KR102174395B1 - Coumarin-3-carboxamide derivatives, preparation method therof, and pharmaceutical composition for use in preventing or treating Urotensin-Ⅱ receptor activity related diseases containing the same as an active ingredient - Google Patents

Abstract

It relates to a coumarin-3-carboxyamide derivative, a preparation method thereof, and a pharmaceutical composition for preventing or treating diseases related to urotensin-II receptor activity comprising the same as an active ingredient, wherein the derivative is an antagonist against the urotensin-II receptor. Congestive heart failure, heart ischemia, myocardial infarction, cardiac hypertrophy, heart fibrosis, coronary artery disease, arteriosclerosis, high blood pressure, asthma, kidney failure, diabetes, vascular inflammation, neurodegenerative disease, stroke, pain, depression, psychosis, cancer, etc. It can be usefully used to prevent or treat diseases related to the same urotensin-II receptor activity.

Description

Coumarin-3-carboxamide derivatives, preparation method therof, and pharmaceutical composition for the prevention or treatment of diseases related to urotensin-II receptor activity containing the same as an active ingredient {Coumarin-3-carboxamide derivatives, preparation method therof, and pharmaceutical composition for use in preventing or treating Urotensin-II receptor activity related diseases containing the same as an active ingredient}

It relates to a coumarin-3-carboxyamide derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating diseases related to urotensin-II receptor activity comprising the same as an active ingredient.

Eurotensin-II is a cysteine-linked cyclic peptide and is known to be one of the most powerful vasoconstrictors known to date, which is 10 times stronger than endoterin-1 (Non-Patent Document 1). Eurotensin-II is composed of 11 amino acids in humans and 14 amino acids in mice, and was first discovered in goby fish, but is now identified in all vertebrates (Non-Patent Document 2).

Eurotensin-II has been reported to induce hypertrophy of cardiomyocytes and proliferation of smooth muscle cells, indicating a relevance in chronic vascular diseases such as heart failure and arteriosclerosis (Non-Patent Document 3). In addition, it has been reported that eurotensin-II increases peripheral vascular tone, a characteristic of chronic heart failure (Non-Patent Document 4). Eurotensin-II is highly expressed in the plasma of patients with renal dysfunction (Non-Patent Document 5). It has been reported that eurotensin-II is also associated with diabetes (Non-Patent Document 6). It has been reported that eurotensin-II is also related to central nervous system disorders (Non-Patent Document 7). It has been shown to overexpress the eurotensin-II receptor in certain tumor cell lines (Non-Patent Document 8).

The physiological activity of eurotensin-II is mediated through activation of the eurotensin-II receptor (UT). Previously, an orphan receptor GPR14, a G-protein-coupling-receptor (GPCR) as a seven-domain transmembrane receptor, was identified as a eurotensin-II receptor (Non-Patent Document 9). The eurotensin-II receptor is expressed in various tissues such as blood vessels, heart, liver, kidney, muscle, and lung (Non-Patent Document 10).

Eurotensin-II receptor antagonists may be useful in the treatment of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, renal failure, diabetes and vascular inflammation. In addition, U-receptor antagonists may be useful in the treatment of central nervous system disorders such as neurodegenerative diseases, stroke, pain, depression and psychosis, and may be useful in the treatment of certain cancers.

The study on the development of urotensin-II receptor antagonists is in progress to derive low-molecular synthetic compounds with various chemical skeletons, breaking away from Urandtide-based peptidomimetic studies.

Ames et al., Nature 1999, 401, 282 Onan et al., Trends Endocrinol. Metab. 2004, 15, 175 Zou et al., FEBS Letters 2001, 508, 57 Lim et al., Circulation 2004, 109, 1212 Totsune et al., Lanceet 2001, 358, 810 Totsune et al., Clin. Sci. 2003, 104, 1 Matsumoto et al., Neurosci. Lett., 2004, 358, 99 Takahashi et al., Peptides, 2003, 24, 301 Elshourbagy et al., Br. J. Pharmacol. 2002, 36, 9 Proulx et al., Peptides 2008, 29, 691

One object of the present invention is to provide a coumarin-3-carboxyamide derivative.

Another object of the present invention is to provide a method for producing a coumarin-3-carboxyamide derivative.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases related to urotensin-II receptor activity, containing a coumarin-3-carboxyamide derivative as an active ingredient.

Another object of the present invention is to provide a health functional food composition for the prevention or improvement of diseases related to urotensin-II receptor activity, containing a coumarin-3-carboxyamide 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 isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Formula 1,

R ¹ is hydrogen, halogen, NO ₂ , CN, straight or branched C _1-10 alkyl or straight or branched C _1-10 alkoxy;

R ² is halogen; And

r is an integer from 1-4).

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

Preparing a compound represented by Formula 2 by reacting a compound represented by Formula 3 with a compound represented by Formula 4 (Step 1); And

There is provided a method for preparing a compound represented by Formula 1, comprising the step of reacting a compound represented by Formula 2 to prepare a compound represented by Formula 11 (Step 2):

[Scheme 1]

(In the above Scheme 1,

R ¹ , R ² and r are as defined in Formula 1 of claim 1; And

PG ^a is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2 -Is one type of amine protecting group selected from the group consisting of trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc)).

According to another aspect of the present invention, the prevention of a disease related to urotensin-II receptor activity comprising the compound represented by Formula 1, its isomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient, or A therapeutic pharmaceutical composition is provided.

According to another aspect of the present invention, the prevention of a disease related to urotensin-II receptor activity comprising the compound represented by Formula 1, its isomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient, or A health functional food composition for improvement is provided.

According to another aspect of the present invention, a subject in need of a pharmaceutical composition or a health functional food composition containing the compound represented by Formula 1, its isomer, solvate, hydrate or pharmaceutically acceptable salt thereof as an active ingredient There is provided a method for preventing or treating a disease related to eurotensin-II receptor activity comprising administering to a patient.

According to another aspect of the present invention, a compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of a disease related to the eurotensin-II receptor activity The use of the containing pharmaceutical composition or dietary supplement composition is provided.

The coumarin-3-carboxyamide derivative of the present invention acts as an antagonist to the eurotensin-II receptor, thereby congesting heart failure, heart ischemia, myocardial infarction, heart hypertrophy, heart fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, renal failure. , Diabetes, vascular inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis, cancer, such as eurotensin-II receptor activity-related diseases can be usefully used to prevent or treat.

Hereinafter, the present invention will be described in detail.

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

[Formula 1]

In Formula 1,

R ¹ is hydrogen, halogen, NO ₂ , CN, straight or branched C _1-10 alkyl or straight or branched C _1-10 alkoxy;

R ² is halogen; And

r is an integer from 1-4.

The R ¹ may be hydrogen, halogen, NO ₂ , CN, straight or branched C _1-6 alkyl or straight or branched C _1-6 alkoxy.

In addition, R ¹ may be hydrogen, halogen, NO ₂ , CN, C _1-4 alkyl or C _1-4 alkoxy.

In addition, R ¹ may be hydrogen, F, Cl, Br, NO ₂ , CN, methyl or methoxy.

R ² may be Br, and may be bonded to the ortho position of piperidine oxy.

The r may be an integer of 1-3, and may be 1 or 2.

는 쿠마린의 벤젠에서 각 CH에

가 결합된 것을 의미하며, 구체적으로 벤젠의 C-R¹ 결합형태를 나타내고, 벤젠에

가 r개 결합될 수 있음을 의미한다. 벤젠에 결합된 각각의

은 동일 또는 상이할 수 있다.In Formula 1,

To each CH in benzene of coumarin

Means bonded, specifically represents the CR ¹ bond form of benzene, and

It means that r can be combined. Each bonded to benzene

May be the same or different.

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

(1) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-coumarin-3-carboxyamide;

(2) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-nitro-coumarin-3-carboxyamide;

(3) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-methoxy-coumarin-3-carboxyamide;

(4) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-coumarin-3-carboxyamide;

(5) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-bromo-coumarin-3-carboxyamide;

(6) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-methyl-coumarin-3-carboxyamide;

(7) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-fluoro-coumarin-3-carboxyamide;

(8) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-cyano-coumarin-3-carboxyamide;

(9) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-methoxy-coumarin-3-carboxyamide;

(10) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-methyl-coumarin-3-carboxyamide;

(11) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-fluoro-coumarin-3-carboxyamide;

(12) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-chloro-coumarin-3-carboxyamide;

(13) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-bromo-coumarin-3-carboxyamide;

(14) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-cyano-coumarin-3-carboxyamide;

(15) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-fluoro-coumarin-3-carboxyamide;

(16) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-methyl-coumarin-3-carboxyamide;

(17) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-methyl-coumarin-3-carboxyamide;

(18) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dimethoxy-coumarin-3-carboxy Amide;

(19) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-difluoro-coumarin-3-carboxy Amide;

(20) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dimethyl-coumarin-3-carboxyamide ;

(21) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dichloro-coumarin-3-carboxyamide ;

(22) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-7-methyl-coumarin-3-carboxy Amide;

(23) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-7-fluoro-coumarin-3- Carboxyamide;

(24) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-chloro-6-fluoro-coumarin-3- Carboxyamide;

(25) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-fluoro-6-methyl-coumarin-3- Carboxyamide.

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 May be prepared by filtration and drying, or may be prepared by distilling off 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.

The term “hydrate” refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecule force. Or its salt. The hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force. The hydrate may contain 1 equivalent or more, preferably 1 to 5 equivalents of water. These hydrates may be prepared by crystallizing the compound represented by Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof from water or a solvent containing water.

The term "solvate" refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor include volatile, non-toxic, and/or suitable solvents for administration to humans.

The term “isomer” refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula, but structurally or sterically different. Such isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers. All these isomers and mixtures thereof are also included within the scope of the present invention.

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

Preparing a compound represented by Formula 2 by reacting a compound represented by Formula 3 with a compound represented by Formula 4 (Step 1); And

It provides a method for preparing the compound represented by Formula 1, including the step of reacting the compound represented by Formula 2 to prepare the compound represented by Formula 11 (Step 2).

[Scheme 1]

(In the above Scheme 1,

R ¹ , R ² and r are as defined in Formula 1 of claim 1; And

PG ^a is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2 -Is one type of amine protecting group selected from the group consisting of trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc)).

Hereinafter, the manufacturing method represented by Scheme 1 according to the present invention will be described in detail.

The compound represented by Formula 1 according to the present invention is obtained through condensation and deprotection reactions using a carboxylic acid compound represented by Formula 3 and an amine compound represented by Formula 4 as starting materials as shown in Scheme 1 above. Can be manufactured.

In the method for preparing a compound represented by Formula 1 according to the present invention, 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 2, specifically , The compound represented by Formula 1 may be prepared by condensing the compound represented by Formula 3 and the compound represented by Formula 4 in the presence of a condensing agent, and more specifically, the carboxylic acid compound represented by Formula 3 and Formula 4 A condensation reaction of the amine compound represented by is carried out in the presence of a condensing agent and a base to prepare a compound represented by Formula 1 having an amide bond.

At this time, the condensation reaction can be carried out through two conventional methods, and specific examples are as follows.

Formula 1-A

The compound represented by Formula 3 and the compound represented by Formula 4 in Scheme 1 can be prepared through a method of using a condensing agent in the presence of a base.

At this time, usable condensing agents are organic phosphorus-based reagents, bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl), benzotriazol-1-yloxytris (dimethylamino ) Phosphonium hexafluorophosphate (BOP), diphenylphosphonylazide (DPPA), etc., and carbodiimide-based reagents include dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide ( DIC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), etc., and N,N-carbonyldiimidazole, O -benzotriazole- N ,N,N',N' -tetramethyl-uroninium-hexafluorophosphate (HBTU) and the like can be used.

In addition, the base is used to accelerate the reaction and increase the yield, and the available bases include N,N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N,N-diisopropylethylamine, 1 There are organic bases such as ,8-diazabicyclo[5.4.0]-7-undecene (DBU) or inorganic bases such as sodium bicarbonate, sodium hydroxide, potassium hydroxide, etc., alone or in combination, in an equivalent amount or in excess Can be used.

Further, the reaction solvent is tetrahydrofuran, dioxane, dichloromethane, ether solvents such as 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, dimethylformamide (DMF), dimethylsulfoxide. Side, acetonitrile, etc. can be used alone or in combination. The reaction temperature is from 0° C. to the boiling point of the solvent.

Preparation 1-B

In addition, the carboxylic acid compound represented by Formula 3 in Scheme 1 is used as an acyl halide, a carboxylic anhydride, or an active ester (e.g., p-nitrophenyl ester, N-hydroxysuccin) by a known method. Imide ester, fetafluorophenyl ester, etc.), and then reacted with an amine compound represented by Formula 4 in the presence of a base to obtain a compound represented by Formula 1.

At this time, the base includes a tertiary amine organic base such as triethylamine and diisopropylethylamine, and an inorganic base such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide, etc., alone or in combination. , Can be used in equivalent or excess.

In addition, solvents that can be used in the reaction include ether solvents such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and halogen-containing solvents such as 1,2-dichloromethane or 1,2-dichloroethane. In addition, there are aromatic hydrocarbon solvents such as benzene and toluene, which can be used alone or in combination, and can be reacted without a solvent. The reaction temperature is from 0° C. to the boiling point of the solvent.

In the method for preparing the compound represented by Formula 1 according to the present invention, step 2 is a step of obtaining a compound represented by Formula 1 by reacting the compound represented by Formula 2 obtained in step 1, specifically, the Step 2 is a step of reacting the compound represented by Chemical Formula 2 obtained in Step 1 to remove the amine protecting group through a deprotection reaction to prepare a final compound represented by Chemical Formula 1.

At this time, the amine protecting group is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn) , p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc ), 2-trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc) is one type of amine protecting group selected from the group consisting of, and may be t-butyloxycarbonyl (Boc).

In addition, the reaction conditions of the deprotection reaction are different depending on the type of the amine protecting group, and may be carried out using conventional deprotection reaction conditions.

In the present invention, an acid condition was used, and hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and the like may be used as the acid.

Further, examples of the solvent usable in the reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane, and 1,2-dimethoxyethane; Aromatic hydrocarbon solvents such as benzene, toluene, and xylene; Alcohol solvents such as methanol and ethanol; There are dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, and water, and these may be used alone or in combination.

Furthermore, the reaction temperature can be carried out between the boiling point of the solvent at 0°C.

Preparation of starting material (compound represented by formula 3) 1

As the starting material of Scheme 1, the compound of Formula 3 is shown in Scheme 2 below,

It can be prepared by a manufacturing method including the step (step 1) of obtaining a compound represented by Formula 3 by reacting a compound represented by Formula 5 with a compound represented by Formula 6.

[Scheme 2]

In Scheme 2 above,

R ¹ and r are as defined in Chemical Formula 1.

Hereinafter, the manufacturing method of Scheme 2 will be described in detail.

The preparation method of Scheme 2 includes the step of reacting a compound represented by Formula 5 with a compound represented by Formula 6 to obtain a compound represented by Formula 3, and specifically, 2-hydroxy benzaldehyde represented by Formula 5 And a step of obtaining a compound represented by Formula 3 through a condensation reaction of the compound represented by Formula 6 and a catalyst.

Examples of catalysts that can be used in the reaction include bases such as piperidine acetate, piperidine, ammonium acetate, proline, and triethylamine, and in addition, Lewis acids such as titanium chloride (TiCl ₄ ) and tin chloride (SnCl ₂ ) are used. It is possible.

As the reaction solvent, alcohol-based solvents such as methanol, ethanol, and isopropyl alcohol, dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, and the like may be used alone or in combination.

Preparation 2 of starting material (compound represented by formula 4)

As shown in the following Scheme 3, the compound of Formula 4, which is the starting material of Scheme 1,

Reacting a compound represented by Formula 7 with a compound represented by Formula 8 to obtain a compound represented by Formula 9 (Step 1);

Reacting the compound represented by Formula 9 with the compound represented by Formula 10 to obtain a compound represented by Formula 11 (step 2); And

It can be prepared by a manufacturing method including the step of reacting the compound represented by Formula 11 obtained in step 2 to obtain the compound represented by Formula 4 (step 3).

[Scheme 3]

In Scheme 3 above,

R ² is as defined in Formula 1;

PG ^a is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2 -Is one type of amine protecting group selected from the group consisting of trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc);

PG ^b is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2 -One type of amine protecting group selected from the group consisting of trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc);

The PG ^a and PG ^b are amine protecting groups that are deprotected under different conditions.

Hereinafter, the manufacturing method of Scheme 3 will be described in detail.

In the preparation method of Reaction Scheme 3, step 1 is a step of obtaining a compound represented by Formula 9 by reacting a compound represented by Formula 7 with a compound represented by Formula 8, specifically, OH of the aldehyde compound represented by Formula 8 And OH of the piperidinol compound represented by Formula 9 is a step of preparing a compound represented by Formula 8 through a coupling reaction in the presence of a condensing agent and phosphine.

The condensing agent usable in the above reaction is a dialkyl azo-based reagent, and a representative reagent is diethyl azo dicarboxylate (DEAD), and diisopropyl azo dicarboxylate may also be used. In addition, triphenylphosphine (PPh ₃ ) is a representative phosphine, and trimethylphosphine (PMe ₃ ), triethylphosphine (PEt ₃ ), and the like can be used.

The reaction solvent may be used alone or in combination with an ether solvent such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, etc. have. The reaction temperature is from 0° C. to the boiling point of the solvent.

In the preparation method of Scheme 3, step 2 is a step of obtaining a compound represented by Formula 11 by reacting the compound represented by Formula 9 and the compound represented by Formula 10 obtained in Step 1, specifically, represented by Formula 9. This is a step to obtain a compound represented by Formula 11 by reductive amination reaction between the aldehyde of the aldehyde compound and NH of the piperidine compound represented by Formula 10 in the presence of a metal reducing agent.

The metal reducing agent that can be used in the reaction may be sodium borohydride (NaBH ₄ ), sodium triacetoxy borohydride (NaBH(OAc) ₃ ), sodium cyano borohydride (NaBH ₃ CN).

The reaction solvent can be used alone or in combination with alcohol-based solvents such as methanol and ethanol, tetrahydrofuran, dioxane, and ether-based solvents such as 1,2-dimethoxyethane, and the reaction temperature is from 0 °C to the boiling point of the solvent. to be.

In the preparation method of Scheme 3, step 3 is a step of obtaining a compound represented by Formula 4 by reacting the compound represented by Formula 11 obtained in step 2, and specifically, removing the amine protecting group of the compound represented by Formula 11 This is a step of preparing a compound represented by Chemical Formula 4 by removing through a protection reaction.

At this time, the amine protecting group is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn) , p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc ), 2-trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc) is one type of amine protecting group selected from the group consisting of, and may be t-butyloxycarbonyl (Boc).

In addition, the reaction conditions of the deprotection reaction are different depending on the type of the amine protecting group, and may be carried out using conventional deprotection reaction conditions.

In the present invention, basic conditions were used, and piperidine is a representative base that can be used in the reaction, and in addition to organic bases such as pyrrolidine, pyridine, triethylamine, N , N -diisopropylethylamine, DBU, etc. Or, NaOH, Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ It is possible to use an equivalent or excessive amount of an inorganic base such as.

The reaction solvent may be used alone or in combination with an ether solvent such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, etc. have. The reaction temperature is from 0° C. to the boiling point of the solvent.

Another aspect of the present invention is the prevention or treatment of diseases related to the activity of the eurotensin-II receptor containing the compound represented by Formula 1, its isomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient. It provides a pharmaceutical composition for use.

The diseases related to the activity of the eurotensin-II receptor include blood heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, high blood pressure, asthma, kidney failure, diabetes, vasculitis, neurodegenerative diseases, stroke, pain. , It may be one or more diseases selected from the group consisting of psychosis and cancer.

The compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may antagonize the eurotensin-II receptor.

As a result of measuring the eurotensin-II receptor antagonistic effect of the compound represented by Formula 1 according to the present invention,

It was confirmed that all of the compounds of the examples of the present invention had an antagonistic action against the eurotensin-II receptor at low concentrations. In particular, the compounds of Examples 3-4, 6, 11-13, 16-17, 19, 21, and 23-25 according to the present invention have an antagonistic effect on the urotensin-II receptor even at low concentrations of 30 nM or less with an IC ₅₀ value. As a bar, the antagonistic effect against the eurotensin-II receptor is excellent (see Experimental Example 1 and Table 2).

Therefore, the compound according to the present invention acts as an antagonist to the urotensin-II receptor, so that congestive heart failure, heart ischemia, myocardial infarction, cardiac hypertrophy, heart fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, kidney failure, diabetes , Vascular inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis, and can be usefully used to prevent, ameliorate or treat diseases caused by hyperactivity of the eurotensin-II receptor such as cancer.

The compound represented by Formula 1 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, preservatives, etc. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. As the non-aqueous solvent and suspension, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.

The pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection It depends on how to do it.

At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed in water together with a stabilizer or buffer to prepare a solution or suspension, and the ampoule or vial unit dosage form It can be manufactured with 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 (e.g. silica, talc, stearic acid and its magnesium or calcium salt 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.

Another aspect of the present invention is the prevention or improvement of diseases related to the activity of the eurotensin-II receptor containing the compound represented by Formula 1, its isomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient. It provides a health functional food composition for use.

The diseases related to the activity of the eurotensin-II receptor include blood heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, high blood pressure, asthma, kidney failure, diabetes, vasculitis, neurodegenerative diseases, stroke, pain. , It may be one or more diseases selected from the group consisting of psychosis and cancer.

The compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may antagonize the eurotensin-II receptor.

The compound represented by Formula 1 according to the present invention is a health functional food composition for preventing or improving diseases caused by overactivity of eurotensin-II receptors by exhibiting antagonism of eurotensin-II receptors. Can be added to supplements.

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 Chemical Formula 1 according to the present invention is a variety of nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pects. 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 to provide a pharmaceutical composition or a health functional food composition containing as an active ingredient the compound represented by Formula 1, its isomer, solvate, hydrate or pharmaceutically acceptable salt thereof. It provides a method for preventing or treating a disease related to urotensin-II receptor activity comprising the step of administering.

Another aspect of the present invention contains a compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, in the prevention or treatment of a disease related to eurotensin-II receptor activity. It provides the use of a pharmaceutical 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.

<Production Example 1> Preparation of 6-nitro-coumarin-3-carboxylic acid

After dissolving 232 mg (1.38 mmol) of 2-hydroxy-5-nitrobenzaldehyde in 8 ml of ethanol, 200 mg (1.38 mmol) of Meldrums acid and piperidine were added in a catalytic amount at room temperature for 3 hours. Stirred. After completion of the reaction, concentrated under reduced pressure, acidified with 2N sodium hydroxide, extracted with 30 ml ethyl acetate, washed with 50 ml of an inorganic salt solution, and dried over anhydrous sodium sulfate (Na ₂ SO ₄ ). And concentrated under reduced pressure to give the target compound 37 mg (0.16 mmol) in a yield of 12%.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.81 (d, J = 2.1 Hz, 1H), 8.45 (s, 1H), 8.41 (dd, J = 8.7, 2.1 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H)

<Preparation Example 2> Preparation of 4-[4-[(4-aminopiperidin-1-yl)methyl]-2-bromophenoxy]piperidine-1-tert-butyl carboxylate

Step 1: Preparation of 4-(2-bromo-4-formylphenoxy)piperidine-1-tert-butyl carboxylate

After dissolving 3-bromo-4-hydroxybenzaldehyde (30 g, 149.2 mmol) in 400 ml of tetrahydrofuran, tert -butyl 4-hydroxypiperidine-1-carboxylate (33 g, 164.2 mmol), triphenylphosphine (51 g, 193.96 mmol) were added. 2.2M diethyl azodicarboxylate (88 ml, 193.96 mmol) was slowly added at 0° C. over 15 minutes, followed by stirring for 4 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and 500 ml of ethyl acetate was added. Washed with 3N aqueous sodium hydroxide solution (500 ml). The organic layer was dried over anhydrous sodium sulfate (Na ₂ SO ₄ ), concentrated under reduced pressure, and the filtrate was purified by silica gel column chromatography (normal hexane: ethyl acetate = 3: 1, v/v) to obtain the target compound in a yield of 34%. (19.68 g, 51.21 mmol) was obtained.

Rf = 0.37 (normal hexane: ethyl acetate = 3: 1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.84 (s, 1H), 8.09 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 4.72 -4.76 (m, 1H), 3.56-3.62 (m, 4H), 1.86-1.94 (m, 4H), 1.47 (s, 9H).

Step 2: 4-[4-[[4-[[[(9H-fluoren-9-yl)methoxy]carbonyl]amino]piperidin-1-yl]methyl]-2-bromophenoxy ]Piperidine-1- tert -Preparation of butyl carboxylate

After dissolving 4-(2-bromo-4-formylphenoxy)piperidine-1- tert -butyl carboxylate (12.24 g, 31.85 mmol) prepared in step 1 in 250 ml of dichloromethane. , (9H-fluoren-9-yl)methyl piperidin-4-ylcarbamate hydrochloride (12.57 g, 35.04 mmol) was added and stirred at room temperature for 1 hour, followed by sodium triacetoxyborohydride (8.78) g, 41.41 mmol) was added and stirred at room temperature for 4 hours. After slowly adding 300 ml of water, it was neutralized (pH7) with saturated sodium bicarbonate and extracted with 500 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate (Na ₂ SO ₄ ), concentrated under reduced pressure, and the filtrate was purified by silica gel column chromatography (3% methanol/dichloromethane, v/v) to obtain the target compound in 82% yield (17.91). g, 25.98 mmol) was obtained.

Rf = 0.25 (5% methanol/dichloromethane, v/v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.74 (d, J = 7.4 Hz, 2H), 7.56 (d, J = 7.4 Hz, 2H), 7.50 (s, 1H), 7.39 (dd, J = 7.4, 7.0 Hz, 2H), 7.30 (dd, J = 7.4, 7.0 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.64-4.73 (m, 1H), 4.36-4.44 (m, 2H), 4.17-4.23 (m, 1H), 3.58-4.64 (m, 2H), 3.49-3.54 (m, 2H), 3.43 (s, 2H), 2.78-2.90 ( m, 2H), 2.07-2.18 (m, 2H), 1.82-1.90 (m, 6H), 1.47 (s, 9H), 1.41-1.46 (m, 2H).

Step 3: Preparation of 4-[4-[(4-aminopiperidin-1-yl)methyl]-2-bromophenoxy]piperidine-1-tert-butyl carboxylate

After dissolving the compound (17.91 g, 25.98 mmol) prepared in step 2 in 250 ml of methanol/tetrahydrofuran (2/1, v/v), 2N sodium hydroxide (38.97 ml, 77.94 mmol) was added. It was added and stirred at room temperature for 20 minutes. 200 ml of water was added and extracted with 500 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate (Na ₂ SO ₄ ), concentrated under reduced pressure, and the filtrate was purified by silica gel column chromatography (5% methanol/dichloromethane, v/v) to obtain the target compound in 82% yield (10.35). g, 21.42 mmol) was obtained.

Rf= 0.25 (10% methanol/dichloromethane, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.49 (s, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 4.50-4.55 (m, 1H) , 3.60-3.66 (m, 2H), 3.44-3.50 (m, 2H), 3.38 (s, 2H), 2.77-2.82 (m, 2H), 2.61-2.68 (m, 1H), 1.96-2.03 (m, 2H), 1.82-1.91 (m, 4H), 1.75-1.81 (m, 2H), 1.46 (s, 9H), 1.33-1.42 (m, 2H).

<Example 1> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-coumarin-3-carboxyamide

Step 1: Preparation of 4-(4-((4-(coumarin-3-carboamido)piperidin-1-yl)methyl)phenoxy)piperidine-1-tert-butyl carboxylate

15 mg (0.08 mmol) of coumarin-3-carboxylic acid and 4-(4-((4-aminopiperidin-1-yl)methyl)-2-bromophenoxy)piperidine-1-tert-butyl carboxyl After dissolving 40 mg (0.09 mmol) of 8 in 5 ml of N,N-dimethylformamide, 30 mg (0.12 mmol) of BOPCl and 33 ul (0.24 mmol) of triethylamine were added, followed by stirring at room temperature for 16 hours. After completion of the reaction, extraction was performed with 20 ml of ethyl acetate and 20 ml of water. The organic layer was washed twice with brine. The target compound is dissolved in the water layer. Dry the larvae with anhydrous magnesium sulfate (MgSO ₄ ), and the filtrate is purified by silica gel column chromatography (dichloromethane: methanol, 30: 1, v/v) to obtain the target compound in a pale yellow foam. To give 40 mg (0.06 mmol) in% yield.

Rf =0.24 (dichloromethane: methanol, 20: 1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.92 (s, 1H), 8.84 (d, J = 7.8 Hz, NH), 7.71 (d, J = 7.9 Hz, 1H), 7.68 (dd, J = 8.4, 7.3 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 7.9, 7.3 Hz, 1H), 7.21 (dd, J = 8.6, 1.9 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 4.54-4.59 (m, 1H), 3.99-4.08 (m, 1H), 3.62-3.69 (m, 2H), 3.47-3.55 (m, 2H), 3.46 (s, 2H), 2.80-2.87 (m, 2H), 2.20-2.29 (m, 2H), 1.99-2.06 (m, 2H), 1.83-1.93 (m, 4H), 1.63 -1.72 (m, 2H), 1.49 (s, 9H).

Step 2: N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-coumarin-3-carboxyamide

After dissolving 40 mg (0.06 mmol) of the compound obtained in step 1 in 5 ml of dioxane, 2 ml of HCl (con.) was added, followed by stirring at room temperature for 2 hours. After completion of the reaction, the solvent was concentrated under reduced pressure to obtain 34 mg (0.06 mmol) of the target compound as a white solid in a yield of 99% without silica gel column chromatography purification.

¹ H NMR (500 MHz, CD ₃ OD) δ 8.70 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.3 , 7.3 Hz, 1H), 7.47 (dd, J = 8.6, 2.0 Hz, 1H), 7.32 (dd, J = 8.0, 7.3 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.15 (d , J = 8.6 Hz, 1H), 4.78-4.85 (m, 1H), 4.19 (s, 2H), 4.00-4.08 (m, 1H), 3.42-3.48 (m, 2H), 3.26-3.34 (m, 2H) ), 3.14-3.21 (m, 2H), 3.04-3.12 (m, 2H), 1.79-2.19 (m, 8H).

<Example 2> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-nitro-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, it was carried out in the same manner as in Example 1, except that 18 mg (0.07 mmol) of 6-nitro-coumarin-3-carboxylic acid obtained in Preparation Example 1 was used. 2 mg (0.004 mmol) of the target compound was obtained in a yield of 6% in two steps.

¹ H NMR (500 MHz, CD ₃ OD) δ 8.97 (s, 1H), 8.84 (d, J = 2.2 Hz ,1H), 8.58 (dd, J = 8.8, 2.2 Hz, 1H), 7.86 (d, J = 1.9 Hz ,1H), 7.65 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.8, 1.9 Hz ,1H), 7.30 (d, J = 8.8 Hz, 1H), 4.94-4.98 (m , 1H), 4.32 (s, 2H), 4.14-4.22 (m, 1H), 3.58-3.60 (m, 2H), 3.43-3.45 (m, 2H), 3.29-3.31 (m, 2H), 3.16-3.03 (m, 2H), 2.30-2.34 (m, 2H), 2.12-2.22 (m, 4H), 1.87-1.05 (m, 2H)

<Example 3> N -(1-(3-Bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-methoxy-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, it was carried out in the same manner as in Example 1, except that 14 mg (0.06 mmol) of 6-methoxy-coumarin-3-carboxylic acid was used to integrate the target compound in two steps. 12 mg (0.02 mmol) was obtained in a yield of 39%.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.79 (s, 1H), 8.68 (d, J = 7.5 Hz, 1H), 7.89 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H) , 7.56 (d, J = 2.9 Hz, 1H), 7.47 (d, J = 9.1 Hz, 1H), 7.36 (dd, J = 9.1, 2.9 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H) , 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.99-4.05 (m, 1H), 3.83 (s, 3H), 3.16-3.22 (m, 2H), 3.10-3.15 (m, 2H) , 2.02-2.08 (m, 2H), 2.03-2.14 (m, 5H), 1.83-1.94 (m, 5H)

<Example 4> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, it was carried out in the same manner as in Example 1, except that 21 mg (0.09 mmol) of 6-chloro-coumarin-3-carboxylic acid was used, and the target compound was integrated in two steps 18 To give 9 mg (0.02 mmol) in% yield.

¹ H NMR (500 MHz, CD ₃ OD) δ 8.97 (d, J = 7.1 Hz, 1H), 8.83 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.87 (s, 1H), 7.75 (dd, J = 8.6, 2.3 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 4.95-4.98 (m, 1H), 4.32 (s, 2H), 4.15-4.19 (m, 1H), 3.56-3.60 (m, 2H), 3.40-3.47 (m, 2H), 3.28-3.31 (m, 2H) ), 3.17-3.22 (m, 2H), 2.29-2.32 (m, 2H), 2.09-2.23 (m, 4H), 1.88-1.95 (m, 2H)

<Example 5> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-bromo-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, the target compound was integrated in two steps by performing the same method as in Example 1, except that 20 mg (0.07 mmol) of 6-bromo-coumarin-3-carboxylic acid was used. 2 mg (0.004 mmol) was obtained in a yield of 6%.

¹ H NMR (500 MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.09 (s, 1H), 7.88 (d, J = 8.1 Hz ,1H), 7.80 (s, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 4.78-4.84 (m, 1H), 7.30 (s, 2H), 4.14-4.19 (m, 1H), 3.51-3.66 (m, 4H), 3.43-3.49 (m, 2H), 3.14-3.24 (m, 2H), 2.31-2.33 (m, 2H), 2.12-2.23 (m, 2H) , 1.91-2.00 (m, 2H), 1.77-1.89 (m, 2H)

<Example 6> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-methyl-coumarin-3-carboxyamide

In the same manner as in Example 1, except that instead of using coumarin-3-carboxylic acid, 6-methyl-coumarin-3-carboxylic acid 18 mg (0.08 mmol) was used, the target compound was combined in two steps 41 To give 17 mg (0.03 mmol) in% yield.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.74 (s, 1H), 8.65 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.61 (s, 1H) , 7.62 (dd, J = 8.6, 1.9 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 9.2 Hz, 1H) , 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.97-4.04 (m, 1H), 3.18-3.24 (m, 2H), 3.08-3.14 (m, 2H), 3.02-3.06 (m, 2H) 2H), 2.39 (s, 3H), 2.05-2.15 (m, 5H), 1.89-1.96 (m, 5H)

<Example 7> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-fluoro-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, it was carried out in the same manner as in Example 1, except that 16 mg (0.12 mmol) of 6-fluoro-coumarin-3-carboxylic acid was used, and the target compound was integrated in two steps. 2 mg (0.004 mmol) was obtained in a 4% yield.

¹ H NMR (500 MHz, CD ₃ OD) δ 8.86 (s, 1H), 7.86 (s, 1H), 7.66 (dd, J = 8.0, 2.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H ), 7.55 (ddd, J = 9.2, 8.9, 2.8 Hz, 1H), 7.49 (dd, J = 9.2, 4.3 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.95-4.98 (m, 1H), 4.32 (s, 2H), 4.14-4.20 (m, 1H), 3.58-3.60 (m, 2H), 3.42-3.47 (m, 3H), 3.16-3.22 (m, 2H), 2.30-2.33 ( m, 2H), 2.12-2.23 (m, 5H), 1.87-1.94 (m, 2H)

<Example 8> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-cyano-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, 6-cyano-coumarin-3-carboxylic acid 25 mg (0.12 mmol) was used, and the target compound was integrated in two steps by performing the same method as in Example 1 above. 14 mg (0.02 mmol) was obtained in a yield of 22%.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.75 (s, 1H), 8.57 (d, J = 7.6 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.16 (dd, J = 8.6, 1.6 Hz, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.62 (dd, J = 8.3, 1.3 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 4.84-4.87 (m, 1H), 4.21 (s, 2H), 4.00-4.04 (m, 2H), 3.35-3.37 (m, 2H), 3.17-3.23 (m, 2H) , 3.10-3.15 (m, 2H), 3.02-3.08 (m, 2H), 2.07-2.15 (m, 4H), 1.90-1.97 (m, 4H)

<Example 9> N -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-methoxy-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, it was carried out in the same manner as in Example 1, except that 14 mg (0.06 mmol) of 7-methoxy-coumarin-3-carboxylic acid was used, and the target compound was integrated in two steps. 18 mg (0.03 mmol) was obtained in a yield of 54%.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.81 (s, 1H), 8.59 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.60 (dd, J = 8.6, 1.3 Hz ,1H), 7.32 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 7.06 (dd, J = 8.6, 2.2 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.04 (m, 1H), 3.90 (s, 3H), 3.16-3.23 (m, 2H), 3.08 -3.14 (m, 2H), 3.01-3.07 (m, 2H), 2.03-2.14 (m, 5H), 1.85-1.95 (m, 5H)

<Example 10> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-methyl-coumarin-3-carboxyamide

In the same manner as in Example 1, except that instead of using coumarin-3-carboxylic acid, 7-methyl-coumarin-3-carboxylic acid 17 mg (0.08 mmol) was used, the target compound was integrated in two steps 63 To give 33 mg (0.05 mmol) in% yield.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.79 (s, 1H), 8.63 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 1.9 Hz ,1H), 7.87 (d, J = 7.9 Hz ,1H), 7.60 (dd, J = 7.9, 1.9 Hz ,1H), 7.36 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H) , 4.84-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.05 (m, 1H), 3.18-3.23 (m, 2H), 3.09-3.15 (m, 2H), 3.20-3.08 (m, 2H), 2.46 (s, 3H), 2.04-2.15 (m, 5H), 1.84-1.95 (m, 5H)

<Example 11> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-fluoro-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, in the same manner as in Example 1 except for using 7-fluoro-coumarin-3-carboxylic acid 15 mg (0.07 mmol), the target compound was integrated in two steps. 14 mg (0.02 mmol) was obtained in a 35% yield.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.82 (s, 1H), 8.58 (d, J = 7.5 Hz, 1H), 8.08 (dd, J = 8.9, 6.5 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.59 (dd, J = 8.6, 1.7 Hz, 1H), 7.54 (dd, J = 9.6, 2.4 Hz, 1H), 7.37 (ddd, J = 8.9, 8.6, 2.4 Hz, 1H ), 7.31 (d, J = 8.6 Hz, 1H), 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.99-4.05 (m, 1H), 3.16-3.23 (m, 2H), 3.10- 3.16 (m, 2H), 3.02-3.07 (m, 2H), 2.03-2.15 (m, 5H), 1.85-1.95 (m, 5H)

<Example 12> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-chloro-coumarin-3-carboxyamide

In the same manner as in Example 1, except that instead of using coumarin-3-carboxylic acid, 7-chloro-coumarin-3-carboxylic acid 17 mg (0.07 mmol) was used, the target compound was integrated in two steps 44 To give 19 mg (0.03 mmol) in% yield.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.80 (s, 1H), 8.59 (d, J = 7.3 Hz, 1H), 8.01 (d, J = 8.5 Hz ,1H), 7.90 (d, J = 1.6 Hz, 1H), 7.74 (d, J = 1.6 Hz ,1H), 7.60 (dd, J = 8.5, 1.6 Hz ,1H), 7.53 (dd, J = 8.1, 1.6 Hz, 1H), 7.32 (d, J = 8.1 Hz ,1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.04 (m, 1H), 3.18-3.23 (m, 2H), 3.09-3.16 (m, 2H) , 3.02-3.08 (m, 2H), 2.03-2.15 (m, 5H), 1.86-1.97 (m, 5H)

<Example 13> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-bromo-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, 7-bromo-coumarin-3-carboxylic acid 21 mg (0.07 mmol) was used in the same manner as in Example 1, and the target compound was integrated in two steps. 12 mg (0.02 mmol) was obtained in a yield of 28%.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.79 (s, 1H), 8.59 (d, J = 7.2 Hz ,1H), 7.92 (d, J = 8.1 Hz ,1H), 7.89 (s, 1H) , 7.87 (d, J = 1.7 Hz, 1H), 7.66 (dd, J = 8.1, 1.7 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H) , 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.98-4.03 (m, 1H), 3.17-3.24 (m, 2H), 3.10-3.16 (m, 2H), 3.01-3.09 (m, 3) 2H), 2.02-2.14 (m, 5H), 1.85-1.95 (m, 5H)

<Example 14> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-cyano-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, it was carried out in the same manner as in Example 1, except that 18 mg (0.08 mmol) of 7-cyano-coumarin-3-carboxylic acid was used, and the target compound was integrated in two steps. 10 mg (0.02 mmol) was obtained with a yield of 19%.

¹ H NMR (500 MHz, CD ₃ OD- d ₄ ) δ 8.90 (d, J = 7.0 Hz, 1H), 8.87 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 4.95-4.98 ( m, 1H), 4.32 (s, 2H), 4.16-4.22 (m, 1H), 3.58-3.60 (m, 2H), 3.43-3.37 (m, 2H), 3.30-3.32 (m, 2H), 3.17- 3.22 (m, 2H), 2.28-2.32 (m, 2H), 2.19-2.24 (m, 2H), 2.12-2.16 (m, 2H), 1.93-1.98 (m, 2H)

<Example 15> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-fluoro-coumarin-3-carboxyamide

In the same manner as in Example 1, except for using 8-fluoro-coumarin-3-carboxylic acid 18 mg (0.08 mmol) instead of using coumarin-3-carboxylic acid, the target compound was integrated in two steps. 10 mg (0.02 mmol) was obtained with a yield of 21%.

¹ H NMR (500 MHz, CD ₃ OD) δ 8.93 (d, J = 7.1 Hz, 1H), 8.88 (s, 1H), 7.88 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.58-7.62 (m, 2H), 7.41-7.45 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.95-4.98 (m, 1H), 4.33 (s, 2H), 4.16-4.22 ( m, 1H), 3.58-3.60 (m, 2H), 3.42-3.48 (m, 2H), 3.29-3.32 (m, 2H), 3.15-3.23 (m, 2H), 2.30-2.33 (m, 2H), 2.20-2.25 (m, 2H), 2.10-2.17 (m, 2H), 1.90-1.98 (m, 2H)

<Example 16> N -(1-(3-Bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-methyl-coumarin-3-carboxyamide

In the same manner as in Example 1, except that instead of using coumarin-3-carboxylic acid, 8-methyl-coumarin-3-carboxylic acid 12 mg (0.06 mmol) was used, the target compound was integrated in two steps 58 To give 18 mg (0.03 mmol) in% yield.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.78 (s, 1H), 8.64 (d, J = 7.0 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.62 (dd, J = 8.6, 1.9 Hz, 1H), 7.35 (dd, J = 7.8, 7.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 4.83-4.86 (m, 1H), 4.21 (s, 2H), 3.99-4.05 (m, 1H), 3.35-3.37 (m, 2H), 3.18-3.22 (m, 2H) , 3.09-3.16 (m, 2H), 3.03-3.08 (m, 2H), 2.40 (s, 3H), 2.08-2.15 (m, 4H), 1.89-1.96 (m, 4H)

<Example 17> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-5-chloro-coumarin-3-carboxyamide

In the same manner as in Example 1, except for using 5-chloro-coumarin-3-carboxylic acid 26 mg (0.12 mmol) instead of using coumarin-3-carboxylic acid, the target compound was integrated in two steps 57 To give 36 mg (0.06 mmol) in% yield.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.73 (s, 1H), 8.62 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.76 (dd, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.6, 1.8 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 4.01-4.05 (m, 1H), 3.35-3.37 (m, 2H), 3.17-3.23 (m, 2H), 3.09 -3.15 (m, 2H), 3.02-3.07 (m, 2H), 2.08-2.15 (m, 4H), 1.90-1.96 (m, 4H)

<Example 18> N -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dimethoxy-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, the target compound was prepared in the same manner as in Example 1, except that 22 mg (0.09 mmol) of 6,7-dimethoxy-coumarin-3-carboxylic acid was used. Two steps combined to give 30 mg (0.05 mmol) in 71% yield.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.80 (s, 1H), 8.65 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.59 (dd, J = 8.3, 1.9 Hz, 1H), 7.55 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.22 (s, 1H), 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.98-4.05 (m, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.35-3.38 (m, 2H), 3.17-3.23 (m, 2H), 3.09-3.15 (m, 2H), 3.01-3.07 (m, 2H), 2.08-2.14 (m, 4H), 1.86-1.94 (m, 4H)

<Example 19> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-difluoro-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, the target compound was prepared in the same manner as in Example 1, except that 18 mg (0.08 mmol) of 6,7-difluoro-coumarin-3-carboxylic acid was used. The two-step integration yielded 17 mg (0.03 mmol) in 35% yield.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 8.58 (d, J = 7.5 Hz, 1H), 8.14 (dd, J = 10.1, 8.8 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 11.1, 6.8 Hz, 1H), 7.62 (dd, J = 8.4, 1.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.83- 4.87 (m, 1H), 4.21 (s, 2H), 3.97-4.04 (m, 1H), 3.33-3.36 (m, 2H), 3.17-3.23 (m, 2H), 3.09-3.14 (m, 2H), 3.01-3.08 (m, 2H), 2.07-2.14 (m, 4H), 1.88-1.96 (m, 4H)

<Example 20> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dimethyl-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, 6,7-dimethyl-coumarin-3-carboxylic acid 15 mg (0.07 mmol) was used, and the target compound was prepared in the same manner as in Example 1 above. Step integration yielded 9 mg (0.02 mmol) in 24% yield.

¹ H NMR (500 MHz, CD ₃ OD- d ₄ ) δ 9.04 (d, J = 7.5 Hz, 1H), 8.79 (s, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.59 (s, 1H), 7.58 (dd, J = 8.4, 1.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 4.95-4.98 (m, 1H), 4.33 (s, 2H ), 4.15-4.19 (m, 1H), 3.57-3.60 (m, 2H), 3.42-3.47 (m, 2H), 3.29-3.32 (m, 2H), 3.17-3.22 (m, 2H), 2.43 (s , 3H), 2.37 (s, 3H), 2.30-2.32 (m, 2H), 2.19-2.24 (m, 2H), 2.12-2.17 (m, 4H), 1.90-1.96 (m, 4H)

<Example 21> N -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dichloro-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, 6,7-dichloro-coumarin-3-carboxylic acid was used in the same manner as in Example 1, except that 17 mg (0.06 mmol) was used to prepare two target compounds. Step integration gave 16 mg (0.02 mmol) in a yield of 39%.

¹ H NMR (500 MHz, CD ₃ OD- d ₄ ) δ 8.82 (s, 1H), 8.11 (s, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.74 (s, 1H), 7.57 ( dd, J = 8.2, 1.9 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 4.95-4.98 (m, 1H), 4.32 (s, 2H), 4.14-4.19 (m, 1H), 3.57 -3.59 (m, 2H), 3.42-3.47 (m, 2H), 3.29-3.31 (m, 2H), 3.16-3.21 (m, 2H), 2.29-2.31 (m, 2H), 2.18-2.24 (m, 2H), 2.11-2.16 (m, 2H), 1.87-1.94 (m, 2H)

<Example 22> N -(1-(3-Bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-7-methyl-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, the target compound was prepared in the same manner as in Example 1, except that 24 mg (0.10 mmol) of 6-chloro-7-methyl-coumarin-3-carboxylic acid was used. Two steps combined to give 21 mg (0.03 mmol) in a yield of 38%.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.74 (s, 1H), 8.61 (d, J = 7.5 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J = 1.3 Hz, 1H) , 7.63 (dd, J = 8.4, 1.3 Hz, 1H), 7.58 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.98-4.04 (m, 1H), 3.34-3.36 (m, 2H), 3.17-3.22 (m, 2H), 3.10-3.15 (m, 2H), 3.01-3.07 (m, 2H), 2.46 (s, 3H) ), 2.06-2.16 (m, 4H), 1.89-1.97 (m, 4H)

<Example 23> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-7-fluoro-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, the target compound was carried out in the same manner as in Example 1, except that 24 mg (0.10 mmol) of 6-chloro-7-fluoro-coumarin-3-carboxylic acid was used. To give 25 mg (0.04 mmol) in a yield of 42% in two steps.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 8.56 (d, J = 7.3 Hz, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 9.7 Hz, 1H), 7.61 (dd, J = 8.5, 1.7 Hz ,1H), 7.31 (d, J = 8.5 Hz ,1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.03 (m, 1H), 3.34-3.37 (m, 2H), 3.17-3.22 (m, 2H), 3.09-3.15 (m, 2H), 3.01-3.07 ( m, 2H), 2.05-2.15 (m, 4H), 1.89-1.96 (m, 4H)

<Example 24> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-chloro-6-fluoro-coumarin-3-carboxyamide

The target compound was carried out in the same manner as in Example 1, except that 29 mg (0.12 mmol) of 7-chloro-6-fluoro-coumarin-3-carboxylic acid was used instead of using coumarin-3-carboxylic acid. The two-step integration yielded 20 mg (0.03 mmol) in a yield of 28%.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.74 (s, 1H), 8.60 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 5.9 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 8.5, 1.6 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.05 (m, 1H), 3.34-3.37 (m, 2H), 3.17-3.22 (m, 2H), 3.10-3.15 (m, 2H), 3.01-3.07 ( m, 2H), 2.06-2.15 (m, 4H), 1.88-1.96 (m, 4H)

<Example 25> N Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-fluoro-6-methyl-coumarin-3-carboxyamide

Instead of using coumarin-3-carboxylic acid, the target compound was carried out in the same manner as in Example 1, except that 19 mg (0.08 mmol) of 7-fluoro-6-methyl-coumarin-3-carboxylic acid was used. The two steps combined to give 27 mg (0.05 mmol) in a yield of 63%.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.75 (s, 1H), 8.59 (d, J = 7.3 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.61 (dd, J = 8.4, 1.5 Hz, 1H), 7.50 (d, J = 10.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.99-4.03 (m, 1H), 3.36-3.37 (m, 2H), 3.18-3.22 (m, 2H), 3.11-3.14 (m, 2H), 3.01-3.07 ( m, 2H), 2.30 (s, 3H), 2.06-2.15 (m, 4H), 1.88-1.96 (m, 4H)

The chemical structural formulas of the compounds prepared in Examples 1-25 are summarized and shown in Table 1 below.

Example Chemical structure Example Chemical structure One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

-

<Experimental Example 1> Measurement of urotensin-II receptor binding inhibitory activity of coumarin-3-carboxyamide derivatives

In order to confirm the binding inhibitory activity of the coumarin-3-carboxyamide derivatives according to the present invention to the eurotensin-II receptor, the following experiment was performed using a Filtration-based Time-resolved fluorescence assay based on an automatic filtration method. Performed.

Two kinds of buffer solutions were prepared: washing solution (25 mM HEPES pH 7.4, 5 mM MgCl ₂ , 1 mM CaCl ₂ ) and experimental solution (added to 0.5% BSA to the washing solution), and labeled with 1 uM europium. Eurotensin-concentrated hormone (Europium-labeled Urotensin-II, Eu-UII), PerkinElmer, Turku, Finland) and 1 mM urotensin-concentrated hormone (Eurotensin-II, #070-47, Sigma-Aldrich, St.Louis, MO) , USA) was prepared at 4°C. 1 uM of Eu-UII and 1 mM urotensin-II were diluted to 8 nM (final reaction concentration: 2 nM) and 4 μM (final reaction concentration: 1 μM), respectively. The buffer solution used in all dilution and preparation processes was the experimental solution, and the washing solution was used only when washing the plate at the end. Urotensin-II receptor cell membranes were prepared for the binding assay using HEK293 _UT cell line overexpressing the eurotensin-II receptor cultured in a 100 cm ² flask. When the cells grew more than 90%, the medium was removed, washed twice with PBS buffer, and then 2 ml of 1 mM EDTA-PBS buffer was added and reacted at 37° C. for 5 minutes to harvest the cells. The harvested cells were washed twice with PBS buffer and then suspended in lysis buffer (10 mM Tris pH 7.4, 5 mM Na-EDTA) to which 0.5% Protease Inhibitor cocktail was added, and then crushed with an ultrasonic grinder. Cell debris was removed by centrifugation at 300 g for 5 minutes, and the supernatant was ultracentrifuged at 47000 g for 20 minutes to obtain a precipitate containing the cell membrane fraction. The cell membrane fraction precipitate was dissolved in a storage buffer (50 mM Tris-HCl pH 7.4, 0.5 mM EDTA, 5 mM MgCl2, 10% sucrose), and the concentration was measured by the Bradford method.

After diluting 50 ul of eurotensin-II receptor (30 mg/ml) in 5 ml experimental solution and homogenizing, 8 microplates with filter paper (Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA) were placed 8 Using a channel pipette (multi 8-channel, Eppendorf, Hamburg, Germany), the eurotensin-II receptor was dispensed at 50 ml per well. At this time, 25 ml of Eu-UII and 25 ml of Eurotensin-II were dispensed as a non-specific binding control, and 25 ml of 10% DMSO experimental solution and 25 ml of Eu-MCH were dispensed as a total binding control. Was used. As an experimental group, 25 ml of a novel compound represented by the above formula according to the present invention and 25 ml of Eu-UII were used. Each test compound, Eu-UII and Eurotensin-II, occupied 25% of the total volume during the reaction, so they were prepared at a concentration of 4 times just before addition. Then, it was gently shaken for 15 seconds and reacted for 90 minutes at room temperature.

When the reaction was over, the plate was filtered and washed by applying pressure to a self-made automatic filtration washer (microplate filtration washer, EMBLA, Molecular Devices) that was partially modified. The washing solution was filtered three times at 300 ml per well to remove Eu-UII remaining without reaction. The water on the bottom was wiped off, and a dissociation solution (DELFIA Enhancement solution, PerkinElmer, Turku, Finland) was added to make 150 ml per well. After gently shaking for 15 minutes at room temperature, the value of time-resolved fluorescence (TRF) was measured using a multilabel counter (Victor2, PerkinElmer, Turku, Finland) (emission wavelength: 615 nm, excitation Wavelength: 340 nm), and the parallax fluorescence inhibition rate was calculated by the following equation (1).

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

Example IC ₅₀ (nM) One 44 2 52 3 26 4 20 5 240 6 21 7 53 8 38 9 35 10 40 11 26 12 29 13 16 14 45 15 33 16 30 17 30 18 57 19 22 20 45 21 28 22 34 23 26 24 22 25 26

As shown in Table 2, it was confirmed that all of the compounds of the examples of the present invention had an antagonistic action against the eurotensin-II receptor at a low concentration. In particular, the compounds of Examples 3-4, 6, 11-13, 16-17, 19, 21, and 23-25 according to the present invention have an antagonistic effect on the urotensin-II receptor even at low concentrations of 30 nM or less with an IC ₅₀ value. As a bar, it can be seen that the antagonistic effect against the eurotensin-II receptor is excellent.

Therefore, the compound according to the present invention acts as an antagonist to the urotensin-II receptor, thereby congesting heart failure, heart ischemia, myocardial infarction, cardiac hypertrophy and fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, kidney failure, diabetes, blood vessels. Inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis, cancer, such as eurotensin-II receptor activity-related diseases can be usefully used to prevent or treat.

<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 (10)

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

(In Formula 1,
R ¹ is hydrogen, halogen, NO ₂ , CN, straight or branched C _1-10 alkyl or straight or branched C _1-10 alkoxy;
R ² is halogen; And
r is an integer from 1-4).
The method of claim 1,
The R ¹ is hydrogen, halogen, NO ₂ , CN, a straight-chain or branched C _1-6 alkyl or a straight-chain or branched C _1-6 alkoxy compound, a solvate thereof, a hydrate thereof, or a pharmaceutical thereof An acceptable salt.
The method of claim 1,
The R ¹ is hydrogen, halogen, NO ₂ , CN, C _1-4 alkyl or C _1-4 alkoxy A compound, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ¹ is hydrogen, F, Cl, Br, NO ₂ , CN, methyl or methoxy;
R ² is Br; And
r is 1 or 2, a compound, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
The compound represented by Formula 1 is a compound, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is any one selected from the following compound group:
(1) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-coumarin-3-carboxyamide;
(2) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-nitro-coumarin-3-carboxyamide;
(3) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-methoxy-coumarin-3-carboxyamide;
(4) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-coumarin-3-carboxyamide;
(5) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-bromo-coumarin-3-carboxyamide;
(6) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-methyl-coumarin-3-carboxyamide;
(7) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-fluoro-coumarin-3-carboxyamide;
(8) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-cyano-coumarin-3-carboxyamide;
(9) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-methoxy-coumarin-3-carboxyamide;
(10) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-methyl-coumarin-3-carboxyamide;
(11) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-fluoro-coumarin-3-carboxyamide;
(12) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-chloro-coumarin-3-carboxyamide;
(13) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-bromo-coumarin-3-carboxyamide;
(14) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-cyano-coumarin-3-carboxyamide;
(15) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-fluoro-coumarin-3-carboxyamide;
(16) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-methyl-coumarin-3-carboxyamide;
(17) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-methyl-coumarin-3-carboxyamide;
(18) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dimethoxy-coumarin-3-carboxy Amide;
(19) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-difluoro-coumarin-3-carboxy Amide;
(20) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dimethyl-coumarin-3-carboxyamide ;
(21) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dichloro-coumarin-3-carboxyamide ;
(22) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-7-methyl-coumarin-3-carboxy Amide;
(23) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-7-fluoro-coumarin-3- Carboxyamide;
(24) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-chloro-6-fluoro-coumarin-3- Carboxyamide; and
(25) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-fluoro-6-methyl-coumarin-3- Carboxyamide.
As shown in Scheme 1 below,
Preparing a compound represented by Formula 2 by reacting a compound represented by Formula 3 with a compound represented by Formula 4 (Step 1); And
A method for preparing a compound represented by Formula 1 of claim 1 comprising the step of preparing a compound represented by Formula 1 (step 2) by reacting a compound represented by Formula 2:
[Scheme 1]

(In the above Scheme 1,
R ¹ , R ² and r are as defined in Formula 1 of claim 1; And
PG ^a is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2 -Is one type of amine protecting group selected from the group consisting of trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc)).
A pharmaceutical composition for the prevention or treatment of diseases related to urotensin-II receptor activity containing a compound represented by Formula 1 of claim 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
The diseases related to the activity of the eurotensin-II receptor include blood heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, high blood pressure, asthma, kidney failure, diabetes, vasculitis, neurodegenerative diseases, stroke, pain. , A pharmaceutical composition for prevention or treatment, characterized in that at least one disease selected from the group consisting of psychosis and cancer.
delete The method of claim 7,
The compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is a pharmaceutical composition for prophylaxis or treatment, characterized in that antagonistic action against the eurotensin-II receptor.
It is a health functional food composition for the prevention or improvement of diseases related to urotensin-II receptor activity containing the compound represented by Formula 1 of claim 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
The diseases related to the activity of the eurotensin-II receptor include blood heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, high blood pressure, asthma, kidney failure, diabetes, vasculitis, neurodegenerative diseases, stroke, pain. , Health functional food composition for preventing or improving, characterized in that at least one disease selected from the group consisting of psychosis and cancer.