, except that 2-fluoro-5-trifluoromethylphenylboronic acid was used instead of the phenylboronic acid (yield: 99%).

<Example 9> Preparation of 3-(4-(1-((5-(4-phenoxyphenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid

The target compound was prepared using a method similar to Example 1, except that 4-phenoxyphenylboronic acid was used instead of phenylboronic acid (yield: 79%).

<Example 10> Preparation of 3-(4-(1-((5-(4-ethylphenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid

The target compound was prepared using a method similar to Example 1, except that 4-ethylphenylboronic acid was used instead of phenylboronic acid (yield: 81%).

<Example 11> Preparation of (R)-3-(4-(1-(5-phenylpyrimidin-2-yloxy)pentyl)benzamido)propanoic acid

A target compound was prepared using a method similar to that of Example 1, except that the compound obtained in Preparation Example 3 was used instead of the compound obtained in Preparation Example 1.

<Example 12> Preparation of (S)-3-(4-(1-(5-phenylpyrimidin-2-yloxy)pentyl)benzamido)propanoic acid

A target compound was prepared using a method similar to that of Example 1, except that the compound obtained in Preparation Example 2 was used instead of the compound obtained in Preparation Example 1.

<Example 13> (R)-3-(4-(1-((5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid Manufacture of

A method similar to Example 1 was used, except that the compound obtained in Preparation Example 3 was used instead of the compound obtained in Preparation Example 1, and 4-(tert-butyl)phenylboronic acid was used instead of the phenylboronic acid. To prepare the target compound.

<Example 14> (S)-3-(4-(1-((5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid Manufacture of

A method similar to Example 1 was used, except that the compound obtained in Preparation Example 2 was used instead of the compound obtained in Preparation Example 1, and 4-(tert-butyl)phenylboronic acid was used instead of the phenylboronic acid. To prepare the target compound.

<Example 15> Preparation of (R)-3-(4-(1-((5-(3,5-dichlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid

A method similar to Example 1 was used, except that the compound obtained in Preparation Example 3 was used instead of the compound obtained in Preparation Example 1, and 3,5-dichlorophenylboronic acid was used instead of the phenylboronic acid. The target compound was prepared.

<Example 16> Preparation of (S)-3-(4-(1-((5-(3,5-dichlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid

Using a method similar to Example 1, except that the compound obtained in Preparation Example 2 was used instead of the compound obtained in Preparation Example 1, and 3,5-dichlorophenylboronic acid was used instead of the phenylboronic acid. The target compound was prepared.

<Example 17> Preparation of 3-(4-(1-(5-(4-bromophenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid

The target compound using a method similar to Example 1, except that the compound obtained in Preparation Example 4 was used instead of the compound obtained in Preparation Example 1, and 4-bromophenylboronic acid was used instead of the phenylboronic acid. Was prepared.

<Example 18> Preparation of 3-(4-(1-(5-phenylpyrimidin-2-yloxy)ethyl)benzamido)propanoic acid

A target compound was prepared using a method similar to that of Example 1, except that the compound obtained in Preparation Example 4 was used instead of the compound obtained in Preparation Example 1.

<Example 19> Preparation of 3-(4-(1-(5-(4-chlorophenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid

A target compound was prepared using a method similar to Example 1, except that the compound obtained in Preparation Example 4 was used instead of the compound obtained in Preparation Example 1, and 4-chlorophenylboronic acid was used instead of the phenylboronic acid. Was prepared.

<Example 20> Preparation of 3-(4-(1-(5-(4-(trifluoromethyl)phenyl)pyrimidin-2-yloxy)ethyl)benzamido)propionic acid

A method similar to Example 1 was used, except that the compound obtained in Preparation Example 4 was used instead of the compound obtained in Preparation Example 1, and 4-trifluoromethylphenylboronic acid was used instead of the phenylboronic acid. The compound was prepared.

<Example 21> Preparation of 3-(4-(1-(5-(4-tert-butylphenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid

A method similar to Example 1 was used, except that the compound obtained in Preparation Example 4 was used instead of the compound obtained in Preparation Example 1, and 4-tert-butylphenylboronic acid was used instead of the phenylboronic acid. The compound was prepared.

<Example 22> Preparation of 3-(4-(1-(5-(3,5-dichlorophenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid

A method similar to Example 1 was used, except that the compound obtained in Preparation Example 4 was used instead of the compound obtained in Preparation Example 1, and 3,5-dichlorophenylboronic acid was used instead of the phenylboronic acid. The compound was prepared.

<Example 23> Preparation of 3-(4-(1-(5-(3-methoxyphenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid

The target compound using a method similar to Example 1, except that the compound obtained in Preparation Example 4 was used instead of the compound obtained in Preparation Example 1, and 3-methoxyphenylboronic acid was used instead of the phenylboronic acid. Was prepared.

<Example 24> Preparation of 3-(4-(1-(5-(5-isopropyl-2-methoxyphenyl)pyrimidin-2-yloxy)ethyl)benzamido)propionic acid

A method similar to Example 1, except that the compound obtained in Preparation Example 4 was used instead of the compound obtained in Preparation Example 1, and the 5-isopropyl-2-methoxyphenylboronic acid was used instead of the phenylboronic acid. To prepare the target compound.

<Example 25> 3-(4-(1-(5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yloxy)ethyl)benzamido)propionic acid Manufacture of

Similar to Example 1, except that the compound obtained in Preparation Example 4 was used instead of the compound obtained in Preparation Example 1, and the 2-fluoro-5-trifluoromethylphenylboronic acid was used instead of the phenylboronic acid. The target compound was prepared using the method.

<Example 26> Preparation of 3-(4-(1-(5-(4-tert-butylphenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid

A method similar to Example 1 was used, except that the compound obtained in Preparation Example 5 was used instead of the compound obtained in Preparation Example 1, and 4-tert-butylphenylboronic acid was used instead of the phenylboronic acid. The compound was prepared.

<Example 27> 3-(4-(3-methyl-1-(5-(4-(trifluoromethyl)phenyl)pyrimidin-2-yloxy)butyl)benzamido)propanoic acid Produce

A method similar to Example 1 was used, except that the compound obtained in Preparation Example 5 was used instead of the compound obtained in Preparation Example 1, and 4-trifluoromethylboronic acid was used instead of the phenylboronic acid. The compound was prepared.

<Example 28> Preparation of 3-(4-(3-methyl-1-(5-phenylpyrimidin-2-yloxy)butyl)benzamido)propanoic acid

A target compound was prepared using a method similar to that of Example 1, except that the compound obtained in Preparation Example 5 was used instead of the compound obtained in Preparation Example 1.

<Example 29> Preparation of 3-(4-(1-(5-(3,5-dichlorophenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid

A method similar to Example 1 was used, except that the compound obtained in Preparation Example 5 was used instead of the compound obtained in Preparation Example 1, and 3,5-dichloro phenylboronic acid was used instead of the phenylboronic acid. The compound was prepared.

<Example 30> 3-(4-(1-(5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido) Preparation of propionic acid

Similar to Example 1, except that the compound obtained in Preparation Example 5 was used instead of the compound obtained in Preparation Example 1, and the 2-fluoro-5-trifluoromethylphenylboronic acid was used instead of the phenylboronic acid. The target compound was prepared using the method.

<Example 31> Preparation of 3-(4-(1-(5-(2-chlorophenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid

A target compound was prepared using a method similar to Example 1, except that the compound obtained in Preparation Example 5 was used instead of the compound obtained in Preparation Example 1, and 2-chlorophenylboronic acid was used instead of the phenylboronic acid. Was prepared.

<Example 32> Preparation of 3-(4-(1-(5-(3-chlorophenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid

A target compound was prepared using a method similar to Example 1, except that the compound obtained in Preparation Example 5 was used instead of the compound obtained in Preparation Example 1, and 3-chlorophenylboronic acid was used instead of the phenylboronic acid. Was prepared.

<Example 33> Preparation of 3-(4-(1-(5-(4-chlorophenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid

The target compound was prepared using a method similar to Example 1, except that the compound obtained in Preparation Example 5 was used instead of the compound obtained in Preparation Example 1, and 4-chlorophenylboronic acid was used instead of the phenylboronic acid. Was prepared.

<Example 34> Preparation of 3-(4-(3-methyl-1-(5-(4-phenoxyphenyl)pyrimidin-2-yloxy)butyl)benzamido)propanoic acid

The target compound using a method similar to Example 1, except that the compound obtained in Preparation Example 5 was used instead of the compound obtained in Preparation Example 1, and 4-phenoxyphenylboronic acid was used instead of the phenylboronic acid. Was prepared.

<Example 35> Preparation of 3-(4-(1-(5-(4-ethylphenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid

The target compound was prepared by using a method similar to Example 1, except that the compound obtained in Preparation Example 5 was used instead of the compound obtained in Preparation Example 1, and 4-ethylphenylboronic acid was used instead of the phenylboronic acid. Was prepared.

Table 1 below shows the chemical structures of the compounds prepared in Examples 1 to 16, and Table 2 shows the chemical structures of the compounds prepared in Examples 17 to 35. Table 3 shows the analytical data ( ¹ H NMR, ¹³ C NMR, mass) of the compounds of Examples 1 to 35.

Example Chemical structure Example Chemical structure One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

Example Chemical structure Example Chemical structure 17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

-

Example Analysis data ( ¹ H NMR, ¹³ C NMR, mass) One ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.63 (s, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.44 (m, 4H ), 7.40-7.37 (m, 1H), 6.91, (t, J = 6 Hz, 1H), 6.04 (q, J = 5.4, 7.2 Hz, 1H), 3.71 (q, J = 6, 11.4 Hz, 2H ), 2.69 (t, J = 6 Hz, 2H), 2.12-2.06 (m, 1H), 1.91-1.85 (m, 1H), 1.48-1.43 (m, 1H), 1.38-1.31 (m, 3H), 0.88 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 176.1, 167.5, 163.9, 157.3, 145.5, 134.2, 133.4, 129.3, 128.5, 128.2, 127.1, 126.7, 126.5, 78.7, 36.8, 35.3, 33.7, 27.6, 22.5, 14.0; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₂₅ H ₂₈ N ₃ O ₄ ⁺ 434.2074, found 434.2069 2 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.54 (s, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.49-7.46 (m , 1H), 7.34-7.31 (m, 2H), 7.26-7.24 (m, 1H), 6.92 (t, J = 6Hz, 1H), 6.06 (q, J = 6, 7.8 Hz, 1H), 3.72 (q , J = 6, 11.4 Hz, 2H), 2.70 (t, J = 5.4 Hz, 2H), 2.13-2.07 (m, 1H), 1.92-1.86 (m, 1H), 1.49-1.43 (m, 1H), 1.38-1.33 (m, 3H), 0.88 (t, J = 6.6 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 176.2, 167.5, 163.8, 159.2, 145.4, 133.4, 133.3, 132.8, 131.0, 130.3, 129.8, 127.4, 127.1, 126.9, 126.7, 78.7, 36.7, 35.3, 33.7, 27.6, 22.5, 14.0; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₂₅ H ₂₇ ClN ₃ O ₄ ⁺ 468.1685, found 468.1677 3 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.61 (s, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.43 (m, 1H ), 7.39-7.32 (m, 3H), 6.99 (t, J = 5.9 Hz, 1H), 6.04 (q, J = 6, 7.8 Hz, 1H), 3.70 (q, J = 5.8, 11.5 Hz, 2H) , 2.69 (t, J = 5.4 Hz, 2H), 2.12-2.06 (m, 1H), 1.91-1.85 (m, 1H), 1.47-1.42 (m, 1H), 1.38-1.33 (m, 3H), 0.87 (t, J = 6.6 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 176.2, 167.5, 164.2, 159.6, 157.3, 145.3, 136.0, 135.2, 133.4, 130.5, 128.3, 127.2, 127.2, 126.7, 126.6, 124.6, 78.9, 36.7, 35.3, 33.7, 27.6, 22.5, 14.0; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₂₅ H ₂₇ ClN ₃ O ₄ ⁺ 468.1685, found 468.1677 4 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.61 (s, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 7.8 Hz, 2H), 7.42-7.37 (m , 4H), 6.97, (t, J = 6 Hz, 1H), 6.03 (q, J = 6, 7.8 Hz, 1H), 3.71 (q, J = 6, 11.4 Hz, 2H), 2.69 (t, J = 6 Hz, 2H), 2.12-2.06 (m, 1H), 1.91-1.85 (m, 1H), 1.48-1.42 (m,1H), 1.38-1.31 (m, 3H), 0.87 (t, J = 6.6 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 176.3, 171.3, 167.5, 164.0, 159.6, 157.1, 145.4, 134.6, 133.4, 132.6, 129.5, 127.7, 127.4, 127.1, 126.7, 78.8, 60.5, 36.7, 35.3, 33.7, 27.6, 22.5, 21.1, 14.2, 14.0; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₂₅ H ₂₇ ClN ₃ O ₄ ⁺ 468.1685, found 468.1677 5 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.67 (s, 2H), 7.72 (dd, J = 8.4, 11.6 Hz, 4H), 7.58 (d, J = 8.1 Hz, 2H), 7.51 (d , J = 8.2 Hz, 2H), 6.93 (t, J = 5.9 Hz, 1H), 6.05 (q, J = 6, 7.8 Hz, 1H), 3.72 (q, J = 5.4, 11.4 Hz, 2H), 2.70 (t, J = 5.4 Hz, 2H), 2.14-2.07 (m, 1H), 1.94-1.87 (m, 1H), 1.49-1.43 (m, 1H), 1.39-1.31 (m, 3H), 0.88 (t , J = 7.2 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 176.5, 171.4, 167.6, 164.4, 163.9, 159.6, 157.4, 145.3, 137.8, 133.4, 130.5, 130.3, 127.2, 126.8, 126.7, 126.3, 124.8, 123.0, 79.0, 60.5, 36.6, 35.3, 33.7, 27.6, 22.4, 21.1, 14.2, 14.0; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₂₆ H ₂₇ F ₃ N ₃ O ₄ ⁺ 502.1948, found 502.1943 6 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.62 (s, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.02 (bs, 1H), 6.03 (q, J = 5.4, 7.2 Hz, 1H), 3.68 (d, J = 4.3 Hz, 2H ), 2.65 (bs, 2H), 2.10-2.07 (m, 1H), 1.89-1.85 (m, 1H), 1.43 (m, 1H), 1.33 (s, 9H), 0.86 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 167.5, 163.8, 157.1, 151.4, 145.5, 133.3, 131.3, 128.4, 127.2, 126.7, 126.2, 78.6, 60.5, 50.8, 36.8, 35.4, 34.6, 34.0, 31.3, 27.6, 22.5, 21.1, 14.2, 14.0; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₂₉ H ₃₆ N ₃ O ₄ ⁺ 490.2700, found 490.2685 7 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.59 (s, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.36 (s, 1H ), 7.32 (d, J = 1.8 Hz, 2H), 7.00 (bs, 1H), 6.03 (q, J = 6, 7.8 Hz, 1H), 3.67 (bs, 2H), 2.65 (bs, 2H), 2.12 -2.08 (m, 1H), 1.90-1.85 (m, 1H), 1.47-1.41 (m, 1H), 1.38-1.30 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 167.48, 164.5, 157.3, 145.1, 137.2, 135.9, 133.4, 128.2, 127.2, 126.7, 126.1, 124.9, 79.1, 53.4, 50.8, 36.6, 35.4, 33.9, 27.6, 22.5, 14.2, 14.0; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₂₅ H ₂₈ Cl ₂ N ₃ O ₄ ⁺ 502.1295, found 502.1288 8 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.64 (d, J = 1.2 Hz, 2H), 7.74-7.70 (m, 2H), 7.65-7.62 (m, 2H), 7.51 (d, J = 12 Hz, 2H), 7.29 (t, J = 12 Hz, 1H), 6.90 (t, J = 6 Hz, 1H), 6.06 (q, J = 6 Hz, 1H), 3.71 (q, J = 6, 12 Hz, 2H), 2.69 (t, J = 6 Hz, 2H), 2.14-2.05 (m, 1H), 1.93-1.87 (m, 1H), 1.48-1.42 (m, 1H), 1.38-1.32 (m) , 3H), 0.89-0.85 (m, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 176.3, 167.5, 164.3, 160.5, 159.6, 158.8, 145.2, 144.9, 133.5, 127.5, 127.2, 126.7, 123.2, 122.2, 117.2, 117.0, 111.9, 79.0, 36.6, 35.3, 33.7, 27.6, 22.4, 14.0; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₂₆ H ₂₆ F ₄ N ₃ O ₄ ⁺ 520.1854, found 520.1817 9 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.61 (s, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.40-7.38 (m , 2H), 7.37-7.34 (m, 2H), 7.15-7.12 (m, 1H), 7.07-7.02 (m, 4H), 6.94 (t, J = 5.9 Hz, 1H), 6.03 (q, J = 5.8 , 7.6 Hz, 1H), 3.71 (q, J = 5.9, 11.7 Hz, 2H), 2.69 (t, J = 5.8 Hz, 2H), 2.11-2.05 (m, 1H), 1.91-1.85 (m, 1H) , 1.48-1.40 (m, 1H), 1.37-1.31 (m, 3H), 0.87 (t, J = 7 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 176.2, 167.5, 163.7, 157.8, 157.0, 156.6, 145.5, 133.4, 129.9, 128.9, 128.0, 127.9, 127.1, 126.7, 123.8, 119.3, 119.2, 78.7, 36.7, 35.3, 33.8, 27.6, 22.5, 14.0; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₃₁ H ₃₂ N ₃ O ₅ ⁺ 526.2336, found 526.2334 10 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.61 (s, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 6.90 (bs, 1H), 6.03 (q, J = 5.8, 7.7 Hz, 1H), 3.70 (q, J = 6, 12 Hz , 2H), 2.70-2.66 (m, 4H), 2.12-2.05 (m, 1H), 1.91-1.85 (m, 1H), 1.49-1.44 (m, 1H), 1.38-1.31 (m, 3H), 1.25 (t, J = 7.8 Hz, 5H), 0.87 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 167.4, 163.8, 157.1, 145.5, 144.5, 133.4, 131.6, 128.8, 128.4, 127.1, 126.7, 126.4, 78.6, 36.8, 35.3, 29.7, 28.5, 27.6, 22.5, 15.5, 14.0: HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₂₇ H ₃₂ N ₃ O ₄ ⁺ 462.2387, found 462.2369 11 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.63 (s, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.44 (m, 4H ), 7.40-7.37 (m, 1H), 6.91, (t, J = 6 Hz, 1H), 6.04 (q, J = 5.4, 7.2 Hz, 1H), 3.71 (q, J = 6, 11.4 Hz, 2H ), 2.69 (t, J = 6 Hz, 2H), 2.12-2.06 (m, 1H), 1.91-1.85 (m, 1H), 1.48-1.43 (m, 1H), 1.38-1.31 (m, 3H), 0.88 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 176.1, 167.5, 163.9, 157.3, 145.5, 134.2, 133.4, 129.3, 128.5, 128.2, 127.1, 126.7, 126.5, 78.7, 36.8, 35.3, 33.7, 27.6, 22.5, 14.0; [α] _D +72.6 (c = 0.0012 in CH ₂ Cl ₂ ) 12 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.63 (s, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.44 (m, 4H ), 7.40-7.37 (m, 1H), 6.91, (t, J = 6 Hz, 1H), 6.04 (q, J = 5.4, 7.2 Hz, 1H), 3.71 (q, J = 6, 11.4 Hz, 2H ), 2.69 (t, J = 6 Hz, 2H), 2.12-2.06 (m, 1H), 1.91-1.85 (m, 1H), 1.48-1.43 (m, 1H), 1.38-1.31 (m, 3H), 0.88 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 176.1, 167.5, 163.9, 157.3, 145.5, 134.2, 133.4, 129.3, 128.5, 128.2, 127.1, 126.7, 126.5, 78.7, 36.8, 35.3, 33.7, 27.6, 22.5, 14.0; [α] _D -35.7 (c = 0.0014 in CH ₂ Cl ₂ ) 13 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.62 (s, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.02 (bs, 1H), 6.03 (q, J = 5.4, 7.2 Hz, 1H), 3.68 (d, J = 4.3 Hz, 2H ), 2.65 (bs, 2H), 2.10-2.07 (m, 1H), 1.89-1.85 (m, 1H), 1.43 (m, 1H), 1.33 (s, 9H), 0.86 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 167.5, 163.8, 157.1, 151.4, 145.5, 133.3, 131.3, 128.4, 127.2, 126.7, 126.2, 78.6, 60.5, 50.8, 36.8, 35.4, 34.6, 34.0, 31.3, 27.6, 22.5, 21.1, 14.2, 14.0; [α] _D +31.3 (c = 0.0048 in CH ₂ Cl ₂ ) 14 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.62 (s, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.02 (bs, 1H), 6.03 (q, J = 5.4, 7.2 Hz, 1H), 3.68 (d, J = 4.3 Hz, 2H ), 2.65 (bs, 2H), 2.10-2.07 (m, 1H), 1.89-1.85 (m, 1H), 1.43 (m, 1H), 1.33 (s, 9H), 0.86 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 167.5, 163.8, 157.1, 151.4, 145.5, 133.3, 131.3, 128.4, 127.2, 126.7, 126.2, 78.6, 60.5, 50.8, 36.8, 35.4, 34.6, 34.0, 31.3, 27.6, 22.5, 21.1, 14.2, 14.0; [α] _D -27.3 (c = 0.0037 in CH ₂ Cl ₂ ) 15 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.59 (s, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.36 (s, 1H ), 7.32 (d, J = 1.8 Hz, 2H), 7.00 (bs, 1H), 6.03 (q, J = 6, 7.8 Hz, 1H), 3.67 (bs, 2H), 2.65 (bs, 2H), 2.12 -2.08 (m, 1H), 1.90-1.85 (m, 1H), 1.47-1.41 (m, 1H), 1.38-1.30 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 167.48, 164.5, 157.3, 145.1, 137.2, 135.9, 133.4, 128.2, 127.2, 126.7, 126.1, 124.9, 79.1, 53.4, 50.8, 36.6, 35.4, 33.9, 27.6, 22.5, 14.2, 14.0; [α] _D +34.8 (c = 0.0040 in CH ₂ Cl ₂ ) 16 ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm): 8.59 (s, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.36 (s, 1H ), 7.32 (d, J = 1.8 Hz, 2H), 7.00 (bs, 1H), 6.03 (q, J = 6, 7.8 Hz, 1H), 3.67 (bs, 2H), 2.65 (bs, 2H), 2.12 -2.08 (m, 1H), 1.90-1.85 (m, 1H), 1.47-1.41 (m, 1H), 1.38-1.30 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ (ppm): 167.48, 164.5, 157.3, 145.1, 137.2, 135.9, 133.4, 128.2, 127.2, 126.7, 126.1, 124.9, 79.1, 53.4, 50.8, 36.6, 35.4, 33.9, 27.6, 22.5, 14.2, 14.0; [α] _D -26.2 (c = 0.0046 in CH ₂ Cl ₂ ) 17 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.47 (s, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.14 (t, J = 5.9 Hz , 1H), 6.07 (q, J = 6.5 Hz, 1H), 3.69 (q, J = 5.9 Hz, 2H), 2.67 (t, J = 5.9 Hz, 2H), 1.65 (d, J = 6.6 Hz, 3H ); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.0, 171.4, 167.6, 162.9, 159.6, 145.8, 133.4, 127.3, 126.1, 111.9, 75.4, 60.5, 35.4, 33.7, 22.8, 21.1, 14.2. 18 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.66 (s, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 3.4 Hz , 4H), 7.38 (m, 1H), 7.10 (t, J = 5.8 Hz, 1H), 6.20 (q, J = 6.5 Hz, 1H), 3.70 (q, J = 5.8 Hz, 2H), 2.68 (t , J = 5.8 Hz, 2H), 1.68 (d, J = 6.6 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.0, 171.3, 167.6, 163.6, 157.3, 146.2, 134.1, 133.4, 129.3, 128.5, 128.3, 127.3, 126.5, 126.2, 74.8, 60.5, 35.4, 33.8, 22.9, 21.1 , 14.2. 19 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.63 (s, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.41 (q, J = 9.4 Hz , 4H), 6.93 (t, J = 5.8 Hz, 1H), 6.20 (q, J = 6.6 Hz, 1H), 3.71 (q, J = 5.9 Hz, 2H), 2.69 (t, J = 5.8 Hz, 2H ), 1.69 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl ₃ ) δ 167.4, 163.8, 157.2, 146.2, 134.6, 133.4, 132.7, 129.5, 127.8, 127.4, 127.2, 126.2, 74.9, 35.3, 33.7, 29.7, 23.0. 20 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.68 (s, 2H), 7.73 (dd, J = 6.8 Hz, 4H), 7.60 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.3 Hz , 2H), 6.83 (t, J = 6.1 Hz, 1H), 6.22 (q, J = 6.6 Hz, 1H), 3.72 (q, J = 5.9 Hz, 2H), 2.70 (t, J = 5.9 Hz, 2H ), 1.72 (d, J = 6.6 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 157.5, 146.2, 127.2, 126.8, 126.2, 75.1, 35.2, 33.4, 23.0. 21 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.65 (s, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.5 Hz , 2H), 7.41 (d, J = 8.5 Hz, 2H), 6.95 (t, J = 5.9 Hz, 1H), 6.20 (q, J = 6.5 Hz, 1H), 3.71 (q, J = 5.9 Hz, 3H ), 2.70 (t, J = 5.8 Hz, 2H), 1.69 (d, J = 6.6 Hz, 3H), 1.34 (s, 9H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.0, 167.4, 163.5, 159.6, 157.1, 151.5, 146.3, 133.4, 131.2, 128.4, 127.2, 126.3, 126.2, 74.7, 35.3, 34.6, 33.7, 31.3, 29.7, 23.0 . 22 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.62 (s, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 1.8 Hz , 2H), 7.14 (t, J = 5.9 Hz, 1H), 6.19 (q, J = 6.5 Hz, 1H), 3.69 (q, J = 5.9 Hz, 2H), 2.67 (t, J = 5.8 Hz, 2H ), 1.68 (d, J = 6.6 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 167.6, 164.2, 159.6, 157.3, 146.0, 137.1, 135.9, 133.4, 128.2, 127.3, 126.2, 126.1, 124.9, 75.2, 60.5, 35.5, 22.9, 21.1, 14.2. 23 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.65 (s, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.37 (t, J = 8.0 Hz , 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.98 (t, J = 1.9 Hz, 1H), 6.93 (q, J = 3.4 Hz, 1H), 6.20 (q, J = 6.5 Hz, 1H ), 3.84 (s, 3H), 3.71 (q, J = 5.7 Hz, 2H), 2.69 (t, J = 5.6 Hz, 2H), 1.69 (d, J = 6.6 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 167.4, 163.8, 160.2, 157.3, 146.3, 135.6, 133.4, 130.4, 128.4, 127.2, 126.2, 118.9, 113.5, 112.4, 74.8, 60.5, 55.4, 35.3, 29.7, 23.0 , 14.2. 24 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.63 (s, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.20 (dd, J = 3.5 Hz , 1H), 7.13 (t, J = 5.9 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.20 (q, J = 6.5 Hz, 1H ), 3.77 (s, 3H), 3.71 (q, J = 5.8 Hz, 2H), 2.88 (m, 1H), 2.69 (t, J = 5.9 Hz, 2H), 1.67 (d, J = 6.6 Hz, 3H ), 1.23 (d, J = 6.9 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 175.9, 171.3, 167.6, 162.9, 159.1, 154.5, 146.4, 141.7, 133.3, 128.1, 127.5, 127.3, 126.3, 126.2, 122.9, 111.2, 74.6, 60.5, 55.6, 35.4 , 33.8, 33.3, 29.7, 24.2, 23.0, 21.1, 14.2. 25 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.66 (s, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 5.5 Hz, 2H), 7.52 (d, J = 8.2 Hz , 2H), 7.30 (t, J = 9.2 Hz, 1H), 7.06 (t, J = 6.0 Hz, 1H), 6.22 (q, J = 6.5 Hz, 1H), 3.70 (q, J = 5.9 Hz, 2H ), 2.68 (t, J = 5.9 Hz, 2H), 1.70 (d, J = 6.6 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.1, 167.6, 164.0, 159.6, 158.8, 146.0, 133.4, 127.3, 126.2, 124.3, 123.1, 123.0, 122.2, 117.2, 117.1, 75.2, 60.5, 35.4, 33.7, 22.9 , 21.1, 14.2. 26 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.62 (s, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.6 Hz , 2H), 7.39 (d, J = 8.6 Hz, 2H), 6.83 (t, J = 6.1 Hz, 1H), 6.14 (q, J = 4.7 Hz, 1H), 3.72 (q, J = 5.9 Hz, 2H ), 2.70 (t, J = 5.9 Hz, 2H), 2.07 (m, 1H), 1.81 (m, 1H), 1.63 (m, 1H), 0.98 (dd, J = 6.4 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.0, 167.4, 163.8, 163.2, 157.1, 151.4, 145.9, 133.3, 131.3, 128.4, 127.1, 126.7, 126.2, 46.4, 35.2, 34.6, 33.6, 31.3, 24.7, 23.0 , 22.2. 27 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.66 (s, 2H), 7.71 (dd, J = 7.2 Hz, 4H), 7.57 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.3 Hz , 2H), 6.98 (t, J = 5.9 Hz, 1H), 6.15 (q, J = 4.7 Hz, 1H), 3.70 (q, J = 5.9 Hz, 2H), 2.68 (t, J = 5.8 Hz, 2H ), 2.08 (m, 1H), 1.79 (m, 1H), 1.64 (m, 1H), 0.98 (dd, J = 6.9 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.2, 167.5, 164.4, 157.5, 145.6, 137.8, 133.4, 130.5, 127.2, 126.8, 126.7, 126.3, 126.2, 126.2, 77.3, 60.5, 46.2, 35.3, 33.7, 31.2 , 24.7, 23.0, 22.2, 14.2. 28 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.63 (s, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.43 (t, J = 2.7 Hz , 4H), 7.37 (m, 1H), 7.07 (t, J = 6.0 Hz, 1H), 6.14 (q, J = 4.7 Hz, 1H), 3.70 (q, J = 5.9 Hz, 2H), 2.67 (t , J = 5.9 Hz, 2H), 2.07 (m, 1H), 1.80 (m, 1H), 1.63 (m, 1H), 0.97 (dd, J = 6.4 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.0, 171.3, 167.5, 163.8, 157.2, 145.7, 134.1, 133.4, 129.3, 128.5, 128.2, 127.2, 126.6, 126.5, 60.5, 46.3, 35.4, 33.8, 24.7, 23.0 , 22.2, 21.1, 14.2. 29 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.59 (s, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.36 (t, J = 1.8 Hz , 1H), 7.32 (d, J = 1.9 Hz, 2H), 6.95 (t, J = 6.1 Hz, 1H), 6.13 (q, J = 4.7 Hz, 1H), 3.70 (q, J = 5.9 Hz, 2H ), 2.68 (t, J = 5.9 Hz, 2H), 2.07 (m, 1H), 1.77 (m, 1H), 1.63 (m, 1H), 0.97 (dd, J = 7.2 Hz, 7H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.3, 167.5, 164.5, 157.3, 145.5, 137.2, 135.9, 133.4, 128.2, 127.2, 126.7, 126.1, 124.9, 77.5, 60.5, 46.2, 35.3, 33.7, 24.7, 23.0 , 22.2, 21.1, 14.2. 30 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.63 (s, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.62 (m, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.28 (t, J = 9.1 Hz, 1H), 7.04 (t, J = 6.0 Hz, 1H), 6.15 (q, J = 4.7 Hz, 1H), 3.69 (q, J = 5.9 Hz, 2H), 2.67 (t , J = 5.9 Hz, 2H), 2.07 (m, 1H), 1.77 (m, 1H), 1.63 (m, 1H), 0.96 (dd, J = 6.7 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.3, 167.6, 164.2, 158.8, 158.7, 145.5, 133.4, 127.2, 126.7, 124.3, 123.1, 123.0, 122.2, 117.2, 117.0, 77.4, 60.5, 46.2, 35.4, 33.7 , 24.7, 22.9, 22.2, 21.0, 14.2. 31 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.54 (s, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.48 (q, J = 3.1 Hz , 1H), 7.32 (q, J = 3.1 Hz, 2H), 7.25 (q, J = 3.1 Hz, 1H), 6.92 (t, J = 5.9 Hz, 1H), 6.16 (q, J = 4.7 Hz, 1H ), 3.71 (q, J = 5.9 Hz, 2H), 2.70 (t, J = 5.8 Hz, 2H), 2.08 (m, 1H), 1.80 (m, 1H), 1.64 (m, 1H), 0.98 (dd , J = 6.0 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.3, 167.5, 163.7, 159.2, 145.7, 133.4, 133.3, 132.8, 131.0, 130.3, 129.8, 127.4, 127.2, 126.8, 126.7, 46.3, 35.3, 33.7, 24.7, 23.0 , 22.3. 32 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.61 (s, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.44 (t, J = 1.6 Hz , 1H), 7.36 (m, 2H), 7.32 (m, 1H), 6.87 (t, J = 6.1 Hz, 1H), 6.14 (q, J = 4.7 Hz, 1H), 3.71 (q, J = 5.9 Hz , 2H), 2.70 (t, J = 5.9 Hz, 2H), 2.08 (m, 1H), 1.80 (m, 1H), 1.64 (m, 1H), 0.98 (dd, J = 6.9 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.4, 167.4, 164.2, 157.3, 145.7, 136.0, 135.2, 133.4, 130.5, 128.3, 127.2, 126.7, 126.6, 124.6, 60.5, 46.2, 35.2, 33.7, 31.6, 24.7 , 23.0, 22.7, 22.2, 14.2, 14.1. 33 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.60 (s, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.39 (m, 4H), 7.05 (m, 1H), 6.89 (t, J = 6.0 Hz, 1H), 6.14 (q, J = 4.7 Hz, 1H), 3.71 (q, J = 5.9 Hz, 2H), 2.69 (t, J = 5.8 Hz , 2H), 2.07 (m, 1H), 1.80 (m, 1H), 1.63 (m, 1H), 0.98 (dd, J = 6.7 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.3, 167.5, 164.0, 157.1, 157.0, 145.7, 134.5, 133.4, 132.6, 129.9, 129.5, 127.9, 127.7, 127.2, 126.7, 123.8, 119.3, 119.2, 60.5, 46.2 , 35.3, 33.7, 24.7, 23.0, 22.2, 14.2. 34 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.60 (s, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.6 Hz , 2H), 7.36 (t, J = 8.0 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 7.05 (dd, J = 7.3 Hz, 3H), 6.87 (t, J = 6.0 Hz, 1H ), 6.13 (q, J = 4.7 Hz, 1H), 3.71 (q, J = 5.9 Hz, 2H), 2.69 (t, J = 5.8 Hz, 2H), 2.08 (m, 1H), 1.80 (m, 1H ), 1.63 (m, 1H), 0.97 (dd, J = 6.4 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.1, 167.4, 163.7, 157.8, 157.0, 156.6, 145.8, 133.4, 129.9, 129.5, 129.0, 128.0, 127.9, 127.7, 127.1, 126.7, 123.8, 119.3, 119.2, 46.3 , 35.2, 33.7, 24.7, 23.0, 22.2. 35 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.61 (s, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz , 2H), 7.27 (d, J = 9.0 Hz, 2H), 6.92 (t, J = 6.0 Hz, 1H), 6.13 (q, J = 4.7 Hz, 1H), 3.71 (q, J = 5.9 Hz, 2H ), 2.68 (m, 4H), 2.08 (m, 1H), 1.79 (m, 1H), 1.63 (m, 1H), 1.25 (t, J = 7.6 Hz, 3H), 0.97 (dd, J = 6.4 Hz , 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.3, 167.5, 163.7, 157.1, 145.9, 144.5, 133.3, 131.5, 128.8, 128.5, 127.2, 126.7, 126.4, 60.5, 46.3, 35.3, 33.7, 28.5, 24.7, 23.0 , 22.2, 15.5, 14.2, 14.1.

<Comparative Example 1> (S)-3-(4-(1-(4'-tert-butyl-2,6-dimethyldiphenyl-4-yloxy)-4,4,4-trifluorobutyl) Benz Amido) Propanoic Acid

LY-2409021, which is well known as a (GCGR (glucagon receptor) antagonist, was prepared according to the following scheme.

Step 1: Preparation of methyl 4-(4,4,4-trifluoro-1-hydroxybutyl)benzoate

Using methyl 4-formylbenzoate (2.00 g, 12.2 mmol) as a starting material (3,3,3-trifluoropropyl)magnesium bromide (24.0 ml, 12.2 mmol) and dry THF (tetrahydrofuran) (40 ml) at 0 ℃ Reacted for 1 hour. The reaction product was checked by TLC to confirm that the starting material disappeared, and then acidified to pH 2 by adding 1N HCl, and extracted with ethyl ester (300 ml). It was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.69 g, yield: 53%) as a white solid by column chromatography.

Step 2: Preparation of methyl 4-(4,4,4-trifluorobutanoyl)benzoate

Using the compound (1.69 g, 6.44 mmol) obtained in step 1 of Comparative Example 1 as a starting material, PDC (Pyridinium Dichromate) (3.60 g, 9.67 mmol), 4ÅMS (molecular sieves) (500 mg) and DCM (Dichloromethane) (32 ml) was used and reacted for 5 hours at room temperature. After filtering with Celite, it was concentrated under reduced pressure to obtain the title compound (940 mg, yield: 56%) as a white solid by column chromatography.

Step 3: Preparation of (R)-methyl 4-(4,4,4-trifluoro-1-hydroxybutyl)benzoate

Using the compound obtained in step 2 (940 mg, 3.61 mmol) as a starting material, ( S) -Me-CBS catalyst (100 mg, 0.361 mmol), BH ₃ -THF complex (5.40 ml, 5.42 mmol) and dry THF (18 ml) was used and reacted at 0°C for 12 hours. Extracted with ethyl ester (300 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (856 mg, yield: 90%) as a white solid by column chromatography.

Step 4: Preparation of (S)-methyl 4-(1-(4-bromo-3,5-dimethylphenoxy)-4,4,4-trifluorobutyl)benzoate

Using the compound of step 3 (856 mg, 3.26 mmol) as starting materials, 5-bromo-2-hydroxypyrimidine (996 mg, 3.92 mmo), DIAD (Diisopropyl azodicarboxylate) (0.80 ml, 4.24 mmol), PPh ₃ (Triphenylphosphine) (1.10 g, 4.24 mmol) and THF (16 ml) were used to react at room temperature for 12 hours. After washing with the addition of ethyl acetate (300 ml), water and Brine, it was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (746 mg, yield: 51%) as an oil by column chromatography.

Step 5: Preparation of (S)-4-(1-(4-bromo-3,5-dimethylphenoxy)-4,4,4-trifluorobutyl)benzoic acid

Using the compound of step 4 (746 mg, 1.68 mmol) as starting materials LiOH-H ₂ O (141 mg, 3.35 mmol) and THF: H ₂ O (v:v=1.5:1) (13 ml) It was reacted at room temperature for 12 hours. 1N HCl was added, acidified to pH 2, and extracted with ethyl ester (100 ml). It was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (693 mg, yield: 96%) as a white solid by column chromatography.

Step 6: (S)-ethyl 3-(4-(1-(4-bromo-3,5-dimethylphenoxy)-4,4,4-trifluorobutyl)benzamido)propanoate Produce

Using the compound of step 5 (693 mg, 1.61 mmol) as a starting material, betaalanine ethyl ester hydrochloride (494 mg, 3.22 mmol), HOBt (492 mg, 3.22 mmol), EDCI (616 mg, 3.22 mmol), DIEA ( 0.84 ml, 4.82 mmol) and DMF (8 ml) were used to react at 50 ^o C for 1 hour. Extracted with ethyl ester (300 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (760 mg, yield: 89%) as an oil by column chromatography.

Step 7: (S)-ethyl 3-(4-(1-(4'-tert-butyl-2,6-dimethyldiphenyl-4-yloxy)-4,4,4-trifluorobutyl)benz Preparation of amido) propanoate

Using the compound obtained in step 6 (760 mg, 1.43 mmol) as a starting material, phenyl boronic acid (383 mg, 2.149 mmol), Na ₂ CO ₃ (456 mg, 4.30 mmol), Pd (dppf) Cl ₂ (52.4 mg, 0.072 mmol), and DMF (dimethylformamide) (7.17 ml) were used to react at 90° C. for 12 hours. Extracted with ethyl ester (300 ml), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and column chromatography to obtain the title compound (690 mg, yield: 82%) as an oil.

Step 8: (S)-3-(4-(1-(4'-tert-butyl-2,6-dimethyldiphenyl-4-yloxy)-4,4,4-trifluorobutyl)benzami Figure) Preparation of propanoic acid (LY-2409021)

Using the compound obtained in step 7 (80 mg, 0.137 mmol) as a starting material, LiOH-H ₂ O (11.5 mg, 0.274 mmol), THF:H ₂ O (1.5:1=v:v) (1 ml) And reacted at room temperature for 12 hours. 1N HCl was added, acidified to pH 2, and extracted with ethyl ester (30 ml). It was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (50.0 mg, yield: 65%) as a white solid by column chromatography.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.75 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H) , 6.96 (d, J = 8.1 Hz, 2H), 6.74 (s, 1H), 6.52 (s, 2H), 5.21 (s, 1H), 3.72 (d, J = 5.5 Hz, 2H), 2.72 (m, 2H), 2.30 (m, 2H), 2.12 (s, 6H), 1.91 (s, 9H).

<Comparative Example 2> N-(3-cyano-6-(1,1-dimethylpropyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl)-2-ethylbutanamide Preparation of (sc-203972)

Sc-203972, well known as a glucagon receptor (GCGR) antagonist, was purchased and prepared from Santa Curz Biotechnology (CAS 438618-32-7).

<Preparation of experimental material> and <Test method>

The manufacturing method and experimental method of the materials (cells, animal models, etc.) used in the experimental examples of the present invention are shown below.

1. Cell culture

The cAMP Hunter ^TM CHO-K1 GCGR Gs cell line (CHO-K1 GCGR Gs cells) expressing human GCGR (Glucagon receptor) was purchased from DiscoveRx (Fremont, USA). Cells were maintained in CHO-K1 medium (DiscoverX, Fremont, USA). Primary mouse hepatocytes were treated with 10% fetal bovine serum (FBS, GibcoBL, Grand Island, NY, USA) and 1% antibiotic (100 unit/ml penicillin) and 100 μg/ml streptomycin. ; GibcoBL, Grand Island, NY, USA) containing HepatoZYME (GibcoBL, Grand Island, NY, USA). Cells were maintained under subconfluent conditions in a humidified incubator at 37°C with ambient oxygen and 5% CO2.

2. Isolation of primary mouse hepatocytes

Isolation of hepatocytes was performed as follows. 10 week old male C57BL/6N mice were anesthetized with 150 μl of ketamine per mouse. Perfusion buffer I was used to perfuse through the portal vein for 10 minutes, and then perfusion buffer II was perfused for 5 minutes. The liver was removed, and hepatocytes were separated by dissecting in cold high glucose DMEM (cold high glucose DMEM). Cells were centrifuged at 4° C. for 5 minutes at 50 g, washed with cold high glucose DMEM, and then centrifuged at 4° C. at 50 g for 5 minutes. Hepatocytes were separated by Percoll gradient centrifugation (250 g for 5 minutes at 4° C. without interruption). The isolated hepatocytes were maintained in HepatoZYME (GibcoBL, Grand Island, NY, USA) containing 10% FBS and 1% antibiotics.

3. Cytotoxicity analysis (In vitro)

The cytotoxicity of the compound represented by Formula 1 of the present invention was determined by Cell Counting Kit-8 (CCK-8) assay (Dojindo, Japan). Mouse primary hepatocytes were inoculated into a 96-well plate at 1 x 10 ⁴ cells/well, and under a cell plating reagent (DiscoverX, Fremont, USA), an example compound of the present invention was added at 20 μM for 24 hours. Treated during. One day after treatment, CCK-8 solution was added and the cells were incubated at 37° C. for 2 hours. Absorbance was recorded at 450 nm using a microplate reader (VersaMax, Molecular Devices). Three independent experiments were performed in triplicate.

4. Measurement of cAMP generation

CHO-K1 GCGR Gs cells were maintained in CHO-K1 medium (DiscoverX, Fremont, USA). A 96-well plate was inoculated with 1 × 10 ⁴ cells/well. The next day, cells were treated with the example compound (20 μM) in PBS for 15 minutes at 37° C. and 5% CO ₂ . After incubation, 0.1 nM glucagon and 10 μM forskolin were added, and the cells were further incubated at 37° C. and 5% CO ₂ for 30 minutes. cAMP was measured using the HitHunter® cAMP Assay for Small Molecules Kit (DiscoveRx, Fremont, USA) according to the manufacturer's instructions. Luminescence was measured using Victor 3 (Perkin Elmer, Waltham, MA, USA).

5. Measurement of glucose production in mouse primary hepatocytes

Mouse primary hepatocytes were inoculated into 12-well plates at 2.5 × 10 ⁵ cells/well. After 24 hours, the cells were washed twice in a preheated glucose-free DMEM (glucose-free DMEM) medium, and cultured in glucose-free DMEM for 3 hours. Cells were treated with example compounds (20 μM), gluconeogenic substrates (20 mM sodium lactate and 2 mM sodium pyruvate) and 10 nM glucagon. After 30 minutes, glucose in the medium was quantified using a glucose assay kit (Sigma-Aldrich, St. Louis, MO, USA) and corrected to the cell protein concentration. Five independent experiments were performed in triplicate.

6. Evaluation of antihyperglycemic effect in diabetic mouse model (db/db mice)

A 6-week-old male db/db mouse was purchased from the Korea Research Institute of Bioscience and Biotechnology (KRIBB; Daejeon Metropolitan City, Korea), and at the Animal Management Center of the Cancer and Diabetes Research Institute, Lee Gil Ya, Gachon University School of Medicine, Korea. Was maintained in specific pathogen-free conditions in a temperature-controlled room in a 12-hour light-dark cycle that allowed free ingestion. A db/db mouse with a blood glucose level of 400 mg/dL or more was used in the experiment. Example 11 (in the drawing, (R)-7a), Example 12 (in the drawing, (S)-7a) or Comparative Example 1 (in the drawing, LY2409021) (9% excipient with 10% DMSO in sterile water ( cremophore)) compound was intubated once a day for 4 weeks in an amount of 50 mg/kg and administered orally. Example 11, Example 12, or Comparative Example 1 At the 4th week of administration of the compound, blood glucose levels were checked using a glucose analyzer (Onetouch® Ultra, Lifescan, Johnson & Johnson, Milpitas, CA, USA). All animal experiments were approved by the Institutional Animal Care and Use Committee of the Cancer and Diabetes Research Institute.

7. Glucagon challenge assay

Diabetic db / db mice in Example 11 (in the drawing, (R)-7a), Example 12 (in the drawing, (S)-7a) or Comparative Example (in the drawing, LY2409021) (10% DMSO in sterile water 9% excipient (dissolved in cremophore)) compound was intubated once a day for 4 weeks in an amount of 50mg/kg and administered orally. Four weeks after drug administration, mice were fasted for 5 hours, and then the compound of Example 11, Example 12 or Comparative Example was orally administered by a gastric tube in an amount of 50 mg/kg. One hour later, glucagon was injected intraperitoneally at a dose of 15 μg/kg, and blood glucose levels were measured at 15, 30, 45 and 60 minutes after glucagon injection.

8. Statistical analysis

All data are expressed as mean±standard error. According to Fisher's protected Least Significant Difference test using Graph Pad Prism software, several group comparisons were performed by analysis of variance (ANOVA) at * p <0.05, ** p <0.01 or *** p <0.001. IC ₅₀ values were validated for three independent validation test compounds and calculated using Graph Pad Prism software.

<Experimental Example 1> Cytotoxicity evaluation

In order to evaluate the cytotoxicity of the compound represented by Formula 1 of the present invention, the following experiment was performed, and the results are shown in FIG. 1.

Mouse primary hepatocytes were treated with the compounds of Examples 1 to 10 at 20 μM each for 24 hours, and cell viability was measured through Cell Counting Kit-8 (CCK-8).

1 shows the evaluation of the cell viability of the Example compound.

7a: Example 1, 7b: Example 2, 7c: Example 3, 7d: Example 4, 7e: Example 5, 7f: Example 6, 7g: Example 7, 7h: Example 8, 7i: Example 9, 7j: Example 10, GA: Comparative Example 2

As shown in Figure 1, it can be seen that the example compound according to the present invention exhibits a cell viability of 80% or more.

Therefore, it was confirmed that the compound represented by Chemical Formula 1 of the present invention does not exhibit cytotoxicity and is safe.

<Experimental Example 2> GCGR activity inhibition effect evaluation

1) cAMP production inhibitory effect

Glucagon promotes the breakdown of glycogen and production of glucose by mediating the GCGR (Glucagon receptor) in the liver, thereby increasing fasting blood sugar. GCGR acts primarily through the cAMP-protein kinase A (PKA) pathway. When GCGR is activated by glucagon, the intracellular cAMP level is increased by activation of adenylate cyclase, followed by PKA (protein kinase A) activation. Accordingly, in order to evaluate the effect of the compound represented by Formula 1 of the present invention on inhibiting GCGR signal transduction, the following experiment was performed.

In order to evaluate the GCGR signal transduction inhibitory effect of the compound represented by Chemical Formula 1, reporter cell line cAMP Hunter ^TM CHO-K1 GCGR Gs cells were used in Examples 1 to 10 of the present invention. The cAMP level was measured. The results are shown in FIG. 2.

Figure 2 shows the intracellular glucagon-induced cAMP production rate according to the treatment of the compound of the present invention.

7a: Example 1, 7b: Example 2, 7c: Example 3, 7d: Example 4, 7e: Example 5, 7f: Example 6, 7g: Example 7, 7h: Example 8, 7i: Example 9, 7j: Example 10, GA: Comparative Example 2

As shown in Figure 2,

It was confirmed that glucagon treatment (Vehicle) increased cAMP production, and when the example compounds according to the present invention were treated, cAMP production induced by glucacon was inhibited. It can be seen that most of the compounds of the examples of the present invention exhibit a cAMP inhibitory effect of 60% or more when 10 μM is used.

Accordingly, it can be seen that the compound represented by Formula 1 of the present invention inhibits the production of cAMP induced by glucagon, and thus exhibits an effect of inhibiting GCGR signal transduction.

2) Evaluation of inhibition of glucose production

When GCGR is activated, glucose production is increased, and the following experiment was performed to determine the degree of inhibition of GCGR activity by evaluating the rate of glucose production when the compound represented by Formula 1 of the present invention was treated, and the results are shown in FIG. Shown in.

In the presence of 10 nM glucagon and gluconeogenic substrates (2 mM sodium pyruvate and 20 mM sodium lactate), mouse primary hepatocytes were subjected to Examples 1 to 10 compounds (20 μM ). The amount of glucose produced was measured 30 minutes after treatment with glucagon.

Figure 3 shows the intracellular glucagon-induced glucose production rate according to the treatment of the compound of the present invention.

7a: Example 1, 7b: Example 2, 7c: Example 3, 7d: Example 4, 7e: Example 5, 7f: Example 6, 7g: Example 7, 7h: Example 8, 7i: Example 9, 7j: Example 10, GA: Comparative Example 2

As shown in Figure 3,

Most of the example compounds of the present invention inhibited the production of glucose induced by glucagon in mouse primary hepatocytes, and in particular, the compounds of Examples 1, 6, 7, 9 and 10 showed an inhibitory effect of 60% or more, of which, Examples 6 and 7 showed a remarkable inhibitory effect of 80% or more.

Therefore, the reduction in the production of glucose induced by glucagon by treatment of the compound represented by Formula 1 of the present invention suggests that the compound represented by Formula 1 of the present invention inhibits GCGR activity.

3) Evaluation of the dose-dependent cAMP production inhibitory effect of the compound

In order to evaluate the dose-dependent inhibitory effect of the compounds of Examples 1, 6, 7, 9 and 10 showing excellent inhibitory effect on glucose production in Experimental Example 2.-2) on glucagon-induced cAMP production in CHO-K1 GCGR Gs cells The following experiment was performed, and the results are shown in FIG. 4.

The dose-dependent inhibitory effect of the compounds of Examples 1, 6, 7, 9 and 10 on the production of glucagon-induced cAMP in CHO-K1 GCGR Gs cells was evaluated. cAMP production was measured in CHO-K1 GCGR Gs cells after treatment with 0.0001, 0.001, 0.01, 0.1, 1, 10 or 100 μM of the Example compound and 0.1 nM glucagon. The results are representative of three independent experiments. ** p <0.01 vs. Vehicle, GA; GCGR antagonist I (Santa Cruz Biotechnology, sc-203972)

Figure 4 shows the results of evaluating the degree of inhibition of glucagon-induced cAMP production according to the treatment concentration of the compound of the present invention.

7a: Example 1, 7f: Example 6, 7g: Example 7, 7i: Example 9, 7j: Example 10

As shown in Figure 4,

Example compounds of the present invention exhibited a low IC ₅₀ value of 20 μM or less, and it can be seen that even when treated at a low concentration, they exhibit excellent cAMP production inhibitory effects.In particular, Examples 1, 6 and 7 are 4.1 μM, respectively, It was confirmed that the IC ₅₀ value was significantly lower than 7 μM with 6.0 μM and 6.9 μM, indicating excellent cAMP production inhibitory effect.

Therefore, the compound represented by Formula 1 of the present invention exhibits an effect of inhibiting cAMP production even at a low concentration, which indicates that the compound represented by Formula 1 of the present invention has excellent effect of inhibiting GCGR activity by inhibiting GCGR signal transduction. Suggests.

<Experimental Example 3> Evaluation of the effect of inhibiting glucose production according to the concentration of the compound

Activation of GCGR by glucagon promotes glucose production by inducing glycogenolysis and gluconeogenesis in the liver. In order to evaluate the effect of inhibiting glucose production by concentration of the compound represented by Formula 1 according to the present invention, the following experiment was performed, and the results are shown in FIG. 5.

Using the compounds of Examples 1, 6, and 7 derived through performing Experimental Example 2, the dose-dependent glucose production inhibitory effect of the compound represented by Formula 1 was evaluated. Mouse primary hepatocytes were 1, 5, 10, 20, 50 in the presence of 10 nM of glucagon and gluconeogenic substrates (2 mM sodium pyruvate and 20 mM sodium lactate). Or 100 μM of the example compound. Glucose production was measured with a glucose assay kit. The results are representative of three independent experiments. ^* p <0.05, ^** p <0.01, or ^*** p <0.001 vs. 10 nM Glucagon (black bar)

Figure 5 shows the glucagon-induced glucose production rate according to the treatment concentration of the compound of the present invention.

7a: Example 1, 7f: Example 6, 7g: Example 7

As shown in Figure 5,

It was confirmed that the compounds of Examples 1, 6 and 7 dose-dependently inhibited glucagon-induced glucose production. In particular, it was confirmed that the compounds of Examples 1 and 6 exhibited an inhibitory effect of 50% or more when treated with 10 μM, thereby exhibiting an excellent glucose inhibitory effect.

Therefore, the compound represented by Formula 1 of the present invention exhibits an inhibitory effect on glucose production even at a low concentration, which suggests that the compound represented by Formula 1 of the present invention has an excellent effect of inhibiting GCGR activity.

<Experimental Example 4> Pharmacokinetic analysis

Pharmacokinetic analysis of the compound represented by Formula 1 of the present invention was performed.

The analysis was performed using the compounds of Examples 1 and 6 that showed the best effect in Experimental Example 3, and Examples 1 and 6 were administered to C57BL/6 mice at 10 mg/kg by oral gavage, and The levels of compounds in the blood were measured after 0.25, 0.5, 0.75, 1, 2, 3, 4, 6 and 8 hours. The results are shown in Table 4 below.

Example C _max (ng/ml) AUC (hr×ng/ml) T _max (h) One 9460 ± 640 27256 ± 2183 0.67 ± 0.0 6 2885 ± 205 6256 ± 1266 0.84 ± 0.17

As shown in Table 4, it was confirmed that the compounds according to the present invention exhibited excellent values in all of the highest blood concentration (C _max ), drug bioavailability (AUC), and maximum blood concentration arrival time (T _max ). In particular, it was confirmed that the compound of Example 1 exhibited a value superior to that of Example 6 at all values, and thus had remarkably excellent drug activity.

<Experimental Example 5> Evaluation of the inhibitory effect on glucose production of the enantiomer of the compound

In the compound represented by Formula 1 of the present invention, a chiral center exists, and in order to evaluate the pharmacological effect of the compound according to the chirality of the compound, the following experiment was performed, and the results are shown in FIG. 6 Shown in.

Examples The experiments were performed using the compounds of Examples 1 and 6, which exhibited high pharmacological effects, and the compounds of Examples 11, 12, 15 and 16, which are enantiomers thereof. Mouse primary hepatocytes in the presence of 10 nM of glucagon and gluconeogenic substrates (2 mM sodium pyruvate and 20 mM sodium lactate) for 3 hours in Examples 1 and 6 and Examples 11, 12, 15 and 16 compounds, which are their enantiomers, were treated with 20 μM. 30 minutes after treatment with glucagon, the amount of glucose produced was measured.

6 shows the results of measuring the inhibitory effect of glucagon-induced glucose production according to the enantiomeric compound treatment.

7a: Example 1, (S)-7a: Example 12, (R)-7a: Example 11, 7f: Example 6, (S)-7f: Example 16, (R)-7f: Example 15

As shown in Figure 6,

Example 1 and its enantiomers (Examples 11 and 12) significantly reduced glucagon-induced glucose production, and in particular, Example 11 in (R) form was a racemate, Example 1 or (S) It exhibited a remarkably superior inhibitory effect than the form of Example 12.

Example 6 and its enantiomers (Examples 15 and 16) also significantly reduced glucagon-induced glucose production, but showed a lower effect than Example 1 and its enantiomers.

<Experimental Example 6> Evaluation of glucose cytotoxicity of enantiomers of compounds

Since a chiral center exists in the compound represented by Formula 1 of the present invention, the following experiment was performed to evaluate the cytotoxicity of the compound according to the chirality of the compound, and the results are shown in FIG. 7 Shown in.

Examples The experiments were performed using the compounds of Examples 1 and 6, which exhibited high pharmacological effects, and the compounds of Examples 11, 12, 15 and 16, which are enantiomers thereof. The mouse primary hepatocytes were treated with Examples 1 and 6 and the compounds of Examples 11, 12, 15 and 16, which are enantiomers thereof, at 20 μM for 24 hours, and cell viability was measured by CCK-8 assay. ^* p <0.05, ^** p <0.01, or ^*** p <0.001 vs. Vehicle, ^# p <0.05, ^## p <0.01 or ^### p <0.001

7 shows the results of measuring the cell viability according to the treatment of the enantiomeric compound.

7a: Example 1, (S)-7a: Example 12, (R)-7a: Example 11, 7f: Example 6, (S)-7f: Example 16, (R)-7f: Example 15

As shown in Figure 7,

Example 1 and its enantiomers (Examples 11 and 12) showed low cytotoxicity with a cell viability of 70% or more, and in particular, Example 11 in (R) form was a racemate, Example 1 or ( S) showed remarkably better cell viability than Example 12 in form, and it was confirmed that there was no cytotoxicity.

Example 6 and Example 15 of the (R) form of the enantiomers thereof had low cytotoxicity with a cell viability of 80% or more, whereas Example 16 of the (S) form exhibited a strong cytotoxic effect.

<Experimental Example 7> Evaluation of the effect of lowering blood sugar in mice

In order to evaluate the in vivo pharmacological effect of the compound represented by Formula 1 of the present invention, the effect of lowering blood sugar in a diabetic mouse model was evaluated, and the results are shown in FIGS. 8 and 9.

1) Evaluation of hypoglycemic effect according to compound administration in diabetic mouse model

Experiments were performed using Examples 11 and 12, which showed high pharmacological effects. Each of Examples 11 and 12 and Comparative Example 1 was orally administered to diabetic db/db mice once a day for 4 weeks at 50 mg/kg. After 4 weeks of treatment, blood glucose levels were measured. The results are shown in FIG. 8.

8 shows the results of measuring the blood glucose concentration according to the compound treatment.

(S)-7a: Example 12, (R)-7a: Example 11, LY-2409021: Comparative Example 1

As shown in Figure 8,

The blood glucose (glucose, glucose) level showed a blood sugar lowering effect in both Examples 11 and 12 compared to the control (Vehicle). In particular, it was confirmed that the compound of Example 11 was statistically significantly reduced.

2) Evaluation of the hypoglycemic effect of the compound on the increase in glucagon-induced blood sugar in a diabetic mouse model

In a diabetic mouse model, the following glucagon challenge assay was performed to evaluate whether the compound represented by Chemical Formula 1 of the present invention can lower the blood sugar induced by glucagon, and the results are shown in FIG. 9 Shown in.

After fasting diabetic db/db mice for 5 hours, the compounds of Examples 11 and 12 and Comparative Example 1 were orally administered at 50 mg/kg. After 1 hour, 15 μg/kg of glucagon was injected intraperitoneally. After glucagon injection, blood glucose levels were measured after 15, 30, 45 and 60 minutes. (n = 4-6 / group) ^* p <0.05, ^** p <0.01 or ^*** p <0.001 vs. Vehicle group

9 shows the change in blood glucagon-induced glucose concentration according to the compound treatment.

(S)-7a: Example 12, (R)-7a: Example 11, LY-2409021: Comparative Example 1

As shown in Figure 9,

When administering Examples 11 and 12 to diabetic db/db mice to which 15 μg/kg of glucagon was administered, it was confirmed that blood glucose induced by glucagon was reduced.

The above results suggest that the compound represented by Formula 1 of the present invention has a GCGR antagonistic effect in a diabetic mouse model, and from this, the compound represented by Formula 1 of the present invention can be usefully used in the treatment of diabetes. Able to know.

Therefore, it was confirmed that the compound represented by Formula 1 of the present invention exhibits excellent inhibitory effect on cAMP or glucagon production, inhibits GCGR activity, and exhibits excellent hypoglycemic effect in vitro as well as in vivo, and has low cytotoxicity As safety has been verified, it can be usefully used in the treatment of metabolic diseases, especially diabetes, which are diseases related to GCGR activity.

<Experimental Example 8> GCGR signal transduction inhibition effect evaluation

In order to evaluate the GCGR signal transduction inhibitory effect of the compound represented by Formula 1 of the present invention, the reporter cell line cAMP Hunter ^TM CHO-K1 GCGR Gs cells were used to treat the compound represented by Formula 1 of the present invention. The level of cAMP in the cells was measured accordingly. The results are shown in FIG. 10. In this experiment, the compounds of Examples 1-10 and 17-35 were treated with 5, 10 and 20 μM, respectively, and cAMP levels were measured.

Figure 10 shows by evaluating the GCGR signaling inhibitory effect of the Example compound.

SD-366: Example 17, SD-367: Example 18, SD-368: Example 19, SD-369: Example 20, SD-370: Example 21, SD-371: Example 22, SD- 372: Example 23, SD-373: Example 24, SD-374: Example 25, SD-375: Example 26, SD-376: Example 27, SD-499: Example 28, SD-500: Example 29, SD-501: Example 30, SD-502: Example 31, SD-503: Example 32, SD-504: Example 33, SD-505: Example 34, SD-506: Example 35, 7a: Example 1, 7b: Example 2, 7c: Example 3, 7d: Example 4, 7e: Example 5, 7f: Example 6, 7g: Example 7, 7h: Example 8, 7i: Example 9, 7j: Example 10

As shown in Figure 10,

It was confirmed that glucagon treatment (Vehicle) increased cAMP production, and when the example compounds according to the present invention were treated, cAMP production induced by glucacon was inhibited. In particular, it can be seen that the compounds of Examples 1-10 of the present invention exhibit excellent effects by reducing cAMP production by 50% or more even when 5 μM is used.

That is, it can be seen that the compound represented by Formula 1 according to the present invention inhibits GCGR signal transduction.

<Formulation Example 1> Preparation of powder

2g of derivatives represented by Formula 1

1g lactose

The above ingredients were mixed and filled in an airtight cloth to prepare a powder.

<Formulation Example 2> Preparation of tablets

100 mg of derivatives represented by Formula 1

Corn starch 100 mg

100 mg lactose

2 mg of magnesium stearate

After mixing the above ingredients, tablets were prepared by tableting according to a conventional tablet preparation method.

<Formulation Example 3> Preparation of capsules

100 mg of derivatives represented by Formula 1

Corn starch 100 mg

100 mg lactose

2 mg of magnesium stearate

After mixing the above ingredients, a gelatin capsule was filled according to a conventional capsule preparation method to prepare a capsule.

<Formulation Example 4> Preparation of injection

100 mg of derivatives represented by Formula 1

Mannitol 180 mg

Na ₂ HPO ₄ ㆍ2H ₂ O 26 mg

Distilled water 2974 mg

According to a conventional method for preparing injections, injections were prepared by containing the above ingredients in the indicated amount.

<Formulation Example 5> Preparation of health food

500 ng of derivatives represented by formula 1

Vitamin mixture right amount

70mg vitamin A acetate

1.0mg vitamin E

0.13mg vitamin

0.15mg vitamin B2

0.5mg vitamin B6

0.2mg vitamin B12

10mg vitamin C

10mg biotin

1.7 mg of nicotinic acid amide

50mg folic acid

0.5mg calcium pantothenate

Suitable amount of inorganic mixture

1.75 mg ferrous sulfate

Zinc oxide 0.82mg

25.3mg magnesium carbonate

15 mg of potassium monophosphate

Dicalcium phosphate 55mg

90mg potassium citrate

100mg calcium carbonate

Magnesium chloride 24.8mg

The composition ratio of the vitamin and mineral mixture is relatively suitable for health food, but it may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method. , To prepare granules, and can be used to prepare a health food composition according to a conventional method.

<Formulation Example 6> Preparation of health drink

500 ng of derivatives represented by formula 1

1000mg citric acid

100g oligosaccharide

2g plum concentrate

1 g taurine

Total 900ml with purified water

After mixing the above ingredients according to a normal health drink manufacturing method, stirring and heating at 85° C. for about 1 hour, the resulting solution is filtered and obtained in a sterilized container, sealed and sterilized, and then stored in a refrigerator. Used in preparation.

The composition ratio is a mixture of ingredients suitable for a relatively preferred beverage in a preferred embodiment, but the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand class, the country of demand, and the purpose of use.

Claims (13)

A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1,
R ¹ is independently hydrogen, halogen, straight-chain or branched C _1-10 alkyl unsubstituted or substituted with one or more halogens, straight-chain or branched C _1-10 alkoxy unsubstituted or substituted with one or more halogens, non-substituted Cyclic C _6-10 aryl or unsubstituted C _6-10 aryloxy;
R ² is unsubstituted straight or branched C _1-10 alkyl;
R ³ is independently hydrogen, halogen, straight-chain or branched C _1-10 alkyl unsubstituted or substituted with one or more halogens, or straight-chain or branched C _1-10 alkoxy unsubstituted or substituted with one or more halogens;
l is an integer from 1 to 5;
m is an integer from 1 to 4; And
n is an integer from 1 to 7),

Is a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that the alkyloxy bonded to phenyl is bonded to the para position.
The method of claim 1,
R ¹ is independently hydrogen, halogen, straight or branched C _1-6 alkyl unsubstituted or substituted with one or more halogens, straight or branched C _1-6 alkoxy unsubstituted or substituted with one or more halogens, Unsubstituted phenyl or unsubstituted phenoxy;
R ² is unsubstituted straight or branched C _1-6 alkyl;
R ³ is independently hydrogen, halogen, straight-chain or branched C _1-6 alkyl unsubstituted or substituted with one or more halogens, or straight-chain or branched C _1-6 alkoxy unsubstituted or substituted with one or more halogens;
l is an integer from 1 to 3;
m is 1 or 2; And
n is a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that an integer of 1 to 5.
The method of claim 1,
R ¹ is independently hydrogen, halogen, straight or branched C _1-4 alkyl unsubstituted or substituted with one or more halogens, straight or branched C _1-4 alkoxy unsubstituted or substituted with one or more halogens, Unsubstituted phenyl or unsubstituted phenoxy;
R ² is unsubstituted straight or branched C _1-4 alkyl;
R ³ is independently hydrogen, halogen, straight-chain or branched C _1-3 alkyl unsubstituted or substituted with one or more halogens, or straight-chain or branched C _1-3 alkoxy unsubstituted or substituted with one or more halogens;
l is 1 or 2;
m is 1; And
n is an integer of 1 to 3, a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ¹ is independently hydrogen, OMe, Cl, Et, i-Pr, t-Bu, CF ₃ or phenoxy;
R ² is Me, i-Bu or n-Bu;
R ³ is hydrogen;
l is 1 or 2;
m is 1; And
n is a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that 2.
delete The method of claim 1,
The compound represented by Formula 1 is a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is any one selected from the following compound group:
<1> 3-(4-(1-((5-phenylpyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<2> 3-(4-(1-((5-(2-chlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<3> 3-(4-(1-((5-(3-chlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<4> 3-(4-(1-((5-(4-chlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<5> 3-(4-(1-((5-(4-trifluoromethylphenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<6> 3-(4-(1-((5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<7> 3-(4-(1-((5-(3,5-dichlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<8> 3-(4-(1-((5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid ;
<9> 3-(4-(1-((5-(4-phenoxyphenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<10> 3-(4-(1-((5-(4-Ethylphenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<11> (R)-3-(4-(1-(5-phenylpyrimidin-2-yloxy)pentyl)benzamido)propanoic acid;
<12> (S)-3-(4-(1-(5-phenylpyrimidin-2-yloxy)pentyl)benzamido)propanoic acid;
<13> (R)-3-(4-(1-((5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<14> (S)-3-(4-(1-((5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<15> (R)-3-(4-(1-((5-(3,5-dichlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<16> (S)-3-(4-(1-((5-(3,5-dichlorophenyl)pyrimidin-2-yl)oxy)pentyl)benzamido)propanoic acid;
<17> 3-(4-(1-(5-(4-bromophenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;
<18> 3-(4-(1-(5-phenylpyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;
<19> 3-(4-(1-(5-(4-chlorophenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;
<20> 3-(4-(1-(5-(4-(trifluoromethyl)phenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;
<21> 3-(4-(1-(5-(4-tert-butylphenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;
<22> 3-(4-(1-(5-(3,5-dichlorophenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;
<23> 3-(4-(1-(5-(3-methoxyphenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;
<24> 3-(4-(1-(5-(5-isopropyl-2-methoxyphenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;
<25> 3-(4-(1-(5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yloxy)ethyl)benzamido)propanoic acid;
<26> 3-(4-(1-(5-(4-tert-butylphenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid;
<27> 3-(4-(3-methyl-1-(5-(4-(trifluoromethyl)phenyl)pyrimidin-2-yloxy)butyl)benzamido)propanoic acid;
<28> 3-(4-(3-methyl-1-(5-phenylpyrimidin-2-yloxy)butyl)benzamido)propanoic acid;
<29> 3-(4-(1-(5-(3,5-dichlorophenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid;
<30> 3-(4-(1-(5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propano Ripe acid;
<31> 3-(4-(1-(5-(2-chlorophenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid;
<32> 3-(4-(1-(5-(3-chlorophenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid;
<33> 3-(4-(1-(5-(4-chlorophenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid;
<34> 3-(4-(3-methyl-1-(5-(4-phenoxyphenyl)pyrimidin-2-yloxy)butyl)benzamido)propanoic acid; And
<35> 3-(4-(1-(5-(4-ethylphenyl)pyrimidin-2-yloxy)-3-methylbutyl)benzamido)propanoic acid.
As shown in Scheme 1 below,
Reacting the compound represented by Formula 3 with the compound represented by Formula 4 to obtain a compound represented by Formula 2 (Step 1); And
A method of preparing a compound represented by Formula 1 of claim 1, comprising the step of obtaining a compound represented by Formula 1 by hydrolyzing the compound represented by Formula 2 obtained in Step 1 (Step 2):
[Scheme 1]

(In the above scheme 1,
R ¹ , R ² , R ³ , l, m and n are as defined in Formula 1 of claim 1;
R ⁴ is straight or branched C _1-5 alkyl;
X ¹ is halogen;
L ¹ is

or

ego; And

Is bonded in the para position with alkyloxy bonded to phenyl).
A pharmaceutical composition for preventing or treating metabolic diseases containing the compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
The method of claim 8,
The metabolic disease is any one selected from the group consisting of diabetes, obesity, hyperlipidemia, hypertension, hyperinsulinemia, fatty liver, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome (Syndrome X), and dyslipidemia. Pharmaceutical composition characterized by.
The method of claim 8,
The pharmaceutical composition, characterized in that the compound inhibits GCGR (Glucagon Receptor) activity.
The method of claim 8,
The pharmaceutical composition, characterized in that the compound exhibits a blood glucose lowering effect in blood.
The method of claim 8,
The pharmaceutical composition, characterized in that the compound inhibits cAMP production or glucose production induced by glucagon.
A health functional food composition for preventing or improving metabolic diseases containing the compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

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