HK1176061B

HK1176061B - Novel benzamide derivatives

Info

Publication number: HK1176061B
Application number: HK13103256.8A
Authority: HK
Inventors: 金舜会; 任元彬; 崔成鹤; 崔善镐; 孙铸姬; 成铉贞; 金敉延; 赵康勋; 孙兑炅
Original assignee: 东亚制药株式会社
Priority date: 2010-04-23
Filing date: 2011-04-18
Publication date: 2016-02-19

Description

Novel benzamide derivatives

Technical Field

The present invention relates to a novel benzamide derivative of formula 1 (to be described below) or a pharmaceutically acceptable salt thereof, a method for preparing the same, and 5-HT comprising the same as an active ingredient₄A receptor agonist.

Background

Serotonin (5-HT) is a widely distributed neurotransmitter in the body. Currently 7 serotonin subclasses are known. In particular, 5-HT₄The elucidation of the receptor and confirmation of its pharmaceutical action have been acceptedTo a great extent.

In general, 5-HT is found₄Receptor agonists are useful for the treatment of various disease conditions such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, Irritable Bowel Syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorders, emesis, migraine, nervous system disease, pain, cardiovascular disorders, heart failure, cardiac arrhythmias, diabetes and sleep apnea syndrome (see Tips,1992,13,141; Ford A.P.D.W. et al, Med.Res.Rev.,1993,13.633; Gullikson G.W. et al, Drug Dev.Res.,1992,26,405; Richard M.Eglen et al, Tips,1995,16,391; Bockaaert J. et al, CNS Drugs,1,6; Romanli M.N. et al, Arzhenhexy/Drug Res, 43, 1993, Kaune.J. 1993; Romane.R.R.J. 344, Romanli et al, Scheim. J. 1993, Nazeek, Torex.J. 344, Romanli, et al, Scheim. Torex.N. 344, Romanli, 1993, Romane.R. J. Tokaineb.R. et al, 43,913).

Although 5-HT₄Receptor agonists have been used in large amounts, but at present there is little 5-HT₄Receptor agonist compounds are used clinically. For this reason, there is a need for 5-HT which can exhibit excellent medical effects with minimal adverse side effects₄A receptor agonist.

Benzamide derivatives have several prominent pharmacological effects. These excellent pharmacological effects of benzamide derivatives are due to their effect on the nervous system, which is controlled by serotonin, which is a neurotransmitter. The effects of serotonin, i.e., the pharmacological effects of benzamide derivatives, have been implicated extensively over the years in a variety of diseases and conditions. In addition, a great deal of research has been focused on the sites of serotonin production and storage and the location of serotonin receptors to determine the relationship between the location of serotonin receptors and various disease states or conditions in humans.

Cisapride (cisapride) is a typical 5-HT₄A receptor agonist which is one of benzamide derivatives. U.S. Pat. Nos. 4,962,115, 5,057,525 and 5,137,896 disclose N- (3-hydroxy-4-piperidinyl) benzamides, including cisapride. These compounds are known to stimulate gastrointestinal motility. Further, us patent No. 5,864,039 discloses benzamide derivatives.

To this end, the present inventors have succeeded in synthesizing novel benzamide derivatives by reacting them with 5-HT₄The receptor binds strongly to exhibit agonistic activity and good gastrointestinal absorption, and can minimize adverse side effects. The present invention has been completed based on this finding.

Disclosure of Invention

Technical problem

The present invention is intended to provide a novel benzamide derivative or a pharmaceutically acceptable salt thereof and a method for preparing the same.

Further, the present invention intends to provide 5-HT containing the novel benzamide derivative or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient₄A receptor agonist.

Technical scheme

The present invention provides a novel benzamide derivative represented by formula 1 (a compound of formula 1); or a pharmaceutically acceptable salt thereof:

wherein m represents an integer of 1 to 10; q represents a heteroaromatic ring or phenyl, wherein the heteroaromatic ring or phenyl is independently substituted with 0, 1,2 or 3 substituents selected from alkyl, alkoxy, hydroxy, cyano, nitro and halogen.

Throughout this specification the following terms will have the following meanings, unless otherwise indicated.

The term "alkyl" as used herein refers to a straight or branched, monovalent, saturated radical containing only carbon and hydrogen atomsC₁-C₂₀A hydrocarbon group. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, 2-dimethylpropyl, butyl, isobutyl, sec-butyl, tert-butyl, 3-methylbutyl, pentyl, 3-methylpentyl, 4-methylpentyl, n-hexyl, 2-ethylhexyl, octyl and dodecyl.

The term "alkoxy" as used herein refers to the group-OR, wherein R represents an alkyl group as defined above. Examples of the alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, n-hexyloxy and 2-ethylhexyloxy.

The term "heteroaryl ring" as used herein refers to an aromatic or bicyclic aromatic ring containing 1 to 4 heteroatoms selected from O, N or S. Examples of heteroaromatic rings include pyrrole, imidazole, triazole, tetrazole, pyridine, pyrimidine, oxazole, oxadiazole, isoxazole, indole, quinoline, and benzofuran.

Further, the present invention provides a novel benzamide derivative represented by formula 1 or a pharmaceutically acceptable salt thereof, wherein m represents an integer of 1 to 5; and Q represents a heteroaromatic ring or phenyl group, wherein the heteroaromatic ring or phenyl group is independently substituted with 0, 1,2 or 3 substituents selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy and halogen, wherein the heteroaromatic ring is C independently containing 1 to 4 heteroatoms selected from N, O or S₁-C₁₂Aromatic ring or C₁-C₁₂Bicyclic aromatic rings.

In the present invention, the pharmaceutically acceptable salt may be an acid addition salt with an acceptable free acid. The free acid may be an inorganic acid or an organic acid. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Examples of the organic acid include citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galacturonic acid, pamoic acid, glutamic acid, and aspartic acid.

In addition, the compound of formula 1 or a pharmaceutically acceptable salt thereof may exhibit polymorphism, and may also exist in the form of a solvate (e.g., hydrate, etc.).

Further, the present invention relates to a novel benzamide derivative selected from the group consisting of:

(1) n- ((1- (3- (1,2, 4-triazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(2) N- ((1- (3- (tetrazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(3) N- ((1- (3- (indol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(4) N- ((1- (3- (2-methylimidazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(5) N- ((1- (5- (indol-1-yl) pentyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(6) N- ((1- (5- (1,2, 3-triazol-1-yl) pentyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(7) N- ((1- (3- (1,2, 3-triazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(8) N- ((1- (3- (1,2, 3-triazol-2-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(9) N- ((1- (piperidin-3-ylmethyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(10) N- ((1- ((1-methylindol-3-yl) methyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(11) N- ((1- (imidazol-2-ylmethyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(12) N- ((1- ((1-methylpyrrole-2-yl) methyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(13) N- ((1- (4-fluorobenzyl) piperidine-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(14) N- ((1- (4-hydroxybenzyl) piperidine-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(15) N- ((1- (2- (indol-3-yl) ethyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(16) N- ((1- (3- (tetrazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide hydrochloride,

(17) N- ((1- (5- (1,2, 3-triazol-1-yl) pentyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide hydrochloride,

(18) N- ((1- (3- (1,2, 3-triazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide hydrochloride,

(19) N- ((1- ((1-methylindol-3-yl) methyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide hydrochloride,

(20) N- ((1- (4-fluorobenzyl) piperidine-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide hydrochloride,

(21) N- ((1- (4-hydroxybenzyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide hydrochloride, and pharmaceutically acceptable salts thereof.

In addition, the present invention provides a method for preparing the benzamide derivative of formula 1 or a pharmaceutically acceptable salt thereof.

The present invention provides a process for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula 2 or a pharmaceutically acceptable salt thereof with a compound of formula 3 in the presence of a base to introduce the compound of formula 3 at the amine at the 1-position of the piperidine ring of the compound of formula 2 or a pharmaceutically acceptable salt thereof, thereby preparing the compound of formula 1 (hereinafter referred to as "preparation process 1").

[ formula 3]

Y-(CH₂)_m-Q

In the above formula, m and Q are as defined in formula 1, and Y represents a halogen atom or C₁-C₄An alkyl sulfonate.

In the preparation method 1 of the present invention, the base is preferably selected from potassium carbonate, potassium iodide, triethylamine, diisopropylethylamine and a mixture thereof, the solvent may be dimethylformamide, dimethylacetamide, acetone, 1, 4-dioxane, etc., and the reaction may be performed at a temperature of 50 ℃ to 140 ℃.

The present invention provides a process for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula 2 or a pharmaceutically acceptable salt thereof with a compound of formula 11 in the presence of a reducing agent to prepare a compound of formula 1 (hereinafter referred to as "preparation process 2").

In the above formula, Q is as defined in formula 1, and m represents an integer of 1.

In the preparation method 2 of the present invention, the reducing agent is preferably sodium cyanoborohydride and acetic acid, or sodium borohydride, and the solvent may be C₁-C₆A lower alcohol, preferably ethanol or methanol, and the reaction may be carried out at a temperature of 50 ℃ to 100 ℃.

The compound of formula 2 or a pharmaceutically acceptable salt thereof in preparation method 1 or preparation method 2 of the present invention can be prepared by the following steps:

(1) reacting the compound of formula 4 with an amine protecting group-introducing reagent to introduce an amine protecting group at the 1-position amine of the piperidine ring of the compound of formula 4, thereby obtaining a compound of formula 5;

(2) reacting the hydroxyl group of the compound of formula 5 with N-bromosuccinimide and carbon tetrabromide, or with C₁-C₄Reacting an alkylsulfonyl halide in the presence of a base to obtain a compound of formula 6;

(3) reacting the substituent Y of the compound of formula 6 with sodium azide to obtain a compound of formula 7;

(4) reducing the azido substituent of the compound of formula 7 to an amine in the presence of a reducing agent to obtain a compound of formula 8;

(5) reacting a compound of formula 8 with a compound of formula 9 in the presence of an agent that induces amide bond formation to obtain a compound of formula 10; and

(6) deprotecting the amine protecting group of the piperidine ring of the compound of formula 10 in the presence of a base or acid,

in the above formula, Y represents a halogen atom or C₁-C₄An alkyl sulfonate, and Z represents C₁-C₄An alkyl group.

In the method for preparing the compound of formula 2 according to the present invention, the amine-protecting group-introducing reagent of step (1) refers to a reagent conventionally used for protecting amines to prevent amine groups from participating in a reaction. Such reagents, for example, in the presence of tertiary amines such as triethylaminePreferably selected from di-tert-butyl dicarbonate or ethyl chloroformate. The solvent can be C₁-C₆A lower alcohol. The reaction may be carried out under conditions of increasing temperature gradient from 0 ℃ to room temperature.

In the process for preparing the compound of formula 2 according to the present invention, C of step (2)₁-C₄The alkylsulfonyl halide is preferably methanesulfonyl chloride, methanesulfonyl bromide or methanesulfonyl fluoride, the tertiary amine may be triethylamine, diisopropylethylamine or the like, and the solvent may be dichloromethane, chloroform or the like. The reaction may be carried out under conditions of increasing temperature gradient from 0 ℃ to room temperature.

In the method for preparing the compound of formula 2 according to the present invention, the solvent used in step (3) may be dimethylformamide, dimethylacetamide, or the like, and the reaction temperature may be in the range of 80 to 140 ℃.

In the method for preparing the compound of formula 2 according to the present invention, the reducing agent used in step (4) is preferably triphenylphosphine or lithium aluminum hydride, and the solvent used may be tetrahydrofuran. The reaction may be carried out under conditions of an elevated temperature gradient from 0 ℃ to room temperature or may be carried out in the range of 60 to 80 ℃.

In the method for preparing the compound of formula 2 according to the present invention, the reagent inducing amide bond formation used in step (5) refers to a general reagent used by those skilled in the art and used to remove water generated after the reaction to promote an amide bond between a carboxylic acid and an amine, or to activate an amine or a carboxylic acid.

Examples of the agent inducing amide bond formation include: n- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole in the presence of a base; ethyl chloroformate in the presence of a base; and carbonyldiimidazole (carbodiimidazole) in the absence of a base. Here, the base used in combination with N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole or ethyl chloroformate includes triethylamine and diisopropylethylamine. Here, the reaction solvent used may be dimethylformamide, dimethylacetamide, dichloromethane, or the like. The reaction may be carried out under conditions of increasing temperature gradient from 0 ℃ to room temperature.

In the method for preparing the compound of formula 2 according to the present invention, the base or acid of step (6) refers to a base or acid conventionally used for deprotecting a carbamate salt of an amine, and examples thereof include hydrochloric acid, trifluoroacetic acid and potassium hydroxide. The reaction solvent can be 1, 4-dioxane, dichloromethane, or C₁-C₆Lower alcohols, and the like. The reaction may be carried out under conditions of increasing temperature gradient from 0 ℃ to room temperature.

The compound of formula 3 in the present invention may be prepared according to the method in reaction scheme 1 or reaction scheme 2 provided below.

[ reaction scheme 1]

Y-(CH₂)m-Y′+Q-Na—→Y-(CH₂)m-Q

In reaction scheme 1, substituents Q and m are as defined for formula 1, and Y ' both represent halogen atoms, which are preferably different from each other, for example, one of Y and Y ' represents chlorine (Cl) and the other of Y and Y ' represents bromine (Br).

The reaction of reaction scheme 1 may be carried out in the presence of a strong base such as lithium hydride, sodium hydride or potassium hydride in an organic solvent such as dimethylformamide, dimethylacetamide or tetrahydrofuran at a reaction temperature of 0 to 40 ℃ for 1 to 24 hours.

[ reaction scheme 2]

Y″-(CH₂)m-Y″′+Q-H→Y″-(CH₂)m-Q→Y-(CH₂)m-Q

In reaction scheme 2, substituents Q and m are as defined for formula 1, and Y represents C₁-C₄An alkylsulfonyl halide or a halogen atom, Y "represents a hydroxyl group, and Y'" represents a halogen atom selected from Cl, Br or I.

The first reaction step of reaction scheme 2 may be carried out in a solvent such as 1, 4-dioxane or acetone in the presence of a base such as potassium carbonate and potassium iodide at a temperature of 60 to 120 ℃ for 1 to 12 hours.

When Y in formula 3 represents C₁-C₄Alkyl sulfonyl halides, the second reaction step of reaction scheme 2 can be accomplished by reacting Y "- (CH)₂) m-Q and C₁-C₄An alkylsulfonyl halide (e.g., methanesulfonyl chloride, methanesulfonyl bromide, or methanesulfonyl fluoride) is carried out in the presence of a base such as triethylamine or diisopropylethylamine in an organic solvent such as dichloromethane or chloroform at a reaction temperature of 0 to 40 ℃ for 1 to 24 hours.

When the substituent Y of formula 3 represents a halogen atom, the second reaction step of reaction scheme 2 may be carried out in a conventionally known manner for Y "- (CH)₂) m-Q is substituted by halogen. For example, when the substituent Y of formula 3 represents bromine (Br), the reaction may be performed in the presence of one selected from N-bromosuccinimide or carbon tetrabromide and triphenylphosphine in an organic solvent such as dichloromethane at a reaction temperature of 0 to 40 ℃ for 1 to 24 hours.

The acid addition salts of the free base of the compounds of formula 1 may be prepared using conventional methods known in the art, for example by mixing the free base of the compound of formula 1 with a suitable acid in a suitable solvent, followed by formation of the salt by evaporation or by addition of a non-solvent to precipitate the salt. For example, mention may be made of processes which involve treatment of a solution or suspension of the free base with the desired acid in a reaction-inert solvent, followed by concentration under reduced pressure or crystallization or any standard chemical operation to form the desired salt. In one embodiment, the hydrochloride salt of the compound of formula 1 may be prepared by dissolving the free base of the compound of formula 1 in C₁-C₄An alcohol solvent such as ethanol or methanol, hydrochloric acid is added thereto, and the mixture is then stirred at room temperature.

Further, the present invention provides 5-HT containing the compound of formula 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient₄A receptor agonist.

In the present invention, 5-HT₄The receptor agonist may be a composition for preventing or treating a disease selected from the group consisting of: gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, Irritable Bowel Syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, nervous system disease, pain, cardiovascular disorder, heart failure, arrhythmia, diabetes or sleep apnea syndrome.

In the present invention, the 5-HT of the present invention is a compound of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof₄The receptor agonist may also comprise one or more active ingredients that exhibit the same or similar function.

For the purpose of desired administration, the agonist or composition of the present invention may be formulated into various administration forms by additionally adding one or more pharmaceutically acceptable carriers in combination with the above-mentioned active ingredients. Examples of pharmaceutically acceptable carriers include saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol and ethanol. These may be used alone or in any combination thereof. Optionally, other conventional additives such as antioxidants, buffers and bacterial inhibitors may be added. In addition, diluents, dispersants, surfactants, binders and lubricants may be additionally added to prepare injectable formulations such as aqueous solutions, suspensions or emulsions, or oral formulations such as pills, capsules, granules or tablets. Furthermore, the desired administration form may preferably be formulated according to the disease and the ingredient to be treated, using any suitable method known in the art, such as disclosed in "Remington's Pharmaceutical Sciences, mack publishing co.

Furthermore, when the 5-HT of the present invention is used₄When the receptor agonist is intended for oral administration, the content of the compound of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof in the formulation may be in the range of 1 to 95% by weight, and preferably 1 to 95% by weightWithin a range of 70 wt%.

Depending on the desired application, the agonist or composition of the invention may be administered parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) or orally. The dosage of the active ingredient may vary depending on various factors such as the weight, age, sex, health state and dietary habits of the patient, the number and route of administration, excretion rate and severity of the disease. The benzamide derivative of the present invention may be administered at a dose of 1 to 1000. mu.g/kg, preferably about 10 to 500. mu.g/kg, and more preferably about 83 to 167. mu.g/kg, once or several times daily.

In addition, the invention provides methods for preventing, treating or ameliorating 5-HT₄A method for treating diseases caused by the decrease in the effectiveness of receptors, which comprises treating 5-HT comprising a compound of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient₄Administration of a receptor agonist to a subject in need of 5-HT₄Mammals, including humans, which are receptor agonistic. Here, 5-HT₄The receptor agonist may be a composition for preventing or treating a disease selected from the group consisting of: gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, Irritable Bowel Syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, nervous system disease, pain, cardiovascular disorder, heart failure, arrhythmia, diabetes or sleep apnea syndrome.

For the reaction of 5-HT₄Prevention and treatment of diseases caused by reduced receptor availability, 5-HT of the invention₄Receptor agonists may be used alone or in combination with methods of using surgical therapy, hormonal therapy, drug therapy and biological response modifiers.

Beneficial effects

Benzamide derivatives of the invention are useful for 5-HT₄The receptor has excellent affinity, i.e. can reduce gastric emptyingIntermediate capacity and low toxicity, and thus for the treatment of various and 5-HT₄The receptor-related diseases have therapeutic effects.

Examples

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are provided only for explaining the present invention and should not be construed as limiting the scope and spirit of the present invention.

Unless otherwise indicated, the reagents used below were purchased from Aldrich Korea, Acros, Lancaster, TCI, etc., and were performed using a Varian 400MHz spectrometer¹H NMR experiment.

Example 1:

example 1N- ((1- (3- (1,2, 4-triazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro Preparation of (E) -2-methoxybenzamide

1-1.4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide (compound of formula 2) hydrochloric acid Preparation of salts

Step 1 preparation of t-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (Compound of formula 5)

4-Piperidinol (compound of formula 4) (20g,174mmol) was dissolved in methanol (30mL) and the solution was cooled to 0 ℃. Triethylamine (48.8mL,347mmol) and di-t-butyl dicarbonate (56.8g,260mmol) were then added thereto. The reaction mixture was warmed to room temperature, stirred for 2 hours, and concentrated under reduced pressure to remove the solvent. After extraction with dichloromethane and water, the organic layer was washed with citric acid solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (35.25g, 94%).

¹H NMR(CDCl₃,400MHz):4.18-4.04(m,2H),3.47(t,J＝5.6Hz,2H),2.70-2.64(m,2H),1.70-1.56(m,3H),1.42(s,9H),1.16-1.09(m,2H)。

Step 2 preparation of t-butyl 4- ((methylsulfonyloxy) methyl) piperidine-1-carboxylic acid ester (compound of formula 6) Preparation of

Tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (35.25g,164mmol) was dissolved in dichloromethane (300mL) and the solution was cooled to 0 ℃. Subsequently, triethylamine (46.01mL,327mmol) and methanesulfonyl chloride (19.14mL,246mmol) were added thereto. The reaction mixture was warmed to room temperature, stirred for 2 hours, and extracted with dichloromethane and water. The organic layer was washed with a citric acid solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (48g, 100%).

¹H NMR(CDCl₃,400MHz):4.18-4.06(m,2H),4.04(d,J=6.4Hz,2H),2.99(s,3H),2.78-2.62(m,2H),1.92-1.85(m,1H),1.73-1.70(m,2H),1.43(s,9H),1.24-1.13(m,2H).

Step 3 preparation of t-butyl 4- (azidomethyl) piperidine-1-carboxylate (Compound of formula 7)

Tert-butyl 4- ((methylsulfonyloxy) methyl) piperidine-1-carboxylate (48g,163.6mmol) was dissolved in dimethylformamide (500mL) and sodium azide (19.15g,295mmol) was added thereto, followed by stirring at 120 ℃ for 6 hours. After completion of the reaction, the reaction was cooled to room temperature, extracted with ethyl acetate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (35g, 89%).

¹H NMR(CDCl₃,400MHz):4.18-4.00(m,2H),3.16(d,J=6.0Hz,2H),2.72-2.58(m,2H),1.70-1.64(m,3H),1.43(s,9H),1.20-1.08(m,2H).

Step 4 preparation of t-butyl 4- (aminomethyl) piperidine-1-carboxylate (compound of formula 8)

Tert-butyl 4- (azidomethyl) piperidine-1-carboxylate (30g,124.8mmol) was dissolved in tetrahydrofuran (300mL), and triphenylphosphine (39.3g,149.8mmol) was added thereto, followed by stirring at reflux for 2 hours. Water (120mL) was added thereto, followed by stirring under reflux for 3 hours and concentration under reduced pressure. The resulting residue was extracted with ethyl acetate and 1N hydrochloric acid solution, and the aqueous layer was neutralized with 2N sodium hydroxide solution, followed by re-extraction with dichloromethane. The resultant organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (21.16g, 79%).

¹H NMR(CDCl₃,400MHz):4.16-3.98(m,2H),2.69-2.63(m,2H),2.56(d,J=6.8Hz,2H),1.69-1.66(m,2H),1.46-1.38(m,10H),1.10-1.04(m,2H).

Step 5 tert-butyl 4- ((4-amino-5-chloro-2-methoxybenzamido) methyl) piperidine-1-carboxylic acid Preparation of ester (Compound of formula 10)

4-amino-5-chloro-2-methoxybenzoic acid (compound of formula 9) (16.6g,82.28mmol) was dissolved in dimethylformamide (166mL) and the solution was cooled to 0 ℃. Subsequently, tert-butyl 4- (aminomethyl) piperidine-1-carboxylate (21.16g,98.74mmol), triethylamine (11.56mL,246.84mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (EDC,20.51g,106.96mmol) and 1-hydroxybenzotriazole (HOBT, 16.68g,123.42mmol) were added thereto. The reaction mixture was warmed to room temperature, stirred for 4 hours, and extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (31.4g, 96%).

¹H NMR(CDCl₃,400MHz):8.08(s,1H),7.76-7.70(m,1H),6.27(s,1H),4.37(s,2H),4.16-4.04(m,2H),3.88(s,3H),3.34-3.26(m,2H),2.74-2.60(m,2H),1.80-1.63(m,3H),1.42(s,9H),1.20-1.10(m,2H).

Step 6-4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide (compound of formula 2) Preparation of hydrochloride salts

Tert-butyl 4- ((4-amino-5-chloro-2-methoxybenzamido) methyl) piperidine-1-carboxylate (30.7g,77.16mmol) was dissolved in 1, 4-dioxane (300mL) and a solution of 4M hydrochloride salt (220mL) in 1, 4-dioxane was added thereto. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give the title compound (24g, 93%).

¹H NMR(CD₃OD,400MHz):7.84(s,1H),6.84(s,1H),3.95(s,3H),3.42-3.29(m,6H),3.01-2.95(m,2H),1.98-1.93(m,3H),1.54-1.42(m,2H).

Preparation of 1-2.1- (3-chloropropyl) -1,2, 4-triazole (compound of formula 3)

1,2, 4-triazole sodium salt (5g,54.91mmol) was dissolved in dimethylformamide (50mL) and the solution was cooled to 0 ℃. Subsequently, sodium hydride (60%,2.86g,71.38mmol) was added thereto, followed by stirring for 30 minutes. To this was added 1-bromo-3-chloropropane (6.5mL,65.89mmol), followed by stirring at room temperature for 12 hours, and the reaction was terminated by adding a saturated solution of ammonium chloride. After extraction with ethyl acetate and water, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by column chromatography to obtain the title compound (2.77g, 35%).

¹H NMR(CDCl₃,400MHz):8.08(s,1H),7.94(s,1H),4.36(t,J=6.4Hz,2H),3.45(t,J=6Hz,2H),2.35-2.30(m,2H).

1-3N- ((1- (3- (1,2, 4-triazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methyl Preparation of oxybenzamides (Compounds of formula 1)

4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide (compound of formula 2) hydrochloride (500mg,1.5mmol) was dissolved in dimethylformamide (10mL), and 1- (3-chloropropyl) -1,2, 4-triazole (compound of formula 3) (306mg,2.1mmol), potassium carbonate (497mg,3.6mmol) and potassium iodide (50mg,0.3mmol) were added thereto. The reaction was stirred at 100 ℃ for 8 hours and quenched by the addition of water. After extraction with ethyl acetate and water, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by column chromatography to give the title compound (55mg, 9%).

¹H NMR(CDCl₃,400MHz):8.09(s,1H),8.04(s,1H),7.91(s,1H),7.78-7.70(m,1H),6.27(s,1H),4.35(s,2H),4.22(t,J=6.4Hz,2H),3.88(s,3H),3.30(t,J=6.4Hz,2H),2.85-2.81(m,2H),2.24(t,J=6.4Hz,2H),2.06-2.00(m,2H),1.97-1.90(m,2H),1.78-1.50(m,3H),1.39-1.28(m,2H).

Example 2N- ((1- (3- (tetrazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methyl Preparation of oxybenzamides

1- (3-chloropropyl) -tetrazole was prepared using 1H-tetrazole and 1-bromo-3-chloropropane as starting materials for < examples 1-2>, and subsequently the title compound (186mg) was obtained using 1- (3-chloropropyl) -tetrazole and 4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride as starting materials for < examples 1-3 >.

¹H NMR(CDCl₃,400MHz):8.60(s,1H),8.07(s,1H),7.75-7.68(m,1H),6.28(s,1H),4.49(t,J=6.8Hz,2H),4.39(s,2H),3.88(s,3H),3.30(t,J=6.4Hz,2H),2.79-2.76(m,2H),2.23(t,J=6.8Hz,2H),2.10-2.05(m,2H),1.92-1.86(m,2H),1.75-1.69(m,2H),1.62-1.50(m,1H),1.35-1.23(m,2H).

Example 3N- ((1- (3- (indol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methyl Preparation of oxybenzamides

1- (3-chloropropyl) -indole was prepared using indole and 1-bromo-3-chloropropane as starting materials of < example 1-2>, and then 1- (3-chloropropyl) -indole and 4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride were used as starting materials of < example 1-3> to obtain the title compound (26 mg).

¹H NMR(CDCl₃,400MHz):8.09(s,1H),7.85-7.76(m,1H),7.60(d,J=7.6Hz,1H),7.34(d,J=8.0Hz,1H),7.15(t,J=7.2Hz,1H),7.10-7.07(m,2H),6.45(d,J=3.2Hz,1H),6.27(s,1H),4.34(s,2H),4.18(t,J=7.2Hz,2H),3.88(s,3H),3.32(t,J=6.4Hz,2H),2.88-2.85(m,2H),2.26(t,J=7.2Hz,2H),2.03-1.97(m,2H),1.90-1.80(m,2H),1.73-1.60(m,3H),1.40-1.32(m,2H).

Example 4N- ((1- (3- (2-methylimidazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro Preparation of (E) -2-methoxybenzamide

1- (3-chloropropyl) -2-methylimidazole was prepared using 2-methylimidazole and 1-bromo-3-chloropropane as starting materials of < example 1-2>, and then 1- (3-chloropropyl) -2-methylimidazole and 4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride were used as starting materials of < example 1-3> to obtain the title compound (226 mg).

¹H NMR(CDCl₃,400MHz):8.06(s,1H),7.78-7.69(m,1H),6.85(s,1H),6.78(s,1H),6.27(s,1H),4.46(s,2H),3.87-3.83(m,5H),3.29(t,J=6.0Hz,2H),2.85-2.79(m,2H),2.34(s,3H),2.22(t,J=6.8Hz,2H),1.90-1.83(m,4H),1.72-1.67(m,2H),1.63-1.50(m,1H),1.32-1.26(m,2H).

Example 5N- ((1- (5- (indol-1-yl) pentyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methyl Preparation of oxybenzamides

The title compound (250mg) was obtained by using indole and 1-bromo-5-chloropentane as starting materials for < example 1-2> to prepare 1- (5-chloropentyl) -indole, followed by using 1- (5-chloropentyl) -indole and 4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride as starting materials for < example 1-3 >.

¹H NMR(CDCl₃,400MHz):8.09(s,1H),7.75-7.69(m,1H),7.60(d,J=8.0Hz,1H),7.31(d,J=7.6Hz,1H),7.19-7.16(m,1H),7.09-7.05(m,2H),6.47-6.44(m,1H),6.26(s,1H),4.34(s,2H),4.11-4.08(m,2H),3.87(s,3H),3.30(t,J=6.0Hz,2H),2.92-2.86(m,2H),2.28-2.20(m,2H),1.91-1.80(m,4H),1.72-1.48(m,5H),1.39-1.26(m,4H).

Example 6N- ((1- (5- (1,2, 3-triazol-1-yl) pentyl) piperidin-4-yl) methyl) -4-Amino-5-chloro Preparation of (E) -2-methoxybenzamide

1- (5-chloropentyl) -1,2, 3-triazole was prepared using 1,2, 3-triazole and 1-bromo-5-chloropentane as starting materials for < example 1-2>, and then 1- (5-chloropentyl) -1,2, 3-triazole and 4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride were used as starting materials for < example 1-3> to obtain the title compound (225 mg).

¹H NMR(CDCl₃,400MHz):8.06(s,1H),7.79-7.70(m,1H),7.67(s,1H),7.52(s,1H),6.27(s,1H),4.41(s,2H),4.35(t,J=6.8Hz,2H),3.86(s,3H),3.28(t,J=6.0Hz,2H),2.92-2.88(m,2H),2.28(t,J=7.6Hz,2H),1.94-1.84(m,4H),1.72-1.68(m,2H),1.66-1.46(m,3H),1.34-1.21(m,4H).

Example 7N- ((1- (3- (1,2, 3-triazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro Preparation of (E) -2-methoxybenzamide

Step 1 preparation of 3- (1,2, 3-triazol-1-yl) propanol

1,2, 3-triazole (2g,28.96mmol) was dissolved in 1, 4-dioxane (40mL), and potassium carbonate (8g,57.92mmol), potassium iodide (962mg,5.79mmol) and 3-bromopropanol (3.3mL,43.43mmol) were added thereto, followed by stirring at 100 ℃ for 3 hours. After completion of the reaction, the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resultant residue was purified by column chromatography to give the title compound (2.5g, 68%).

¹H NMR(CDCl₃,400MHz):7.68(s,1H),7.59(s,1H),4.54(t,J=6.8Hz,2H),3.62(q,J=5.6Hz,2H),2.44(t,J=5.2Hz,1H),2.15-2.10(m,2H).

Step 2 preparation of 3- (1,2, 3-triazol-1-yl) propylmethanesulfonate

3- (1,2, 3-triazol-1-yl) propanol (2.5g,19.66mmol) was dissolved in dichloromethane (50mL) and the solution was cooled to 0 ℃. Subsequently, triethylamine (5.53mL,39.32mmol) and methanesulfonyl chloride (2.3mL,29.5mmol) were added thereto. The reaction mixture was warmed to room temperature, stirred for 2 hours, extracted with dichloromethane and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by column chromatography to give the title compound (3.01g, 75%).

¹H NMR(CDCl₃,400MHz):7.72(s,1H),7.63(s,1H),4.55(t,J=6.8Hz,2H),4.22(t,J=6Hz,2H),3.03(s,3H),2.40-2.36(m,2H).

Step 3N- ((1- (3- (1,2, 3-triazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2- Preparation of methoxybenzamide

4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide (the compound of formula 2) hydrochloride (400mg,1.2mmol) was dissolved in dimethylformamide (10mL), and 3- (1,2, 3-triazol-1-yl) propyl methanesulfonate (the compound of formula 3) (344mg,1.68mmol), triethylamine (0.5mL,3.591mmol), potassium carbonate (232mg,1.68mmol) and potassium iodide (40mg,0.24mmol) were added thereto, followed by stirring at 120 ℃ for 4 hours. After completion of the reaction, the reaction was cooled to room temperature, extracted with ethyl acetate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by column chromatography to give the title compound (185mg, 38%).

¹H NMR(CDCl₃,400MHz):8.09(s,1H),7.74-7.70(m,1H),7.67(s,1H),7.54(s,1H),6.27(s,1H),4.43(t,J=6.8Hz,2H),4.35(s,2H),3.88(s,3H),3.31(t,J=6.4Hz,2H),2.85-2.82(m,2H),2.27(t,J=6.8Hz,2H),2.07-2.04(m,2H),1.92-1.86(m,2H),1.73-1.69(m,2H),1.62-1.50(m,1H),1.34-1.22(m,2H).

Example 8N- ((1- (3- (1,2, 3-triazol-2-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro Preparation of (E) -2-methoxybenzamide

Using 3- (1,2, 3-triazol-2-yl) propanol and 4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride obtained as by-products in step 1 of example 7 as starting materials, the title compound (250mg) was obtained in the same manner as in < example 7 >.

¹H NMR(CDCl₃,400MHz):8.03(s,1H),7.83-7.75(m,1H),7.53(s,2H),6.25(s,1H),4.50-4.42(m,4H),3.82(s,3H),3.26(t,J=6.0Hz,2H),2.86-2.83(m,2H),2.31-2.27(m,2H),2.12-2.05(m,2H),1.89-1.83(m,2H),1.67-1.64(m,2H),1.60-1.50(m,1H),1.31-1.20(m,2H).

Example 9N- ((1- (pyridin-3-ylmethyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxy Preparation of benzamides

4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride (1g,2.99mmol) was dissolved in methanol (40mL), and 3-pyridinecarboxaldehyde (0.42mL,4.49mmol), acetic acid (1mL) and sodium cyanoborohydride (470mg,7.48mmol) were added thereto, followed by stirring at 60 ℃ for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, extracted with dichloromethane and water, and then washed with sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant residue was purified by column chromatography to give the title compound (355mg, 30%).

¹H NMR(CDCl₃,400MHz):8.07(s,1H),7.74-7.69(m,1H),7.65(d,J=7.6Hz,1H),7.37(s,1H),7.30(d,J=8.4Hz,1H),7.25-7.22(m,1H),7.19-7.15(m,1H),6.26(s,1H),4.42(s,2H),3.83(s,3H),3.77(s,3H),3.28(t,J=5.6Hz,2H),2.95-2.82(m,4H),2.19-2.14(m,4H),1.91-1.85(m,2H),1.80-1.72(m,2H),1.69-1.63(m,2H),1.61-1.53(m,1H),1.32-1.15(m,5H).

Example 10N- ((1- ((1-methylindol-3-yl) methyl) piperidin-4-yl) methyl) -4-amino-5-chloro Preparation of (E) -2-methoxybenzamide

The title compound (60mg) was obtained in the same manner as in < example 9> using 1-methylindole-3-carbaldehyde and 4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride as starting materials.

¹H NMR(CDCl₃,400MHz):8.02(s,1H),7.82-7.75(m,1H),7.56(d,J=8.4Hz,1H),7.33-7.22(m,3H),7.12(t,J=7.2Hz,1H),6.27(s,1H),4.38(s,2H),4.01(s,2H),3.87(s,3H),3.79(s,3H),3.30-3.23(m,2H),2.46-2.37(m,2H),1.88-1.75(m,3H),1.59-1.50(m,2H).

Example 11N- ((1- (imidazol-2-ylmethyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxy Preparation of phenylbenzamides

The title compound (123mg) was obtained in the same manner as in < example 9> using 2-imidazolecarboxaldehyde and 4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride as starting materials.

¹H NMR(CDCl₃,400MHz):8.07(s,1H),7.75-7.66(m,1H),6.96(s,2H),6.27(s,1H),4.38(s,2H),3.87(s,3H),3.61(s,2H),3.31(t,J=6.8Hz,2H),2.85-2.80(m,2H),2.11-2.04(m,2H),1.74-1.69(m,2H),1.63-1.53(m,1H),1.34-1.23(m,2H).

Example 12N- ((1- ((1-Methylpyrrol-2-yl) methyl) piperidin-4-yl) methyl) -4-amino-5-chloro Preparation of (E) -2-methoxybenzamide

The title compound (50mg) was obtained in the same manner as in < example 9> using 1-methyl-2-pyrrolecarboxaldehyde and 4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride as starting materials.

¹H NMR(CDCl₃,400MHz):8.08(s,1H),7.75-7.64(m,1H),6.57-6.53(m,1H),6.26(s,1H),6.00-5.96(m,1H),5.95-5.93(m,1H),4.38(s,2H),3.85(s,3H),3.60(s,2H),3.28(t,J=6.8Hz,2H),2.86-2.82(m,2H),1.92-1.84(m,2H),1.68-1.63(m,2H),1.61-1.53(m,1H),1.30-1.19(m,2H).

Example 13N- ((1- (4-Fluorobenzyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzyl Preparation of amides

The title compound (215mg) was obtained in the same manner as in < example 9> using 4-fluorobenzaldehyde and 4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride as starting materials.

¹H NMR(CDCl₃,400MHz):8.07(s,1H),7.75-7.68(m,1H),7.27-7.21(m,2H),7.00-6.94(m,2H),6.26(s,1H),4.36(s,2H),3.86(s,3H),3.46-3.43(m,2H),3.28(t,J=6.4Hz,2H),2.87-2.84(m,2H),2.01-1.91(m,2H),1.70-1.56(m,3H),1.36-1.20(m,2H).

Example 14N- ((1- (4-hydroxybenzyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzene Preparation of carboxamides

The title compound (75mg) was obtained in the same manner as in < example 9> using 4-hydroxybenzaldehyde and 4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride as starting materials.

¹H NMR(CDCl₃,400MHz):7.81(s,1H),7.19(d,J=8.8Hz,2H),6.75(s,J=8.8Hz,2H),6.20(s,1H),4.40(s,2H),3.76(s,2H),3.32-3.24(m,5H),3.12-3.05(m,2H),2.68-2.59(m,2H),1.80-1.72(m,3H),1.27-1.12(m,2H).

Example 15N- ((1- (2- (indol-3-yl) ethyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methyl Preparation of oxybenzamides

Step 1 preparation of 2- (indol-3-yl) ethanol

Indole-3-acetic acid (5g,28.54mmol) was dissolved in diethyl ether (100mL) and the solution was cooled to 0 ℃. Lithium aluminum hydride (1.19g,31.39mmol) was added thereto, followed by stirring for 4 hours. The reaction was stopped by the addition of water and 10% sodium hydroxide solution. The reaction mixture was filtered through Celite (Celite) and concentrated under reduced pressure. The resultant residue was purified by column chromatography to give the title compound (1.24g, 27%).

¹H NMR(CDCl₃,400MHz):8.10-7.96(bs,1H),7.61(d,J=7.6Hz,1H),7.36(dd,J=8Hz,0.8Hz,1H),7.24-7.17(m,1H),7.15-7.07(m,2H),3.92-3.87(m,2H),3.05-3.00(m,2H).

Step 2 preparation of 3- (2-bromoethyl) -indole (compound of formula 3)

2- (indol-3-yl) ethanol (623mg,3.86mmol) was dissolved in dichloromethane (20mL) and the solution was cooled to 0 ℃. Subsequently, triphenylphosphine (1.12g,4.25mmol) and tetrabromomethane (1.41g,4.25mmol) were added thereto, followed by stirring for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The resultant residue was purified by column chromatography to give the title compound (765mg, 88%).

¹H NMR(CDCl₃,400MHz):8.10-7.88(bs,1H),7.58(d,J=8Hz,1H),7.38-7.34(m,1H),7.24-7.20(m,1H),7.19-7.08(m,2H),3.65-3.60(m,2H),3.35-3.30(m,2H).

Step 3N- ((1- (2- (indol-3-yl) ethyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxy Preparation of phenylbenzamides

The title compound (190mg) was obtained in the same manner as in < examples 1 to 3> using 3- (2-bromoethyl) -indole and 4-amino-5-chloro-2-methoxy- (piperidin-4-ylmethyl) benzamide hydrochloride as starting materials.

¹H NMR(CDCl₃,400MHz):8.09(s,1H),8.05(s,1H),7.81-7.75(m,1H),7.59(d,J=7.6Hz,1H),7.33(d,J=8.4Hz,1H),7.16(t,J=7.2Hz,1H),7.09(t,J=7.6Hz,1H),7.00(d,J=1.6Hz,1H),6.27(s,1H),4,36(s,2H),3.88(s,3H),3,32(t,J=6.4Hz,2H),3.12-3.07(m,2H),3.01-2.96(m,2H),2.73-2.69(m,2H),2.11-2.04(m,2H),1.79-1.75(m,2H),1.74-1.63(m,1H),1.49-1.38(m,2H).

Example 16N- ((1- (3- (tetrazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methyl Preparation of oxybenzamide hydrochloride

N- ((1- (3- (tetrazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide (example 2) (517mg,1.27mmol) was dissolved in ethanol (10mL), and 12N hydrochloride solution (0.16mL,1.90mmol) was added thereto. The reaction mixture was stirred at room temperature for 12 hours, followed by filtration to give the title compound (417mg, 74%).

¹H NMR(DMSO-d6,400MHz):10.52(s,1H),9.47(s,1H),8.02-7.99(m,1H),7.64(s,1H),6.47(s,1H),5.95(s,2H),4.59-4.56(m,2H),3.81(s,3H),3.45-3.42(m,2H),3.18-3.08(m,2H),3.04-2.98(m,2H),2.87-2.79(m,2H),2.35-2.31(m,2H),1.90-1.89(m,1H),1.78-1.75(m,2H),1.58-1.52(m,2H).

Example 17N- ((1- (5- (1,2, 3-triazol-1-yl) pentyl) piperidin-4-yl) methyl) -4-amino-5-chloro Preparation of (E) -2-methoxybenzamide hydrochloride

The title compound (112mg,35%) was obtained in the same manner as in < example 16> using N- ((1- (5- (1,2, 3-triazol-1-yl) pentyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide (example 6) as a starting material.

¹H NMR(DMSO-d6,400MHz):10.06(s,1H),8.14(s,1H),8.02-7.99(m,1H),7.71(s,1H),7.64(s,1H),6.47(s,1H),5.95(s,2H),4.40-4.37(m,2H),3.81(s,3H),3.40-3.32(m,2H),3.18-3.12(m,2H),2.96-2.90(m,2H),2.84-2.75(m,2H),1.87-1.70(m,7H),1.59-1.48(m,2H),1.25-1.17(m,2H).

Example 18N- ((1- (3- (1,2, 3-triazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro Preparation of (E) -2-methoxybenzamide hydrochloride

The title compound (291mg,93%) was obtained in the same manner as in < example 16> using N- ((1- (3- (1,2, 3-triazol-1-yl) propyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide (example 7) as a starting material.

¹H NMR(DMSO-d6,400MHz):10.67(s,1H),8.19(s,1H),8.02-7.99(m,1H),7.74(s,1H),7.64(s,1H),6.48(s,1H),5.93(bs,2H),4.51-4.47(m,2H),3.81(s,3H),3.44-3.41(m,2H),3.34-3.31(m,2H),2.98-2.96(m,2H),2.87-2.79(m,2H),2.34-2.299m,2H),1.96-1.86(m,1H),1.77-1.74(m,2H),1.60-1.54(m,2H).

Example 19N- ((1- ((1-methylindol-3-yl) methyl) piperidin-4-yl) methyl) -4-amino-5-chloro Preparation of (E) -2-methoxybenzamide hydrochloride

The title compound (237mg,44%) was obtained in the same manner as in < example 16> using N- ((1- ((1-methylindol-3-yl) methyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide (example 10) as a starting material.

¹H NMR(DMSO-d6,400MHz):10.34(s,1H),7.96-7.93(m,1H),7.79(d,J=8Hz,1H),7.64-7.59(m,2H),7.47(d,J=8Hz,1H),7.22-7.19(m,1H),7.14-7.10(m,1H),6.47(s,1H),4.36(d,J=4.4Hz,2H),3.81(s,3H),3.79(s,3H),3.40-3.37(m,2H),3.14-3.11(m,2H),2.90-2.82(m,2H),1.77-1.71(m,3H),1.53-1.48(m,2H).

Example 20N- ((1- (4-Fluorobenzyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzyl Preparation of amide hydrochloride

The title compound (569mg,87%) was obtained in the same manner as in < example 16> using N- ((1- (4-fluorobenzyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide (example 13) as a starting material.

¹H NMR(DMSO-d6,400MHz):10.78(s,1H),7.98-7.96(m,1H),7.73-7.63(m,3H),7.30-7.25(m,2H),6.47(s,1H),5.94(s,2H),4.22(d,J=4.8Hz,2H),3.80(s,3H),3.29-3.26(m,2H),3.14-3.07(m,2H),2.86-2.78(m,2H),1.89-1.85(m,1H),1.77-1.74(m,2H),1.59-1.53(m,2H).

Example 21N- ((1- (4-hydroxybenzyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzene Preparation of formamide hydrochloride

The title compound (158mg,97%) was obtained in the same manner as in < example 16> using N- ((1- (4-hydroxybenzyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide (example 14) as a starting material.

¹H NMR(DMSO-d6,400MHz):10.25(s,1H),7.98-7.96(m,1H),7.63(s,1H),7.34(d,J=6.4Hz,2H),6.80(d,J=6.4Hz,2H),6.47(s,1H),4.08(d,J=3.6Hz,2H),3.80(s,3H),3.28-3.25(m,2H),3.15-3.12(m,2H),2.82-2.74(m,2H),1.77-1.62(m,3H),1.54-1.48(m,2H).

EXAMPLE 1 Compound p-5-HT ₄ Binding affinity of receptor

According to the literature [ Wyngaert et al, Journal of Neurochemistry, (1997)69,1810-]The method disclosed in (1) determines the activity of a compound on human 5-HT₄Binding affinity of the receptor. For this purpose, the expression of 5-HT was constructed₄COS-7 cells of the receptor were homogenized to obtain a membrane homogenate, which was then used in binding assays. For binding assays, membrane homogenates were separately combined with different concentrations of test substance and [ H3]]GR113808(Amersham Biosciences) and incubated. The concentrations of each test substance were set to 4. mu.M, 1. mu.M, 0.25. mu.M and 0.0625. mu.M, respectively, and [ H3]]The concentration of-GR 113808 was set to 0.595 nM. After incubation was complete, the reaction product was collected in a GF/B glass fiber filter using a Packard cell harvester, followed by determination of bound radioactivity using a liquid cell scintillation counter (packardtopocount NXT R.R., Perkin Elmer). Radioligands with 5-HT₄Specific binding of the receptor was calculated by subtracting the nonspecific binding of the radioligand from the total radioligand binding. For different concentrations of test substance, IC₅₀From radioligands with 5-HT₄Characteristics of the receptorCalculate% inhibition of specific binding. The results are shown in table 1 below.

[ Table 1]

Compound (I)	IC₅₀(nM)
		Cisapride	0.362
Example 1	0.226
		Example 2	0.164
Example 3	0.039
		Example 4	0.229
Example 5	0.005
		Example 6	0.103
Example 7	0.067
		Example 8	0.182
Example 9	0.267
		Example 10	0.076
Example 11	0.454
		Example 12	0.421
Example 13	0.134
		Example 14	0.375
Example 15	0.002

As can be seen from Table 1, the compounds of the present invention inhibit radioligand and 5-HT at similar concentrations or at lower concentrations than cisapride as a control₄Specific binding of the receptor, thus indicating that the compounds of the invention are directed to 5-HT₄The receptor has a strong binding affinity.

Experimental example 2 evaluation of gastric emptying

Gastric emptying was evaluated based on the method described in Iwanaga Y et al, Jpn J Pharmacol.1991,56(3), 261-. As experimental animals, SD rats (240 to 250g) were used and divided into a plurality of groups (n =5 to 6). The day prior to the experiment, animals were fasted for 18 hours. The test substances were formulated in the form of their suspensions in 0.5% (w/v) methylcellulose and administered orally to the animals at a dose of 5 mg/kg. 1 hour after oral administration of the test substance, 2mL of a semi-solid diet was orally administered to the animals. The semi-solid diet is in the form of a "porridge" formulated by comminuting a standard solid diet with distilled water in a mixer. 50 minutes after administration of the semi-solid diet, animals were sacrificed by neck amputation. After the abdominal incision was made, the stomach was removed from the animal. The weight of the diet remaining in the stomach was measured to thereby determine the gastric emptying rate (%). Gastric emptying rate was calculated according to the following formula. The results are shown in table 2 below.

Gastric emptying rate (%) = (1-X/Y) × 100

X weight of diet remaining in the stomach taken 50 minutes after eating.

Y: weight of diet remaining in the stomach immediately after eating.

[ Table 2]

Compound (I)	Gastric emptying rate (%)
		Control (0.5% methyl cellulose)	32.2
Example 1	43.0
		Example 2	52.8
Example 3	45.2
		Example 4	46.4
Example 5	52.0
		Example 6	46.0
Example 7	56.1
		Example 8	49.1
Example 9	51.2
		Example 10	59.1
Example 11	43.1
		Example 12	62.0
Example 13	52.3
		Example 14	42.1
Fruit of Chinese wolfberryExample 15	41.3

As can be seen from table 2, administration of the compound of the present invention resulted in a significant improvement in gastric emptying compared to the group treated with methylcellulose as a control, thereby indicating that the compound of the present invention promotes gastrointestinal motility.

Experimental example 3 acute oral toxicity of Compounds in mice

To examine the acute toxicity of the compounds of the present invention, the following experiment was performed.

200mg of each example compound was ground in 1% hydroxypropyl methylcellulose, and the resulting ground product was then orally administered to 5-week-old male ICR mice (20g [ 2g, n =5) at a dose of 1g/10 mL/kg. The minimal lethal dose (MLD, mg/kg) of each compound was investigated by observing the mortality, body weight, clinical symptoms, etc. of the animals over the entire experimental period of 2 weeks. The results are shown in table 3 below.

[ Table 3]

Compound (I)	Minimum lethal dose (MLD, mg/kg)
		Example 1	>1000
Example 2	>1000
		Example 3	>1000
Example 4	>1000
		Example 5	>1000
Example 6	>1000
		Example 7	>1000
Example 8	>1000
		Example 9	>1000
Example 10	>1000
		Example 11	>1000
Example 12	>1000
		Example 13	>1000
Example 14	>1000
		Example 15	>1000

As can be seen from the acute toxicity test results of table 3, all compounds used in the test showed MLD higher than 1000mg/kg, thereby indicating that the compounds of the present invention are safe for use.

EXAMPLE 4 binding affinity of pharmaceutical Compounds for hERG receptor

The binding affinity of compounds for the potassium (K +) channel of the human ether-a-go-go related gene (hERG) involved in cardiac QT prolongation was determined in MDS Pharma Service (Catalog No. 265900). Membrane homogenates were obtained from mammalian HEK-293 cells expressing the hERG potassium channel and subsequently used in binding assays. For binding assay experiments, membrane homogenates were mixed and incubated with 10. mu.M test substance and 1.5nM [ H3] -astemizole (Perkin Elmer), respectively. After incubation was complete, radioactivity bound to the hERG K + channel was counted. The affinity of each test substance for the hERG K + channel was calculated from the% inhibition of specific binding of the radioligand to the hERG K + channel resulting from the action of the test substance. The results are shown in table 4 below.

[ Table 4]

Compound (I)	Inhibition (%, 10. mu.M)
		Example 1	1
Example 2	4
		Example 4	14
Example 6	8
		Example 7	7
Example 8	15
		Example 9	6
Example 11	21
		Example 12	32
Example 13	52
		Example 14	40

Cardiac arrhythmias (which are fatal side effects) occur as a result of cardiac QT prolongation, which is caused by too high affinity of the drug for the hERG receptor. The compounds of the present invention show less than 50% inhibition rate even at a dose of 10 μ M and thus have low binding affinity for the hERG receptor, thereby suggesting that the compounds of the present invention show significantly low risk of causing arrhythmia.

Claims

1. A compound of formula 1:

[ formula 1]

Wherein m represents an integer of 1 to 5; q represents a heteroaromatic ring, wherein the heteroaromatic ring is independently selected from 0, 1,2 or 3 from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy and halogen, wherein saidHeteroaryl ring is C independently containing 1 to 4 heteroatoms selected from N, O or S₁-C₁₂Aromatic ring or C₁-C₁₂Bicyclic aromatic rings.

2. The compound of formula 1 or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula 1 or a pharmaceutically acceptable salt thereof is selected from the group of compounds consisting of:

(9) N- ((1- (pyridin-3-ylmethyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide,

(19) N- ((1- ((1-methylindol-3-yl) methyl) piperidin-4-yl) methyl) -4-amino-5-chloro-2-methoxybenzamide hydrochloride, and

their pharmaceutically acceptable salts.

3. A method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula 2 or a pharmaceutically acceptable salt thereof with a compound of formula 3 in the presence of a base to introduce the compound of formula 3 at the amine-1-position of the piperidine ring of the compound of formula 2 or a pharmaceutically acceptable salt thereof, thereby preparing the compound of formula 1,

[ formula 1]

[ formula 2]

[ formula 3]

Y-(CH2)_m-Q

Wherein m and Q are as defined in claim 1, and Y represents a halogen atom or C₁-C₄An alkyl sulfonate.

4. The process of claim 3, wherein the base is selected from the group consisting of potassium carbonate, potassium iodide, triethylamine, diisopropylethylamine, and mixtures thereof.

5. A method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula 2 or a pharmaceutically acceptable salt thereof with a compound of formula 11 in the presence of a reducing agent to prepare a compound of formula 1,

[ formula 1]

[ formula 2]

[ formula 11]

Wherein Q is as defined in claim 1, and m represents the integer 1.

6. The method of claim 5, wherein the reducing agent is sodium cyanoborohydride and acetic acid, or sodium borohydride.

7. The method of claim 3 or 5, wherein the compound of formula 2 or a pharmaceutically acceptable salt thereof is prepared by:

[ formula 2]

[ formula 4]

[ formula 5]

[ formula 6]

[ formula 7]

[ formula 8]

[ formula 9]

[ formula 10]

Wherein Y represents a halogen atom or C₁-C₄An alkyl sulfonate, and Z represents C₁-C₄An alkyl group.

8. The process of claim 7 wherein the amine protecting group introducing reagent of step (1) is di-tert-butyl dicarbonate or ethyl chloroformate in the presence of a tertiary amine base.

9. The method of claim 7, wherein C of step (2)₁-C₄The alkyl sulfonyl halide is methane sulfonyl chloride, methane sulfonyl bromide or methane sulfonyl fluoride.

10. The process of claim 7, wherein the reducing agent of step (4) is triphenylphosphine or lithium aluminum hydride.

11. The method of claim 7, wherein the agent that induces amide bond formation of step (5) is selected from the group consisting of: n- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole in the presence of a base; ethyl chloroformate in the presence of a base; and carbonyldiimidazole in the absence of a base.

12. The process of claim 7, wherein the base or acid of step (6) is selected from hydrochloric acid, trifluoroacetic acid or potassium hydroxide.

13. 5-HT containing a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient₄Receptor agonists:

[ formula 1]

Wherein m represents an integer of 1 to 5; q represents a heteroaromatic ring, wherein the heteroaromatic ring is independently selected from 0, 1,2 or 3 from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy and halogen, wherein the heteroaromatic ring is C independently containing 1 to 4 heteroatoms selected from N, O or S₁-C₁₂Aromatic ring or C₁-C₁₂Bicyclic aromatic rings.

14. The agonist of claim 13, wherein the compound of formula 1 or a pharmaceutically acceptable salt thereof is selected from the group of compounds consisting of:

their pharmaceutically acceptable salts.

15. The agonist of claim 13 or 14, wherein the 5-HT₄A receptor agonist is a composition for preventing or treating a disease selected from the group consisting of: gastrointestinal disorders, Irritable Bowel Syndrome (IBS), dyspepsia, nausea, Alzheimer's disease, cognitive disorders, emesis, neurological disorders, pain, cardiovascular disorders, diabetes or sleep apnea syndrome.

16. Use of a compound of formula 1 or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 as an active ingredient in the preparation of a medicament for the prevention, treatment or amelioration of symptoms due to 5-HT₄The use of a compound of formula (I) in the manufacture of a medicament for the treatment of a disease caused by reduced receptor availability.

17. The use according to claim 16, wherein the disease is selected from the group consisting of: gastrointestinal disorders, Irritable Bowel Syndrome (IBS), dyspepsia, nausea, Alzheimer's disease, cognitive disorders, emesis, neurological disorders, pain, cardiovascular disorders, diabetes or sleep apnea syndrome.

18. The agonist according to claim 15, wherein the dyspepsia is selected from non-ulcer dyspepsia, functional dyspepsia and constipation, the gastrointestinal disorder is selected from gastric motility disorder and gastroesophageal disorder, the nervous system disorder is central nervous system disorder, the pain is migraine, and the cardiovascular disorder is selected from heart failure and arrhythmia.

19. The agonist of claim 18, wherein the gastroesophageal disorder is selected from the group consisting of gastroesophageal reflux disease and esophagitis.

20. The use of claim 17, wherein the dyspepsia is selected from non-ulcer dyspepsia, functional dyspepsia and constipation, the gastrointestinal disorder is selected from gastric motility disorder and gastroesophageal disorder, the nervous system disorder is central nervous system disorder, the pain is migraine, and the cardiovascular disorder is selected from heart failure and arrhythmia.

21. The use according to claim 20, wherein the gastroesophageal disorder is selected from the group consisting of gastroesophageal reflux disease and esophagitis.